WO2017180248A9

WO2017180248A9 - Enantioenriched viridicatumtoxin b analogs

Info

Publication number: WO2017180248A9
Application number: PCT/US2017/019216
Authority: WO
Inventors: Kyriacos C. Nicolaou; Guodu LIU
Original assignee: William Marsh Rice University
Priority date: 2016-04-15
Filing date: 2017-02-23
Publication date: 2018-11-01
Also published as: WO2017180248A1

Abstract

In one aspect, the present disclosure provides derivatives of viridicatumtoxin of the formula wherein the variables are as defined herein. Also provided herein are compositions and methods of treating a bacterial infection, a viral infection, or in the treatment of cancer. The present disclosure also provides methods of synthesizing enantiopure viridicatumtoxin and other anthrone compounds.

Description

DESCRIPTION

ENANTIOENRICHED VIRIDICATUMTOXIN B ANALOGS

This application claims the benefit of priority to U.S. Provisional Application Serial No. 62/322,935, filed on April 15, 2016, the entire contents of which are hereby incorporated by reference.

BACKGROUND

This invention was made with government support under Grant Number AI055475 awarded by the National Institutes of Health. The government has certain rights in the invention.

1. Field

This disclosure relates to the fields of medicine, pharmacology, chemistry, antimicrobial activity, and oncology. In particular, new compounds, compositions, methods of treatment, and methods of synthesis relating to viridicatumtoxin and derivatives thereof are disclosed.

2. Related Art

Since the discovery of chlortetracycline (4; FIG. 1A) in the late 1940's, tetracycline antibiotics such as chlortetracycline (4), oxytetracycline (5), and tetracycline (6) have been commonly prescribed to treat bacterial infections (Duggar, 1948). Throughout the years, as bacterial resistance grew or improved therapeutic properties were needed, additional therapeutic agents including second generation tetracycline derivatives such as minocycline (7) and doxycycline (8) and third generation tetracycline derivatives such as tigecycline (9) and eravacycline (TP-434, 10) have been developed (FIG. 1A) (TaUy, et al, 1995; Sutcliffe, et al, 2013; Chopra and Roberts, 2001).

Since the discovery of the commercial importance of these molecules for the biological activity, many efforts have been undertaken to synthesize tetracycline derivatives including recent efforts by the Myers (Charest, et al, 2005; Charest, et al, 2005; Brubaker and Myers, 2007; Sun, et al, 2008; Kummer, et al, 2011 ; Wright and Myers, 2011) and Evans groups (Wzorek, et al, 2012). While there have been many attempts to prepare these compounds, new and improved methods resulting in enantiopure anthrones such as those contained in viridicatumtoxin B are still in demand.

In 2008, Kim, et al, isolated viridicatumtoxin B (1) from Penicillium sp. FR11 along with viridicatumtoxin A (2). This compound was investigated through NMR spectroscopy and assigned the structure V but this original structure has been revised based upon further analysis and after the total synthesis of viridicatumtoxin B (Nicoloau, et al, 2013). These compounds have been shown to have potent antibacterial properties in a number of bacterial strains including both Gram-positive and Gram-negative bacteria (Kim, et al, 2008). Without being bound by theory, further study and analysis suggests that the viridicatumtoxin' s antibacterial properties arise not by binding to the 30S subunit of the ribosome like many tetracycline compounds but by inhibiting UPP synthase, an enzyme associated with bacterial peptidoglycan biosynthesis (Inokoshi, et al, 2013; Koyama, et al, 2013). Furthermore, viridicatumtoxin A (2) shows promising anticancer activity against a selection of cancer cell lines (NIH Results of Viridicatumtoxin A NCI 60 Cell line assay) as well as shows antiviral activity (WO 2009/008906).

As such, new analogs of viridicatumtoxin could provide access to a more efficacious antimicrobial or cancer drug and new methods of their synthesis could allow cost effective clinical access to these compound for use in the treatment of microbial infections and as chemo therapeutic agents.

SUMMARY

Thus, in accordance with the present disclosure, there is provided a compound of the formula:

Ri and Ri' are each independently hydrogen, hydroxy, alkoxv(c<8), substituted alkoxy(c<8), acyloxy(c<8), or substituted acyloxy(c<8>; or Ri and Ri ' are taken together and are oxo;

R2 is hydrogen, amino, alkylamino(c<8), substituted alkylamino(c<8), dialkylamino(c<i2), or substituted dialkylaminO(c<i2);

R3 is hydrogen or a group of the formula: -Y-R7, wherein:

Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R7 is hydrogen, amino, alkylamino(c<8), substituted alkylamino(c<8), dialkylamino(c<i2), substituted dialkylamino(c<i2), heterocycloalkyl(c<i2), or substituted heterocycloalkyl(c<i2);

R4 is hydroxy, oxo, alkoxy(c<8), or substituted alkoxy(c<8); and

R5 and R6 are each independently hydrogen, alkyl(c<8), or substituted alkyl(c<8);

provided that when R2 is hydrogen and R3 is hydrogen or methyl, then Ri is not methoxy or Ri and Ri ' are not oxo;

or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds are further defined as:

wherein:

Ri and Ri ' are each independently alkoxy(c<8), substituted alkoxy(c<s), acyloxy(c<8), or substituted acyloxy₍c<8);

R2 is hydrogen, amino, alkylaminO(c<8), substituted alkylamin0(c<8), dialkylaminO(c<i2), or substituted dialkylamino(c<i2);

R3 is hydrogen or a group of the formula: -Y-R7, wherein:

Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R7 is hydrogen, amino, alkylaminO(c<8), substituted alkylaminO(c<8), dialkylaminO(c<i2), substituted dialkylamino(c<i2), heterocycloalkyl(c<i2), or substituted heterocycloalkyl(c i2);

R4 is hydroxy, oxo, alkoxy(c<8), or substituted a]koxy(c<8); and

wherein:

Ri and Ri' are each independently hydrogen, hydroxy, alkoxy(c<8), substituted alkoxy(c<8), acyloxy(c<8), or substituted acyloxy(c<8); or Ri and Ri ' are taken together and are oxo;

R2 is amino, alkylamino(c<8), substituted alkylamino(c<8), dialkylamino(c<i2), or substituted dialkylamino(c<i2);

R3 is hydrogen or a group of the formula: -Y-R7, wherein:

Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R4 is hydroxy, oxo, alkoxy(c<8), or substituted alkoxy(c<8); and

wherein:

R3 is a group of the formula: -Y-R7, wherein:

Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R4 is hydroxy, oxo, alkoxy(c<8), or substituted alkoxy(c<8); and

provided that when R2 is hydrogen and R3 is methyl, then Ri is not methoxy or Ri and Ri' are not oxo; or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds are further defined as:

wherein:

R3 is a group of the formula: -Y-R7, wherein:

Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R7 is amino, alkylamino(c<8), substituted alkylamino(c<8), dialkylaminO(c<i2), substituted dialkylamino(c<i2), heterocycloalkyl(c<i2), or substituted heterocycloalkyl(c<i2); R4 is hydroxy, oxo, aIkoxy(c<8), or substituted aIkoxy(c<8); and

or a pharmaceutically acceptable salt thereof.

In some embodiments, Ri and Ri ' are taken together and are oxo. In some embodiments, Ri is aIkoxy₍c<6) or substituted alkoxy(c<6). In other embodiments, Ri is hydrogen. In some embodiments, Ri ' is alkoxy(c<6) or substituted alkoxy(c<6). In other embodiments, Ri ' is hydrogen. In some embodiments, R2 is hydrogen. In some embodiments, R2 is dialkylamino₍c<8) or substituted dialkylaminO(c<8).

In some embodiments, R3 is hydrogen. In other embodiments, R3 is -Y-R7, wherein:

Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R7 is amino, alkylamino(c<8), substituted alkylamino(c<8), dialkylamino(c<i2), substituted dialkylaminO(c<i2), heterocycloalkyl(c<i2), or substituted heterocycloalkyl(c<i2).

In some embodiments, Y is alkanediyl(c<6) or substituted alkanediyl(c<6). In some embodiments, R7 is dialkylamino(c<i2) or substituted dialkylamino(c<i2). In other embodiments, R7 is heterocycloalkyl(c<i2) or sub s tituted hetero cyclo alkyl(c< 12).

In some embodiments, R4 is hydroxy. In other embodiments, R4 is oxo. In some embodiments, R5 is hydrogen. In some embodiments, R6 is hydrogen.

In some embodiments, the compound is present as greater than 80% of a single stereoisomer. In some embodiments, the compound is present as greater than 90% of a single stereoisomer. In some embodiments, the compound is present as greater than 95% of a single stereoisomer. In some embodiments, the compounds are further defi

or a pharmaceutically acceptable salt thereof. In yet another aspect, the present disclosure provides compounds of the formula:

or a pharmaceutically acceptable salt thereof;

wherein the compound is enantiomerically enriched such that the compound is present as at least 80% of the depicted stereoisomer.

In some embodiments, the compound is present as at least 90% of the depicted stereoisomer. In some embodiments, the compound is present as at least 95% of the depicted stereoisomer.

In still yet another aspect, the present disclosure provides pharmaceutical compositions comprising: (A) a compound described herein; and

(B) an excipient.

In some embodiments, the pharmaceutical compositions are formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intra vesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in cremes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion. In some embodiments, the pharmaceutical compositions are formulated as a unit dose.

In yet another aspect, the present disclosure provides methods of treating a disease or disorder comprising administering a pharmaceutically effective amount of a compound or composition described herein.

In some embodiments, the disease or disorder is a microbial infection such as a bacterial infection. In some embodiments, the infection is by a Gram-positive or Gram-negative bacteria. In some embodiments, the disease is a bacteria infection by Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Acinetobacter baumannii, Escherichia coli, Acinetobacter calcoaceticus, Staphycococcus epidermidis, Pseudomonas aeruginosa, Klebsiella aerogenes, Candida albicans, Salmonella typhinurium, Streptococcus pneumoniae, Micrococcus luteus, Bacillus cerues, or Bacillus subtilis. In some embodiments, the disease is a bacterial infection by Staphylococcus aureus 503, Staphylococcus aureus 209, Staphylococcus aureus RN420, methicillin-resistant Staphylococcus aureus CCARM 3167, methicillin-resistant Staphylococcus aureus 371, methicillin-resistant Staphylococcus aureus CCARM 3506, quinolone-resistant Staphylococcus aureus CCARM 3505, quinolone-resistant Staphylococcus aureus CCARM 3519, Bacillus subtilis KCTC 1021, Bacillus cerues KCTC 1661, Micrococcus luteus KCTC 1056, Streptococcus pneumoniae KCTC 3932, Streptococcus pneumoniae KCTC 5412, Enterococcus faecium 501, Enterococcus faeci m KCTC 3122, Enterococcus faecalis 5613, Enterococcus faecalis KCTC 5191, Enterococcus faecalis KCTC 3511, Staphycococcus epidermidis KCTC 3958, Salmonella typhinurium KCTC 1926, Acinetobacter calcoaceticus KCTC 2357, Escherichia coli CCARM 1358, Escherichia coli KCTC 1682, Pseudomonas aeruginosa KCTC 2004, Pseudomonas aeruginosa KCTC 2742, Klebsiella aerogenes KCTC 2619, Acinetobacter baumannii AB210, or Candida albicans KCTC 7535. In some embodiments, the bacteria is a drug-resistant bacteria.

In some embodiments, the methods further comprise administering a second therapeutic agent such as an antibiotic. In some embodiments, the second therapeutic agent is a tetracycline antibiotic. In some embodiments, the second therapeutic agent is viridicatumtoxin A, viridicatumtoxin B, vancomycin, tetracycline, spirohexaline, minocycline, tigecycline, doxycycline, a β-lactam antibiotic, an aminoglycoside antibiotic, a sulfonamide antibiotic, a macro lide antibiotic, a glycopeptide antibioitic, an ansamycin antibiotic, an oxazolidinone antibiotic, a quinolone antibiotic, a streptogramin antibiotic, or a lipopeptide antibiotic.

In other embodiments, the microbial infection is a viral infection such as a poxvirus. In some embodiments, the poxvirus is variola virus, vaccinia virus, or molluscum contagiosum. In some embodiments, the methods further comprise administering a second therapeutic agent. In some embodiments, the second therapeutic agent is an interferon or antiviral compound.

In other embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. In some embodiments, the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, gastrointestinal tract, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid.

In some embodiments, the methods further comprise administering a second therapeutic agent. In some embodiments, the second therapeutic agent is a second chemotherapeutic agent, radiotherapy, immunotherapy, or surgery.

In still yet another aspect, the present disclosure provides methods of inhibiting the activity of a bacterial ribosome for the treatment of a disease or disorder comprising administering a compound or composition described herein.

In still yet another aspect, the present disclosure provides methods of inhibiting the activity of a bacterial UPP synthase for the treatment of a disease or disorder comprising administering a compound or composition described herein.

In yet another aspect, the present disclosure provides methods of preparing a compound of the formula:

wherein:

Ri, R2, and R3 are each independently hydrogen, alkyl(c<8), substituted alkyl(c<8), cycloalkyl<c<8), or substituted cycloalkyl(c<8);

R4 is hydroxy, alkylsilyloxy(c<i8), substituted alkylsilyloxy(c<i8), alkylarylsilyloxy(c<i8), substituted alkylarylsilyloxy(c<i 8), alkylaralkylsilyloxy(c<is), substituted alkylaralkylsilyloxy(c<i 8), or - ORa, wherein:

R_a is a hydroxy protecting group;

Rs, R6, R7, and Rs are each independently hydroxy, alkoxy(c<i2), substituted alkoxy(c<i2), alkenyloxy(c<i2), substituted alkenyloxy(c<i2), alkynyloxy(c<i2), substituted alkynyloxy(c<i2), aryloxy(c<i2), substituted aryloxy(c<i2), aralkoxy(c<i2), substituted aralkoxy(c<i2), or -ORb, wherein:

Rb is a hydroxy protecting group;

Xi is O or NR_C, wherein:

R_c is hydrogen, alkyl(c<i 8), or substituted alkyl(c<8);

comprising reacting a compound of the formula:

wherein:

R5, R6, R7, and Rs are as defined above;

with a compound of the formula:

wherien:

Rs, R6, R7, and Rs are as defined above;

Yi is a leaving group; in the presence of a phase transfer catalyst and a base under conditions sufficient to cause a reaction. In some embodiments, the phase transfer catalyst is a compound of the formula:

wherein:

R9 is alkyl(c<8), alkenyl(c<8), or a substituted version of either of these groups;

Rio and Rn are each independently alkyl(c<i 8), alkenyl(c<i8), aryl(c<i8), aralkyl(c<i8), or a substituted version of any of these groups;

R12 is hydrogen, hydroxy, alkoxy(c<i2), substituted alkoxy(c<i2), acyloxy₍;c<i2), substituted acyloxy(c<i2), aralkyl(c<i2), or substituted aralkyl(c<i2);

X2 is a monovalent anion; and

n is 1, 2, or 3.

In some embodiments, the phase transfer catalyst is a compound of the formula:

In some embodiments, the base is a metal carbonate such as cesium carbonate. In some embodiments, the methods comprise adding the base as a solution in water. In some embodiments, the base as a solution in water comprises 20% to about 60% base. In some embodiments, the base as a solution in water comprises 40% base.

In some embodiments, the methods comprise adding from about 5 equivalents to about 25 equivalents of the base relative to the compound of formula III. In some embodiments, the methods comprise adding about 10 equivalents of the base. In some embodiments, the methods comprise adding from about 1.0 equivalents to about 5 equivalents of the compound of formula IV relative to the compound of formula III. In some embodiments, the methods comprise adding about 1.1 equivalents of the compound of formula IV. In some embodiments, the methods comprise adding from about 0.1 mol% to about 20 mol% of the phase transfer catalyst. In some embodiments, the methods comprise adding from about 0.1 mol% to about 5 mol% of the phase transfer catalyst. In some embodiments, the methods further comprise an organic solvent. In some embodiments, the organic solvent is a haloa]kane₍c<8) such as dichloroethane or methylene chloride. In some embodiments, the methods further comprise reacting at a temperature from about -80 °C to about 25 °C such as from about -40 °C to about 0 °C. In some embodiments, the methods comprise reacting for a time period from about 6 hours to about 1 week such as about 1 day to about 4 days.

In some embodiments, the methods further comprise reacting the compound of formula II with a fluoride source to produce a compound of formula:

wherein:

Ri , R2, and R3 are each independently hydrogen, alkyl(c<8), substituted alkyl(c<8), cycloalkyl(c<8), or substituted cycloalkyl(c<8);

R5, R6, R7, and Rs are each independently hydroxy, alkoxy(c<i2), substituted alkoxy(c<i2), alkenyloxy(c<i2), substituted alkenyloxy(c≤i2), alkynyloxy(c<i2), substituted alkynyloxy(c<i2), aryloxy(c<i2), substituted aryloxy(c<i2), aralkoxy(c<i2), substituted aralkoxy(c<i2), or -ORb, wherein:

Rb is a hydroxy protecting group;

Xi is O or NRc, wherein:

Rc is hydrogen, alkyl(c≤i 8), or substituted alkyl(c<8);

or a salt thereof. In some embodiments, the methods further comprise a purification step.

In some embodiments, one or more steps of the reaction further comprises purifying the reaction in a purification step. In some embodiments, the purification method is chromatography. In some embodiments, the purification method is column chromatography or high performance liquid chromatography.

It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein. For example, an aldehyde synthesized by one method may be used in the preparation of a final compound according to a different method.

The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." The word "about" means plus or minus 5% of the stated number.

Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE FIGURES

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed.

FIGS. 1A & B - Structures of bacterial tetracyclines and designed analogs (1A) and fungal tetracyclines (IB)

FIG. 2 - The X-ray derived ORTEP representation of 6a.

FIG. 3 - Molecular structures of viridicatumtoxins (1 and 2) and spirohexaline (3).

FIG. 4 - The X-ray derived ORTEP representation of (-)-ll.

FIG. 5 - Proposed mechanism of stereoselective spirocyclization of substituted anthrone (65,17 ?)-6 to pentacycle (65,15 ?)-4 through carbonium species A (viridicatumtoxin numbering for all intermediates and compounds).

FIG. 6 - The X-ray derived ORTEP representation of (+)-!!.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present disclosure relates to a series of analogs of viridicatumtoxin and an improved synthetic pathway to obtain viridicatumtoxin and its analogs. In some aspects, the analogs of the fungal secondary metabolites viridicatumtoxin A and B are useful as potent antibiotics against a variety of Gram-positive and certain Gram-negative bacterial strains. In the present disclosure, a collection of viridicatumtoxin analogs are synthesized and their antibiotic profile is evaluated. Additionally, this class of compounds has shown activity in a number of cancer cell lines. These and other aspects of the disclosure are described in greater detail below.

I. Compounds and Formulations Thereof

The compounds provided by the present disclosure are shown, for example, above in the summary section and in the claims below. They may be made using the methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated by reference herein.

The viridicatumtoxin analogs of the present disclosure may contain one or more asymmetrically- substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present disclosure can have the (S) or the (R) configuration.

Chemical formulas used to represent the viridicatumtoxin analogs of the present disclosure will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended.

The viridicatumtoxin analogs of the present disclosure may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise.

In addition, atoms making up the viridicatumtoxin analogs of the present disclosure are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³C and ¹⁴C.

The viridicatumtoxin analogs of the present disclosure may also exist in prodrug form. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in some methods of the present disclosure may, if desired, be delivered in prodrug form. Thus, the present disclosure contemplates prodrugs of compounds of the present disclosure as well as methods of delivering prodrugs. Prodrugs of the compounds employed in the disclosure may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly, prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.

It should be recognized that the particular anion or cation forming a part of any salt form of a compound provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." Where the solvent is water, the complex is known as a '¾ydrate." It will also be appreciated that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof are within the scope of the present disclosure.

B. Formulations

In some embodiments of the present disclosure, the compounds are included a pharmaceutical formulation. Materials for use in the preparation of microspheres and/or microcapsules are, e.g., biodegradable/bioerodible polymers such as polygalactia poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl- L-glutamine), and poly(lactic acid). Biocompatible carriers that may be used when formulating a controlled release parenteral formulation are carbohydrates (e.g., dextrans), proteins (e.g., albumin), lipoproteins, or antibodies. Materials for use in implants can be non-biodegradable (e.g., polydimethyl siloxane) or biodegradable (e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid) or poly(ortho esters) or combinations thereof).

Formulations for oral use include tablets containing the active ingredient(s) (e.g., viridicatumtoxin and its derivatives) in a mixture with non-toxic pharmaceutically acceptable excipients. Such formulations are known to the skilled artisan. Excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like. The tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period. The coating may be adapted to release the active drug in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active drug until after passage of the stomach (enteric coating). The coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose). Furthermore, a time delay material, such as, e.g., glyceryl monostearate or glyceryl distearate may be employed.

II. Microbial Infections

A. Bacterial Infections

In some aspects of the present disclosure, the compounds disclosed herein may be used to treat a bacterial infection. While humans contain numerous different bacteria on and inside their bodies, an imbalance in bacterial levels or the introduction of pathogenic bacteria can cause a symptomatic bacterial infection. Pathogenic bacteria cause a variety of different diseases including but not limited to numerous foodborne illness, typhoid fever, tuberculosis, pneumonia, syphilis, and leprosy.

Additionally, different bacteria have a wide range of interactions with the body and those interactions can modulate ability of the bacteria to cause an infection. For example, bacteria can be conditionally pathogenic such that they only cause an infection under specific conditions. For example, Staphylococcus and Streptococcus bacteria exist in the normal human bacterial biome, but these bacteria when they are allowed to colonize other parts of the body causing a skin infection, pneumonia, or sepsis. Other bacteria are known as opportunistic pathogens and only cause diseases in a patient with a weakened immune system or another disease or disorder.

Bacteria can also be intracellular pathogens which can grow and reproduce within the cells of the host organism. Such bacteria can be divided into two major categories as either obligate intracellular parasites or facultative intracellular parasites. Obligate intracellular parasites require the host cell in order to reproduce and include such bacteria as but are not limited to Chlamydophila, Rickettsia, and Ehrlichia which are known to cause pneumonia, urinary tract infections, typhus, and Rocky Mountain spotted fever. Facultative intracellular parasites can reproduce either intracellular or extracellular. Some non-limiting examples of facultative intracellular parasites include Salmonella, Listeria, Legionella, Mycobacterium, and Brucella which are known to cause food poisoning, typhoid fever, sepsis, meningitis, Legionnaire's disease, tuberculosis, leprosy, and brucellosis.

Finally, bacterial infections could be targeted to a specific location in or on the body. For example, bacteria could be harmless if only exposed to the specific organs, but when it comes in contact with a specific organ or tissue, the bacteria can begin replicating and cause a bacterial infection.

In particular, the inventors contemplate treatment of bacterial infections, including those caused by

Staphyloccoccus aureus. S. aureus is a major human pathogen, causing a wide variety of illnesses ranging from mild skin and soft tissue infections and food poisoning to life-threatening illnesses such as deep post-surgical infections, septicaemia, endocarditis, necrotizing pneumonia, and toxic shock syndrome. These organisms have a remarkable ability to accumulate additional antibiotic resistance determinants, resulting in the formation of multiply-drug-resistant strains.

Methicillin, being the first semi-synthetic penicillin to be developed, was introduced in 1959 to overcome the problem of penicillin-resistant S. aureus due to β-lactamase (penicillinase) production (Livermore, 2000). However, methicillin-resistant S. aureus (MRSA) strains were identified soon after the introduction of methicillin (Barber, 1961 ; Jevons, 1961 ). MRSA have acquired and integrated into their genome a 21 - to 67-kb mobile genetic element, termed the staphylococcal cassette chromosome mec (SCCmec) that harbors the methicillin resistance (mecA) gene and other antibiotic resistance determinants (Ito et ah, 2001 ; Ito et ah, 2004; Ma et al, 2002). The mecA gene encodes an altered additional low affinity penicillin-binding protein (PBP2a) that confers broad resistance to all penicillin-related compounds including cephalosporins and carbapenems that are currently some of the most potent broad-spectrum drugs available (Hackbarth & Chambers, 1989). Since their first identification, strains of MRSA have spread and become established as major nosocomial (hospital- acquired (HA)-MRSA) pathogens worldwide (Ayliffe, 1997; Crossley et al, 1979; Panlilio et al, 1992; Voss et al, 1994). These organisms have evolved and emerged as a major cause of community-acquired infections (CA-MRSA) in healthy individuals lacking traditional risk factors for infection, and are causing community- outbreaks, which pose a significant threat to public health. i. Gram-Positive Bacteria

In some aspects of the present disclosure, the compounds disclosed herein may be used to treat a bacterial infection by a Gram-positive bacteria. Gram-positive bacteria contain a thick peptidoglycan layer within the cell wall which prevents the bacteria from releasing the stain when dyed with crystal violet. Without being bound by theory, the Gram-positive bacteria are often more susceptible to antibiotics. Generally, Gram- positive bacteria, in addition to the thick peptidoglycan layer, also comprise a lipid monolayer and contain teichoic acids which react with lipids to form lipoteichoic acids that can act as a chelating agent. Additionally, in Gram-positive bacteria, the peptidoglycan layer is outer surface of the bacteria. Many Gram-positive bacteria have been known to cause disease including, but are not limited to. Streptococcus, Staphylococcus, Corynebacterium, Enterococcus, Listeria, Bacillus, Clostridium, Rathybacter, Leifsonia, and Clavibacter. ii. Gram-Negative Bacteria

In some aspects of the present disclosure, the compounds disclosed herein may be used to treat a bacterial infection by a Gram-negative bacteria. Gram-negative bacteria do not retain the crystal violet stain after washing with alcohol. Gram-negative bacteria, on the other hand, have a thin peptidoglycan layer with an outer membrane of lipopolysaccharides and phospholipids as well as a space between the peptidoglycan and the outer cell membrane called the periplasmic space. Gram-negative bacterial generally do not have teichoic acids or lipoteichoic acids in their outer coating. Generally, Gram-negative bacteria also release some endotoxin and contain prions which act as molecular transport units for specific compounds. Most bacteria are Gram-negative. Some non-limiting examples of Gram-negative bacteria include Bordetella, Borrelia, Burcelia, Campylobacte ia, Escherichia, Francisella, Haemophilus, Helicobacter, Legionella, Leptospira, Neisseria, Pseudomonas, Rickettsia, Salmonella, Shigella, Treponema, Vibrio, and Yersinia. iii. Gram-Indeterminate Bacteria

In some aspects of the present disclosure, the compounds disclosed herein may be used to treat a bacterial infection by a Gram-indeterminate bacteria. Gram-indeterminate bacteria do not full stain or partially stain when exposed to crystal violet. Without being bound by theory, a Gram-indeterminate bacteria may exhibit some of the properties of the Gram-positive and Gram-negative bacteria. A non-limiting example of a Gram- indeterminate bacteria include Mycobacterium tuberculosis or Mycobacterium leprae.

B. Viral Infections

In some aspects of the present disclosure, the compounds disclosed herein may be used to treat a viral infection. Similarly, virus can also exist in pathogenic form which can lead to human diseases. Viral infections are typically not treated directly but rather symptomatically since virus often have a self-limiting life cycle. Viral infections can also be more difficult to diagnosis than a bacterial infection since viral infections often do result in the concomitant increase in white blood cell counts. Some non-limiting examples of pathogenic virus include influenza virus, smallpox, BK virus, JC virus, human papillomavirus, adenovirus, herpes simplex type 1, herpes simplex type 2, varicella-zoster virus, Epstein barr virus, human cytomegalovirus, human herpesvirus type 8, Norwalk virus, human bocavirus, rubella virus, hepatitis E virus, hepatitis B virus, human immunodeficiency virus (HIV), Ebola virus, rabies virus, rotavirus, and hepatitis D virus.

III. Hyperproliferative Diseases

A. Cancer and Other Hyperproliferative Disease

While hyperproliferative diseases can be associated with any disease which causes a cell to begin to reproduce uncontrollably, the prototypical example is cancer. One of the key elements of cancer is that the cell's normal apoptotic cycle is interrupted and thus agents that interrupt the growth of the cells are important as therapeutic agents for treating these diseases. In this disclosure, the viridicatumtoxin derivatives may be used to lead to decreased cell counts and as such can potentially be used to treat a variety of types of cancer lines. In various aspects, it is anticipated that the viridicatumtoxin derivatives of the present disclosure may be used to treat virtually any malignancy.

Cancer cells that may be treated with the compounds of the present disclosure include but are not limited to cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, pancreas, testis, tongue, cervix, or uterus. In addition, the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma, malignant; Sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malig melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; mahgnant lymphoma; hodgkin's disease; hodgkin's; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non- hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; eryfhroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia. In certain aspects, the tumor may comprise an osteosarcoma, angiosarcoma, rhabdosarcoma, leiomyosarcoma, Ewing sarcoma, glioblastoma, neuroblastoma, or leukemia. III. Therapies

A. Pharmaceutical Formulations and Routes of Administration

Where clinical applications are contemplated, it will be necessary to prepare pharmaceutical compositions in a form appropriate for the intended application. In some embodiments, such formulation with the compounds of the present disclosure is contemplated. Generally, this will entail preparing compositions that are essentially free of pyrogens, as well as other impurities that could be harmful to humans or animals.

One will generally desire to employ appropriate salts and buffers to render delivery vectors stable and allow for uptake by target cells. Buffers also will be employed when recombinant cells are introduced into a patient. Aqueous compositions of the present disclosure comprise an effective amount of the vector to cells, dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. Such compositions also are referred to as inocula. The phrase "pharmaceutically or pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the vectors or cells of the present disclosure, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.

The active compositions of the present disclosure may include classic pharmaceutical preparations.

Administration of these compositions according to the present disclosure will be via any common route so long as the target tissue is available via that route. Such routes include oral, nasal, buccal, rectal, vaginal or topical route. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intramuscular, intratumoral, intraperitoneal, or intravenous injection. Such compositions would normally be administered as pharmaceutically acceptable compositions, described supra.

The active compounds may also be administered parenterally or intraperitoneally. Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

For oral administration viridicatumtoxin and its derivatives may be incorporated with excipients and used in the form of non-ingestible mouthwashes and dentifrices. A mouthwash may be prepared incorporating the active ingredient in the required amount in an appropriate solvent, such as a sodium borate solution (Dobell's Solution). Alternatively, the active ingredient may be incorporated into an antiseptic wash containing sodium borate, glycerin and potassium bicarbonate. The active ingredient may also be dispersed in dentifrices, including: gels, pastes, powders and slurries. The active ingredient may be added in a therapeutically effective amount to a paste dentifrice that may include water, binders, abrasives, flavoring agents, foaming agents, and humectants.

The compositions of the present disclosure may be formulated in a neutral or salt form. Pharmaceutically-acceptable salts include the acid addition salts and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 mL of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences," 15th Edition, pages 1035-1038 and 1570-1580, 1990). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA's Devision of Biological Standards and Quality Control of the Office of Complience and Biologies Quality.

B. Methods of Treatment

In particular, the compositions that may be used in treating microbial infections and cancer in a subject {e.g., a human subject) are disclosed herein. The compositions described above are preferably administered to a mammal {e.g., rodent, human, non-human primates, canine, bovine, ovine, equine, feline, etc) in an effective amount, that is, an amount capable of producing a desirable result in a treated subject {e.g., causing apoptosis of cancerous cells or killing bacterial cells). Toxicity and therapeutic efficacy of the compositions utilized in methods of the disclosure can be determined by standard pharmaceutical procedures. As is well known in the medical and veterinary arts, dosage for any one animal depends on many factors, including the subject's size, body surface area, body weight, age, the particular composition to be administered, time and route of administration, general health, the clinical symptoms of the infection or cancer and other drugs being administered concurrently. A composition as described herein is typically administered at a dosage that inhibits the growth or proliferation of a bacterial cell, inhibits the growth of a biofilm, or induces death of cancerous cells {e.g., induces apoptosis of a cancer cell), as assayed by identifying a reduction in hematological parameters (Complete blood count (CBC)), or cancer cell growth or proliferation. In some embodiments, in the experiments described herein and based upon dosing of other tetracycline compounds, the amount of the viridicatumtoxin derivatives used to inhibit bacterial growth, treat a viral infection, or induce apoptosis of the cancer cells is calculated to be from about 0.01 mg to about 10,000 mg/day. In some embodiments, the amount is from about 1 mg to about 1,000 mg/day. In some embodiments, these dosings may be reduced or increased based upon the biological factors of a particular patient such as increased or decreased metabolic breakdown of the drug or decreased uptake by the digestive tract if administered orally. Addtionally, the new derivatives of viridicatumtoxin may be more efficacious and thus a smaller dose is required to achieve a similar effect. Such a dose is typically administered once a day for a few weeks or until sufficient reducing in cancer cells has been achieved.

The therapeutic methods of the disclosure (which include prophylactic treatment) in general include administration of a therapeutically effective amount of the compositions described herein to a subject in need thereof, including a mammal, particularly a human. Such treatment will be suitably administered to subjects, particularly humans, suffering from, having, susceptible to, or at risk for a disease, disorder, or symptom thereof. Determination of those subjects "at risk" can be made by any objective or subjective determination by a diagnostic test or opinion of a subject or health care provider (e.g., genetic test, enzyme or protein marker, marker (as defined herein), family history, and the like).

In one embodiment, the disclosure provides a method of monitoring treatment progress. The method includes the step of determining a level of changes in hematological parameters and/or cancer stem cell (CSC) analysis with cell surface proteins as diagnostic markers (which can include, for example, but are not limited to CD34, CD38, CD90, and CD117) or diagnostic measurement {e.g., screen, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof associated with cancer {e.g., leukemia) in which the subject has been administered a therapeutic amount of a composition as described herein. The level of marker determined in the method can be compared to known levels of marker either in healthy normal controls or in other afflicted patients to establish the subject's disease status. In preferred embodiments, a second level of marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy. In certain preferred embodiments, a pre- treatment level of marker in the subject is determined prior to beginning treatment according to the methods described herein; this pre-treatment level of marker can then be compared to the level of marker in the subject after the treatment commences, to determine the efficacy of the treatment.

C. Combination Therapies

It is envisioned that the viridicatumtoxin derivatives described herein may be used in combination therapies with an additional antimicrobial agent such as anti-viral, antibiotic, or a compound which mitigates one or more of the side effects experienced by the patient.

Furthermore, it is very common in the field of cancer therapy to combine therapeutic modalities. The foUowing is a general discussion of therapies that may be used in conjunction with the therapies of the present disclosure.

To treat cancers using the methods and compositions of the present disclosure, one would generally contact a tumor cell or subject with a compound and at least one other therapy. These therapies would be provided in a combined amount effective to achieve a reduction in one or more disease parameter(s). This process may involve contacting the cells/subjects with the both agents/therapies at the same time, e.g., using a single composition or pharmacological formulation that includes both agents, or by contacting the cell/subject with two distinct compositions or formulations, at the same time, wherein one composition includes the compound and the other includes the other agent.

Alternatively, viridicatumtoxin derivatives of the present disclosure may precede or follow the other treatment by intervals ranging from minutes to weeks. One would generally ensure that a significant period of time did not expire between the time of each delivery, such that the therapies would still be able to exert an advantageously combined effect on the cell/subject. In such instances, it is contemplated that one would contact the cell with both modalities within about 12-24 hours of each other, within about 6-12 hours of each other, or with a delay time of only about 12 hours. In some situations, it may be desirable to extend the time period for treatment significantly; however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations.

It also is conceivable that more than one administration of either the compound or the other therapy will be desired. Various combinations may be employed, where a compound of the present disclosure is "A," and the other therapy is "B," as exemplified below:

A/B/A B/A/B B/B/A A/A/B B/A/A A B/B B B/B/A B/B/A/B

A/A/B/B A/B/A/B A B/B/A B/B/A A B/A B/A B/A/A B B B B/A

A/A/A/B B/A/A/A A/B/A/A A/A/B/A A B B/B B/A B/B B/B/A/B

Antimicrobial gents or factors suitable for use in a combined therapy with agents according to the present disclosure against an infectious disease include antibiotics such as penicillins, cephalosporins, carbapenems, macrolides, aminoglycosides, quinolones (including fluoroquinolones), sulfonamides and tetracylcines. In particular, one may use combination therapies for treating MRSA. Both CA-MRSA and HA- MRSA are resistant to traditional anti-staphylococcal beta-lactam antibiotics, such as cephalexin. CA-MRSA has a greater spectrum of antimicrobial susceptibility, including to sulfa drugs (like co- trimoxazole/trimethoprim-sulfamethoxazole), tetracyclines (like doxycycline and minocycline) and clindamycin (for osteomyelitis), but the drug of choice for treating CA-MRSA is now believed to be vancomycin, according to a Henry Ford Hospital Study. HA-MRSA is resistant even to these antibiotics and often is susceptible only to vancomycin. Newer drugs, such as linezolid (belonging to the newer oxazolidinones class) and daptomycin, are effective against both CA-MRSA and HA-MRSA. The Infectious Disease Society of America recommends vancomycin, linezolid, or clindamycin (if susceptible) for treating patients with MRSA pneumonia. Ceftaroline, a fifth generation cephalosporin, is the first beta-lactam antibiotic approved in the U.S. to treat MRSA infections (skin and soft tissue or community acquired pneumonia only).

Quinolone-resistant S. aureus is another emerging pathogen that may be treated with compounds according to the present disclosure, optionally in combination with vancomycin, teicoplanin and linezolid.

Vancomycin and teicoplanin are glycopeptide antibiotics used to treat MRSA infections. Teicoplanin is a structural congener of vancomycin that has a similar activity spectrum but a longer half -life. Because the oral absorption of vancomycin and teicoplanin is very low, these agents must be administered intravenously to control systemic infections. Treatment of MRSA infection with vancomycin can be complicated, due to its inconvenient route of administration. Moreover, many clinicians believe that the efficacy of vancomycin against MRSA is inferior to that of anti-staphylococcal beta-lactam antibiotics against methicillin-susceptible Staphylococcus aureus (MSSA).

Several newly discovered strains of MRSA show antibiotic resistance even to vancomycin and teicoplanin. These new evolutions of the MRSA bacterium have been dubbed Vancomycin intermediate- resistant Staphylococcus aureus (VISA). Linezolid, quinupristin/dalfopristin, daptomycin, ceftaroline, and tigecycline are used to treat more severe infections that do not respond to glycopeptides such as vancomycin. Current guidelines recommend daptomycin for VISA bloodstream infections and endocarditis. Studies also suggest that allicin, a compound found in garlic, may prove to be effective in the treatment of MRSA.

Other combinations are contemplated. The following is a general discussion of antibiotic, antiviral, and cancer therapies that may be used in combination with the compounds of the present disclosure.

1. Antibiotics

The term "antibiotics" are drugs which may be used to treat a bacterial infection through either inhibiting the growth of bacteria or killing bacteria. Without being bound by theory, it is believed that antibiotics can be classified into two major classes: bactericidal agents that kill bacteria or bacteriostatic agents that slow down or prevent the growth of bacteria.

The first commericallly available antibiotic was released in the 1930's. Since then, many different antibiotics have been developed and widely prescribed. In 2010, on average, 4 in 5 Americans are prescribed antibiotics annually. Given the prevalence of antibiotics, bacteria have started to develop resistance to specific antibiotics and antibiotic mechanisms. Without being bound by theory, the use of antibiotics in combination with another antibiotic may modulate resistance and enhance the efficacy of one or both agents.

In some embodiments, antibiotics can fall into a wide range of classes. In some embodiments, the compounds of the present disclosure may be used in conjunction with another antibiotic. In some embodiments, the compounds may be used in conjunction with a narrow spectrum antibiotic which targets a specific bacteria type. In some non-limiting examples of bactericidal antibiotics include penicillin, cephalosporin, polymyxin, rifamycin, lipiarmycin, quinolones, and sulfonamides. In some non-limiting examples of bacteriostatic antibiotics include macrolides, lincosamides, or tetracyclines. In some embodiments, the antibiotic is an aminoglycoside such as kanamycin and streptomycin, an ansamycin such as rifaximin and geldanamycin, a carbacephem such as loracarbef, a carbapenem such as ertapenem, imipenem, a cephalosporin such as cephalexin, cefixime, cefepime, and ceftobiprole, a glycopeptide such as vancomycin or teicoplanin, a lincosamide such as lincomycin and clindamycin, a lipopeptide such as daptomycin, a macrolide such as clarithromycin, spiramycin, azithromycin, and telithromycin, a monobactam such as aztreonam, a nitrofuran such as furazolidone and nitrofurantoin, an oxazolidonones such as linezolid, a penicillin such as amoxicillin, azlocillin, flucloxacillin, and penicillin G, an antibiotic polypeptide such as bacitracin, polymyxin B, and colistin, a quinolone such as ciprofloxacin, levofloxacin, and gatifloxacin, a sulfonamide such as silver sulfadiazine, mefenide, sulfadimethoxine, or sulfasalazine, or a tetracycline such as demeclocycline, doxycycline, minocycline, oxytetracycline, or tetracycline. In some embodiments, the compounds could be combined with a drug which acts against mycobacteria such as cycloserine, capreomycin, ethionamide, rifampicin, rifabutin, rifapentine, and streptomycin. Other antibiotics that are contemplated for combination therapies may include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin, dalfopristin, thiamphenicol, tigecycline, tinidazole, or trimethoprim.

2. Antivirals

The term "antiviral" or "antiviral agents" are drugs which may be used to treat a viral infection. In general, antiviral agents act via two major mechanisms: preventing viral entry into the cell and inhibiting viral synthesis. Without being bound by theory, viral replication can be inhibited by using agents that mimic either the virus-associated proteins and thus block the cellular receptors or using agents that mimic the cellular receptors and thus block the virus-associated proteins. Furthermore, agents which cause an uncoating of the virus can also be used as antiviral agents.

The second mechanism of viral inhibition is preventing or interrupting viral synthesis. Such drugs can target different proteins associated with the replication of viral DNA including reverse transcriptase, integrase, transcription factors, or ribozymes. Additionally, the therapeutic agent interrupts translation by acting as an antisense DNA strain, inhibiting the formation of protein processing or assembly, or acting as virus protease inhibitors. Finally, an anti-viral agent could additionally inhibit the release of the virus after viral production in the cell.

Additionally, anti-viral agents could modulate the bodies own immune system to fight a viral infection. Without being bound by theory, the anti-viral agent which stimulates the immune system may be used with a wide variety of viral infections. In some embodiments, the present disclosure provides methods of using the disclosed compounds in a combination therapy with an anti-viral agent as described above. In some non-limiting examples, the anti-viral agent is abacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balavir, boceprevirertet, cidofovir, combivir, dolutegravir, daruavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, ecoliever, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type I, type II, and type III, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, sofosbuvir, stavudine, telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, traporved, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, or zidovudine. In some embodiments, the anti-viral agents is an anti-retroviral, a fusion inhibitor, an integrase inhibitor, an interferon, a nucleoside analogues, a protease inhibitor, a reverse transcriptase inhibitor, a synergistic enhancer, or a natural product such as tea tree oil.

3. Chemotherapy

The term "chemotherapy" refers to the use of drugs to treat cancer. A "chemo therapeutic agent" is used to connote a compound or composition that is administered in the treatment of cancer. These agents or drugs are categorized by their mode of activity within a cell, for example, whether and at what stage they affect the cell cycle. Alternatively, an agent may be characterized based on its ability to directly cross-link DNA, to intercalate into DNA, or to induce chromosomal and mitotic aberrations by affecting nucleic acid synthesis. Most chemotherapeutic agents fall into the following categories: alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, and nitrosoureas.

Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB 1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γι¹ and calicheamicin ooi¹; dynemicin, including dynemicin A uncialamycin and derivatives thereof; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino- doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK polysaccharide complex); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluorometlhylornithine (DMFO); retinoids such as retinoic acid; capecitabine; cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP 16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol, paclitaxel, docetaxel, gemcitabien, navelbine, farnesyl-protein tansferase inhibitors, transplatinum, 5-fluorouracil, vincristin, vinblastin and methotrexate and pharmaceutically acceptable salts, acids or derivatives of any of the above.

4. Radiotherapy

Radiotherapy, also called radiation therapy, is the treatment of cancer and other diseases with ionizing radiation. Ionizing radiation deposits energy that injures or destroys cells in the area being treated by damaging their genetic material, making it impossible for these cells to continue to grow. Although radiation damages both cancer cells and normal cells, the latter are able to repair themselves and function properly.

Radiation therapy used according to the present disclosure may include, but is not limited to, the use of γ-rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells. Other forms of DNA damaging factors are also contemplated such as microwaves and UV -irradiation. It is most likely that all of these factors induce a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes. Dosage ranges for X-rays range from daily doses of 12.9 to 51.6 mC kg for prolonged periods of time (3 to 4 wk), to single doses of 0.516 to 1.55 C kg. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells. Radiotherapy may comprise the use of radiolabeled antibodies to deliver doses of radiation directly to the cancer site (radioimmuno therapy). Antibodies are highly specific proteins that are made by the body in response to the presence of antigens (substances recognized as foreign by the immune system). Some tumor cells contain specific antigens that trigger the production of tumor-specific antibodies. Large quantities of these antibodies can be made in the laboratory and attached to radioactive substances (a process known as radiolabeling). Once injected into the body, the antibodies actively seek out the cancer cells, which are destroyed by the cell-killing (cytotoxic) action of the radiation. This approach can minimize the risk of radiation damage to normal cells.

Conformal radiotherapy uses the same radiotherapy machine, a linear accelerator, as the normal radiotherapy treatment but metal blocks are placed in the path of the x-ray beam to alter its shape to match that of the cancer. This ensures that a higher radiation dose is given to the tumor. Normal surrounding cells and nearby structures receive a lower dose of radiation, so the possibility of side effects is reduced. A device called a multi-leaf collimator has been developed and may be used as an alternative to the metal blocks. The multi-leaf collimator consists of a number of metal sheets which are fixed to the linear accelerator. Each layer can be adjusted so that the radiotherapy beams can be shaped to the treatment area without the need for metal blocks. Precise positioning of the radiotherapy machine is very important for conformal radiotherapy treatment and a special scanning machine may be used to check the position of internal organs at the beginning of each treatment.

High-resolution intensity modulated radiotherapy also uses a multi-leaf collimator. During this treatment the layers of the multi-leaf collimator are moved while the treatment is being given. This method is likely to achieve even more precise shaping of the treatment beams and allows the dose of radiotherapy to be constant over the whole treatment area.

Although research studies have shown that conformal radiotherapy and intensity modulated radiotherapy may reduce the side effects of radiotherapy treatment, it is possible that shaping the treatment area so precisely could stop microscopic cancer cells just outside the treatment area being destroyed. This means that the risk of the cancer coming back in the future may be higher with these specialized radiotherapy techniques.

Scientists also are looking for ways to increase the effectiveness of radiation therapy. Two types of investigational drugs are being studied for their effect on cells undergoing radiation. Radiosensitizers make the tumor cells more likely to be damaged, and radioprotectors protect normal tissues from the effects of radiation. Hyperthermia, the use of heat, is also being studied for its effectiveness in sensitizing tissue to radiation. 5. Immunotherapy

In the context of cancer treatment, immunotherapeutics, generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells. Trastuzumab (Herceptin™) is such an example. The immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell. The antibody alone may serve as an effector of therapy or it may recruit other cells to actually affect cell killing. The antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve merely as a targeting agent. Alternatively, the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target. Various effector cells include cytotoxic T cells and NK cells. The combination of therapeutic modalities, i.e., direct cytotoxic activity and inhibition or reduction of ErbB2 would provide therapeutic benefit in the treatment of ErbB2 overexpressing cancers.

In one aspect of immunotherapy, the tumor cell must bear some marker that is amenable to targeting, i.e., is not present on the majority of other cells. Many tumor markers exist and any of these may be suitable for targeting in the context of the present disclosure. Common tumor markers include carcinoembryonic antigen, prostate specific antigen, urinary tumor associated antigen, fetal antigen, tyrosinase (p97), gp68, TAG- 72, HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B and pl55. An alternative aspect of immunotherapy is to combine anticancer effects with immune stimulatory effects. Immune stimulating molecules also exist including: cytokines such as IL-2, IL-4, IL-12, GM-CSF, γ-IFN, chemokines such as MIP-1, MCP-1, IL-8 and growth factors such as FLT3 ligand. Combining immune stimulating molecules, either as proteins or using gene delivery in combination with a tumor suppressor has been shown to enhance anti-tumor effects (Ju et al, 2000). Moreover, antibodies against any of these compounds may be used to target the anti-cancer agents discussed herein.

Examples of immunotherapies currently under investigation or in use are immune adjuvants e.g., Mycobacterium bovis, Plasmodium falciparum, dinitrochlorobenzene and aromatic compounds (U.S. Patents 5,801,005 and 5,739,169; Hui and Hashimoto, 1998; Christodoulides et al, 1998), cytokine therapy, e.g., interferons α, β, and y; IL-l, GM-CSF and TNF (Bukowski et al, 1998; Davidson et al, 1998; Hellstrand et al, 1998) gene therapy, e.g., TNF, IL-1, IL-2, p53 (Qin et al, 1998; Austin- Ward and Villaseca, 1998; U.S. Patents 5,830,880 and 5,846,945) and monoclonal antibodies, e.g., anti-ganglioside GM2, anti-HER-2, anti-pl85 (Pietras et al, 1998; Hanibuchi et al, 1998; U.S. Patent 5,824,311). It is contemplated that one or more anticancer therapies may be employed with the gene silencing therapies described herein.

In active immunotherapy, an antigenic peptide, polypeptide or protein, or an autologous or allogenic tumor cell composition or "vaccine" is administered, generally with a distinct bacterial adjuvant (Ravindranath and Morton, 1991 ; Morton et al, 1992; Mitchell et al, 1990; Mitchell et al, 1993).

In adoptive immunotherapy, the patient's circulating lymphocytes, or tumor-infiltrated lymphocytes, are isolated in vitro, activated by lymphokines such as IL-2 or transduced with genes for tumor necrosis, and readministered (Rosenberg et al, 1988; 1989).

6. Surgery

Approximately 60% of persons with cancer will undergo surgery of some type, which includes preventative, diagnostic or staging, curative, and palliative surgery. Curative surgery is a cancer treatment that may be used in conjunction with other therapies, such as the treatment of the present disclosure, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy and/or alternative therapies.

Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed. Tumor resection refers to physical removal of at least part of a tumor. In addition to tumor resection, treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and microscopically controlled surgery (Mohs' surgery). It is further contemplated that the present disclosure may be used in conjunction with removal of superficial cancers, precancers, or incidental amounts of normal tissue. Upon excision of part or all of cancerous cells, tissue, or tumor, a cavity may be formed in the body. Treatment may be accomplished by perfusion, direct injection or local application of the area with an additional anti-cancer therapy. Such treatment may be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. These treatments may be of varying dosages as well.

In some particular embodiments, after removal of the tumor, an adjuvant treatment with a compound of the present disclosure is believe to be particularly efficacious in reducing the reoccurance of the tumor. Additionally, the compounds of the present disclosure can also be used in a neoadjuvant setting.

7. Other Agents

It is contemplated that other agents may be used with the present disclosure. These additional agents include immunomodulatory agents, agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adhesion, agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers, or other biological agents. Immunomodulatory agents include tumor necrosis factor; interferon alpha, beta, and gamma; IL-2 and other cytokines; F42K and other cytokine analogs; or MIP-1, ΜΙΡ-Ιβ, MCP-1, RANTES, and other chemokines. It is further contemplated that the upregulation of cell surface receptors or their ligands such as Fas/Fas ligand, DR4 or DR5/TRAIL (Apo-2 ligand) would potentiate the apoptotic inducing abilities of the present disclosure by establishment of an autocrine or paracrine effect on hyperproliferative cells. Increases intercellular signaling by elevating the number of GAP junctions would increase the anti-hyperproliferative effects on the neighboring hyperproliferative cell population. In other embodiments, cytostatic or differentiation agents may be used in combination with the present disclosure to improve the anti-hyerproliferative efficacy of the treatments. Inhibitors of cell adhesion are contemplated to improve the efficacy of the present disclosure. Examples of cell adhesion inhibitors are focal adhesion kinase (FAKs) inhibitors and Lovastatin. It is further contemplated that other agents that increase the sensitivity of a hyperproliferative cell to apoptosis, such as the antibody c225, could be used in combination with the present disclosure to improve the treatment efficacy.

There have been many advances in the therapy of cancer following the introduction of cytotoxic chemotherapeutic drugs. However, one of the consequences of chemotherapy is the development/acquisition of drug-resistant phenotypes and the development of multiple drug resistance. The development of drug resistance remains a major obstacle in the treatment of such tumors and therefore, there is an obvious need for alternative approaches such as gene therapy.

Another form of therapy for use in conjunction with chemotherapy, radiation therapy or biological therapy includes hyperthermia, which is a procedure in which a patient's tissue is exposed to high temperatures (up to 106°F). External or internal heating devices may be involved in the application of local, regional, or whole-body hyperthermia. Local hyperthermia involves the application of heat to a small area, such as a tumor. Heat may be generated externally with high-frequency waves targeting a tumor from a device outside the body. Internal heat may involve a sterile probe, including thin, heated wires or hollow tubes filled with warm water, implanted microwave antennae, or radiofrequency electrodes. A patient's organ or a limb is heated for regional therapy, which is accomplished using devices that produce high energy, such as magnets. Alternatively, some of the patient's blood may be removed and heated before being perfused into an area that will be internally heated. Whole-body heating may also be implemented in cases where cancer has spread throughout the body. Warm-water blankets, hot wax, inductive coils, and thermal chambers may be used for this purpose.

The skilled artisan is directed to "Remington's Pharmaceutical Sciences" 15th Edition, chapter 33, in particular pages 624-652. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.

It also should be pointed out that any of the foregoing therapies may prove useful by themselves in treating cancer.

IV. Synthetic Methods

In some aspects, the compounds of this disclosure can be synthesized using the methods of organic chemistry as described in this application. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated by reference herein

A. Process Scale-Up

The synthetic methods described herein can be further modified and optimized for preparative, pilot- or large-scale production, either batch of continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Practical Process Research & Development (2000), which is incorporated by reference herein. The synthetic method described herein may be used to produce preparative scale amounts of viridicatumtoxin and derivatives thereof.

B. Chemical Definitions

When used in the context of a chemical group: "hydrogen" means -H; "hydroxy" means -OH; "oxo" means =0; "carbonyl" means -C(=0)-; "carboxy" means -C(=0)OH (also written as -COOH or -CO2H); "halo" means independently -F, -CI, -Br or -I; "amino" means -NH2; "hydroxyamino" means -NHOH; "nitro" means -NO2; imino means =NH; "cyano" means -CN; "isocyanate" means -N=C=0; "azido" means -N3; in a monovalent context "phosphate" means -OP(O)(OIfh or a deprotonated form thereof; in a divalent context "phosphate" means -OP(0)(OH)0- or a deprotonated form thereof; "mercapto" means -SH; and "fhio" means =S; "sulfo" means -SO3H, "sulfonyl" means -S(0)2-; and "sulfinyl" means -S(O)-.

In the context of chemical formulas, the symbol "-" means a single bond, "=" means a double bond, and "≡" means triple bond. The symbol " " represents an optional bond, which if present is either single or double. The symbol "==" represents a single bond or a double bond. Thus, for example, the formula includes and And it is understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol when connecting one or two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it covers all stereoisomers as well as mixtures thereof. The symbol " ^/ w "_? when drawn perpendicularly across a bond

(e.g. , |— CH₃ for methyl) indicates a point of attachment of the group. It is noted that the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment. The symbol " " means a single bond where the group attached to the thick end of the wedge is "out of the page." The symbol " """I " means a single bond where the group attached to the thick end of the wedge is "into the page". The symbol " ^»ΛΛΛ " means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.

When a group "R" is depicted as a "floating group" on a ring system, for example, in the formula:

then R may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed. When a group "R" is depicted as a "floating group" on a fused ring system, as for example in the formula:

then R may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise. Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals -CH-), so long as a stable structure is formed. In the example depicted, R may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula above, the subscript letter "y" immediately following the group "R" enclosed in parentheses, represents a numeric variable. Unless specified otherwise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydrogen atoms of the ring or ring system.

For the groups and classes below, the following parenthetical subscripts further define the group/class as follows: "(Cn)" defines the exact number (n) of carbon atoms in the group/class. "(C<n)" defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number as small as possible for the group in question, e.g., it is understood that the minimum number of carbon atoms in the group "alkenyl(c<8)" or the class "alkene(c<8)" is two. For example, "alkoxy(c≤io)" designates those alkoxy groups having from 1 to 10 carbon atoms. (Cn-n') defines both the minimum (n) and maximum number (η') of carbon atoms in the group. Similarly, "alkyl(C2-io)" designates those alkyl groups having from 2 to 10 carbon atoms.

The term "saturated" as used herein means the compound or group so modified has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. In the case of substituted versions of saturated groups, one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded.

The term "aliphatic" when used without the "substituted" modifier signifies that the compound/group so modified is an acyclic or cyclic, but non-aromatic hydrocarbon compound or group. In aliphatic compounds/groups, the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds/groups can be saturated, that is joined by single bonds (alkanes/alkyl), or unsaturated, with one or more double bonds (alkenes/alkenyl) or with one or more triple bonds (alkynes/alkynyl).

The term "alkyl" when used without the "substituted" modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups -CH3 (Me), -CH2CH3 (Et), -CH2CH2CH3 (n-Pr or propyl), -CH(CH₃)₂ ^'-Pr, 'Pr or isopropyl), -CH2CH2CH2CH3 (ra-Bu), -CH(CH₃)CH₂CH₃ (sec-butyl), -CH₂CH(CH₃)₂ (isobutyl), -C(CH3) (ierf-butyl, f-butyl, f-Bu or ¾u), and -CH2C(CH3) (neo-pentyl) are non-limiting examples of alkyl groups. The term "alkanediyl" when used without the "substituted" modifier refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, -CH2- (methylene), -CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2CH2- are non- limiting examples of alkanediyl groups. The term "alkylidene" when used without the "substituted" modifier refers to the divalent group =CRR' in which R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: =CH2,

An "alkane" refers to the compound H-R, wherein R is alkyl as this term is defined above. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH₂, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)2, -C(0)NH₂, -OC(0)CH₃, or -S(0)₂NH₂. The following groups are non-limiting examples of substituted alkyl groups: -CH₂OH, -CH₂C1, -CF₃, -CH₂CN, -CH₂C(0)OH, -CH₂C(0)OCH₃, -CH₂C(0)NH₂, -CH₂C(0)CH₃, -CH2OCH3, -CH₂OC(0)CH₃, -CH₂NH₂, -CH₂N(CH₃)2, and -CH2CH2CI. The term "haloalkyl" is a subset of substituted alkyl, in which one or more hydrogen atoms has been substituted with a halo group and no other atoms aside from carbon, hydrogen and halogen are present. The group, -CH2CI is a non-limiting example of a haloalkyl. The term "fluoroalkyl" is a subset of substituted alkyl, in which one or more hydrogen has been substituted with a fluoro group and no other atoms aside from carbon, hydrogen and fluorine are present. The groups, -CH2F, -CF₃, and -CH2CF3 are non-limiting examples of fluoroalkyl groups.

The term "cycloalkyl" when used without the "substituted" modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forms part of one or more non- aromatic ring structures, a cyclo or cyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples of cycloalkyl groups include: -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl. The term "cycloalkanediyl" when used without the "substituted" modifier refers to a divalent saturated aliphatic group with one or two carbon atom as the point(s) of attachment, said carbon atom(s) forms part of one or more non-aromatic ring structures, a cyclo or cyclic structure, no

carbon-carbon double or triple bonds, and no atoms other than carbon and hydi

are non-limiting examples of cycloalkanediyl groups. A

"cycloalkane" refers to the compound H-R, wherein R is cycloalkyl as this term is defined above. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH₂, -N0₂, -C0₂H, -CO₂CH₃, -CN, -SH, -OCH3, -OCH₂CH₃, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH₂, -OC(0)CH₃, or -S(0)₂NH₂. The following

groups are non-limiting examples of substituted cycloalkyl groups: -C(OH)(CH₂)¾

, or

The term "alkenyl" when used without the "substituted" modifier refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples of alkenyl groups include: -CH=CH₂ (vinyl), -CH=CHCH3, -CH=CHCH₂CH₃, -CH₂CH=CH₂ (allyl), -CH₂CH=CHCH₃, and -CH=CHCH=CH₂. The term "alkenediyl" when used without the "substituted" modifier refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups, -CH=CH-, -CH=C(CH3)CH₂- and -CH=CHCH₂-, are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms "alkene" and refer to a compound having the formula H-R, wherein R is alkenyl as this term is defined above. A "terminal alkene" refers to an alkene having just one carbon-carbon double bond, wherein that bond forms a vinyl group at one end of the molecule. When any of these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH₂, -N0₂, -C0₂H, -C0₂CH₃, -CN, -SH, -OCH3, -OCH₂CH₃, -C(0)CH₃, -NHCH3, -NHCH₂CH₃, -N(CH₃)₂, -C(0)NH₂, -OC(0)CH₃, or -S(0)₂NH₂. The groups, -CH=CHF, -CH=CHC1 and -CH=CHBr, are non-limiting examples of substituted alkenyl groups. The term "alkynyl" when used without the "substituted" modifier refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups, -C≡CH, -C≡CC]¾, and -CH2C≡CC¾, are non-limiting examples of alkynyl groups. An "alkyne" refers to the compound H-R, wherein R is alkynyl. When any of these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -N¾, -NO₂, -CO₂H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH¾ -OC(0)CH₃, or -S(0)₂NH₂.

The term "aryl" when used without the "substituted" modifier refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more six-membered aromatic ring structure, wherein the ring atoms are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl. The term "arenediyl" when used without the "substituted" modifier refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structure(s) wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen. As used herein, the term does not preclude the presence of one or more alkyl, aryl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting). Non-limiting ex

An "arene" refers to the compound H-R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes. When any of these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -N¾, -NO2, -CO2H,

-CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH¾

-OC(0)CH₃, or -S(0)₂NH₂.

The term "aralkyl" when used without the "substituted" modifier refers to the monovalent group

-alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples of aralkyls are: phenylmethyl (benzyl, Bn) and 2-phenyl- ethyl. When the term aralkyl is used with the "substituted" modifier one or more hydrogen atom from the alkanediyl and/or the aryl group has been independently replaced by -OH, -F, -CI, -Br, -I, -N¾, -NO₂, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH₂, -OC(0)CH₃, or -S(0)₂NH₂. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)- methyl, and 2-chloro-2-phenyl-eth-l-yl.

The term "heteroaryl" when used without the "substituted" modifier refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl, aryl, and/or aralkyl groups (carbon number limitation permitting) attached to the aromatic ring or aromatic ring system. Non- limiting examples of heteroaryl groups include furanyl, imidazolyl, indolyl, indazolyl (Im), isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridinyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term 'W-heteroaryl" refers to a heteroaryl group with a nitrogen atom as the point of attachment. The term "heteroarenediyl" when used without the "substituted" modifier refers to an divalent aromatic group, with two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aromatic nitrogen atom as the two points of attachment, said atoms forming part of one or more aromatic ring structure(s) wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting). As used herein, the term does not preclude the presence of one or more alkyl, aryl, and/or aralkyl groups (carbon number limitation permitting) attached to the aromatic ring or aromatic ring system. Non-limiting examples of heteroarenediyl groups include:

A "heteroarene" refers to the compound H-R, wherein R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. When these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH₂, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH₂, -OC(0)CH₃, or -S(0)₂NH₂.

The term "heteroaralkyl" when used without the "substituted" modifier refers to the monovalent group -alkanediyl-heteroaryl, in which the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. Non-limiting examples of heteroaralkyls are: 2-pyridylmethyl and 2-indazolyl- ethyl. When the term heteroaralkyl is used with the "substituted" modifier one or more hydrogen atom from the alkanediyl and/or the heteroaryl group has been independently replaced by -OH, -F, -CI, -Br, -I, -N¾, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH₂, -OC(0)CH₃, or -S(0)₂NH₂. Non-limiting examples of substituted heteroaralkyls are: (3-chloroquinolyl)-methyl, and 2-chloro-2-thienyl-eth-l-yl.

The term "heterocycloalkyl" when used without the "substituted" modifier refers to a monovalent non- aromatic group with a carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more non-aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the ring or ring system. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, oxiranyl, and oxetanyl. The term "iV-heterocycloalkyl" refers to a heterocycloalkyl group with a nitrogen atom as the point of attachment. The term "heterocycloalkanediyl" when used without the "substituted" modifier refers to an divalent cyclic group, with two carbon atoms, two nitrogen atoms, or one carbon atom and one nitrogen atom as the two points of attachment, said atoms forming part of one or more ring structure(s) wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting). As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the ring or ring system. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkanediyl groups include:

When these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH₂, -NC¾ -C0₂H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)¾ -C(0)NH₂, -OC(0)CH₃, -S(0)₂NH₂, or -C(0)OC(CH₃)₃ (ferf-butyloxycarbonyl, BOC).

The term "acyl" when used without the "substituted" modifier refers to the group -C(0)R, in which R is a hydrogen, alkyl, cycloalkyl, aryl, aralkyl or heteroaryl, as those terms are defined above. The groups, -CHO, -C(0)CH₃ (acetyl, Ac), -C(0)CH₂CH₃, -C(0)CH₂CH₂CH₃, -C(0)CH(CH₃)2, -C(0)CH(CH₂)₂, -C(0)C₆H₅, -C(0)C₆H4CH₃, -C(0)CH₂C₆H₅, -C(0)(imidazolyl) are non-limiting examples of acyl groups. A "thioacyl" is defined in an analogous manner, except that the oxygen atom of the group -C(0)R has been replaced with a sulfur atom, -C(S)R. The term "aldehyde" corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a -CHO group. When any of these terms are used with the "substituted" modifier one or more hydrogen atom (including a hydrogen atom directly attached the carbonyl or thiocarbonyl group, if any) has been independently replaced by -OH, -F, -CI, -Br, -I, -N¾, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH3, -NHCH2CH3, -N(CH₃)₂, -C(0)NH₂, -OC(0)CH₃, or -S(0)₂NH₂. The groups, -C(0)CH₂CF₃, -CO^ (carboxyl), -C0₂CH₃ (methylcarboxyl), -C0₂CH₂CH₃, -C(0)NH₂ (carbamoyl), and -CON(CH₃)₂, are non-limiting examples of substituted acyl groups.

The term "alkylamino" when used without the "substituted" modifier refers to the group -NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples of alkylamino groups include: -NHCH₃ and -NHCH₂CH₃. The term "dialkylamino" when used without the "substituted" modifier refers to the group -NRR', in which R and R' can each independently be the same or different alkyl groups, or R and R' can be taken together to represent an alkanediyl. Non-limiting examples of dialkylamino groups include: -N(CH₃)₂, -N(CH₃)(CH₂CH₃), and iV-pyrrolidinyl. The terms "alkoxyamino", "cycloalkylamino", "alkenylamino", "cycloalkenylamino", "alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", "heterocycloalkylamino" and "alkylsulfonylamino" when used without the "substituted" modifier, refers to groups, defined as -NHR, in which R is alkoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkylsulfonyl, respectively. A non-limiting example of an arylamino group is -NHC6H5. The term "amido" (acylamino), when used without the "substituted" modifier, refers to the group -NHR, in which R is acyl, as that term is defined above. A non-limiting example of an amido group is -NHC(0)CH₃. The term "alkylimino" when used without the "substituted" modifier refers to the divalent group =NR, in which R is an alkyl, as that term is defined above. The term "alkylaminodiyl" refers to the divalent group -NH-alkanediyl- -NH-alkanediyl-NH-, or -alkanediyl-NH- alkanediyl-. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH₂, -N0₂, -C0₂H, -C0₂CH₃, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(0)NH₂, -OC(0)CH₃, or -S(0)₂NH₂. The groups -NHC(0)OCH₃ and -NHC(0)NHCH₃ are non-limiting examples of substituted amido groups.

The term "alkoxy" when used without the "substituted" modifier refers to the group -OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: -OCH₃ (methoxy), -OCH₂CH₃ (ethoxy), -OCH₂CH₂CH₃, -OCH(CH₃)₂ (isopropoxy), and -OC(CH₃)₃ (fert-butoxy). The terms "cycloalkoxy", "alkenyloxy", "alkynyloxy", "aryloxy", "aralkoxy", "heteroaryloxy", "heterocycloalkoxy", "acyloxy", "alkylsilyloxy", "alkylarylsilyloxy", and "alkylaralkylsilyloxy", when used without the "substituted" modifier, refers to groups, defined as -OR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, acyl, alkylsilyl, alkylarylsilyl, or alkylaralkylsilyl, respectively. The term "alkoxydiyl" refers to the divalent group -O-alkanediyl-, -O-alkanediyl-0-, or -alkanediyl-O-alkanediyl-. The term "alkylthio" and "acylthio" when used without the "substituted" modifier refers to the group -SR, in which R is an alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term "ether" corresponds to an alkane or cycloalkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy or cycloalkoxy group. W^rhen any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH₂, -NO2, -C0₂H, -C0₂CH₃, -CN, -SH, -OCH₃, -OCH₂CH₃, -C(0)CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -C(0)NH₂, -OC(0)CH₃, or -S(0)₂NH₂. The term "alkylsilyl" when used without the "substituted" modifier refers to a monovalent group, defined as -S1H2R, -SiHRR', or -SiRR'R", in which R, R' and R" can be the same or different alkyl groups, or any combination of two of R, R' and R" can be taken together to represent an alkanediyl. The groups, -S1H2CH3, -SiH(CH3)2, -Si(CI¾)3 and -Si(CH3)2C(CH3)3, are non-limiting examples of unsubstituted alkylsilyl groups. The terms arylsilyl and aralkylsilyl refer to a monovalent group in which R, R' and R" as shown above are aryl and aralkyl groups, respectively. The term "substituted alkylsilyl" refers -S1H2R, -SiHRR', or -SiRR'R", in which at least one of R, R' and R" is a substituted alkyl or two of R, R' and R" can be taken together to represent a substituted alkanediyl. When more than one of R, R' and R" is a substituted alkyl, they can be the same or different. Any of R, R' and R" that are not either substituted alkyl or substituted alkanediyl, can be either alkyl, either the same or different, or can be taken together to represent a alkanediyl with two or more saturated carbon atoms, at least two of which are attached to the silicon atom. The term "arylsilyl" or "aralkylsilyl" refers to the group as defined above where at least one of R, R', or R" is an aryl or aralkyl group as those groups are defined above. Similarly, the term "alkylarylsilyl" or "alkylaralkylsily " when used without the "substituted" modifier refer to monovalent groups, in which R, R' and R" can be the same or different alkyl or aryl groups or the same or different alkyl and aralkyl groups, as those terms are defined above. A substituted version of any of these groups refers to a group in which one or more of the alkyl, aryl, or aralkyl groups is substituted as those terms are defined above.

A "base" in the context of this application is a compound which has a lone pair of electron that can accept a proton. Non-limiting examples of a base can include triethylamine, a metal hydroxide, a metal alkoxide, a metal hydride, or a metal alkane. An alkyllithium or organolithium is a compound of the formula alkyl(c<i2)- Li. A nitrogenous base is an alkylamine, dialkylamino, trialkylamine, nitrogen containing heterocycloalkane or heteroarene wherein the base can accept a proton to form a positively charged species. For example, but not limited to, a nitrogenous base could be 4,4-dimethylpyridine, pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene, diisopropylethylamine, or triethylamine. A metal alkoxide is an alkoxy group wherein rather than the oxygen atom which was the point of connectivity has an extra electron and thus a negative charge which is charged balanced by the metal ion. For example, a metal alkoxide could be a sodium tert-butoxide or potassium methoxide. A metal carbonate is a carbonate anion with two monovalent cations or a divalent cation. Some non-limiting examples include sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, or magnesium carbonate.

A "fluoride source" in the context of this application is a reagent which generates or contains a fluoride ion. Some non-limiting examples include hydrofluoric acid, metal fluoride, or tetrabutylammonium fluoride.

A "linker" in the context of this application is divalent chemical group which may be used to join one or more molecules to the compound of the instant disclosure. In some embodiments, the linker contains a reactive functional group, such as a carboxyl, an amide, a amine, a hydroxy, a mercapto, an aldehyde, or a ketone on each end that be used to join one or more molecules to the compounds of the instant disclosure. In some non-limiting examples, -CH2CH2CH2CH2-, -C(0)CH₂CH₂CH2-, -OCH2CH2NH-, -NHCH2CH2NH-, and -(OCH2CH2)_n- wherein n is between 1-1000, are linkers.

A "leaving group" in the context of this application is a group which has the ability to be displaced from the molecule through nucleophilic attack. This group may also convert a hydroxyl group into a better leaving group by stabilizing the charge on the oxygen when the atom bears a negative charge thus making the hydroxyl group more susceptible to a nucleophilic attack and displacement. In some embodiments, the leaving group may be a halogen atom such as a bromine atom or a iodine atom.

A "metal" in the context of this application is a transition metal or a metal of groups I or II. In some embodiments, a metal is lithium, sodium, or potassium. In other embodiments, a metal is calcium or magnesium.

An "anion" is a negatively charged cation. For example, a "monovalent anion" is a negatively charged cation with a single negative charge. Some non-limiting examples of anions include chloride, bromide, fluoride, iodide, acetate, nitrate, phosphate, sulfate, or hydroxide.

An "amine protecting group" is well understood in the art. An amine protecting group is a group which prevents the reactivity of the amine group during a reaction which modifies some other portion of the molecule and can be easily removed to generate the desired amine. Amine protecting groups can be found at least in Greene and Wuts, 1999, which is incorporated herein by reference. Some non-limiting examples of amino protecting groups include formyl, acetyl, propionyl, pivaloyl, f-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, G-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxycarbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l-methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, r-butyloxycarbonyl (Boc), diisopropy methoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2- trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9- methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Additionally, the "amine protecting group" can be a divalent protecting group such that both hydrogen atoms on a primary amine are replaced with a single protecting group. In such a situation the amine protecting group can be phthalimide (phth) or a substituted derivative thereof wherein the term "substituted" is as defined above. In some embodiments, the halogenated phthalimide derivative may be tetrachlorophthalimide (TCphth).

A "hydroxyl protecting group" is well understood in the art. A hydroxyl protecting group is a group which prevents the reactivity of the hydroxyl group during a reaction which modifies some other portion of the molecule and can be easily removed to generate the desired hydroxyl. Hydroxyl protecting groups can be found at least in Greene and Wuts, 1999, which is incorporated herein by reference. Some non-limiting examples of hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, f-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p- toluenesulfonyl and the like; acyloxy groups such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p- memoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 - (/7-biphenylyl)- 1 -methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, i-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimefhylsilyl- ethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluoreny 1-9 -methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.

A "thiol protecting group" is well understood in the art. A thiol protecting group is a group which prevents the reactivity of the mercapto group during a reaction which modifies some other portion of the molecule and can be easily removed to generate the desired mercapto group. Thiol protecting groups can be found at least in Greene and Wuts, 1999, which is incorporated herein by reference. Some non-limiting examples of thiol protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, i-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p- toluenesulfonyl and the like; acyloxy groups such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p- methoxybenzyloxycarbonyk p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, /7-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 - (jp-biphenylyl)- 1 -methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, r-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2- trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9- methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.

An "excipient" is a pharmaceutically acceptable substance formulated along with the active ingredient(s) of a medication, pharmaceutical composition, formulation, or drug delivery system. Excipients may be used, for example, to stabilize the composition, to bulk up the composition (thus often referred to as "bulking agents," "fillers," or "diluents" when used for this purpose), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable versions of antiadherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles. The main excipient that serves as a medium for conveying the active ingredient is usually called the vehicle. Excipients may also be used in the manufacturing process, for example, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The suitability of an excipient will typically vary depending on the route of administration, the dosage form, the active ingredient, as well as other factors.

As used herein, the term "patient" or "subject" refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human patients are adults, juveniles, infants and fetuses.

As generally used herein "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

"Pharmaceutically acceptable salts" means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, /7-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, A -methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, 2002.

A "pharmaceutically acceptable carrier," "drug carrier," or simply "carrier" is a pharmaceutically acceptable substance formulated along with the active ingredient medication that is involved in carrying, delivering and/or transporting a chemical agent. Drug carriers may be used to improve the delivery and the effectiveness of drugs, including for example, controlled-release technology to modulate drug bioavailability, decrease drug metabolism, and/or reduce drug toxicity. Some drug carriers may increase the effectiveness of drug delivery to the specific target sites. Examples of carriers include: liposomes, microspheres (e.g., made of poly(lactic-co-glycolic) acid), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virosomes, and dendrimers.

A "stereoisomer" or "optical isomer" is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other, like left and right hands. "Diastereomers" are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedrally substituted carbon atoms), the total number of hypothetically possible stereoisomers will not exceed 2ⁿ, where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its (R) form, (S) form, or as a mixture of the (R) and (S) forms, including racemic and non-racemic mixtures. As used herein, the phrase "substantially free from other stereoisomers" means that the composition contains < 15%, more preferably < 10%, even more preferably < 5%, or most preferably < 1 % of another stereoisomer(s).

V. Examples

The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

EXAMPLE 1 - Enantioselective Synthesis of Viridicatumtoxin and Analogs Thereof

A. As mmetric Alkylation of Anthrones.

Scheme 1 below describes in retrosynthetic format the strategy employed in earlier first total synthesis of viridicatumtoxin B (1) in which the target molecule was traced back to key building blocks 5, 7 and 8 through advanced intermediates 4 and 6, with the latter being the first key chiral compound enroute to 1. The asymmetric generation of intermediate 6 through alkylation of anthrone 7 with cyclic allylic bromide 8, therefore, became the key challenge for an asymmetric route to viridicatumtoxin B and its analogues. This challenge was expected to be difficult not only due to the potential propensity of alkylation product 6 to CIO (anthrone numbering) racemization under the required basic conditions but also because of its perceived sensitivity to isomerize under the Lewis acid-mediated spirocyclization conditions to form the next advanced intermediate, chiral pentacyclic compound 4 (viridicatumtoxin numbering). Although numerous asymmetric alkylations have been reported (Trost et al, 2006; Trost, 2004; Trost and Crawley, 2003; Trost and Van Vranken, 1996; Trost, 1996; Maruoka and Ooi, 2003; Ooi and Maruoka, 2007; Trost and Bunt, 1994; Shih et al, 2010; Liu et al, 2011 ; Provencher et al , 2011 ; Ceban et al , 2015), a practical asymmetric alkylation of anthrones 7 was not available.

Scheme 1: A

Focusing on known asymmetric alkylation reactions (Trost et al, 2006; Trost, 2004; Trost and Crawley, 2003; Trost and Van Vranken, 1996; Trost, 1996; Maruoka and Ooi, 2003; Ooi and Maruoka, 2007; Trost and Bunt, 1994; Shih et al, 2010; Liu et al, 2011 ; Provencher et al, 2011; Ceban et al, 2015), the initial studies pointed to phase transfer catalysts as promising for further studies. Brief exploration of phase transfer catalysts PTC1 (Corey et al, 1997; Corey et al, 1998) and PTC2 (Kitamura et al, 2005) and chiral base catalyst PTC3 (Iwabuchi et al, 1999) identified the Corey catalyst (PTCl) as the most practical and efficient to pursue as a lead scaffold for further optimization (see Table 1, entries 1-3). Thus, following this pathpointing observation, a series of catalysts [newly synthesized: PTC5, PTC7-PTC13 and PTC15; previously reported: PTC4 (Lee and Wong, 1994; Lian et al, 2010), PTC6 (Kobbelgaard et al, 2006; Liang et al, 2014), PTC 14 (Zeng et al, 2013; Adam et al, 2002; Xie et al, 2014), and PTC16 (Johnston et al, 2015; Li et al, 2013), Table 1, entries 4-18; for further catalysts synthesized and tested] were tested for their efficiency in the anthrone alkylation reaction with racemic [(/?,£)-] or enantiopure [(R)- or (5)-] allylic bromide 8 in a two-phase solvent system (50% aq. K0H:CH₂C1₂) at -78 to 0 °C. As seen in Table 1 , the best results were obtained with PTC15 and the (R)- enantiomer of allylic bromide 8 [(/?)-8, 99% substrate conversion, 75% yield, 89: 11 dr, entry 17], although the reaction with (R,S)-8 also performed well (99% substrate conversion, 75% yield and 86: 14 dr, entry 15). The performance of PTC9 and PTC14 were also of note (entries 9 and 14, respectively, Table 1). The significant difference in diastereo selectivity observed with the (S)-enantiomer of 8 [(S)-8, entry 16, 83:17 dr] drew considerable interest. The ability to synthesize the antipode of alkylation product 6 was demonstrated by using the (S)-enantiomer of allylic bromide 8 and catalyst PTC16 (pseudo-enantiomer of PTC14, prepared from cinchonidine, 99% substrate conversion, 76% yield, 13:87 dr, entry 18, Table 1).

The superiority of catalysts PTC8, PTC9, PTC 15 and PTC16 (Table 1, entries 8, 9, 15-18), all of which include an electron withdrawing group on their benzyloxy residue, as opposed to relatively electron rich catalysts carrying a benzyloxy substituent (e.g. PTC4, entry 4, Table 1), is in line with Maruoka's work (Nelson et ai, 2001). This trend is further corroborated with the observed superiority of catalysts PTC39, PTC40 and PTC41 (all of which contain fluorine atoms on their benzyloxy residue, see Example 3) over PTC38, whose benzyloxy moiety includes an electron rich residue {e.g., Me, see Example 3).

Table 1. Catalyst Optimization of Alkvlation of Anthrone 7 with AUylic Bromide 8 [( ?) and/or

(S)Y

Entry Catalyst 8 (R¹, R² Conv. (%) Yield (%) dr (%)^c

1 PTC1 (S) and (R) >99 78 62:38

2 PTC2 (S) and (R) 90 70 61:39

3 PTC3 (S) and (R) >99 75 55:45

4 PTC4 (S) and (R) >99 77 63:37

5 PTC5 (S) and (R) >99 76 58:42

6 PTC6 (S) and (R) >99 74 60:40

7 PTC7 (S) and (R) >99 76 62:38

8 PTC8 (S) and (R) >99 73 82: 18

9 PTC9 (S) and (R) 80 70 83: 17

10 PTC 10 (S) and (R) >99 72 80:20

1 1 PTC 11 (S) and (R) >99 70 79:21

12 PTC 12 (S) and (R) >99 72 58:42

13 PTC 13 (5) and (R) >99 75 64:36

14 PTC 14 (5) and (R) >99 76 84: 16

15 PTC 15 (5) and (R) >99 75 86: 14

16 PTC 15 (S) >99 75 83: 17

17 PTC 15 OR) >99 75 89: 11 Entry Catalyst 8 (R¹, R²)* Conv. (%) Yield (%) dr (%)^e

18 PTC16^e (S) >99 76 13:87

^Reaction conditions: anthrone 7 (0.10 mmol), allylic bromide 8 (0.11 mmol), PTC cat. (10 mol%), CH₂C1₂ (0.9 mL), 50% aq. KOH (0.3 mL), -78 to 0 °C, 8 h. ''Allylic bromides (R)-8 and (5)-8 were prepared through a standard sequence (Nicolaou et al, 2013; Nicolaou et al., 2014) involving CBS reduction (Corey et al., 1987) of an intermediate enone. The diastereoisomeric ratio (dr) was determined by HPLC using a chira!Pak AD-H column, the dr ratios for entries 1-15 were determined from the HPLC peak areas corresponding to (105)- 6:(10R)-6. ΪΓΟό is the pseudo-enantiomer of PTC14.

Striving for higher asymmetric induction and efficiency, and beyond catalyst and alkylating agent absolute configuration optimization, the effect of reaction conditions and catalyst loading on the alkylation of anthrone 7 with TBS-protected alkylating agent (R)-8 and catalyst PTC15 was then investigated. Table 2 summarizes the results of this study that involved changes in the aqueous base, organic solvent, temperature, reaction time and catalyst loading. Initial experiments (entries 1-6, Table 2) led to the identification of 40% aq.

CS2CO3 and CH2CI2 as the optimal base and solvent, respectively (entry 5, 0 °C, 10 mol% cat., 75% yield, 92:8 dr, Table 2). Changing the solvent from CH₂CI₂ to (Cft^Ck increased the dr slightly (93:7, entry 7, Table 2), while decreasing the temperature steadily from 0 to -30 °C led to further improvements in the dr with proportional increases in reaction time as expected (93:7; 94:6; 95:5; entries 12-14, respectively, Table 2).

Stepwise decrease of catalyst loading from 10 to 0.1 mol% resulted in a slight increase of efficiency, in a relative inverse relationship with the reaction time (95:5 to 96:4 dr, entries 14 to 16, Table 2). The lower yield (due to decreased rate and conversion) reflected in entry 16 (Table 2, 15% yield) with 0.1 mol% catalyst loading provided an unaccepable limit, thereby leading the 0.5 mol% catalyst loading as the most practical with regard to reaction rate, yield, and diastereoselectivity for future studies (72% yield, 95:5 dr, 40% aq. CS2CO3, (Ο¾)2θ2,

-30 °C, 180 h, entry 17, Table 2).

Table 2.

Base θ Time Cat.* Yield

Entry Solvent dr^e

(aq. solution) (°C) (h) (mol%) (%)

1 50% KOH CH2CI2 0 8 10 77 89:11

2 50% NaOH CH2CI2 0 8 10 77 89:11

3 50% CS2CO3 CH2CI2 0 8 10 77 91 :9

4 50% K2CO3 CH2CI2 0 8 10 75 91 :9

5 40% CS2CO3 CH2CI2 0 8 10 75 92:8

6 30% Cs₂C0₃ CH2CI2 0 8 10 73 91 :9

7 40% Cs₂C0₃ (CH₂)₂Cl2 0 8 10 72 93:7

8 40% CS2CO3 CHCI3 0 8 10 60 85:15

9 40% CS2CO3 CCI4 0 8 10 50 81 :19

10 40% CS2CO3 PhMe 0 8 10 78 84:16

11 40% CS2CO3 EtOAc 0 8 10 65 78:22

12 40% Cs₂C0₃ (CH₂)₂C1₂ -10 24 10 72 93:7

13 40% CS2CO3 (CH₂)₂Cl2 -20 72 10 72 94:6

14 40% CS2CO3 (CH₂)2Cl2 -30 180 10 72 95:5

15 40% CS2CO3 (CH₂)2C1₂ -30 180 1 72 95:5 Base θ Time Cat.^¾ Yield

Solvent dr^e

(aq. solution) (°C) (h) (mol%) ( )

40% Cs₂C0₃ (CH₂)₂C1₂ -30 200 0.1 15 96:4

40% i -.AJ ;. ; 80 3 ;S

"Reaction conditions: anthrone 7 (0.10 mmol), allylic bromide (R)-S (0.1 1 mmol), PTC15, solvent (0.9 mL), aq. base solution (0.3 mL). *Cat. = catalyst loading. The dr [(10S)-6:(10/?)-6] was determined by HPLC using a chiralPak AD-H column, see Example 3. ^Reaction was ran on 5 mmol scale (anthrone). For further studies on possible CIO racemization of the alkylation product under basic conditions, see Example 3.

Inspired by the effect of the chirality of the alkylating agent on the diastereoselectivity of the anthrone alkylation reaction as described above (Table 1) investigations were carried out on a series of allylic bromides

(7?)-8 varying in size of silyl protecting groups. For this investigation the catalyst PTC15 and the conditions of entry 18 rather than those of entry 17 (Table 2) due to the shorter reaction time (for convenience) were used. As shown in Table 3, the results of this study indicated a correlation between the bulkiness of the silyl protecting group and asymmetric induction. Thus, the most effective groups inducing the highest diastereoselectivities were those leading to products 6d [tris(trimethyls ilyl) silyl : 95:5 dr, 55% yield], 6b (thexyldimethylsilyl: 95:5 dr, 74% yield), and 6 (fert-butyldimethylsilyl: 94:6 dr, 72% yield). Because of the lower yield of the reaction with tris(trimethylsilyl)silyl-protected allylic bromide (/?)-8d, alkylating agents (/?)-8b (thexyldimethylsilyl) and (R)-8 (iert-butyldimethylsilyl) were chosen as the most attractive for further optimization.

The absolute configuration of substituted anthrone 6a (m.p. 165-166 °C) resulting from the diastereoselective alkylation of anthrone 5, allylic bromide (7?)-8a and PTC15 as described in Scheme 2 was determined by X-ray crystallographic analysis (see ORTEP, FIG. 2) (CCDC 144791 1 contains the supplementary crystallographic data of 6a for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre). The crystallization of 6a allowed its absolute configuration assignment to be determined at this point, while all other products in Scheme 2 were foams in nature.

Scheme 2: Asymmetric Alkylation with Different Allylic Bromides"

95:5 dr)"'^c

6f (77%, 93:7 dr)'- I (73%, 89:11 tir†>^c 6h (70%, 89:1 1 dr)''

"Reaction conditions: anthrone 7 (0.10 mmol), allylic bromides (R)-[S, 8a-8h] (0.11 mmol), PTC 15 (1 mol%), (CH₂)₂Cl2 (0.9 mL), 40% aq. Cs₂C0₃ (0.3 mL), -20 °C, 72 h. isolated yield. he dr [(105):(10 ?)] was determined by HPLC using a chiralPak AD-H column, see SI. ^Also shown in Table 2, this reaction was repeated in this study as a further confirmation of its diastereoselectivity. TBS = tert-butyldimethylsilyl, TBDPS = tert- butyldiphenylsilyl.

Finally, the CI and C5 substituent effects on the diastereoselectivity of the anthrone alkylation using the thexyldimethylsilyl-protected bromide ( ?)-8b, anfhrones 7, 7i-7p, and PTC15 was explored under the optimized conditions as shown in Table 4. These studies revealed that substituents at the CI position of the anthrone substrates smaller than OBn (e.g., 6b, 95:5 dr) resulted in decreased diastereoselectivities (e.g., 6i: 90:10 dr; 6j: 93:7 dr) while larger substituents at this position led to increased diastereoselectivities (e.g. 6k: 92:8 dr; 61: 98:2 dr). The significant increase in diastereoselectivity for product 61 carrying the p-trifluoro methyl benzyloxy group was notable. When taken together with the finding that a benzyloxy group at C5 (e.g., 6m), instead of methoxy, increased the diastereoselectivity to 99: 1 dr, the reaction led to increased improvements in the diastereoselectivity. Thus, the highest diastereoselectivities were obtained for the combinations of anthrone substrates (7n, 7o, 7p) and alkylating agent (R)-8b, which led to highly enantioenriched products 6n (>99:1 dr), 6o (99:1 dr), and 6p (>99: 1 dr) as shown in Scheme 3. Scheme 4: Asymmetric Alkylation with Different Anthrones"

6n 6o 6p

"Reaction conditions: anthrones 7, 7i-7p (0.10 mmol), (R)-Sb (0.11 mmol), PTC 15 (1 mol%), (CH₂)2C1₂ (0.9 mL), 40% aq. Cs₂C0₃ (0.3 mL), -20 ^CC, 72 h. isolated yield. ^cThe dr [(10S):(10/?)] was determined by HPLC using chiralPak AD-H column, see Example 3. ^dAlso shown in Scheme 2, this reaction was repeated in this study as a further confirmation of its diastereoselectivity. ^eThe dr was determined by HPLC using chiralPak AD-H column after benzylation of the product, see Example 3.

B. Enantioselective Total Synthesis and Absolute Configuration of (-)- Viridicatumtoxin B.

With an efficient and highly enantioselective synthesis of 10-substituted anthrones, the total synthesis of enantiopure viridicatumtoxin B was developed in an attempt to determine its absolute configuration. Given that the literature reports on the structures of viridicatumtoxin A (2, FIG. 1: absolute configuration confirmed by X-ray crystallographic analysis) [Silverton et al, 1982] and spirohexaline (Inokoshi et al, 2013) (3, reported structure, FIG. 3) suggested opposite absolute configurations for these two siblings, the absolute configuration of viridicatumtoxin B to target first was of limited interest. Since the asymmetric synthesis of anthrones revealed a higher diastereoselectivity for PTC15 (leading to the corresponding C 10-substituted anthrones, see Table 1) than PTC16 (leading to the antipodal enantiomer), the former was employed as a means to reach one of the enantiomers of viridicatumtoxin B (1).

To this end, substrate anthrone 7, alkylating agent allylic bromide ( f)-8, and catalyst PTC15 was adopted in an attempt to construct the first chiral intermediate (65,17/f)-6 and convert it stereospecifically to the pending intermediate, spiropentacycle (6S,15 ?)-4, enroute to viridicatumtoxin B (Scheme 5). The reaction was carried out with caution given the sensitivity of the substrate and the conditions involved in this spirocyclization. As shown in Scheme 1, the reaction of anthrone 7 (3.01 g, 8.00 mmol) with allylic bromide ( ?)-8 (3.06 g, 8.80 mmol) under the influence of PTC15 (0.5 mol%) was carried out on gram scale, delivering the expected substituted anthrone (65,17/?)-6 in 72% yield and 95:5 dr. The latter was subjected to optimized Lewis acid-mediated spirocyclization conditions (BF₃*Et20, 5 mol%) to afford spiropentacycle (6S,15/?)-4 in 74% yield with no loss of enantiopurity (95:5 er, see details in Example 3). Recrystallization of (65,15 ?)-4 from hexanes:CH2Cl2 (50:1) led to further enantioenrichment of this intermediate (> 99: 1 er). After unsuccessful attempts to prepare a crystalline, heavy atom-containing derivative of (65,15 ?)-4 for absolute configuration determination purposes (including the newly formed spirocenter), the latter first was subjected to the action of diacetoxyiodo-benzene (PIDA) and then to camphorsulfonic acid (CSA) in MeOttCI-hCk, conditions that led to p-quinomethide (-)-9 (via the corresponding dimethoxyketal) in 81 % overall yield. Treatment of (-)-9 with p-bromobenzoyl chloride under basic conditions furnished crystalline derivative (-)-ll (m.p. 220-221 °C), whose single crystal X-ray crystallographic analysis (see ORTEP, FIG. 4) [CCDC 1503479 contains the supplementary crystallographic data of 11 for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre] revealed that indeed the single stereocenter (C15, viridicatumtoxin numbering) within intermediate (-)-9, to be converted to virididatumtoxin B, was of the shown chirality. Chiral HPLC analysis confirmed its homogenuity as a single enantiomer (see details in Example 3). This absolute configuration corresponds to that suggested for spirohexaline (3) (Inokoshi et al, 2013), rather than that determined for viridicatumtoxin A (2) (Silverton et al, 1982).

Scheme 5: Enantioselective Synthesis of the BCDEF Fragment (65, 15R)-4 of (-)-Viridicatumtoxin

B [(-)-! and Its Absolute Configuration"

"Reagents and conditions: (a) 7 (3.01 g, 8.00 mmol scale), PTC15 (0.5 mol%) 40% aq. Cs₂C0₃, (Ofe^Cb, -30 °C, 10 days, 72%, 95:5 dr; (b) BF₃'Et₂0 (0.05 equiv), CH₂C1₂, -78 to 0 °C, 30 min, 74%, 95:5 er; (c) hexanes:CH₂Cl2 (50:l), 91%, >99: 1 er; (d) PIDA (1.2 equiv), MeOH:CH₂Cl2 (1 :1), 0 °C, 30 min, 25 °C, 30 min; (e) CSA (0.07 equiv), CH2CI2, 0 °C, 5 min, 81 % for two steps; (f) 10 (5.0 equiv), DMAP (10 equiv), Et₃N (30 equiv), CH2CI2, 25 °C, 6 h, 95%. Note: to avoid confusion, the numbering on (6S,17tf)-6, (65,15R)- 4 and (-)-9 in this Scheme and FIG. 4 is based on the viridicatumtoxin numbering, as opposed to the carbon numbering of compound (105,14R)-6 (see Table 1), which is the same compound as (65,17/?)-6, but numbered based on the anthrone numbering. Without wishing to be bound by any theory, it is believe that the faithful transfer of absolute configuration from C6 (viridicatumtoxin numbering) in intermediate (65,17R)-6 to C15 in (6S,15R)-4 is the consequence of the carbonium- mediated spirocyclization that requires attack of the C7 position on the aromatic ring onto C15 carbonium ion from the "top" side of a sterically controlled transition state (A: preferred; B: sterically congested), in which the gem-dimethyl groups play a non-negotiable steric control (see FIG. 5).

To obtain both enantiomeric forms of viridicatumtoxin B prompted further development with this enantiomer of key building block (-)-9, whose absolute configuration has been just determined, and whose single stereocenter (15R) was destined to control the stereochemistry of all others en route to the targeted molecule. This analysis also allowed an opportunity along with a way to optimize the process from the original one that delivered racemic viridicatumtoxin B (1) (Nicolaou et al, 2013; Nicolaou et al, 2014). Scheme 6 summarizes the optimized synthesis of (-)-viridicatumtoxin B [(-)-l] starting with enantiopure precursor (-)- 9.

Scheme 6: Total Synthesis of Enantiopure (-)- Viridicatumtoxin B [(-)-!]"

"Reagents and conditions: (a) PIDA (1.2 equiv), MeOH:CH₂Cl₂ (10:1), 25 °C, 1.5 h, 86%; (b) 5 (1.1 equiv), ?BuOK (1.2 equiv), PTC14 (0.01 equiv), toluene, -50 °C, 48 h, 88%, 4:1 dr; (c) TBAF (10 equiv), NH₄F (20 equiv), degassed THE, 25 °C, 5 min, 87%, 4: 1 dr; (d) [Ni(acac)₂] (0.2 equiv), DMDO (3.0 equiv), THF, -78 °C, 3 h, 52% (4:1 dr, 72% brsm), 28% recovered (-)-14; (e) NaCNBH₃ (4 equiv), THF, -78 °C, 1.5 h, 48% for (-)- 17, 12% for (+)-16, chromatographically separated; (f) 2 N aq. HC1, THF, 25 °C, 5 h, quant; (g) NaBH(OAc)₃ (1.2 equiv), EtOAc:acetone (1 :1), 40 °C, 2 h, 46%; (h) TBSOTf (4 x 10 equiv), 2,6-lutidine (4 x 15 equiv), CH₂C1₂, 0 to 25 °C for four times, totaling 2 h, 76%; (i) KHMDS (3.4 equiv), THF, -78 °C, 1 h; then freshly prepared Davis oxaziridine (3.9 equiv), -78 °C, 2 h, 32% of (+)-21 (55% brsm) + 42% recovered (+)-20; (j) HF'pyridine (excess, added at 0 °C in four portions), MeCN, 0 to 55 °C for four times, totaling 20 h, 72% (product 22 exists in equilibrium with its 1 ,5-lactol isomeric form); (k) DMP solution in CH2CI2 (0.3 M, 1.8 equiv, added in two portions at 0 °C), (CH₂)2C1¾ 0 to 50 °C for two times, totaling 2 h, 82%; (1) H₂, Pd black (4.9 equiv), l,4-dioxane:MeOH (1 : 1), 25 °C, 10 min, 96%.

Thus, dearomatization of (-)-9 with PIDA in MeOH/CH2Cl2 furnished, in 90% yield, dimethoxy semi- quinone (-)-12. In an effort to improve the low diastereoselectivity (ca 2:1 dr) (Nicolaou et al, 2013; Nicolaou et al, 2014) of the coupling of racemic 12 with oxazoline 5, the reaction (fBuOK, -50 °C, 48 h) was performed in the presence of chiral catalyst PTC14 in the hope that the chiral catalyst would add a degree of stereocontrol. The formation of the expected heptacycle product (+)-13, was observed in 88% yield and with ca 4: 1 dr, as opposed to 91 % yield and ca 2:1 dr in the original prodedure, a significant improvement since the major diastereoisomer was the desired one as shown in Scheme 6. Complexation of ligand PTC14 with the initially formed anion of oxazoline 5 followed by preferred attack on substrate (-)-12 from the "bottom" side may explain the observed diastereoselectivity. The diastereoselectivity described for this reaction in this reaction refers to the C15 and C4/C4a stereocenters with the latter being of the syn configuration with respect to the H- residue on C4a. The 4: 1 mixture of Teoc derivative (+)-13 was transformed to the decarboxylated ketoenol (-)- 14 as previously described (Nicolaou et al, 2013; Nicolaou et al, 2014). The hydroxylation of (-)-14 was improved in terms of both yield and diastereoselectivity from the original (36%, 2: 1 dr, 60% based on recovered starting material) through optimized conditions [THF, 0.2 equiv Ni(acac)2, 3.0 equiv DMDO, THF, -78 °C, 3 h, 52%, 4: 1 dr, 72% based on recovered starting material]. Without wishing to be bound by any theory, it is believe that this improvement may be attributed to increased reactivity of Ni(acac)2 in THF as solvent (as opposed to the originally used CH2CI2), an effect that resulted in a cleaner and faster reaction. The reduction of (-)-15 (4:1 diastereomeric mixture) with NaCNB¾ allowed convenient separation of the resulting isomeric products (+)-16 and (-)-17 through standard chromatographic techniques, with the latter now obtained from (-)-13 with improved overall diastereoselectivity (ca 4:1) as opposed to ca 2: 1 in the earlier route (Nicolaou et al, 2013; Nicolaou et al, 2014). The ketal hydrolysis of the major isomer (-)-17 with aqueous HC1 proceeded well to afford hydroxy triketone (-)-18, whose regio selective reduction with NaBH(OAc)3 furnished dihydroxy diketone (-)-19 (46% yield). Optimization of the conditions of the ensuing silylation of the dihydroxy diketone H-19 with TBSOTf and 2,6-lutidine led to a 15% improvement in the yield of TBS-ether (+)-20 (76% vs 61 % [Nicolaou et al, 2013; Nicolaou et al, 2014]). Finally, the crucial hydroxylation of (+)-20 was enhanced over the original procedure (Nicolaou et a/., 2013; Nicolaou et al, 2014) (32% yield, 55% based on 42% recovered starting material) by optimization of conditions such as utilizing freshly prepared Davis oxaziridine reagent. The recruiting steps proceeded as previously reported for the racemic series (Nicolaou et al, 2013; Nicolaou et al, 2014) to provide enantiopure (-)-viridicatumtoxin B [(-)-l] through intermediates (-)-22 (HF*py, 72% yield; existing as an equilibrium mixture with its 1,5-lactol isomeric form (-)-22') and (-)-23. The latter intermediate was obtained in 82% yield (as compared to 66% for the previous procedure (Nicolaou et al, 2013; Nicolaou et al, 2014) by adding the DMP as a solution in CH₂CI₂ slowly and in portions. Finally, exposure of precursor (-)-23 to hydrogenolysis conditions (¾, Pd black) furnished the desired viridicatumtoxin B, whose levorotatory nature ([a]_D'= -116, c = 0.1, EtOH) led to its absolute configuration assignment as the enantiomer [(-)-l] of the natural product. Besides pointing to the absolute configuration of natural viridicatumtoxin B, without wishing to be bound by any theory, it is believed that this observation also cast doubts over the depicted absolute configuration of spirohexaline in the isolation paper (Inokoshi et al., 2013).

C. Enantioselective Total Synthesis and Absolute Configuration of (+)-Viridicatumtoxin B.

With an enantioselective and improved synthetic route at hand, the road to what was sure to be the correct enantiomer of viridicatumtoxin B was now open. For optimum results, in addition to anthrone 7, the (S)-enantiomer of allylic bromide 8, [(S)-8], and the new catalyst PTC17 (derived from quinine), the latter being the pseudo-enantiomer of PTC15 (derived from quinidine), was used rather than PTC16 that was used in the methodology development study described above (see Table 1). Equipped with the phenolic moiety on its quinoline domain, PTC15 proved its superiority over PTC16, which lacks this phenolic group, as seen in Table 1 (entries 17, 18). This crucial observation prompted us to synthesize PTC17 (see Scheme 3; for details of the synthesis, see Example 3), as we expected it to perform better than PTC16 in the anthrone alkylation step.

Indeed and as shown in Scheme 7, catalyst PTC17 performed well in ensuring high diastereo selectivity in the alkylation of anthrone 7 (6.02 g scale, 16.0 mmol) with allylic bromide (S)-8, affording alkylated anthrone (6R,17S)-6 in 72% yield and 95:5 dr (as opposed to 87: 13 dr obtained with PTC16, see Table 1 , entry 18). The obtained product was purified by recrystallization from hexanes; the racemate crystallized out of the solution and the enriched material [(6 ?,175)-6] was recovered from the mother liquor. The enriched starting material was then subjected to the developed spirocyclization reaction conditions [BF₃*Et₂0 (cat.)] furnishing desired pentacycle (6/?,155)-4 as expected. The absolute configuration of this intermediate was determined by conversion to its p-bromobenzoate derivative (+)-ll, obtained via intermediate (+)-9, as summarized in Scheme 7. The X-ray crystallographic analysis (see ORTEP representation, FIG. 6) of (+)-ll (m.p. 220-221 °C) confirmed its (S) absolute configuration as expected from the results shown in Scheme 7 for its enantiomer.

Scheme 7: Enantioselective Synthesis of the BCDEF Fragment (6/?,15S)-4 of (+)-Viridicatumtoxin B and Its Absolute Configuration"

"Reagents and conditions: (a) 7 (6.02 g, 16.0 mmol scale), PTC17 (0.5 mol%), 40% aq. Cs₂C0₃, (CH₂)2Cl2, -30 °C, 10 days, 73%, 95:5 dr; (b) hexanes, 91%, >99: 1 dr; (c) BF₃'Et₂0 (0.05 equiv), CH₂C1₂, -78 to 0 °C, 30 min, 74%, >99: 1 er; (d) PIDA (1.2 equiv), MeOH:CH₂Cl₂ (1 :1), 0 °C, 30 min, 25 °C, 30 min; (e) CSA (0.07 equiv), CH₂C1₂, 0 °C, 5 min, 80% for two steps; (f) 10 (5.0 equiv), DMAP (10 equiv), Et₃N (30 equiv), CH₂C1₂, 25 °C, 6 h, 95%. ''Note: to avoid confusion, the numbering on (6R,17S)-6, (6R,15S)-4 and (+)-9 in this Scheme is based on the viridicatumtoxin numbering, as opposed to the carbon numbering of compound (10/?,14S)-6 (see Example 3), which is the same compound (65,17/?)-6, but numbered based on the anthrone numbering.

The total synthesis of (+)-viridicatumtoxin B [(+)-l] from key building block spiropentacycle (+)-9 was successfully carried out through the same route and conditions (Similar to Scheme 6), and in similar yields, as those employed for its enantiomeric form [(-)-l] (see Scheme 7 and Example 3 for more details). The prepared viridicatumtoxin B exhibited the same sign of optical rotation as the one reported in the literature for the natural substrate { [αβ² = +118, c = 0.1, EtOH for synthetic (+)-l; [a]^= +18.3, c = 0.2, EtOH for natural (+)-l (Zheng et al, 2008)} . The higher value for the synthetic material may simply reflect its higher purity, while the lower value reported for the natural substance may be due to lower purification and measurement difficulties due to its low natural abundance (Zheng et al, 2008). However, the possibility of the latter occurring in nature in its scalemic form cannot be also excluded at this time.

D. Enantioselective Synthesis of Viridicatumtoxin B Analogues.

With a practical and enantioselective route to viridicatumtoxin B [(+)-l] and its antipode [(-)-l] and their precursors available to us, the construction of a number of their enantiopure analogues was carried out (see Scheme 8). Scheme 8: Synthesized viridicatumtoxin B analogues (+)-VAl, (-)-VA2, (+)-VA3, (-)-VA4, (-)-VA5,

(+)-VA12.

Of interest was comparing the antibacterial properties of the antipodal simpler viridicatumtoxin analogues shown in Scheme 8 such as (+)-VAl, (-)-VA2, (+)-VA3, (-)-VA4, (-)-VA5, (+)-VA6, (-)-VA7, (+)-VA8, (+)-VA9, (-)-VAlO, (-)-VAll and (+)-VA12. Their synthesis proceeded smoothly from their required precursors, all of which were encountered in the earlier synthetic studies toward (+)- and (-)- viridicatumtoxin B as described above.

Scheme 9 summarizes the synthesis of (+)-VAl and (+)-VA3 from precursor (-)-17. Thus, reduction of precursor (-)-17 with NaCNB¾ in AcOH at ambient temperature resulted in the formation of a mixture of 5 ?-methylether (+)-24 (48% yield) and its epimer 5a-methylether (-)-5-ep/-24 (32% yield), which were chromatographically separated. Hydrogenolysis of (+)-24 with Pd black as a catalyst then furnished viridicatumtoxin B analogue (+)-VAl in 95% yield. Similar treatment of (-)-S-epi-24 led to analogue (+)-VA3 in comparable yield as for (+)-VAl (see Scheme 9).

Scheme 9: Enantioselective S nthesis of Viridicatumtoxin B Analogues (+)-VAl and (+)-VA3^a

"Reagents and conditions: (a) NaCNBH₃ (4.0 equiv), AcOH, 25 °C, 30 min, 48% for (+)-24, 32% for (-)-5- epi-24; (b) H₂, Pd black (4.1 equiv), THF:MeOH 1 :1, 25 °C, 10 min, 95%.

Analogues (-)-VA5 and (-)-VA7 were prepared from precursor (+)-16 in two steps, while the

NaCNBH₃ reduction gave (-)-4a,12a-epi-24 in 17% yield and (+)-5,4a,12a-epi^'-24 in 51 % yield, and the following hydrogenolysis of each produced analogues (-)-VA5 and (-)-VA7 in similar yields (see Scheme 10). Scheme 10: Enantioselective Synthesis of Viridicatumtoxin B Analogues {(-)-VA5 [(-)-4a,12a-ep/- VA1], (-)-VA7 [(-)-5,4a,12a-ep/-VAl]}^fl

"Reagents and conditions: (a) NaCNBH₃ (4.0 equiv), AcOH, 25 °C, 30 min, 17% for (-)-4a,12a-e/7i-24, 51% for (+)-5,4a,12a-e/7/-24; (b) H₂, Pd black (4.1 equiv), THF:MeOH 1 : 1, 25 °C, 10 min, 95%.

Analogues (-)-VA2 and (-)-VA4 were similarly prepared from their precursor (+)-17 in comparable yields as for (+)-VAl and (+)-VA3 as summarized in Scheme 11.

Scheme 11: Enantioselective Synthesis of Viridicatumtoxin B Analogues (-)-VA2 and (-)-VA4'

"Reagents and conditions: (a) NaCNBH₃ (4.0 equiv), AcOH, 25 °C, 30 min, 45% for (-)-24, 30% for (+)-5- epi-24; (b) H₂, Pd black (4.1 equiv), THF:MeOH 1 :1, 25 °C, 10 min, 95%.

Analogues (+)-VA6 and (+)-VA8 were similarly prepared from their precursor (-)-16 in comparable yields as for (-)-VA5 and (-)-VA7 as summarized in Scheme 12.

Scheme 12. Enantioselective Synthesis of Viridicatumtoxin B Analogues (+)-VA6 and (+)-VA8^a

"Reagents and conditions: (a) NaCNBH₃ (4.0 equiv), AcOH, 25 °C, 30 min, 16% for (+)-4a,12a-e/>i-24, 48% for (-)-5,4a,12a-e 7i-24; (b) H₂, Pd black (4.1 equiv), THF:MeOH 1 : 1. 25 °C, 10 min, 95%. Analogue (+)-VA9 was obtained by hydrogenolysis of triketone (-)-18 in 95% yield (Scheme 13, A).

Analogue (-)-VAll was synthesized from hydrolysis of precursor (+)-16 (quant, yield), followed by hydrogenolysis with Pd black (Scheme 13, B). Analogues (-)-VAlO and (+)-VA12 were similarly prepared from their respective precursors as summarized in Scheme 13 (C and D).

Scheme 13: Enantioselective Synthesis of Viridicatumtoxin B Analogues (+)-VA9, (-)-VAlO, (-)-VAll and (+)-VA12^a

"Reagents and conditions: Panel A: (a) H₂, Pd black (4.1 equiv), THF:MeOH 1 : 1, 25 °C, 10 min, 95%. Panel B: (a) 2 N aq. HC1, THF, 25 °C, 5 h, quant.; (b) H₂, Pd black (4.1 equiv), THF:MeOH 1 : 1, 25 °C, 10 min, 95%. Panel C: (a) ¾, Pd black (4.1 equiv), THF:MeOH 1 :1 , 25 °C, 10 min, 95%. Panel D: (a) 2 N aq. HC1, THF, 25 °C, 5 h, quant.; (b) H₂, Pd black (4.1 equiv), THF:MeOH 1 : 1, 25 °C, 10 min, 95%.

E. Biological Evaluation of Synthetic (+)- and (-)-Viridicatumtoxin B and Analogues.

The synthesized simpler enantiopure analogues (+)-VAl, (-)-VA2, (+)-VA3, (-)-VA4, (-)-VA5, (+)-

VA6, (-)-VA7, (+)-VA8, (+)-VA9, (-)-VA10, (-)-VAll and (+)-VA12 (see Figure 6 for structures), all lacking the C4a-hydroxyl group so cumbersome to install, together with (+)- and (-)-viridicatumtoxin B [(+)-l and (-)- 1] were tested against a number of bacterial strains and compared to natural viridicatumtoxin B [(+)-!, reported values¹ for E. faecalis KCTC5191, E. faecium KCTC3122, methicillin-resistant Staphylococcus aureus CCARM3167 (MRSA CCARM3167), A. calcoaceticus KCTC2357 and E. coli CCARM1356], minocycline (Minocin^®, CK1), and tigecycline (Tygacil^®, CK2) (see Scheme 13 for structures).

Scheme 13: Molecular structure of tetracycline drugs monocycline (CK1), tigecycline (CK2) (+) and

-)-viridicatumtoxin B [(+)-! and (-)-!].

I(⁺)-1] [(+)-viridicatumtoxin B] [(-)-1] [(-)-viridicatumtoxin B]

As shown in Table 5, the viridicatumtoxins and analogues tested exhibited antibacterial efficacy against Gram-positive bacteria [{E. faecalis S613, E. faecium 105, and methicillin-resistant Staphylococcus aureus 371 (MRSA 371)] but were less active against Gram-negative bacteria (i.e., A. baumannii AB210). Synthetic viridicatumtoxins B [(+)-l and (-)-l] exhibited comparable antibacterial properties against these strains [E. faecalis S613, E. faecium 105, and MRSA 371: MIC = 2, 2, and 4 g/mL, respectively, for (+)-l; MIC = 4, 4, and 8 g/mL, respectively, for (-)-l] to those reported (Zheng et al, 2008) for natural viridicatumtoxin B [(+)- 1] against similar strains {E. faecalis KCTC5191, E. faecium KCTC3122, MRSA CCARM3167: MIC = 2, 0.5, and 0.5 g/mL, respectively). Based on these data, it seems that synthetic (+)-viridicatumtoxin B [(+)-l] is twice as potent as its antipode (-)-viridicatumtoxin B [(-)-l]. It is known that MIC testing has a two-fold error, which makes the values for (+)-viridicatumtoxin B and (-)-viridicatumtoxin B within the error range for their MIC values. Regardless of this error, (+)-viridicatumtoxin B displayed high activity against the Gram-positive strains across the three independent replicates.

For the 5-methoxy analogues (+)-VAl, (-)-VA2, (+)-VA3, (-)-VA4, (-)-VA5, (+)-VA6, (-)-VA7 and (+)-VA8, the potency against the tested strains were generally lower than those of synthetic viridicatumtoxin B [(+)-l], except for analogue (+)-VA6, which exhibited comparable potencies against E. faecalis S613 (MIC = 1 μg mL) and E.faecium 105 (MIC = 2 \iglwL). However, all four 5,12-diketo analogues [(+)-VA9, (-)-VA10, (-)-VAll and (+)-VA12] demonstrated stronger antibacterial properties than synthetic viridicatumtoxin B [(+)- 1] against E. faecalis S613 [(+)-VA9: MIC = 0.5 μg/mL; (-)-VA10: MIC = 1 μg mL, (-)-VAll: MIC = 1 g mL; (+)-VA12: MIC = 1 μ /ηϋ_,], E. faecium 105 [(+)-VA9: MIC = 2 μg/mL; (-)-VA10: MIC = 1 μg/mL, (-)-VAll: MIC = 0.5 μg mL; (+)-VA12: MIC = 1 μg/mL] and MRSA 371 [(+)-VA9: MIC = 2 μg/mL; (-)-VAlO: MIC = 2 μg/mL, (-)-VAll: MIC = 2 μg/mL; (+)-VA12: MIC = 2 g mL] (see Table 5). Without wishing to be bound by any theory, it is believed that these results provide two considerations: first, the C-4a hydroxy group is not critical for activity, and finally, the stereochemical orientation of the molecule is generally unimportant to the activity of the molecule.

The modified synthetic route resulted in enantiopure viridicatumtoxin B with an 0.985% overall yield from key building block 7 as compared to 0.267% yield for the original route to racemic viridicatumtoxin B from the same prochiral intermediate (7). This new methods resulted in a 3.7-fold improved efficiency. Furthermore, these studies revealed a biologically superior and molecularly simpler potential drug candidate [(-)-VA10] than viridicatumtoxin B. This analogue may be prepared from precursor 32 in one step and 95% yield as opposed to the natural product that requires six steps for its generation from the same intermediate and in 11% overall yield. These improvements bode well for compound (-)-VAlO and its siblings compounds, (+)- VA9, (-)-VAll and (+)-VA12, as potential drag candidates for further development. Despite the literature reported activity of viridicatumtoxin B against several Gram-negative bacterial strains (Zheng et al, 2008), the tested compounds proved inactive against A. baumannii AB210.

Table 5. Minimum Inhibitory Concentration (MIC) Data of Compounds Against Gram-positive and Gram-negative Bacteria and Comparison with Selected Literature Data

^aMIC assays were run in triplicate; data are given in units of g/mL; ''Taken from reference (Zheng et al., 2008) for comparison; ^cEnantiopure material [(+)-l] isol from Penicillium sp. FRl 1 was used in reference (Zheng et al. , 2008).

EXAMPLE 2 - General Methods and Materials

All reactions were carried out under an argon atmosphere unless otherwise noted. Methylene chloride (CH2CI2), tetrahydrofuran (THF), toluene, methanol (MeOH), dimethylformamide (DMF), diisopropylethylamine, and triethylamine were dried prior to use by passage through an activated alumina column unless otherwise noted (Pangborn, et al., 1996). Anhydrous 1,2-dichloroethane [(Q-b^CF], ethyl acetate, chloroform(CHCl3) and tetrachloromethane(CCi4) were purchased from commercial suppliers and stored under argon. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise noted. Yields refer to chromatographically and spectra scopically (Ή NMR) homogenous material, unless otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out on S-2 0.25 mm E. Merck silica gel plates (60F-254) and were visualized using UV light and an ethanolic solution of phosphomolybdic acid and cerium sulfate or an aqueous solution of potassium permanganate. Flash column chromatography using E. Merck silica gel (60, particle size 0.040-0.063 mm) was performed as described by Still (Still, et al, 1978). NMR spectra were recorded on a Bruker DRX-600 equipped with a 5 mm DCH cryoprobe, a Bruker 500 UltraShield or a Varian Mercury-300BB spectrometer and referenced using the residual undeuterated solvent signal for ¾ NMR [δ_Η = 7.26 (CDC1₃), 5.32 (CD₂C1₂), 7.16 (C₆D₆), 2.05 (acetone-t/e), 2.50 (DMSO-de), and 3.31 (CD3OD) ppm] and ¹³C deuterated solvent signal for ¹³C NMR [5c = 77.16 (CDCF), 53.84 (CD₂C1₂), 128.06 (C₆D₆), 29.84 (acetone-de), 39.50 (DMSO- ), and 49.00 (CD₃OD) ppm], or using an external reference for ¹⁹F NMR [5F = 0 (CC1₃F) ppm] . The following abbreviations were used to designate the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad, ap = apparent.

ATR-Infrared (IR) spectra were recorded on a Perkin-Elmer 100 series FT-IR spectrometer. High- resolution mass spectra (HRMS) were recorded on an Agilent LC/MSD/TOF mass spectrometer using ESI (electrospray ionization) or CI (Chemical ionization); or a Shimadzu Ion Trap-TOF using ESI. Optical rotations were recorded on a POLARTRONIC M100 polarimeter at 589 nm, and are reported in units of 10^_1 (deg cm² g^-1). Melting points were recorded on a Fisher-Johns 12-144 melting point apparatus or a Thomas Hoover uni- melt capillary melting point apparatus. Crystallizations were carried out from the solvents given in parentheses after the melting points. X-Ray crystallographic analysis data were collected using a Bruker Smart-APEX instrument (CCD detector) or a Bruker Kappa APEX-II instrument (CCD detector). HPLC analyses and purifications were performed on a Shimadzu LC system with UV VIS detector using chiralcel columns or an Atlantis prep T3 OBD column. EXAMPLE 3 - Compound Characterization

(1) Phase Transfer Catalyst (PTC) Synthesis

cinchonine (PTC) (PTC)

General procedure for the PTC synthesis: The PTCs were synthesized according to as described in the literature (Corey and Bo, 1997; Lian et al, 2010).

Procedure A: To a stirred suspension of cinchonine (589 mg, 2.00 mmol, l .O equiv) in THF (20 mL) was added desired bromide derivative (R'-Br, 2.00mmol, l .O equiv), and the mixture was refluxed at 80 °C for 3 h, then cooled to 25 °C and poured into Et₂0 (80 mL). The solid was filtered off and recrystallized from MeOH/Et₂0 to obtain product S-1 as a crystalline solid. Procedure B: To a stirred suspension of S-1 (2.00mmol, l .O equiv) in CH2CI2 (lOmL) was added bromide derivative (R²-Br, 6.00mmol, 3.0 equiv) and 50% aq. KOH (l .OOmL, lO.Ommol, lO equiv). The resulting mixture was stirred vigorously at 25 °C for 4 h. The mixture was diluted with H2O (10 mL) and extracted with CH₂CI₂ (3 x lOmL). The combined organic extracts were dried over anhydrous NazSC , filtered and concentrated under reduced pressure. Recrystallization of the residue from MeOH/Et20 afforded product S-2 as a slightly yellow solid.

PTC1 (Corey et al, 1998), PTC2 (Kitamura et al, 2005), PTC18 (Ooi et al, 2003), PTC19 (Park et al, 2002), PTC20 (Shen et al, 2006) and PTC21 ((Rubina et al, 1987) were purchased from Acros, J & K Chemicals, Inc., Sigma-Aldrich, and TCI. All other catalysts were synthesized following the above described procedures. Previously reported catalysts were characterized by comparing their literature physical data (PTC3 (Iwabuchi et al, 1999), PTC4 (Lee and Wong, 1991), PTC6 (Kobbelgaard et al, 2014; Liang et al, 2014), PTC8 (Scott et al, 2008), PTC14 (Zeng et al, 2013; Adam et al, 2002; Xie et al, 2014), PTC16 (Johnston et al, 2015; Li et al, 2013), PTC22 (Moss et al, 2008), PTC24 (Zhang etal, 2009), PTC25 (Zhang et al, 2009), PTC26 (Diez-Barra et al, 1998), PTC27 (Lee and Wong, 1991), PTC28(Lee and Wong, 1991), PTC29 (Scott et al, 2008), PTC32 (Arai et al, 1998), PTC33 (Arai et al, 1999), PTC34 (Li et al, 2013), PTC35 (Borszeky et al, 1999), PTC36 (Borszeky et al, 1999), PTC37 (Jew et al, 2002), PTC39 (Belyk et al, 2010), and PTC40 (Belyk ei fl/., 2010)).

(3 9S)-l-AU l-9-{[4-(trifluorometh l)benzyl]oxy}cinchonan-l-ium bromide (PTC5): According to general procedures A and B, cinchonine (589 mg, 2.00 mmol, l.Oequiv) was reacted with allyl bromide (173 μί, 242 mg, 2.00 mmol, l.Oequiv), followed by l-(bromomethyl)-4-(trifluoromethyl)benzene (1.43 g, 6.00 mmol, 3.0 equiv) to give product PTC5 (928 mg, 1.60 mmol, 80% yield for two steps) as a slightly yellow solid. PTC5: R_f=0.50 (silica gel, 10% MeOH in CH₂C1₂); [af^ =+73.3 (c = 1.0, CH₂C1₂); m.p. = 139-141 °C

(MeOHEt₂0); FT-IR (film) v_mm: 3410, 3076, 2953, 2882, 1640,1619, 1590, 1570, 1533, 1509, 1461, 1421, 1400, 1323,1272, 1235, 1211, 1163, 1121, 1113, 1065, 1018, 997, 950, 925, 872, 850, 826, 800, 779, 760, 722, 679, 668 cm-¹; ¾ NMR: (CDC1₃, 600 MHz) δ 8.96 (d, 7=3.6Hz, IH), 8.59 (d, 7=7.4Hz, IH), 8.14 (d, 7=8.2 Hz, IH), 7.86 (s, IH), 7.78 (ap t, 7= 7.1Hz, IH), 7.67 (d, 7=7.6Hz, 2H), 7.57 (d, 7=7.8Hz, IH), 7.50 (d, 7=7.6Hz, 2H), 6.24-6.15 (m, 2H), 5.92-5.75 (m, 2H), 5.71 (d, 7=9.9Hz, IH), 5.41 (s, IH), 5.22 (d, 7= 10.4Hz, 1H),5.08 (d, 7= 17.2 Hz, 1H),4.75 (b, IH), 4.72 (d, 7= 11.7 Hz, IH), 4.62 (apt, 7= 10.6 Hz, IH), 4.19 (s, IH), 4.05 (s, IH), 4.03-3.95 (m, IH), 3.74 (t, 7=10.7Hz, IH), 3.62 (s, IH), 2.76 (d, 7=7.4Hz, IH), 2.36 (s, IH), 1.98 (s, IH), 1.95 (d, 7=12.2Hz, IH), 1.82 (d, 7=9.0Hz, IH), 1.09 (s, IH) ppm; ¹³C NMR (151MHz,CDCl₃,) δ 149.6, 148.7, 139.8, 139.5, 135.4, 131.3 (q, 7= 32.7 Hz), 130.5 (b), 130.4(b), 129.5, 129.3 (b), 128.6, 128.3, 126.1 (q, 7=3.4Hz), 125.2, 124.2123.9 (q, 7= 272.1 Hz) 118.9 (b), 118.1, 74.2 (b), 70.8, 65.9 (b), 61.7, 56.6, 56.0, 37.6, 27.0, 23.6, 21.9 ppm; ¹⁹F NMR (282MHz, CDCI3) δ -61.8 (s) ppm; HRMS (ESI) calcd for C3oH₃₂F₃N₂0⁺ [ -Br]⁺ 493.2461, found 493.2462.

(3^,95)-1 4^Trifluoromethyl)benzyl]-9-{[4-(trifluoromethyl)benzyl]oxy}cinchonan-l-ium bromide (PTC7): According to general procedures A and B, cinchonine (589 mg, 2.0 mmol, l.Oequiv) was treated with l-(bromomethyl)-4-(trifluoromethyl)benzene (478 mg, 2.00 mmol, l.Oequiv), followed by 1- (bromomethyl)-4-(trifluoromethyl)benzene (1.43 g, 6.00mmol, 3.0equiv) to give product PTC7 (1.12g, 1.58 mmol, 79% yield for two steps) as a slightly yellow solid. PTC7: R_f=0.60 (silica gel, 10% MeOH in CH₂C1₂); [ =+79.2 (c=1.0, CH₂C1₂); m.p. = 157-159 °C (MeOH/Et₂0); FT-IR (film) v_max: 3396, 2950,

1639, 1620, 1590, 1571, 1509, 1461, 1423, 1405, 1375, 1323, 1235, 1212, 1164, 1117, 1066, 1036, 1018, 933,

865, 852, 832, 799, 779, 760, 710, 682, 654 cm ; ¾ NMR (600 MHz, CDC1₃) δ 8.98 (d, 7=4.4Hz, 1 H), 8.94

(bs, IH), 8.10 (d, 7=8.5Hz, IH), 7.92-7.79 (m, 3H), 7.77-7.68 (m, 3H), 7.72 (d, 7=7.4Hz, 2H), 7.68-7.54

(m, 5 H), 6.61 (d, 7= 11.8 Hz, 1 H), 6.38 (s, 1 H), 5.95-5.70 (m, 1 H), 5.44 (s, 1 H), 5.27 (d, 7= 10.4Hz, 1 H), 5.09 (d, 7= 17.2Hz, 1 H), 4.87 (d, 7= 11.9 Hz, 1 H), 4.70 (d, 7= 11.8 Hz, 1 H), 4.32 (d, 7= 10.2Hz, 1 H), 4.09-4.08 (m, IH), 3.41-3.22 (m, IH), 2.74 (ap q, 7=10.1, 9.5 Hz, IH), 2.44 (ap q, 7=8.8Hz, IH), 2.36 (bs, IH), 1.97 (s, IH), 1.94-1.86 (m, IH), 1.82-1.73 (m, IH), 1.13 (s, lH)ppm; ¹³C NMR (151 MHz, CDC1₃) δ 149.4, 148.6, 140.1, 139.3, 135.1, 134.6, 132.60 (q, 7= 32.8 Hz), 131.31 (q, 7= 32.9 Hz), 131.0, 130.5 (b), 130.0(b), 129.3(b), 128.8, 128.5, 126.25 (q, 7= 3.7 Hz), 125.98 (q, 7=3.8 Hz), 125.1, 123.8 (q, 7=272.1 Hz), 123.5 (q, 7=272.8 Hz), 118.8 (b), 118.3, 74.8 (b), 71.1, 66.2 (b), 60.8, 56.0, 54.7, 37.6, 27.0, 23.4, 22.1 ppm; ¹⁹F NMR (282MHz, CDCI3) δ -61.8 (s), -62.1 (s) ppm; HRMS (ESI) calcd for C₃5H33F₆N20⁺ [ -Br]⁺ 611.2492, found 611.2483.

(3^,9S)-9-Hydroxy-l-[2-nitro-4-(trifluoromethyl)benzyl]cinchonan-l-ium bromide (PTC9): According to general procedure A, cinchonine (589 mg, 2.00 mmol, l.Oequiv) was treated with 1- (bromomethyl)-2-nitro-4-(trifluoromethyl)benzene (568 mg, 2.00 mmol, l.Oequiv) to give product PTC9 (1.04g, 1.80mmol, 90% yield) as a white solid. PTC9: R_f=0.30 (silica gel, 10% MeOH in CH2CI2);

[a]_p =+235.2 (c= 1.0, MeOH); m.p. = 210-212°C (dec, MeOH/Et₂0); FT-IR (film) v_max: 3386, 3212, 2955, 2891, 1631, 1591.1575, 1543, 1508, 1462, 1415, 1348, 1327, 1292, 1236, 1211, 1183, 1162, 1134, 1093, 1042, 1028, 1003, 933, 901, 862,829, 814, 797, 777, 764, 714, 691, 655 cnr¹; ¾ NMR (600 MHz, DMSO- ) δ 8.99 (d, 7=4.4Hz, IH), 8.61 (s, IH), 8.45 (ap t, 7=8.6Hz, 2H), 8.39 (dd, 7=7.2, 1.3 Hz, IH), 8.11 (d, 7=8.3Hz, 1 H), 7.85 (ddd, 7= 8.3, 7.0, 1.0 Hz, 1 H), 7.82 (d, 7=4.4Hz, 1 H), 7.75 (ddd, 7 = 8.1, 6.9, 1.2 Hz, 1 H), 6.93 (d, 7=2.2 Hz, IH), 6.52 (s, IH), 6.06-5.90 (m, IH), 5.69 (d, 7= 13.1 Hz, IH), 5.62-5.45 (m, IH), 5.23 (d, 7= 10.4Hz, IH), 5.15 (d, 7=17.3Hz, IH), 4.22- Λ0 (m, 2 H), 4.08 (ap t, 7=9.4 Hz, IH), 3.33-3.14 (m, 2 H), 2.59 (dd, 7= 16.9, 8.3 Hz, IH), 2.33-2.19 (m, IH), 1.87 (s, IH), 1.84-1.77 (m, IH), 1.75-1.72 (m, IH), 1.11- 0.95 (m, IH) ppm; ¹³C NMR (151 MHz, DMSO-4) δ 151.5, 150.2, 147.6, 144.8, 138.2, 136.9, 131.8 (q, 7=33.9 Hz), 130.1 (q, 7=4.1 Hz), 129.8, 129.4, 127.2, 126.0, 124.4, 123.9, 123.2 (q, 7=4.0Hz), 122.8 (q, 7=272.9 Hz), 120.0, 117.0, 67.6, 65.2, 56.3, 56.0, 54.8, 36.9, 25.9, 23.1, 20.7 ppm; ¹⁹F NMR (282 MHz, DMSO- 4) δ -60.7 (s) ppm; HRMS (ESI) calcd for CavftvFsNsCV [ -Br]⁺ 498.1999, found 498.2000.

quinidine or quinine S-3orS-4 PTC10, PTC11, PTC15, PTC17

(3 ,9S)-Cinchonan-6',9-diol (S-3): Catalyst precursor S-3 was prepared following a similar procedure as above starting from quinidine (Shi et al, 2007). To a stirred solution of quinidine (3.25 g, lO.O mmol, 1.0 equiv) in CH2C 12 (200 mL) flushed with argon was added a solution of BBr₃ (3.78 mL, 40.0 mmol. 4.0 equiv) in CH2CI2 (30 mL) dropwise at -78 °C. The reaction mixture was allowed to warm to 25 °C and then refluxed at 40 °C for 2 h. Then, the reaction was quenched by addition of 40% aq. NH₄OH solution (lOOmL) at 0 °C, followed by addition of ¾0 (lOOmL) and CH2CI2 (lOOmL). The two layers were separated and the aqueous layer was extracted with CH2CI2 (3 x lOOmL), the combined organic phases were dried over anhydrous Na2SC>4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, EtOAc:Et₃N:MeOH, 50: 1 :2) to give precursor S-3 (2.89 g, 9.31 mmol, 93% yield) as a yellow solid. The spectral data of this compound matched those reported in the literature (Li et al, 2004).

(3 9S)-l-[3-Fluoro-4-(trifluoromethyl)benzyl]-6',9-dihydroxy-cinchonan-l-ium bromide

(PTC10): According to general procedure A, catalyst precursor S-3 (621 mg, 2.00 mmol, l .O equiv) was treated with 4-(bromomethyl)-2-fluoro-l-(trifluoromethyl)benzene (514mg, 2.00 mmol, l.Oequiv) to give product PTC10 (978 mg, 1.74 mmol, 87% yield) as a white solid. PTC10: R_f=0.20 (silica gel, 10% MeOH in CH2CI2);

[a]_p = +180.5 (c= 1.0, MeOH); m.p. = 216-218 °C (dec., MeOH/Et₂0); FT-IR (film) v_max: 3172, 2890, 2815,

1621, 1587, 1531, 1513, 1466, 1438, 1404, 1326, 1293, 1254, 1239, 1219, 1180, 1135, 1081, 1044, 1027, 1006, 927, 854, 790, 773, 760, 735, 695, 680 cm^"1; H NMR (600 MHz, DMSO-Je) 5 10.05 (s, 1 H), 8.74 (d, 7= 4.4 Hz, I H), 8.13 (d, = 11.4Hz, I H), 8.01 (ap t, 7=7.8 Hz, 1 H), 7.95-7.92 (m, 2H), 7.76 (d, 7=2.2Hz, 1 H), 7.68 (d, 7=4.4Hz, I H), 7.35 (dd, 7=9.0, 2.3 Hz, I H), 6.75 (d, 7=4.0Hz, I H), 6.31 (s, I H), 6.05-5.94 (m, I H), 5.37 (d, 7= 12.3 Hz, I H), 5.24 (s, I H), 5.22 (d, 7=6.8 Hz, I H), 5.13 (d, 7= 12.3 Hz, I H), 4.25 (ddd, 7= 11.5, 8.5, 2.3 Hz, 1 H), 4.08 (ap t, 7= 10.7Hz, 1 H), 3.96 (ap t, 7=9.4Hz, 1 H), 3.54 (ap t, 7= 11.3 Hz, 1 H), 3.14-3.06 (m, I H), 2.70-2.52 (m, I H), 2.36-2.21 (m, I H), 1.89 (s, I H), 1.82-1.72 (m, 2 H), 1.12-1.06 (m, I H) ppm; ¹ C NMR (151 MHz, DMSO- ) δ 158.59 (d, 7= 254.4Hz), 156.0, 146.7, 142.9, 142.6, 137.1, δ 135.57 (d, 7=8.2Hz), 131.4, 130.74 (d, 7=3.6 Hz), 127.76 (q, 7=4.5 Hz), 125.5, 122.50 (q, 7=272.2Hz), 122.46 (d, 7=21.2Hz), 121.8, 119.8, 118.02 (qd, 7= 32.6, 11.9 Hz), 117.1, 104.7, 67.5, 64.8, 60.5, 56.2, 54.2, 36.8, 26.2, 23.1 , 20.6 ppm; ¹⁹F NMR (282MHz, DMSO- ) δ -59.24 (d, 7= 12.3 Hz, 3 F, CF₃), -114.1—114.0 (m, I F, CarF) ppm; HRMS (ESI) calcd for C2₇H2₇F₄N202⁺ [ -Br]⁺ 487.2003, found 487.2002.

(3 95)-6',9-Dihydroxy-l-[2-nitro-4-(trifluoromethyl)benzyl]cinchonan-l-ium bromide (PTC11):

According to general procedure A, catalyst intermediate S-3 (621 mg, 2.00 mmol, 1.0 equiv) was treated with 1 - (bromomethyl)-2-nitro-4-(trifluoromethyl)benzene (568 mg, 2.00 mmol, 1.0 equiv) to give product PTC11 (967 mg, 1.72 mmol, 86% yield) as a pale yellow solid. PTC11: R_f=0.25 (silica gel, 10% MeOH in CH₂C1₂);

[a]_p =+236.8 (c= 1.0, MeOH); m.p. = 200-202 °C (dec, MeOH/Et₂0); FT-IR (film) v_max: 3205, 2959, 1621, 1594, 1577, 1543, 1508, 1465, 1396, 1349, 1327, 1291, 1270, 1237, 1221, 1184, 1161, 1138,1094, 1043, 1004, 929, 901, 861, 832, 782, 760, 730, 714, 693 cm-¹; ¾ NMR (600 MHz, DMSO-rfe) δ 9.96 (s, IH), 8.74 (d, 7=4.4 Hz, IH), 8.61 (s, IH), 8.51 (d, 7=8.1 Hz, lH),8.39(d, 7=7.0Hz, 1H),7.95 (d, 7= 9.0Hz, 1 H), 7.81 (d, 7=2.3 Hz, IH), 7.68 (d, 7=4.4Hz, IH), 7.38 (dd, 7=9.1, 2.4Hz, IH), 6.86 (d, 7=2.2Hz, IH), 6.32 (s, IH), 6.08-5.90 (m, IH), 5.74 (d, 7=13.4Hz, IH), 5.59 (d, 7= 13.0 Hz, IH), 5.22 (d, 7=10.4Hz, IH), 5.14 (d, 7= 17.3Hz, IH), 4.17 (ap t, 7=9.8 Hz, 2H), 4.08 (ap t, 7=9.5Hz, IH), 3.32-3.22 (m, 2H), 2.58 (dd, 7=16.8, 8.2Hz, IH), 2.35-2.14 (m, IH), 1.91-1.70 (m,3H), 1.14-0.97 (m, lH)ppm; ¹³C NMR (151 MHz, DMSO- ) δ 156.0, 151.6, 146.7, 142.9, 142.5, 138.3, 136.9, 131.9 (q, 7=33.5Hz), 131.3, 130.1 (q, 7=2.9 Hz), 126.0, 125.6, 123.3 (q, 7=3.4Hz), 122.8 (q, 7= 273.6Hz), 121.8, 119.8, 117.1, 104.8, 67.4, 65.4, 56.22, 56.17, 54.8, 37.0, 25.9, 23.2, 20.7 ppm; ¹⁹F NMR (282MHz, CDC1₃) δ -62.4 (s) ppm; HRMS (ESI) calcd for C27H27F3N3 V [ -Br]⁺ 514.1948, found 514.1945.

(3 9S)-l-[3-Fluoro-4-(trifluoromethyl)benzyl]-9-hydroxy-6'-methoxycinchonan-l-ium bromide (PTC12): According to general procedure A, quinidine (649 mg, 2.00 mmol, 1.0 equiv) was treated with 4- (bromomethyl)-2-fluoro-l-(trifluoromethyl)benzene (514mg, 2.00mmol, l.Oequiv) to give product PTC12 (1.06g, 1.82mmol, 91% yield) as a white solid. PTC12: R_f=0.30 (silica gel, 10% MeOH in CH₂C1₂);

[CG_D =+160.2 (c= 1.0, CH₂C1₂); m.p. = 182-184 °C (dec, MeOH/Et₂0); FT-IR (film) v_mm: 3225, 2946, 2832,

1622,1588, 1509, 1473, 1460, 1437, 1394, 1357, 1324, 1296, 1255, 1241, 1227, 1208, 1179, 1131, 1093, 1049, 1025, 1007, 958, 932, 916, 899, 850, 828, 774, 760, 739, 718, 693, 679 cnr¹; ¾ NMR (600 MHz, CDCI3) δ 8.48 (d, 7=4.2Hz, IH), 7.84 (d, 7= 10.3 Hz, IH), 7.77 (d, 7=9.2Hz, IH), 7.70 (d, 7=7.8 Hz, IH), 7.67 (d, 7=4.3 Hz, IH), 7.50-7.48 (m, 2H), 7.05 (dd, 7=9.1, 2.1Hz, IH), 6.55 (d, 7=5.2Hz, IH), 6.38 (s, IH), 5.85 (ddd, 7=17.4, 10.4, 7.1Hz, IH), 5.76 (d, 7=12.0Hz, IH), 5.69 (d, 7= 12.0 Hz, 1 H), 5.22-5.17 (m, 2H), 4.53 (ap t, 7= 10.0Hz, 2H), 4.18^1.07 (m, 1 H), 3.79 (s, 3H), 3.24 (ap t, 7= 11.4Hz, 1 H), 2.77 (dd, 7=20.5, 9.9 Hz, 1 H), 2.38 (dd, J= 16.8, 8.5 Hz, 1 H), 2.35-2.27 (m, 1 H), 1.81 (s, 1 H), 1.72-1.63 (m, 2H), 0.97-0.85 (m, 1 H) ppm; ¹³C NMR (151 MHz, CDC1₃) δ 159.3 (d, 7=259.1 Hz), 158.1, 147.0, 144.0, 142.4, 135.2, 134.2 (d, 7=7.7 Hz), 131.6, 130.02 (d, 7= 3.5 Hz), 127.7 (d, 7= 3.2Hz), 126.1, 122.5 (d, 7=21.4Hz), 122.0 (q, 7=272.7 Hz), 120.62, 120.56, 120.3 (qd, 7= 33.7, 12.5 Hz), 118.4, 103.0, 67.9, 66.7, 60.3, 56.6, 56.3, 54.6, 38.1, 27.0, 23.8, 21.9 ppm; ¹⁹F NMR (282MHz, CDCI3) 5 -60.85 (d, 7= 12.5 Hz, 3 F, CF₃), -110.5—110.8 (m, 1 F, CarF) ppm; HRMS (ESI) calcd for C28H₂9F₄N₂02⁺ [ -Br]⁺ 501.2160, found 501.2162.

(3^,9S)-9-Hydroxy-6'-methoxy-l-[2-nitro-4-(trifluoromethyl)benzyl]cinchonan-l-ium bromide (PTC13): According to general procedure A, quinidine (649 mg, 2.00 mmol, l .O equiv) was treated with 1- (bromomethyl)-2-nitro-4-(trifluoromethyl)benzene (568 mg, 2.00 mmol, l.Oequiv) to give product PTC13 (1.08 g, 1.78 mmol, 89% yield) as a white solid. PTC13: R_f=0.40 (silica gel, 10% MeOH in CH₂C1₂);

[CG_D = +209.8 (c= 1.0, CH₂C1₂); m.p. = 196-198 °C (dec, MeOH/Et₂0); FT-IR (film) v_miK: 3352, 2945, 2833,

1622, 1591, 1578, 1543, 1508, 1472, 1460, 1433, 1414, 1352, 1325, 1291, 1261, 1242, 1228, 1206, 1182, 1161, 1137, 1093, 1022, 933, 916, 900, 863, 829, 781, 756, 718, 690 cm-¹; Ή NMR (600 MHz, CDCI3) δ 8.66 (d, 7=7.6 Hz, 1 H), 8.61 (d, 7=4.0 Hz, 1 H), 8.25 (s, 1 H), 7.95 (d, 7=7.7 Hz, 1 H), 7.87 (d, 7= 9.1 Hz, 1 H), 7.71 (d, 7=3.9 Hz, 1 H), 7.24 (d, 7=5.8 Hz, 1 H), 7.12 (s, 1 H), 6.68 (d, 7=4.1 Hz, 1 H), 6.51 (s, 1 H), 6.47 (d, 7= 12.5 Hz, 1 H), 5.94-5.83 (m, 1 H), 5.69 (d, 7= 12.2Hz, 1 H), 5.19-5.05 (m, 2H), 4.72^1.50 (m, 1 H), 3.95 (s, 3 H), 3.84 (s, 1 H), 3.76-3.66 (m, 1 H), 3.33 (ap t 7= 11. l Hz, 1 H), 2.97 (d, 7= 8.7Hz, 1 H), 2.50 (d, 7=7.5 Hz, 1 H), 2.46- 2.36 (m, 1 H), 1.83 (s, 1 H), 1.77 (s, 1 H), 1.68 (d, 7=8.7 Hz, 1 H), 0.96 (s, 1 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 158.7, 150.9, 147.6, 144.3, 142.3, 139.6, 135.2, 134.55 (q, 7= 34.9 Hz), 132.3, 131.09 (q, 7= 3.1 Hz), 125.6, 125.5, 123.32 (q, 7=3.5 Hz), 122.3, 122.24 (q, 7=273.5 Hz), 120.7, 119.5, 100.1, 70.6, 64.7, 57.7, 56.08, 56.06, 55.1, 38.4, 26.7, 24.2, 21.6 ppm; ¹⁹F NMR (282MHz, CDCI3) δ -62.4 (s) ppm; HRMS (ESI) calcd for C₂8H₂₉F3N₃04⁺ [M-Br]⁺ 528.2105, found 528.2103.

(3^,9S)-6',9-Dihydroxy-l-[4-(trifluoromethyl)benzyl]cinchonan-l-ium bromide (PTC15):

According to general procedure A, catalyst intermediate S-3 (621 mg, 2.00 mmol, l.Oequiv) was treated with l-(bromomefhyl)-4-(trifluoromethyl)benzene (478 mg, 2.00 mmol, l .Oequiv) to give product PTC15 (989 mg,

1.80mmol, 90% yield) as a white solid. PTC15: R_f=0.25 (silica gel, 10% MeOH in CH₂C1₂); [a]² ₎ ² =+176.0

(c= 1.0, MeOH); m.p. =254-256 °C (dec, MeOH/Et₂0); FT-IR (film) v_max: 3493, 3378, 3026, 2930, 2851, 1657, 1503, 1451, 1410, 1324, 1287, 1245, 1218, 1196, 1168, 1119, 1091,1069, 1039, 1027, 1019, 1011, 990, 977, 933, 914, 881, 870, 862, 846, 826, 802, 775, 759, 729, 698, 689, 671 cm-¹ ; ¾ NMR (600 MHz, DMSO- ) δ 10.10 (s, 1 H), 8.72 (d, 7= 4.4Hz, 1 H), 8.06 (d, 7= 8.0Hz, 2 H), 7.93 (d, 7=5.9 Hz, 2H), 7.92 (d, 7=7.0Hz, 1 H), 7.72 (d, 7=2.2Hz, 1 H), 7.66 (d, 7=4.4Hz, 1 H), 7.33 (dd, 7=9.1, 2.4Hz, 1 H), 6.75 (d, 7=4.0Hz, 1 H), 6.32 (s, 1 H), 5.98 (ddd, 7= 17.4, 10.5, 7.0Hz, l H), 5.30 (d, 7= 12.2Hz, 1 H), 5.19 (dd, 7= 13.9, 8.8 Hz, 2 H), 5.12 (d, 7= 12.3 Hz, 1 H), 4.21 (ddd, 7= 11.3, 8.2, 2.2 Hz, 1 H), 4.05 (dd, 7= 11.4, 9.6 Hz, 1 H), 3.95 (ap t, 7=9.4Hz, 1 H), 3.46 (ap t, 7= 11.4Hz, 1 H), 3.01 (ap q, 7= 10.0Hz, 1 H), 2.62 (ap q, 8.4Hz, 1 H), 2.30-2.26 (mt, 1 H), 1.86 (s, 1 H), 1.81- 1.69 (m, 2H), 1.14-1.01 (m, 1 H) ppm; ¹ C NMR (151 MHz, DMSO- ) δ 156.0, 146.7, 142.9, 142.6, 137.1, 134.8, 132.5, 131.4, 130.4 (q, 7= 31.9 Hz), 125.7 (q, 7= 3.6 Hz), 125.5, 124.0 (q, 7=272.4Hz), 121.8, 119.8, 117.0, 104.7, 67.3, 64.7, 61.2, 56.1, 53.9, 36.7, 26.3, 23.0, 20.6 ppm; ¹⁹F NMR (282MHz, DMSCWe) δ -60.3 (s) ppm ; HRMS (ESI) calcd for C27H28F₃N₂02⁺ [ -Br]⁺ 469.2097, found 469.2094.

(3 ,8«,9/?)-Cinchonan-6',9-diol (S-4): Catalyst precursor S-4 was prepared following a similar procedure as above starting from quinine (Shi et al., 2007). To a stirred solution of quinine (3.25 g, 10.0 mmol, 1.0 equiv) in C¾C 11 (200 mL) flushed with argon was added a solution of BBr3 (3.78 mL, 40.0 mmol, 4.0 equiv) in CH2CI2 (30 mL) dropwise at -78 °C. The reaction mixture was allowed to warm to 25 °C and then refluxed at 40 °C for 2 h. Then, the reaction was quenched by addition of 40% aq. NH4OH solution (lOOmL) at 0 °C, followed by addition of H2O (lOOmL) and CH2CI2 (lOOmL). The two layers were separated and the aqueous layer was extracted with CH2CI2 (3 x lOOmL), the combined organic phases were dried over anhydrous Na₂S0₄, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, EtOAc:Et₃N:MeOH, 50: 1 :2) to give precursor S-4 (2.89 g, 9.30mmol, 93% yield) as a yellow solid. The spectral data of this compound matched those reported in the literature (Li et al., 2004).

(3 8a,9/f)-6',9-Dihydroxy-l-[4-(trifluoromethyl)benzyl]cinchonan-l-ium bromide (PTC17): According to general procedure A, catalyst intermediate S-4 (621 mg, 2.00 mmol, 1.0 equiv) was treated with l-(bromomethyl)-4-(trifluoromethyl)benzene (478 mg, 2.00 mmol, 1.0 equiv) to give product PTC17 (989 mg,

1.82 mmol, 90% yield) as a white solid. PTC17: R_f=0.25 (silica gel, 10% MeOH in CH2CI2); [θ] =-178.0 (c= 1.0, MeOH); m.p. = 259-260 °C (dec, MeOH/Et₂0); FT-IR (film) v_max: 3210, 2953, 2851, 1621, 1534, 1466, 1423, 1408, 1327, 1238, 1221, 1161, 1122, 1068, 1037, 1018, 1003, 981, 927, 879, 863, 834, 783, 735, 691 cnr 'HNMR (600MHz, DMSO- ) δ 10.16 (s, 1H),8.73 (d, 7=4.2Hz, 1H),8.02 (d, 7=7.8 Hz, 2 H), 7.99-7.89 (m, 3H),7.68 (d, 7=4.1 Hz, 1H),7.53 (s, IH), 7.36 (d, 7= 8.2 Hz, 1 H), 6.61 (d, 7=3.8Hz, IH), 6.39 (s, IH), 5.71 (ddd, 7=17.1, 10.4, 6.5 Hz, 1H),5.37 (d, 7=12.2Hz, 1H),5.20 (d, 7=17.3Hz, IH), 5.11 (d, 7=12.1Hz, 1 H), 4.99 (d, 7= 10.5Hz, 1 H), 4.28 (ap bt, 1 H), 3.94 (t, 7=8.3Hz, 1 H), 3.82 (d, 7= 11.2 Hz, 1 H), 3.32 (s, 1 H), 3.25-3.20 (m, 1 H), 2.67 (bs, 1 H), 2.18-2.13 (m, IH), 2.12-2.07 (m, lH),2.00(bs, IH), 1.82-1.77 (m, IH), 1.35 (ddd, 7= 16.6, 8.0, 3.1Hz, 1 H) ppm; ¹³C NMR (151 MHz, DMSO-de) δ 156.0, 146.7, 143.0, 142.9, 138.0, 134.8, 132.7, 131.5, 130.4 (q, 7=31.9 Hz), 125.7 (q, 7=4.4Hz), 125.5, 124.0 (q, 7=272.4Hz), 121.8, 119.9, 116.5, 104.3, 68.163.9, 61.9, 59.1, 50.7, 36.9, 25.8, 24.2, 20.5 ppm; ¹⁹F NMR (282MHz, DMSO-rfe) δ -55.6 (s) ppm; HRMS (ESI) calcd for C27H₂9BrF₃N₂02⁺ [ +H]⁺ 549.1359, found 549.1360.

(3£,9S) -AUyl-9-hydroxycinchonan-l-ium bromide (PTC23): According to general procedure A, cinchonine (589 mg, 2.00 mmol, 1.0 equiv) was treated with allyl bromide (173 μί, 242 mg, 2.00 mmol, 1.0 equiv) to give product PTC23 (756mg, 1.84 mmol, 92% yield) as a white solid. PTC23: R_f=0.50 (silica gel, 10%

MeOH in CH₂C1₂); [ f^ = +147.5 (c= 1.0, CH₂C1₂); m.p. = 234-236 °C (dec, MeOH/Et₂0); FT-IR (film) v_max: 3379,3180, 2952, 2882,1639, 1616, 1590, 1571, 1509, 1460, 1423, 1388, 1340, 1314, 1296, 1262, 1235, 1209, 1164, 1123, 1094, 1052, 1038, 1021, 995, 951, 934, 894, 871, 815, 797,776, 763, 719, 673 cnT¹; ¾ NMR (600MHz, CDCI3) δ 8.82 (d,7=4.4Hz, IH), 8.12 (d, 7=7.7Hz, 1 H), 7.80-7.78 (m, 2H), 7.33-7.28 (m, 2H), 6.37 (bs, 2H), 6.23-5.98 (m, 2H), 5.86 (ddd, 7=17.5, 10.5, 7.3Hz, IH), 5.68 (d, 7=9.8Hz, IH), 5.40 (dd, 7=11.7, 6.5Hz, IH), 5.28-5.10 (m, 2H), 4.84 (dd, 7=12.1, 7.0Hz, IH), 4.44 (t, 7=10.1Hz, IH), 3.94 (t, 7=11.3Hz, IH), 3.80 (a t, 7=9.3 Hz, IH), 3.58 (ap t, 7=11.5Hz, 1 H), 3.38 (ap q, 7=9.6Hz, 1 H), 2.60 (ap q, 7=8.7Hz, 1 H), 2.15 (ap t, 7= 11.2 Hz, 1 H), 1.90-1.73 (m, 2H), 1.66 (ap q, 7= 10.5 Hz, 1 H), 0.78-0.70 (m, 1 H) ppm; ¹³CNMR(151MHz,CDCl₃) δ 149.8, 147.4, 144.4, 135.2, 130.3, 129.8, 128.7, 127.4, 125.0, 123.9, 123.0, 119.8, 118.0, 66.3, 64.9, 61.1, 56.3, 55.4, 38.0, 27.0, 23.7, 21.2 ppm; HRMS (ESI) calcd for C₂₂H₂₇N₂0⁺ [M- Br]⁺ 335.2118, found 335.2116.

(3 9S)-l-[2-Fluoro-3-(trifluoromethyl)benzyl]-9-hydroxycinchonan-l-ium bromide (PTC30):

According to general procedure A, cinchonine (589 mg, 2.00 mmol, 1.0 equiv) was treated with 1- (bromomethyl)-2-fluoro-3-(trifluoromethyl)benzene (514mg, 2.00 mmol, 1.0 equiv) to give product PTC30 (972mg, 1.76mmol, 88% yield) as a white solid. PTC30: R_f=0.35 (silica gel, 10% MeOH in OfcCh); [C¾ =+158.7 (c= 1.0, MeOH); m.p. = 238-240 °C (dec, MeOH/Et₂0); FT-IR (film) v_max: 3380, 3188, 2956, 2898, 1625, 1592, 1572, 1509, 1480, 1461, 1423, 1394, 1328, 1234, 1212, 1186, 1168, 1132, 1092, 1041, 1027, 1002, 1980, 935, 910, 874, 829, 812, 797, 777, 765, 749, 736, 687, 670 cm-¹; ¾ NMR (600 MHz, DMSO- ) δ 8.99 (d, 7= 4.4 Hz, 1H), 8.42 (d, 7=8.3 Hz, 1H), 8.29 (ap t, 7=6.9Hz, 1H), 8.11 (d, 7=8.3 Hz, 1H), 8.05 (ap t, 7=7.0Hz, 1H), 7.88-7.80 (m, 2H), 7.75 (ap t, 7=7.5 Hz, 1 H), 7.66 (ap t, 7=7.7Hz, 1 H), 6.90 (d, 7=3.4Hz, 1H), 6.53 (s, 1H), 6.02 (ddd, 7=17.4, 10.4, 7.1Hz, 1H), 5.34-5.10 (m, 4H), 4.25 (ddd, 7=11.1, 8.3, 2.0Hz, 1H), 4.08-4.03 (m,2H), 3.43 (ap t, 7= 11.1 Hz, 1H), 3.23 (ap q, 7= 10.1 Hz, 1H), 2.66 (ap q, 7=8.2Hz, 1H), 2.30 (ap t, /= 11.6Hz, 1H), 1.89 (s, 1H), 1.82-1.59 (m, 2H), 1.10-1.03 (m, 1H) ppm; ¹³C NMR (151MHz, DMSO-rfe) δ 158.7 (d,7= 257.4Hz), 150.1, 147.6, 144.8, 140.7, 137.0, 130.0 (q,7=4.4Hz), 129.7, 129.4, 127.2, 125.5 (d, 7=3.5Hz), 124.3, 123.9, 122.5 (q, 7=272.5Hz), 120.1, 117.49 (qd, 7=32.5, 12.9 Hz), 117.47 (d, 7= 12.6Hz), 117.0, 67.2, 64.8, 55.8, 55.1, 54.4, 36.8, 26.0, 23.0, 20.7 ppm; ¹⁹F NMR (282MHz, DMSO- ) δ -58.95 (d, 7= 13.0Hz, 3 F, CF₃), -133.7—133.9 (m, 1 F, CarF) ppm; HRMS (ESI) calcd for C27H27F₄N₂0⁺ [M- Br]⁺ 471.2054, found 471.2068.

(3^,9S)-9-Hydroxy-l-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzyl]cin-chonan-l-ium bromide

(PTC31): According to general procedure A, cinchonine (589 mg, 2.00mmol, l.Oequiv) was treated with 1- (bromomethyl)-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene (334 ]_, 622 mg, 2.00 mmol, l.Oequiv) give product PTC31 (1.03 g, 1.70mmol, 85% yield) as a white solid. PTC31: R_f=0.15 (silica gel, 10% MeOH in

CH₂C1₂); [α]_β =+129.2 (c=1.0, MeOH); m.p.= 184-186 °C (dec., MeOH/Et₂0); FT-IR (film) v_max: 3382, 3192, 2960, 2898, 1666, 1640, 1591, 1573, 1499, 1463, 1412, 1387, 1333, 1226, 1188, 1152, 1097, 1050,1037, 1028, 1004, 962, 945, 873, 817, 798, 778, 763, 717, 685 cm⁴; ¾ NMR (600 MHz, DMSO- ) δ 9.00 (d, 7=4.5 Hz, 1H),8.45 (d, 7=8.4 Hz, 1H), 8.11 (d, 7=8.3 Hz, 1H), 7.87-7.84 (m, 2 H), 7.76 (apt, 7=7.7 Hz, 1H), 7.00 (d, 7=3.4Hz, 1 H), 6.48 (d, 7=3.5 Hz, 1 H), 6.02 (ddd, 7= 17.3, 10.4, 7.0Hz, 1 H), 5.36 (d, 7= 13.4Hz, 1 H), 5.28-5.17 (m, 3H), 4.27-4.16 (m, 2H), 3.92 (ap t, 7=10.9Hz, 1H), 3.58 (ap t, 7=11.2Hz, 1H), 3.50 (ap q, 7=9.7 Hz, 1 H), 2.59 (ap q, 7= 9.0Hz, 1 H), 2.25 (ap t, 7= 12.0 Hz, 1 H), 1.93-1.78 (m, 3 H), 1.06-0.98 (m, 1 H) ppm; ¹³C MR (151 MHz, DMSO- ) δ 150.2, 147.6, 146.54 (dd, 7=251.7, 13.8Hz), 144.6, 143.85 (dd, 7=257.1, 17.2Hz), 136.8, 129.7, 129.5, 127.1, 124.4, 124.0, 120.5 (q, 7=274.9 Hz), 120.2, 117.2, 112.85 (t, 7= 16.5 Hz), 110.8-110.0 (m), 67.2, 65.3, 56.3, 54.5, 50.4, 37.2, 25.6, 23.2, 20.9 ppm; ¹⁹F NMR (282MHz, DMSO-rfe) δ -54.90 (t, 7=21. lHz, 3F, CF₃), -132.0 (bs, 2F, 2xC_rF), -139.5 (bs, 2F, 2 x CarF) ppm; HRMS (ESI) calcd for C27H24F₇N₂0⁺ [ -Br]⁺ 525.1771, found 525.1765.

(3^,8a,9?)-9-Hydroxy-l-(4-methylbenzyl)cinchonan-l-ium bromide (PTC38): According to general procedure A, cinchonidine (589 mg, 2.00 mmol, l.Oequiv) was treated with 1 -(bromomethyl)-4- methylbenzene (370mg, 2.00 mmol, l.Oequiv) to give product PTC38 (873 mg, 1.82 mmol, 91% yield) as a white solid. PTC38: R_f=0.50 (silica gel, 10% MeOH inCH₂Cl₂); [a]²² =-185.2 (c= 1.0, CH₂Cl₂);m.p. =226- 228 °C (dec, MeOH/Et₂0); FT-IR (film) v_max: 3199, 2945, 2821, 1640, 1615, 1590, 1571, 1509, 1481, 1459, 1420, 1409, 1389, 1345, 1318, 1265, 1233, 1221, 1208, 1191, 1163, 1116, 1060, 1027, 1007, 951, 943, 926, 898, 882, 858, 815, 803, 775, 755, 726, 697, 671 cm-¹; ¾ NMR (600 MHz, CDCb) δ 8.76 (d, 7=4.4Hz, 1 H), 8.15 (d, 7=8.1 Hz, 1 H), 7.77 (d, 7=4.4 Hz, 1 H), 7.60 (d, 7=7.9 Hz, 1 H), 7.51 (d, 7=7.5 Hz, 2H), 7.14-7.08 (m, 2H), 6.89 (d, 7=7.7Hz, 2H), 6.54 (d, 7=5.9 Hz, 1 H), 6.45 (s, 1 H), 5.92 (d, 7= 12.0Hz, 1 H), 5.42 (d, 7= 12.0 Hz, 1 H), 5.37 (ddd, 7= 16.8, 10.8, 6.1 Hz, 1 H), 5.25 (d, 7= 17.3 Hz, 1 H), 4.86 (d, 7= 10.5 Hz, 1 H), 4.54 (dd, 7= 16.9, 10.4Hz, IH), 4.11 (t, 7=9.0 Hz, 1 H), 3.86 (d, 7=13. lHz, IH), 3.09-3.04 (m,2H), 2.42 (s, 1H),2.26 (s,3H), 2.02 (dd, 7= 15.9, 7.9Hz, IH), 1.86 (s, IH), 1.84-1.75 (m, IH), 1.53 (dd, 7=18.6, 11.7Hz, IH), 1.06-0.88 (m, 1 H) ppm; ¹³C NMR (151 MHz, CDC1₃) δ 149.3, 146.9, 144.6, 139.8, 136.0, 133.9, 129.4, 129.1, 128.4, 127.3, 123.8, 123.5, 123.0, 119.7, 117.7, 66.7, 65.0, 61.9, 59.8, 50.1, 37.7, 26.4, 25.0, 22.3, 21.3 ppm; HRMS (ESI) calcd for C₂₇H₃iN₂0⁺ [ -Br]⁺ 399.2431, found 399.2431.

(3 8a,9/?)-9-Hydroxy-l-[4-(trifluoromethoxy)benzyl]cinchonan-l-ium bromide (PTC41):

According to general procedure A, cinchonidine (589mg, 2.00mmol, l.Oequiv) was treated with 1- (bromomethyl)-4-(trifluoromethoxy)benzene (320 μί, 510mg, 2.00 mmol, l.Oequiv) to give product PTC41

(l.Olg, 1.84mmol, 92% yield) as a white solid. PTC41: R_f=0.40 (silica gel, 10% MeOH in CH₂C1₂); [a]²² = -138.0 (c= 1.0, CH₂C1₂); m.p. =234-236 °C (dec, MeOH/Et₂0); FT-IR (film) v_max: 3197, 2999, 2950, 1640, 1612, 1591, 1571, 1509, 1482, 1462, 1421, 1390, 1307, 1253, 1219, 1205, 1161, 1115, 1061, 1037, 1022, 1003, 984, 925, 899, 881, 857, 829, 799, 775, 755, 733, 672 cm^"1; Ή NMR (600MHz, CDCI3) δ 8.76 (d, 7=4.4Hz, 1 H), 8.20-8.08 (m, 1 H), 7.77 (d, 7=4.4Hz, 1 H), 7.74 (d, 7=7.9 Hz, 2H), 7.59-7.48 (m, 1 H), 7.03-7.01 (m, 2H), 6.98 (d, 7=8.0Hz, 2H), 6.49 (d, 7=5.8Hz, IH), 6.46-6.44 (m, IH), 6.19 (d, 7= 12.2 Hz, IH), 5.53 (d, 7= 12.2Hz, IH), 5.37 (ddd, 7= 15.6, 10.2, 5. Hz, lH),5.30(d, 7=17.4Hz, IH), 4.88 (d, 7=9.8 Hz, IH), 4.59 (ap q, 7=9.8 Hz, 1 H), 4.17 (ap t, 7=8.7Hz, 1 H), 3.94 (ap dt, 7= 12.9, 2.9Hz, 1 H), 3.03 (ap td, 7= 12.0, 2.7Hz, 1H),2.98 (dd, 7=12.8, 10.7 Hz, IH), 2.48 (bs, 1 H), 2.07-2.02 (m, 1 H), 1.91 (bs, IH), 1.83-1.74 (m, IH), 1.60 (ap q, 7= 11.5, 11.5 Hz, 1 H), 1.02-0.93 (m, 1 H) ppm; ¹³C NMR (151 MHz, CDC1₃) δ 150.5, 149.2, 146.7, 144.3, 135.8, 135.7, 129.4, 128.3, 127.2, 125.3, 123.3, 122.6, 120.3 (q, 7=258.1 Hz), 120.1, 119.6, 117.9, 66.8, 65.2, 60.7, 59.8, 50.2, 37.7, 26.3, 25.0, 22.5 ppm; ¹⁹F NMR (282 MHz, CDCI3) δ -56.8 (s) ppm; HRMS (ESI) calcd for C27H28F₃N₂02⁺ [ -Br]⁺ 469.2097, found 469.2100.

(3^,95)-6'-Hydroxy-1 4-(trifluoromethyl)benzyl]-10,ll-dihydro-3,9-epoxycinchonan-l-ium bromide (PTC42): According to general procedure A, PTC3 (621 mg, 2.00 mmol, l .O equiv) was treated with l-(bromomethyl)-4-(trifluoromethyl)benzene (478 mg, 2.00mmol, l .O equiv) to give product PTC42 (1.04g,

1.90 mmol, 95% yield) as a white solid. PTC42: R_f=0.50 (silica gel, 10% MeOH in CH2CI2); [a]²² = -37.2 (c= 1.0, CH2CI2); m.p. =226-228 °C (dec, MeOH Et₂0); FT-IR (film) v_mai: 3407, 3085, 2984, 2949, 2912, 1620, 1589, 1529, 1496, 1479, 1463, 1444, 1427, 1399, 1375, 1363, 1331, 1284, 1240, 1221, 1156, 1125, 1117, 1096, 1068, 1041, 1021, 1010, 988, 936, 925, 910, 857, 848, 833, 791, 788, 763, 739, 703, 665 cm-¹; ¾ NMR (600MHz, DMSO- ) δ 10.45 (s, 1 H), 8.79 (d, /=4.4Hz, 1 H), 8.14-7.94 (m, 5 H), 7.69 (d, 7=4.3 Hz, 1 H), 7.38 (dd, 7=9.1, 2.3 Hz, 1 H), 7.26 (d, 7=2.2Hz, 1 H), 6.81 (s, 1 H), 5.55 (d, 7= 12.4Hz, 1 H), 5.01 (d, 7= 12.4 Hz, 1 H), 4.56 (d, 7= 12.2Hz, 1 H), 4.47 (d, 7=6.3 Hz, 1 H), 3.89 (dd, 7= 18.7, 9.1 Hz, 1 H), 3.60 (t, 7=6.5 Hz, 1 H), 3.51 (d, 7= 12.3 Hz, l H), 3.29 (dd, 7= 10.7, 9.2Hz, 1 H), 2.39 (s, 1 H), 1.78-1.62 (m, 5 H), 0.99 (ap t, 7=7.4Hz, 3 H) ppm; ¹³C NMR (151 MHz, DMSO-ά) δ 156.7, 147.4, 143.4 139.2, 134.7, 133.2, 132.4, 130.96 (q, 7=31.9 Hz), 126.4 (q, 7=3.9 Hz), 126.2, 124.5 (q, 7= 272.6 Hz), 122.5, 120.0, 103.7, 76.6, 69.9, 69.6, 61.9, 60.3, 52.3, 32.3, 26.6, 22.6, 22.2, 7.4 ppm; ¹⁹F NMR (282MHz, DMSO-de) δ -60.3 (s) ppm; HRMS (ESI) calcd for C27H28F3N2 V [M-Br]⁺ 469.2097, found 469.2109.

2,3-Dimethoxy-10-oxo-19-[4-(trifluoromethyl)benzyl]strychnidin-19-ium bromide (PTC43):

According to general procedure A, brucine (789 mg, 2.00 mmol, l .O equiv) was treated with l-(bromomethyl)- 4-(trifluoromethyl)benzene (478 mg, 2.00 mmol, l .O equiv) to give product PTC43 (1.14g, 1.80mmol, 90% yield) as a white solid. PTC43: R_f=0.60 (silica gel, 10% MeOH in CH₂C1₂); [ f^ =+66.2 (c= 1.0, CH2CI2); m.p. = 235-237 °C (dec, MeOH/Et₂0); FT-IR (film) v_max: 2408, 2960, 2884, 2839, 1654, 1500, 1466, 1447, 1402, 1323, 1282, 1259, 1218, 1198, 1169, 1115, 1086, 1067, 1049, 1036, 1018, 990, 940, 896, 848, 829, 803, 784, 757, 729, 703, 690, 671 cm^"1; ¾ NMR (600 MHz, CDCI3) δ 8.12 (d, 7=7.8 Hz, 2H), 7.69 (s, 1 H), 7.60 (d, 7=7.9 Hz, 2H), 6.90 (s, 1 H), 6.27 (s, 1 H), 5.94 (d, 7= 12.4 Hz, 1 H), 5.78 (d, /= 12.4 Hz, 1 H), 4.86 (d, 7= 12.9 Hz, 1 H), 4.70 (s, 1 H), 4.34-4.26 (m, 1 H), 4.26-4.11 (m, 2 H), 3.98 (dd, 7= 14.2, 5.5 Hz, 1 H), 3.93- 3.80 (m, 8 H), 3.48 (ap td, 7= 13.4, 5.4Hz, 1 H), 3.25 (s, 1 H), 3.21 (d, 7= 15.7 Hz, 1 H), 3.08 (dd, 7= 17.9, 8.4Hz, 1 H), 2.61 (dd, 7= 17.8, 1.9 Hz, 1 H), 2.00 (ap td, /= 13.8, 7.0Hz, 1 H), 1.92-1.83 (m, 1 H), 1.63 (d, 7= 15.1 Hz, 1 H), 1.30 (d, 7= 10.4Hz, 1 H) ppm; ¹³C NMR (151 MHz, CDC1₃) 5 168.2, 150.3, 146.7, 136.7, 135.3, 134.2, 132.8 (q, 7= 33.0Hz), 132.6, 132.4, 125.9 (q, 7= 3.2Hz), 123.2 (q, 7= 272.6 Hz), 118.2, 105.6, 100.8, 77.2, 72.0, 67.0, 64.0, 63.5, 59.1, 57.7, 57.1, 56.2, 52.7, 46.9, 41.9, 39.7, 29.9, 25.7 ppm; ¹⁹F NMR (282MHz, CDCI3) δ -62.2 (s) ppm; HRMS (ESI) calcd for C31H32F3N2 V [ -Br]⁺ 553.2309, found 553.2309.

(22a)-21,22-Dihydroxy-2,3-dimethoxy-21,22-dihydrostrychnidin-10-one (S-5): The dihydroxylation of brucine was prepared following a literature procedure (Kim et al, 2009). To a stirred solution of brucine (5.00 g, 11.6 mmol, l.O equiv) in a mixture of acetone (45 mL), ferf-butanol (2.5 mL), and H2O (2.5 mL), was added 4-methylmorpholine iV-oxide monohydrate (1.73 g, 12.8 mmol, l . l equiv) followed by dropwise addition of osmium tetroxide (500 ί, 69.6 μπιο1, 4 wt% in water, 0.006 equiv). The resulting suspension was stirred for 24 h, after which time the resulting solids were collected by filtration. The solids were washed with dichloromethane (2 x 80mL) and dried under high vacuum for 24 h to give analytically pure brucine-diol S-5 (4.50 g, 10.4mmol, 90% yield). The physical and spectroscopic data of this compound matched those reported in the literature (Kim et al, 2009).

(22«)-21,22-Dihydroxy-2,3-dimethoxy-10-oxo-19-[4-(trifluoromethyl)benzyl]-21,22- dihydrostrychnidin-19-ium bromide (PTC44): According to general procedure A, brucine-diol S-5 (857 mg, 2.00 mmol, l .O equiv) was treated with l-(bromomethyl)-4-(trifluoromethyl)benzene (478 mg, 2.00 mmol, l .Oequiv) to give product PTC44 (1.23 g, 1.84 mmol, 92% yield) as a white solid. PTC44: R_f=0.30 (silica gel, 10% MeOH in CH₂C1 ); [α] = +79.0 (c = 1.0, CH₂C1₂); m.p. =248-250°C (dec, MeOH/Et₂0); FT-IR (film) 3493, 3378, 3026, 2930, 2851, 1657, 1503, 1451, 1410, 1324, 1287, 1245, 1218, 1196, 1168, 1119, 1091, 1069, 1039, 1027, 1019, 1011, 990, 977, 933, 914, 881 , 870, 862, 846, 826, 802, 775, 759, 729, 698, 689, 671 cm-¹; ¾ NMR (600 MHz, DMSO- ) δ 8.02 (d, 7= 7.9Hz, 2H), 7.86 (d, 7= 8.1 Hz, 2H), 7.66 (s, 1 H), 7.54 (s, 1 H), 571 (d, 7=6.2Hz, 1 H), 5.57 (s, 1 H), 5.53 (d, 7= 12.2Hz, l H), 5.09 (d, 7= 12.1 Hz, 1 H), 4.89 (s, 1 H), 4.54-Φ.49 (m, 2 H), 4.19 (dd, 7= 12.6, 6.6Hz, 1 H), 3.92-3.84 (m, 1 H), 3.80 (s, 3 H), 3.71 (s, 3 H), 3.56 (dd, 7= 13.4, 6.8 Hz, 1 H), 3.46-3.44 (m, 1 H), 3.24 (s, 1 H), 3.05 (ap t, 7=9.5Hz, 1 H), 2.97 (d, 7= 15.2Hz, 1 H), 2.88 (d, 7= 15.3 Hz, 1 H), 2.78-2.60 (m, 3 H), 2.47 (d, 7= 1.5 Hz, 1 H), 2.40 (s, 1 H), 2.10 (ap t, 7= 11.9Hz, 1 H), 1.83- 1.76 (m, 1 H), 1.72 (d, 7= 15.2Hz, 1 H) ppm; ¹³C NMR (151 MHz, DMSO- ) δ 168.5, 149.3, 146.5, 134.2, 134.0, 133.6, 130.4 (q, 7= 32.0Hz), 125.8 (q, 7= 3.4Hz), 124.0 (q, 7=272.4Hz), 122.7, 107.6, 99.8, 72.60, 72.57, 72.1, 71.6, 65.9, 64.2, 62.4, 61.9, 57.3, 56.6, 55.7, 50.4, 48.5, 40.0, 38.8, 31.7, 23.1 ppm; ¹⁹F NMR (282MHz, DMSO-<f₆) δ -60.4 (s) ppm; HRMS (ESI) calcd for C₃iH₃4F₃N₂06⁺ [M-Br]⁺ 587.2363, found 587.2367.

(3) Asymmetric Alkylation of Anthrone 5 and Allylic Bromide 6 with Different Catalysts

General procedure for asymmetric alkylation of anthrone: To a mixture of anthrone 7 (37.6 mg,

ΙΟΟμηιοΙ, l .O equiv), allylic bromide 8 [(R,S)-, (R)- or (S)-; 38.2 mg, ΠΟμηιοΙ, 1.1 equiv] and PTC catalyst (phase transfer catalyst, ΙΟ.ΟμιηοΙ, 10 mol%, 0.1 equiv) in CH₂C1₂ (l .OmL) under argon, was added 50% aq. KOH solution (0.3 mL) dropwise at -78 °C. The reaction mixture was stirred vigorously and then allowed to warm to 0 °C. Stirring was continued at this temperature for 8 h. The mixture was then quenched by addition of water (lOmL) and extracted with CH2CI2 (3 x lOmL). The combined organic phases were dried over anhydrous Na₂S04, filtered, and concentrated to give a crude oil, which was purified by flash column chromatography on silica gel (2%→5%→10% EtOAc:hexanes) to give enantioenriched alkylated anthrone 6 as a yellow foam.

General procedure for preparing racemic alkylated anthrone: To a solution of anthrone 7 (37.6 mg, ΙΟΟμιηοΙ, l.Oequiv), allylic bromide 8 [(R,S)-, (R)- or (S)-; 38.2 mg, Ι ΙΟ μιηοΙ, 1.1 equiv] in DMF (l mL) under argon, was added Na₂C0₃ (10.6 mg, l .OOmmol, lO equiv), The reaction mixture was shielded from light and stirred vigorously for 1 h in the dark. The reaction was quenched by addition of water (10 mL) and was then further diluted with EtOAc (lO mL). The aqueous phase was extracted with EtOAc (2 x l0mL), and the combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced pressure to give a crude oil, which was purified by flash column chromatography on silica gel (2%→5%→10% EtOAc:hexanes) to give racemic alkylated anthrone 6 as a yellow foam.

Table 1. Additional Results for the Asymmetric Alkylation of Anthrone 7 with AUylic Bromides 8 Using

e

PTC42 PTC43 PTC44

Entry Catalyst Con. (%) Yield(%) dr(%) ⁰

1 PTC 17 80 70 52:48

2 PTC 18 >99 75 53: 47

3 PTC 19 60 68 54:46

4 PTC20 >99 77 61 :39

5 PTC21 >99 76 55:45

6 PTC22 >99 74 58:42

7 PTC23 >99 76 57:43

8 PTC24 >99 73 62:38

9 PTC25 80 70 65:35

10 PTC26 >99 72 63:37

11 PTC27 >99 70 58:42

12 PTC28 >99 72 79:21

13 PTC29 >99 75 55:45

14 PTC30 >99 76 56:44 15 PTC31 >99 75 51 :49

16 PTC32 >99 76 61 :19

17 PTC33 >99 77 43:57

18 PTC34 >99 76 47:53

19 PTC35 >99 75 49:51

20 PTC36 >99 75 42:58

21 PTC37 >99 75 39:61

22 PTC38 >99 72 27:73

23 PTC39 >99 70 32:68

24 PTC40 >99 72 30:70

25 PTC41 >99 75 64:36

26 PTC42 >99 77 42:58

29 PTC43 >99 78 56:44

"Reaction conditions: anthrone 5 (0.1 mmol), allylic bromide 6 (0.11 mmol), PTC catalyst (10 mol%), CH2CI2 (0.9 niL), 50% aq KOH (0.3 niL), -78 °C to 0 °C, 8 h. » The diastereomeric ratio (er) was determined by HPLC using chiralPak

(105)-l-(Benzyloxy)-10-[(3-{[teri-butyl(dimethyl)silyl]oxy}-2,6,6-trimethyl-cyclohex-l-en-l- yl)methyl]-8-hydroxy-3,5-dimethoxyanthracen-9(10 )-one [enantioenriched (105)-6J: yellow foam, 48.2 mg, 75.0 μπιοΐ, 75% yield, 86: 14 dr. Diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/2^'PrOH: 98/2, 220 nm): 5.24 min for (10 ?,145)-6; 5.46 min for (10 ?,14 ?)-6; 5.94 min for (105,14R)-6; 8.48 min for (10S,145)-6. The dr ratios with respect to the newly established stereochemistry at C-10 (viridicatumtoxin numbering) for all entries using racemic allylic bromide (/?,S)-8 were determined from the HPLC peak areas corresponding to (105)-6:(10/?)-6. Thus, the diastereomeric ratio regarding the stereoselectivity at C-10 for the experiment listed within the manuscript (Table 1, entry 15) using racemic allylic bromide ( ?,5)-8 was calculated as follows using data derived from the acquired HPLC chromatogram {vide infra): dr = [(105,14/?)-6 + (105,145)-6] : [(10R,14S)-6 + (10/f,14R)-6]

(50.764% + 35.269%) : (6.704% + 7.262%) = 86.033% : 13.966% approximated to 86 : 14.

[Note: The dr value that can be deduced from the 'H NMR spectra represents a different ratio of stereoisomers due to the lack of differentiation of enantiomers in standard Ή NMR experiments. Thus, the following ratio can be calculated using ¾ NMR data: first pair of enantiomers second pair of enantiomers

[(10S,14K)-6 + (10R,145)-6] : [(10S,145)-6 + (10/?,14R)-6 = (50.764% + 6.704%) : (35.269% + 7.262%) = 57.468% : 42.531 % approximated to 57.5 : 42.5.

Finally, in contrast to the dr ratio calculation explained above (using the HPLC traces), the NMR derived value does not allow for any judgement concerning the obtained stereoselectivity at C-10.]

Enantioenriched (10S 6: R_f=0.50 (silica gel, EtOAc:hexanes 1 :4); [(¾ =+71.9 (c= 1.0, CH2CI2,

86:14 dr); FT-IR (film) v_max: 2932, 2856, 1636, 1599, 1583, 1568, 1472, 1432, 1328, 1265, 1227, 1196, 1164, 1148, 1101, 1034, 1002, 907, 832, 772, 728 cm^"1; This compound exhibited broad NMR signals (both in ¾ NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond. ¾ NMR (600 MHz, CDCI₃) δ 12.70 (s, 1 H, minor), δ 12.69 (s, 1 H, major), 7.57 (d, 7= 7.5 Hz, 2H, major + minor), 7.47-7.35 (m, 2H, major + minor), 7.35-7.27 (m, 1 H, major + minor), 7.06 (d, 7=9.0Hz, 1 H, minor), 7.05 (d, 7= 8.9, 1 H, major), 6.860 (d, 7= 8.9 Hz, 1 H, minor), 6.856 (d, 7= 8.9 Hz, 1 H, major), 6.44 (d, 7=2.2 Hz, 1 H, major), 6.43 (d, 7=2.3 Hz, 1 H, minor), 6.42 (s, 1 H, major), 6.30 (s, 1 H, minor), 5.25 (ABq, ΔδΑΒ = 0.067, 7= 12.7 Hz, 2H, major + minor), 4.64 (s, 1 H, major), 4.56 (s, 1 H, minor), 3.97 (s, 1 H, major), 3.86 (s, 1 H, minor), 3.90 (s, 3 H, minor), 3.89 (s, 3 H, major), 3.84 (s, 3 H), 2.68 (d, 7= 12.5 Hz, 1 H, major + minor), 2.20-0.65 (m, 14 H, major + minor), 0.91 (s, 9 H, major), 0.88 (s, 9 H, minor), 0.10 (s, 3 H, minor), 0.05 (s, 3 H, major), 0.08 (s, 3 H, major), 0.01 (s, 3 H, minor) ppm; ¹³C NMR (151 MHz, CDCI₃)* δ 188.60 (major), 188.55 (minor), 163.75 (major), 163.67 (minor), 161.97 (major), 161.86 (minor), 150.3 (b, major), 149.6 (b, minor), 156.29 (major), 156.26 (minor), 147.72 (major), 147.62 (minor), 136.73 (minor), 136.70 (major), 133.63 (minor), 133.45 (major), 128.69 (major + minor), 127.8 (major + minor), 126.8 (major + minor), 117.78 (major), 117.74 (minor), 117.71 (major), 117.69 (minor), 115.09 (major), 115.05 (minor), 106.73 (b, major), 106.51 (b, minor), 100.19 (b, minor), 100.10 (b, major), 70.8 (major + minor), 56.08 (minor), 56.04 (major), 55.75 (major), 55.57 (minor), 41.12 (major), 40.62 (minor), 35.9 (major + minor), 29.76 (major), 29.69 (minor), 29.08 (major), 28.91 (minor), 26.08 (minor), 26.05 (major), 18.3 (major), 16.6 (minor), -4.0 (major), -4.2 (minor), -4.64 (major), -4.67 (minor) ppm; HRMS (ESI) calcd for C₃9H₅o0₆SiNa⁺ [M+Na]⁺ 665.3269, found 665.3274. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l-(Benzyloxy)-10-[(3-{[teri-butyl(dimethyl)silyl]oxy}-2,6,6-trimethyl-cyclohex-l-en-l- yl)methyl]-8-hydroxy-3,5-dimethoxyanthracen-9(10/7)-one [enantioenriched (105,14/?)-6]: yellow foam, 48.2 mg, 75.0 μπιοΐ, 75% yield, 89: 11 dr. Diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C , flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 5.97 min for (10/?,14fl)-6; 6.74 min for (105,14R)-6.

Enantioenriched (10S,14ff)-6: R_f=0.50 (silica gel, EtOAc:hexanes 1:4); [a]²² =+85.2 (c= 1.0, CH₂C1₂, 89:11 dr); FT-IR (film) v_max: 2932, 2856, 1636, 1599, 1583, 1568, 1472, 1432, 1328, 1265, 1227, 1196, 1164, 1148, 1101, 1034, 1002, 907, 832, 772, 728 cirr¹ ; This compound exhibited broad NMR signals (both in Ή NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600 MHz, CDC1₃) δ 12.68 (s, 1 H, major + minor), 7.57 (d, 7=7.4Hz, 2H, major + minor), 7.39 (ap t, 7=7.7Hz, 2H, major + minor), 7.30 (ap t, 7=7.4Hz, 1 H, major + minor), 7.05 (d, 7=9.0Hz, 1 H, major + minor), 6.86 (d, 7= 8.9 Hz, l H, major + minor), 6.44 (d, 7= 2.2Hz, 1 H, major), 6.43 (d, 7=2.2Hz, 1 H, minor), 6.40 (b, 1 H, major), 6.29 (b, 1 H, minor), 5.25 (ABq, Δ5_ΑΒ = 0.072, 7= 12.6Hz, 2H, major + minor), 4.64 (b, 1 H, major + minor), 3.97 (b, 1 H, major + minor), 3.90 (s, 3 H, minor), 3.89 (s, 3 H, major), 3.84 (s, 3 H, major + minor), 2.70 (d, 7= 10.9 Hz, 1 H, major + minor), 2.10-0.64 (m, 14H, major + minor), 0.92 (s, 9 H, major), 0.91 (s, 9 H, minor), 0.10 (s, 3 H, major), 0.07 (s, 3 H, major), 0.04 (s, 3 H, minor), 0.01 (s, 3 H, minor) ppm; ¹³C NMR (151 MHz, CDCI₃)* δ 188.60 (major), 188.55 (minor), 163.74 (major), 163.66 (minor), 161.97 (major), 161.86 (minor), 156.29 (major), 156.26 (minor), 150.30 (b, major + minor), 147.72 (major), 147.62 (minor), 136.72 (minor), 136.69 (major), 133.63 (minor), 133.45 (major), 128.69 (major + minor), 127.8 (major + minor), 126.8 (major + minor), 117.78 (major), 117.74 (minor), 117.71 (major), 117.69 (minor), 115.09 (major), 115.05 (minor), 106.73 (b, major), 106.51 (b, minor), 100.11 (b, major + minor), 72.7 (b, major + minor), 70.8 (major + minor), 56.08 (minor), 56.04 (major), 55.75 (major), 55.57 (minor), 41.1 (b, major + minor), 38.70 (b, major + minor), 35.94 (major + minor), 29.76 (major), 29.69 (minor), 29.09 (major), 28.91 (minor), 26.07 (minor), 26.04 (major), 18.34 (major + minor), -4.0 (major), -4.2 (minor), -4.65 (major + minor) ppm; HRMS (ESI) calcd for C₃ H₅o06Si a⁺ [ +Na]⁺ 665.3269, found 665.3269. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l Benz lox )-10-{[(35)-3-{[ter but l(dimeth l)sil l]ox }-2,6,6-trimeth lc clohe -l-en-l- yl]methyl}-8-hydroxy-3,5-dimethoxyanthracen-9(10 7)-one [enantioenriched (10S,14S)-6]: yellow foam, 48.2 mg, 75.0 μπιοΐ, 75% yield, 83: 17 dr. Diastereomenc ratio was determined by HPLC (Chiralcel AD-H, 25 °C , flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 5.35 min for (10/?,145)-6; 8.74 min for (105,145)-6. Enantioenriched (105,14S)-6: R_f=0.50 (silica gel, EtOAc:hexanes 1 :4); [of^ =+55.4 (c= 1.0, CH₂C1₂); FT-IR

(film) v_max: 2932, 2856, 1636, 1599, 1583, 1568, 1472, 1432, 1328, 1265, 1227, 1196, 1164, 1148, 1101, 1034, 1002, 907, 832, 772, 728 cirr¹ ; This compound exhibited broad NMR signals (both in H NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond. ¾ NMR (600 MHz, CDCI₃) δ 12.69 (s, 1 H, major), 12.68 (s, 1 H, minor), 7.56 (d, 7=7.6 Hz, 2 H, major + minor), 7.39 (ap t, 7=7.6Hz, 2 H, major + minor), 7.29 (ap t, 7=7.4Hz, 1 H, major + minor), 7.06 (d, 7=9.0Hz, 1 H, major + minor), 6.86 (d, 7= 8.9 Hz, 1 H, major + minor), 6.44 (d, 7= 2.2Hz, 1 H, minor), 6.43 (d, 7=2.2 Hz, 1 H, major), 6.40 (b, 1 H, minor), 6.30 (d, 7= 1.7 Hz, 1 H, major), 5.25 (ABq, A5_AB = 0.073, 7= 12.6 Hz, 2 H, major + minor), 4.57 (b, 1 H, major + minor), 3.90 (s, 3 H, major), 3.89 (s, 3 H, minor), 3.87-3.78 (b, 1 H, major + minor), 3.83 (s, 3 H, major + minor), 2.68 (d, 7= 11.1 Hz, 1 H, major + minor), 2.10-0.64 (m, 14H, major + minor), 0.92 (s, 9 H, minor), 0.88 (s, 9 H, major), 0.10 (s, 3 H, minor), 0.08 (s, 3 H, minor), 0.04 (s, 3 H, major), 0.01 (s, 3 H, major); ¹³C NMR (151 MHz, CDCI₃)* 5 188.60 (minor), 188.55 (major), 163.66 (major + minor), 161.97 (minor), 161.87 (major), 156.29 (minor), 156.26 (major), 149.7 (b, major + minor), 147.72 (minor), 147.62 (major), 136.72 (major), 136.69 (minor), 133.63 (major), 133.45 (minor), 128.7 (major + minor), 127.8 (major + minor), 126.8 (major + minor), 117.78 (minor), 117.74 (major), 117.69 (major + minor), 115.09 (minor), 115.05 (major), 106.51 (b, major + minor), 100.11 (b, major + minor), 71.7 (b, major + minor), 70.7 (major + minor), 56.09 (major), 56.04 (minor), 55.75 (minor), 55.57 (major), 40.6 (b, major + minor), 36.48 (b, major + minor), 35.93 (major + minor), 29.76 (minor), 29.69 (major), 29.11 (minor), 28.91 (major), 26.06 (major), 26.05 (minor), 18.34 (major + minor), 16.58 (major + minor), -4.02 (minor), -4.18 (major), -4.67 (major + minor) ppm; HRMS (ESI) calcd for C₃9H₅o0₆SiNa⁺ [ +Na]⁺ 665.3269, found 665.3272. *Due to signal broadening, not all the ¹³C signals could be identified.

(10 ?)-l-(Benzyloxy)-10-[(3-{[terf-butyl(dimethyl)silyl]oxy}-2,6,6-tri-methylcyclohex-l-en-l- yl)methyl]-8-hydroxy-3,5-dimethoxyanthracen-9(10/7)-one [enantioenriched (10/?,145)-6]: yellow foam, 48.9 mg, 76.0 μηιοΐ, 76% yield, 13:87 dr. Diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C , flow rate: 1 mL/min, hexanes/ZPrOH: 98/2, 220 nm): 5.44 min for (10fi,14S)-6; 9.52 min for (105,145)-6.

Enantioenriched (10R,145)-6: R_f= 0.50 (silica gel, EtOAc:hexanes 1 :4); [a] =-82.8 (c= 1.0, CH₂C1₂); FT-IR

(film) v_max: 2932, 2856, 1636, 1599, 1583, 1568, 1472, 1432, 1328, 1265, 1227, 1196, 1164, 1148, 1101, 1034, 1002, 907, 832, 772, 728 cirT¹; This compound exhibited broad NMR signals (both in H NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; Ή NMR (600 MHz, CDC1₃) δ 12.71 (s, 1 H, minor), 12.70 (s, 1 H, major), 7.57 (d, /=7.4Hz, 2 H, major + minor), 7.39 (ap t, /=7.7Hz, 2 H, major + minor), 7.30 (ap t, J= 7.4 Hz, 1 H, major + minor), 7.05 (d, J= 9.0 Hz, 1 H, major + minor), 6.86 (d, J= 8.9 Hz, 1 H, major + minor), 6.44 (d, 7= 2.3 Hz, 1 H, major), 6.43 (d, 7=2.3 Hz, 1 H, minor), 6.39 (b, 1 H, major), 6.29 (b, 1 H, minor), 5.25 (ABq, Δ5_ΑΒ =0.068, 7= 12.6 Hz, 2H, major + minor), 4.64 (b, 1 H, major), 4.56 (b, 1 H, minor), 3.97 (b, 1 H, major + minor), 3.90 (s, 3 H, minor), 3.89 (s, 3 H, major), 3.84 (s, 3 H, major + minor), 2.69 (b, 1 H, major + minor), 2.10-0.67 (m, 14H, major + minor), 0.92 (s, 9 H, major), 0.88 (s, 9H, minor), 0.10 (s, 3 H, major), 0.08 (s, 3 H, major), 0.05 (s, 3 H, minor), 0.01 (s, 3 H, minor) ppm; ¹³C NMR (151 MHz, CDCI₃)* δ 188.60 (major), 188.55 (minor), 163.75 (major), 163.67 (minor), 161.97 (major), 161.86 (minor), 156.30 (major), 156.27 (minor), 150.22 (b, major + minor), 147.72 (major), 147.62 (minor), 136.74 (minor), 136.71 (major), 133.62 (minor), 133.44 (major), 128.69 (major + minor), 127.8 (major + minor), 126.8 (major + minor), 117.77 (major + minor), 117.71 (major), 117.69 (minor), 115.09 (major), 115.07 (minor), 106.73 (b, major), 106.52 (b, minor), 100.10 (b, major + minor), 72.7 (b, major + minor), 70.7 (major + minor), 56.07 (minor), 56.03 (major), 55.75 (major), 55.57 (minor), 41.1 (b, major + minor), 38.7 (b, major + minor), 35.92 (major + minor), 29.76 (major), 29.70 (minor), 29.09 (major), 28.91 (minor), 26.08 (minor), 26.06 (major), 18.34 (major + minor), -4.0 (major), -4.2 (minor), -4.63 (major + minor) ppm; HRMS (ESI) calcd for C39Hso06SiNa⁺ [ +Na]⁺ 665.3269, found 665.3269. *Due to signal broadening, not all the ¹³C signals could be identified.

rac-(14R)-6 rac-(14R)-6 1 ) Racemic alkylated product under asymmetric alkylation reaction conditions

(10S,14R)-6 (10S,14R)-6

(95:5 dr) (^{95:5 dr})

2) Chiral alkylated product under racemic alkylation reaction conditions

To check the potential problem associated with CIO racemization of the alkylation product, two verification experiments were carried out as shown above. Thus, alkylated racemic (14R)-6 was subjected to the same asymmetric alkylation conditions [1.0 mol% PTC15, 40% aq. Cs₂C0₃, (CH₂)₂Cl2, -20 °C, 72 h]. Under these conditions no enrichment of the recovered starting material was observed, indicating that the asymmetric induction occurs in the alkylation step rather than being a result of deprotonation/asymmetric protonation of the initially formed substituted anthrone. In a second experiment an enriched sample of alkylated product (10S,14 ?)-6 (95:5 dr) were utilized, but this time under racemic conditions (Na2C03, DMF, 25 °C, 1 h) and observed no change in the dr ratio, again indicating that the asymmetric induction in the system occurs at the alkylation state rather than a subsequent equilibration step. Allylic Bromides Synthesis

Methyl 3-hydroxy-2,6,6-trimethylcyclohex-l-ene-l-carboxylate (S-6): Allylic alcohol S-6 was prepared using the published four-step procedure starting from geranic acid (Nicolaou et al, 2013; Nicolaou et al, 2014). The physical and spectroscopic data of this compound matched those reported in the literature (Nicolaou et al, 2013; Nicolaou et al, 2014).

Methyl 2,6,6-trimethyl-3-oxocyclohex-l-ene-l-carboxylate (S-7): Following the general procedure for PDC oxidation of alcohols (Corey and Schmidt, 1979), enone S-7 was prepared. To a solution of allylic alcohol S-6 (9.92 g, 50.0 mmol, 1.0 equiv) in CH2CI2 (250 mL) was added pyridinium dichromate (PDC, 28.2 g, 75.0 mmol, 1.5 equiv) in one portion at 0 °C, and then the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was passed through a pad of silica gel, eluted with 20% EtOAc:hexanes to give enone S-7 as colorless oil (9.32g, 47.5 mmol, 95% yield). The physical and spectroscopic data of this compound matched those reported in the literature (Heather et al, 1976). C0₂Me

(R)-S-8

Methyl (3R)-3-hydroxy-2,6,6-trimethylcyclohex-l-ene-l-carboxylate [(/f)-S-8]: According to general procedure of CBS reduction of ketones (Corey et al, 1987), chiral allylic alcohol (/?)-S-8 was prepared. To a solution of (S)-(-)-2-methyl-CBS-oxazaborolidine (831 mg, 3.00mmol, O. l equiv) in THF (60mL) was added BH₃-THF (30.0 mL, 30.0 mmol, 1 M solution in THF, l.O equiv) at 0 °C, and the solution was stirred for 15 min. A solution of enone S-7 (5.89 g, 30.0 mmol, l .O equiv) in THF (60 mL) was then added dropwise at 0 °C, and the resulting mixture was stirred at this temperature for 1 h. The reaction was then quenched by addition of MeOH (10 mL), concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (10%→20%→40% EtOAc:hexanes) to give chiral allylic alcohol (R)-S-8 [5.65 g, 28.5 mmol, 95% yield, 94% ee (determined by Ή NMR spectroscopic analysis of its mosher ester)] as a colorless oil. The physical and spectroscopic data of this compound matched those reported in the literature (Yoshikawa et al, 1996).

[(3R)-3-{[feri-Butyl(dimethyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en-l-yl]methan-ol [( ?)-S-9]: Following the reported procedure (Nicolaou et al, 2013; Nicolaou et al, 2014), chiral OTBS ether alcohol (R)- S-9 was prepared. Chiral allylic alcohol (R)-S-S (1.56g, 7.80mmol, l .O equiv) was dissolved in CH2CI2 (80mL) at 25 °C. Imidazole (1.06 g, 15.6 mmol, 2.0 equiv) and TBSC1 (1.90g, 12.6 mmol, 1.6 equiv) were added sequentially, and the suspension was stirred at 25 °C for 12 h. The reaction was quenched by addition of saturated NaHCCb solution (50 mL), and the phases were separated. The organic phase was dried over anhydrous NaaSC , filtered, and concentrated under reduced pressure. Residual volatiles were then azeotropically removed with toluene (twice). The crude OTBS ether was dissolved in CH2CI2 (70 mL) and the solution was cooled to -78 °C. DIB AL-H (21.0 mL, 1.0 M solution in hexanes, 21.0 mmol, 2.7 equiv) was added to the stirred reaction mixture over 20 minutes. Then, the reaction mixture was allowed to warm to 0 °C and was stirred at this temperature for 70 min, and then cautiously quenched by addition of methanol (10 mL). The mixture was allowed to warm to 25 °C, and saturated aq. Rochelle salt solution (80 mL) was added. The resulting thick emulsion was vigorously stirred at 25 °C for 5 h. The phases were separated, and the organic phase was dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (5%→10%→15% EtOAc:hexanes) to give chiral OTBS ether alcohol (R)-S-9 (2.12 g, 7.21 mmol, 91% for two steps) as a colorless oil. (R)-S-9: R_f=0.20 (silica gel, EtOAc:hexanes 1 :9); [a]²² =-19.2 (c = 1.0, CH2CI2); FT- IR (neat) v_max: 3451, 2953, 2929, 2857, 1472, 1462, 1361, 1253, 1084, 1061, 1033, 1005, 985, 933, 886, 834, 815, 773, 669 cm^"1 ; >H NMR (600 MHz, CDCL) δ 4.14 (d, J= 11.4Hz, 1 H), 4.09 (d, J= 11.4 Hz, 1 H), 4.00 (ap t, J=5.8 Hz, 1 H), 1.87-1.74 (m, 4H), 1.65-1.57 (m, 2H), 1.37 (ddd, 7= 13.0, 10.4, 2.7 Hz, 1 H), 1.06 (s, 3 H), 1.02 (s, 3 H), 0.90 (s, 9 H), 0.09 (s, 3 H), 0.08 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDC1₃) δ 140.1, 136.1, 71.3, 59.4, 35.5, 34.6, 29.5, 28.2, 28.0, 26.1, 18.3, 16.3, -4.1, -4.5 ppm: HRMS (CI) calcd for Ci₆H₃i0₂Si⁺ [ -H]⁺ 283.2088, found 283.2095.

{[(l ?)-3-(Bromomethyl)-2,4,4-trimethylcyclohex-2-en-l- l]oxy}(feri-butyl)di-methylsilane [(/?)-

8]: Following the reported procedure(Nicolaou et al, 2013; Nicolaou et al, 2014), chiral allylic bromide (R)-S was prepared. To a solution of chiral OTBS ether alcohol (R)-S-9 (2.39 g, 8.40 mmol, l .O equiv) in CH2Q2 (45 mL) was added triethylamine (2.33 mL, 17 mmol, 2.0equiv). The solution was cooled to -50 °C, and methanesulfonyl chloride (1.10 mL, 14.0 mmol, 1.7 equiv) was added dropwise. The solution was stirred at this temperature for 1 h, during which a thick white suspension was formed. A solution of lithium bromide (2.56 g, 2.90 mmol, 3.5 equiv) in THF (lOmL) was then transferred to the reaction flask via cannula over 10 min. The mixture was allowed to warm to -20 °C and was stirred at this temperature for 1 h. The reaction was quenched by pouring the slurry into water (100 mL). The resulting mixture was extracted with hexanes (100 mL), dried over Na₂S0₄, filtered, and concentrated under reduced pressure to give the chiral allylic bromide (R)-S (2.90 g, 8.40 mmol, quant, yield) as a colorless oil. This material was essentially pure, could be stored neat at -40 °C for several months with no signs of decomposition, and could be used directly in further reactions. (R)-S: R_f=0.80

(silica gel, EtOAc:hexanes 1 :10); [a]^² = -75.9 (c = 1.0, CH2CI2); FT-IR (neat) v_max: 2955, 2929, 2856, 1471, 1463, 1387, 1362, 1352, 1250, 1204, 1147, 1139, 1122, 1082, 1050, 1026, 1005, 979, 936, 887, 833, 813, 771, 709, 678 era ¹; Ή NMR (600 MHz, CDCI3) δ 4.05 (d, /= 10.2 Hz, 1 H), 4.02 (ap t, J=6.6 Hz, 1 H), 3.95 (d, /= 10.2Hz, 1 H), 1.83-1.76 (m, 4 H), 1.65-1.54 (m, 2H), 1.42 (m, 1 H), 1.12 (s, 3 H), 1.09 (s, 3 H), 0.90 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCL) δ 139.7, 136.3, 71.5, 35.9, 35.3, 30.3, 29.3, 28.6, 28.1, 26.0, 18.3, 16.6, -4.0, -4.6 ppm; HRMS (CI) calcd for Ci₆H₃₀BrOSi⁺ [M-H]⁺ 345.1244, found 345.1257.

(S)-S-8

Methyl (3S)-3-hydroxy-2,6,6-trimethylcyclohex-l-ene-l-carboxylate [(5)-S-8]: According to the procedure for the preparation of (R)-S-8 as described above, enone S-7 (l .OOg, 5.00 mmol, l .O equiv) and (R)- (+)-2-methyl-CBS-oxazaborolidine (139mg, 500 μπιο1, 0.1 equiv) were reacted to give product (S)-S-8 [939 mg, 4.75 mmol, 95%, 96% ee, (determined by Ή NMR spectroscopic analysis of its mosher ester)] as a colorless oil. (S)-S-8: Rf= 0.50 (silica gel, EtOAc:hexanes 1 :2); [ ]²² =-55.8 (c= 1.0, CH2CI2); FT-IR (neat) v^: 3402, 3940, 2868, 1723, 1654, 1452, 1433, 1385, 1385, 1364, 1344, 1293, 1244, 1223, 1207, 1175, 1138, 1064, 1038, 1019, 1001, 968, 940, 901 , 876, 860, 818, 778, 752, 660 cm-¹ ; ¾ NMR (600 MHz, CDCL) δ 3.98 (ap t, 7=5.1 Hz, 1 H), 3.75 (s, 3 H), 1.96 (dddd, = 13.8, 10.5, 5.2, 3.2 Hz, 1 H), 1.76 (s, 1 H), 1.73 (ddd, 7= 11.1, 5.3, 2.7 Hz, 1 H), 1.60 (ddd, 7= 13.4, 10.5, 3.1 Hz, 2 H), 1.45 (ddd, 7= 13.4, 8.0, 3.2 Hz, 1 H), 1.10 (s, 3 H), 1.08 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDC1₃) δ 170.7, 138.5, 134.0, 68.9, 51.4, 34.4, 33.8, 28.6, 28.4, 27.5, 18.1 ppm; HRMS (ESI) calcd for CnHi80₃Na⁺ [ +Na]⁺ 221.1148, found 221.1147.

[(35)-3-{[fert-Butyl(dimethyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en-l-yl]meth-anol [(S)-S-9]:

According to the same procedure for the preparation of (R)-S-9 as described above, (S)-S-8 (793 mg, 4.00 mmol, 1.0 equiv) was treated with TBSC1 (965 mg, 6.40 mmol, 1.6 equiv) to form the OTBS ether, followed by DIB AL- H (10.8 mL, 1.0M solution in hexanes, 10.8 mmol, 2.7equiv) to generate the primary alcohol from the ester moiety, to give product (5) -S -9 (1.06 g, 3.64 mmol, 91 % for two steps) as a colorless oil. (S)-S-9: Rf= 0.20 (silica gel, EtOAc:hexanes 1 :9); [α]_β =+18.5 (c= 1.0, CH₂C1₂); FT-IR (neat) v_mm: 3451, 2953, 2929, 2857, 1472,

1462, 1361, 1253, 1084, 1061, 1033, 1005, 985, 933, 886, 834, 815, 773, 669 cm-¹ ; ¾ NMR (600 MHz, CDCI3) δ 4.14 (d, 7= 11.4 Hz, 1 H), 4.09 (d, 7= 11.4 Hz, 1 H), 4.00 (ap t, 7=5.8 Hz, 1 H), 1.87-1.74 (m, 4H), 1.65-1.57 (m, 2 H), 1.37 (ddd, 7= 13.0, 10.4, 2.7Hz, 1 H), 1.06 (s, 3 H), 1.02 (s, 3 H), 0.90 (s, 9 H), 0.09 (s, 3 H), 0.08 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCb) δ 140.1, 136.1, 71.3, 59.4, 35.5, 34.6, 29.5, 28.2, 28.0, 26.1, 18.3, 16.3, -4.1, -4.5 ppm; HRMS (CI) calcd for CieHsi feSi* [M-H]⁺ 283.2088, found 283.2095.

{[(l/f)-3-(Bromomethyl)-2,4,4-trimethylcyclohex-2-en-l-yl]oxy}(tert-butyl)di-methylsilane [(S)-

8]: According to the procedure for the preparation of (R)-8 as described above, (S)-S-9 (797 mg, 2.80 mmol, 1.0 equiv) was treated with MsCl (368 μί, 545 mg, 4.76 mmol, 1.7 equiv), followed by LiBr (851 mg, 9.80 mmol, 3.5 equiv), to give chiral allylic bromide (S)-8 (972 mg, 2.80mmol, quant, yield) as colorless oil. The material was analytically pure and could be stored neat at -40 °C for several months with no signs of decomposition.

(S)-8: R_f= 0.80 (silica gel, EtOAc:hexanes 1 :10); [ f^ =+77.8 (c= 1.0, CH2CI2); FT-IR (neat) v_max: 2955, 2929, 2856, 1471, 1463, 1387, 1362, 1352, 1251, 1204, 1147, 1139, 1122, 1082, 1051, 1026, 1005, 936, 887, 833, 813, 771, 730, 709, 678 cm ; ¾ NMR (600 MHz, CDCb) δ 4.05 (d, 7= 10.2Hz, 1 H), 4.02 (ap t, 7= 6.6Hz, 1 H), 3.95 (d, 7= 10.2Hz, 1 H), 1.83-1.76 (m, 4H), 1.65-1.54 (m, 2H), 1.41 (ddd, 7= 13.4, 10.9, 2.5 Hz, 1 H), 1.12 (s, 3 H), 1.09 (s, 3 H), 0.90 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCb) δ 139.7, 136.3, 71.5, 35.9, 35.3, 30.3, 29.3, 28.6, 28.1, 26.0, 18.3, 16.6, -4.0, -4.6 ppm; HRMS (CI) calcd for Ci6H₃oBrOSi⁺ [ -H]⁺ 345.1244, found 345.1258.

[(3R)-3-{[teri-Butyl(diphenyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en-l-yl]- methanol [( ?)-S-10]: According to the procedure for the preparation of {R)-S-9 as described above, allylic alcohol (R)-S-S (397 mg, 2.00 mmol, l .O equiv) was treated with ferf-butyldiphenylsilyl chloride (480 mg, 3.20 mmol, 1.6 equiv), followed by DIB AL-H (5.40 mL, l .OM solution in hexanes, 5.40 mmol, 2.7 equiv) to give product (/?)-S-10 (740mg, 1.80 mmol, 90% yield for two steps) as a colorless oil that slowly solidified to form an amorphous solid. ( ?)-S-10: R_f=0.30 (silica gel, EtOAc:hexanes 1 :9); [ f^ =+9.6 (c = 1.0, CH₂C1₂); FT-IR

(neat) v_max: 3452, 2958, 2930, 2857, 1472, 1427, 1388, 1363, 1352, 1200, 1146, 1105, 1081, 1049, 1026, 1003, 978, 936, 882, 821, 786, 738, 700, 668 cm-¹; ¾ NMR (600 MHz, CDCI3) δ 7.75-7.67 (m, 4H), 7.46-7.34 (m, 6 H), 4.12 (dd, /= 11.3, 4.5 Hz, 1 H), 4.08 (dd, 7= 11.3, 4.1 Hz, 1 H), 4.02 (ap t, 7=5.3 Hz, l H), 1.74 (s, 3 H), 1.68-1.61 (m, 2H), 1.60-1.53 (m, 1 H), 1.26-1.21 (m, 1 H), 1.07 (s, 3 H), 1.06 (s, 9 H), 0.94 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 140.5, 136.2, 135.7, 134.9, 134.3, 129.7, 129.6, 127.7, 127.5, 72.4, 59.3, 35.2, 34.6, 29.0, 28.2, 27.8, 27.3, 19.7, 16.9 ppm; HRMS (CI) calcd for C₂₆H₃₅0₂Si⁺ [M-H]⁺ 407.2401, found 407.2410.

{[(l/f)-3-(Bromomethyl)-2,4,4-trimethylcyclohex-2-en-l-yl]oxy}(teri-butyl)diphenylsilane [(/?)-

8a]: According to the procedure for the preparation of (R)-S as described above, (/?)-S-10 (613 mg, 1.50 mmol, l .O equiv) was reacted sequentially with MsCl (197 ί, 292mg, 2.55 mmol, 1.7 equiv) and LiBr (457 mg, 5.25 mmol, 3.5 equiv) to give chiral allylic bromide (R)-8a (707 mg, 1.50 mmol, quant, yield) as colorless oil. The material was essentially pure and could be stored neat at -40 °C for several months with no signs of decomposition. (R)-Sa: R_f= 0.75 (silica gel, EtOAc:hexanes 1: 10); [af^ = +26.2 (c= 1.0, CH₂C1₂); FT-IR

(neat) 2957, 2931, 2856, 1471, 1427, 1388, 1362, 1350, 1202, 1146, 1105, 1080, 1048, 1026, 1005, 979, 936, 883, 821, 787, 739, 700, 668 cm ¹ ; ¾ NMR (600 MHz, CDCI3) δ 7.73-7.69 (m, 4H), 7.45-7.36 (m, 6 H), 4.05^1.00 (m, 2 H), 3.97 (d, /= 10.1 Hz, 1 H), 1.72 (s, 3 H), 1.68-1.62 (m, 2H), 1.59-1.56 (m, 1 H), 1.28-1.26 (m, 1 H), 1.13 (s, 3 H), 1.06 (s, 9H), 1.04 (s, 3H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 139.1 , 136.9, 136.2 134.7, 134.1, 129.73, 129.66, 127.7, 127.6, 72.3, 35.32, 35.28, 30.1, 28.6, 28.5, 28.0, 27.2, 19.7, 17.4 ppm; HRMS (CI) calcd for C₂₆H34BrOSi⁺ [ -H]⁺ 469.1557, found 469.1550.

[(3/?)-3-{[(2,3-Dimethylbutan-2-yl)(dimethyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en-l- yljmethanol [(/?)-S-ll]: According to the procedure for the preparation of (R)-S-9 as described above, allylic alcohol (R)-S-8 (397 mg, 2.00mmol, l.Oequiv) was reacted sequentially with thexyldimethylsilyl chloride (572 mg, 3.20 mmol, 1.6 equiv) and DIBAL-H (5.40mL, l.OM solution in hexanes, 5.40 mmol, 2.7 equiv) to give product (R)-S-ll (560 mg, 1.78 mmol, 89% for two steps) as a colorless oil. (R)-S-ll: R_f= 0.20 (silica gel,

EtOAc:hexanes 1 :9); [a]²² = -13.8 (c= 1.0, CH₂C1₂); FT-IR (neat) v_max: 3455, 2956, 2867, 1467, 1388, 1376, 1364, 1352, 1251, 1203, 1148, 1138, 1120, 1080, 1051, 1034, 1025, 1007, 979, 936, 886, 876, 840, 828, 772, 707, 678 cm-¹ ; ¾ NMR (600 MHz, CDC1₃) δ 4.10 (ABq, A5AB = 0.040, J= 11.4 Hz, 2H), 3.96 (ap t, J= 5.5 Hz, 1 H), 1.84-1.73 (m, 4 H), 1.68-1.57 (m, 3 H), 1.35 (ddd, 7= 12.3, 9.7, 2.6 Hz, 1 H), 1.05 (s, 3 H), 1.00 (s, 3 H), 0.87 (dd, 7=6.9, 1.6 Hz, 6 H), 0.84 (d, 7= 3.0 Hz, 6 H), 0.12 (d, 7=5.8 Hz, 6 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 141.9, 138.0, 73.0, 61.2, 37.4, 36.6, 36.2, 31.4, 30.1, 30.0, 27.0, 22.5, 22.4, 20.8, 20.7, 18.4, 0.0, -0.6 ppm; HRMS (CI) calcd for Ci₈H₃₅02Si⁺ [ -H]⁺ 311.2401, found 311.2400.

{[(l ?)-3-(Bromomethyl)-2,4,4-trimethylcyclohex-2-en-l-yl]oxy}(2,3-dimethylbutan-2- yl)dimethylsilane [( ?)-8b]: According to the procedure for the preparation of (R)-S as described above, (R)-S- 11 (469 mg, 1.50 mmol, l .O equiv) was reacted sequentially with MsCl (197 μί, 292 mg, 2.55 mmol, 1.7 equiv) and LiBr (457 mg, 5.25 mmol, 3.5 equiv) to give chiral allylic bromide (R)-8b (563 mg, 1.50mmol, quant, yield) as colorless oil. The material was essentially pure and could be stored neat at -40 °C for several months with no signs of decomposition. (fl)-8b: R_f=0.80 (silica gel, EtOAc:hexanes 1: 10); [a]²² =-45.9 (c= 1.0, CH₂Ci2); FT- IR (neat) v_max: 2956, 2866, 1467, 1389, 1377, 1364, 1352, 1250, 1203, 1147, 1138, 1121, 1081, 1050, 1033, 1026, 1008, 979, 936, 885, 875, 840, 827, 772, 708, 677 cm^"1; ¾ NMR (600 MHz, CDCI3) δ 4.10-3.93 (m, 3 H), 1.84-1.73 (m, 4 H), 1.68-1.57 (m, 3 H), 1.43-1.36 (m, 1 H), 1.11 (s, 3 H), 1.09 (s, 3 H), 0.89 (d, 7= 1.6 Hz, 3 H), 0.88 (d, 7= 1.6 Hz, 3 H), 0.851 (s, 3 H), 0.845 (s, 3 H), 0.13 (s, 3 H), 0.12 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCI₃) δ 139.6, 136.2, 71.2, 35.7, 35.3, 34.3, 30.3, 29.1, 28.4, 28.3, 20.5, 20.4, 18.8, 18.7, 16.8, -1.9, -2.6 ppm; HRMS (CI) calcd for Ci8H₃₄BrOSi⁺ [M-H]⁺ 373.1557, found 373.1556.

[(3R)-3-{[Benzyl(dimethyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en-l-yl]methanol [(/?)-S-12]:

According to the procedure for the preparation of (R)-S-9 as described above, allylic alcohol (R)-S-S (397 mg,

2.00 mmol, l.O equiv) was sequentially reacted with benzyldimethylsilyl chloride (547 mg, 3.20 mmol, 1.6 equiv) and DIBAL-H (5.40 mL, 1.0M solution in hexanes, 5.40 mmol, 2.7 equiv) to give product (/?)-S-12 (586 mg, 1.84mmol, 92% for two steps) as a colorless oil. (R)-S-12: R_f=0.25 (silica gel, EtOAc:hexanes 1 :9);

[a]_p = +5.8 (c= 1.0, CH2CI2); FT-IR (neat) v_max: 3456, 2957, 2937, 2865, 1600, 1493, 1470, 1452, 1406, 1388, 1364, 1353, 1251, 1207, 1154, 1121, 1079, 1055, 1028, 981, 936, 904, 889, 835, 817, 796, 762, 698 cm-¹; ¾ NMR (600 MHz, CDCI3) 57.25-7.18 (m, 2H), 7.12-7.05 (m, 3 H), 4.15 (d, J= 10.6 Hz, 1 H), 4.10 (d, /= 11.3 Hz, 1 H), 4.02 (ap t, 7=5.6Hz, 1 H), 2.22 (s, 2H), 1.80-1.75 (m, l H), 1.77 (s, 3 H), 1.65-1.57 (m, 2H), 1.35 (ddd, J= 13.5, 9.9, 2.8 Hz, 1 H), 1.08 (s, 3 H), 1.02 (s, 3 H), 0.13 (s, 3 H), 0.12 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 140.8, 139.2, 135.2, 128.6, 128.3, 124.3, 71.4, 59.3, 35.3, 34.6, 29.4, 28.0, 27.5, 16.3, -1.49, -1.52 ppm; HRMS (CI) calcd for Ci₉H₂90₂Si⁺ [ -H]⁺ 317.1931, found 317.1942.

Benzyl{[(l/?)-3-(bromomethyl)-2,4,4-trimethylcyclohex-2-en-l-yl]oxy}dimethylsilane [(J?)-8c]:

According to the procedure for the preparation of (R)-S as described above, (/?)-S-12 (478 mg, 1.50 mmol, l .O equiv) was reacted sequentially with MsCl (197 ί, 292mg, 2.55 mmol, 1.7 equiv) and LiBr (457 mg, 5.25 mmol, 3.5 equiv) to give chiral allylic bromide (R)-8c (574mg, 1.50 mmol, quant, yield) as colorless oil. The material was essentially pure and could be stored neat at -40 °C for several months with no signs of decomposition. (fl)-8c: R_f= 0.75 (silica gel, EtOAc:hexanes 1 : 10); [CC]_p = +10.7 (c= 1.0, CH2Q2); FT-IR (neat) 2957, 2936, 2866, 1600, 1493, 1470, 1451, 1406, 1387, 1364, 1353, 1251, 1206, 1153, 1121, 1079, 1054, 1028, 980, 936, 904, 889, 836, 817, 795, 761, 698 cm ; ¾ NMR (600 MHz, CDC1₃) δ 7.24-7.19 (m, 2H), 7.09-7.04 (m, 3 H), 4.07-4.00 (m, 2 H), 4.10 (d, 7= 10.1 Hz, 1 H), 2.22 (s, 2H), 1.80-1.75 (m, 1 H), 1.74 (s, 3 H), 1.62-1.55 (m, 2H), 1.42-1.38 (m, 1 H), 1.12 (s, 3 H), 1.11 (s, 3 H), 0.13 (s, 3 H), 0.12 (s, 3 H), ppm: ¹³C NMR (151 MHz, CDCI3) δ 139.2, 138.8, 137.0, 128.6, 128.3, 124.3, 71.6, 35.7, 35.3, 30.0, 29.2, 28.4, 28.1, 27.5, 16.5, -1.46, -1.53 ppm; HRMS (CI) calcd for Ci₉H₂₈BrOSi⁺ [ -H]⁺ 379.1087, found 379.1090.

[(3/?)-3-{[l,l,l,3,3,3-Hexamethyl-2-(trimethylsilyl)trisilan-2-yl]oxy}-2,6,6-trimethylcyclohex-l- en-l-yl]methanol [(/?)-S-13]: According to a similiar procedure for the preparation of (R)-S-9 as described above, allylic alcohol ( ?)-S-8 (397 mg, 2.00 mmol, l .O equiv) was reacted with tris(trimethylsilyl)silyl chloride (905 mg, 3.20 mmol, 1.6equiv) and AyV-dimemylpyridin-4-amine (DMAP; 390 mg, 3.20 mmol, 1.6 equiv) as base, followed by DIBAL-H (5.40mL, 1.0M solution in hexanes, 5.40mmol, 2.7equiv) reduction, to give product (/?)-S-13 (710 mg, 1.70 mmol, 85% for two steps) as a colorless oil. (7?)-S-13: R_f= 0.30 (silica gel, EtOAc:hexanes 1 :9); [a] = -10.2 (c= 1.0, CH₂C1₂); FT-IR (neat) v_max: 3451, 2948, 2894, 1728, 1470, 1438, 1395, 1364, 1346, 1256, 1243, 1203, 1146, 1121, 1077, 1041, 1004, 971, 933, 864, 827, 792, 768, 743, 685, 664 cm-¹ ; ¾ NMR (600MHz, CDCI3) δ 4.10 (ABq, Δ5ΑΒ = 0.032, 7= 11.4 Hz, 2H), 3.70 (ap t, /=5.4Hz, 1 H), 1.85-1.74 (m, 4H), 1.66-1.54 (m, 2H), 1.32 (ddd, J= 13.2, 9.5, 2.8 Hz, 1 H), 1.05 (s, 3 H), 1.00 (s, 3 H), 0.20 (s, 27H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 139.7, 136.0, 75.4, 59.2, 35.2, 34.7, 28.8, 28.1, 27.8, 16.6, 0.8 ppm; HRMS (CI) calcd for Q^ChSi^ [M-H]⁺ 415.2335, found 415.2345.

2-{[(l/i)-3-(Bromomethyl)-2,4,4-trimethylcyclohex-2-en-l-yl]oxy}-l,l,l,3,3,3-hexamethyl-2- (trimethylsilyl)trisilane [(/?)-8d]: According to the procedure for the preparation of (R)-S as described above, ( ?)-S-13 (625 mg, 1.50 mmol, l.O equiv) was reacted sequentially with MsCl (197 ί, 292mg, 2.55 mmol, 1.7 equiv) and LiBr (457 mg, 5.25 mmol, 3.5 equiv) to give chiral allylic bromide (l?)-8d (720 mg, 1.50 mmol, quant, yield) as colorless oil. The material was essentially pure and could be stored neat at -40 °C for several months with no signs of decomposition. (fl)-8d: R_f= 0.85 (silica gel, EtOAc:hexanes 1 :10); [o¾ = -27.0

(c= 1.0, CH2CI2); FT-IR (neat) v_max: 2948, 2894, 1728, 1470, 1438, 1395, 1364, 1346, 1256, 1243, 1203, 1146, 1121, 1077, 1041, 1004, 971, 933, 864, 827, 792, 768, 743, 685, 664 cm-' ; Ή NMR (600 MHz, CDCI3) δ 4.03 (d, J= 10.1 Hz, 1 H), 3.95 (d, J= 10.1 Hz, 1 H), 3.71 (ap t, 7=5.7Hz, 1 H), 1.84-1.72 (m, 4 H), 1.59-1.53 (m, 2H), 1.38-1.31 (m, 1 H), 1.10 (s, 3 H), 1.09 (s, 3 H), 0.20 (s, 27 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 139.7, 136.0, 75.5, 35.5, 35.4, 30.1, 28.6, 28.3, 28.2, 16.9, 0.8 ppm; HRMS (CI) calcd for Ci₉H₄2BrOSi4⁺ [ -H]⁺ 477.1502, found 477.1501.

{(3/?)-2,6,6-Trimethyl-3-[(triisopropylsilyl)oxy]cyclohex-l-en-l-yl}methanol [W-S-14]:

According to the procedure for the preparation of (R)-S-9 as described above, allylic alcohol (R)-S-S (397 mg, 2.00mmol, l .O equiv) was reacted sequentially with triisopropylsilyl chloride (686 μί, 617 mg, 3.20 mmol, 1.6 equiv) and DIBAL-H (5.40 mL, 1.0M solution in hexanes, 5.40 mmol, 2.7 equiv) to give product ( f)-S-14 (575 mg, 1.76mmol, 88% for two steps) as a colorless oil. (R)-S-14: Rf=0.28 (silica gel, EtOAc:hexanes 1 :9); [a]_p = -17.3 (c= 1.0, CH2CI2); FT-IR (neat) 3445, 2943 2890 2864 1464, 1385 1364, 1348, 1245, 1218,

1203, 1178, 1148, 1139, 1122, 1088, 1053, 1027, 1012, 997, 982, 935, 921, 903, 882, 813, 779, 731, 708, 676 cm^"1 ; ¾ NMR (600 MHz, CDCI3) δ 4.17 (ap t, /= 5.5 Hz, 1 H), 4.11 (ABq, A6AB = 0.042, J= 11.4 Hz, 2 H), 1.93- 1.77 (m, 1 H), 1.85 (s, 3 H), 1.72-1.58 (m, 2H), 1.39-1.32 (m, 1 H), 1.26-1.03 (m, 3 H), 1.09 (s, 9 H), 1.08 (s, 9 H), 1.06 (s, 3 H), 1.01 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 139.8, 136.3, 71.6, 59.3, 35.5, 34.6, 29.6, 28.1, 28.0, 18.5, 18.4, 16.5, 13.0 ppm; HRMS (CI) calcd for Ci₉H₃₇02Si⁺ [ -H]⁺ 325.2557, found 325.2556.

{[(l ?)-3-(Bromomethyl)-2,4,4-trimethylcyclohex-2-en-l-yl]oxy}(triisopropyl)silane [( f)-8e]:

According to the procedure for the preparation of (R)-S as described above, (7f)-S-14 (490 mg, 1.50mmol, l.Oequiv) was reacted sequentially with MsCl (197 ί, 292mg, 2.55 mmol, 1.7equiv) and LiBr (457 mg, 5.25 mmol, 3.5 equiv) to give chiral allylic bromide (/?)-8e (584mg, 1.50 mmol, quant, yield) as colorless oil. The material was essentially pure and could be stored neat at -40 °C for several months with no signs of decomposition. (fl)-8e: R_f=0.90 (silica gel, EtOAc:hexanes 1:10); [af^ =-55.5 (c= 1.0, CH₂C1₂); FT-IR (neat) Vm»: 2942, 2892, 2865, 1464, 1384, 1364, 1348, 1244, 1217, 1203, 1177, 1147, 1139, 1122, 1088, 1052, 1027, 1011, 996, 980, 935, 920, 903, 881, 811, 779, 730, 706, 675 cm-'; H NMR (600 MHz, CDC1₃) δ 4.18 (ap t, /=5.9 Hz, 1 H), 4.01 (ABq, Δ5ΑΒ = 0.081, J= 11.4Hz, 2 H), 1.88-1.81 (m, 1 H), 1.84 (s, 3 H), 1.72-1.58 (m, 2 H), 1.40 (ddd, J= 13.1, 10.3, 2.8Hz, 1 H), 1.15-1.03 (m, 3 H), 1.11 (s, 3 H), 1.10 (s, 3 H), 1.092 (s, 9H), 1.087 (s, 9H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 139.9, 136.2, 71.8, 35.8, 35.3, 30.4, 29.3, 28.4, 28.3, 18.5, 18.4, 16.8, 13.0 ppm; HRMS (CI) calcd for Ci₉H₃6BrOSi⁺ [M-H]⁺ 387.1713, found 387.1714.

{(3 ?)-2,6,6-Trimethyl-3-[(triethylsilyl)oxy]cyclohex-l-en-l-yl}methanol [(fl)-S-lS]: According to the procedure for the preparation of (R)-S-9 as described above, allylic alcohol (R)-S-8 (397 mg, 2.00 mmol, l.Oequiv) was reacted sequentially with triethylsilyl chloride (537 ί, 482mg, 3.20mmol, 1.6 equiv) and DIBAL-H (5.40mL, l.OM solution in hexanes, 5.40mmol, 2.7equiv) to give product (R)-S-15 (512mg, 1.80 mmol, 90% for two steps) as a colorless oil. (R)-S-15: Rf=0.35 (silica gel, EtOAc:hexanes 1:9); [ a ] ² _D ² = -8.5 (c= 1.0, CH2CI2); FT-IR (neat) v_max: 3453, 2954, 2938, 2911, 2876, 1468, 1457, 1415, 1364, 1351, 1237, 1203, 1148, 1139, 1122, 1084, 1053, 1006, 978, 936, 883, 823, 792, 741, 726, 686 cm ; ¾ NMR (600 MHz, CDCI3) δ 4.07 (ABq, A5AB =0.043, 7= 10.9Hz, 2H), 3.99 (ap t, 7=5.6Hz, 1 H), 1.88-1.75 (m, 1 H), 1.78 (s, 3 H), 1.65-1.54 (m, 2H), 1.34 (ap t, 7= 11.2Hz, 1 H), 1.03 (s, 3 H), 0.99 (s, 3 H), 0.95 (t, 7=8.0Hz, 9H), 0.61 (q, 7=7.8 Hz, 6H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 140.2, 135.6, 71.1, 59.1, 35.4, 34.5, 29.5, 28.0, 27.8, 16.1, 7.0, 5.2 ppm; HRMS (CI) calcd for Ci₆H₃i0₂Si⁺ [ -H]⁺ 283.2088, found 283.2090.

{[(l f)-3-(Bromomethyl)-2,4,4-trimethylcyclohex-2-en-l- l]oxy}(triethyl)silane t(^)-8f]:

According to the same procedure for the preparation of (R)-S described above, (/f)-S-15 (427 mg, 1.50 mmol, l .O equiv) was reacted sequentially with MsCl (197 ί, 292mg, 2.55 mmol, 1.7 equiv) and LiBr (457 mg, 5.25 mmol, 3.5 equiv) to give chiral allylic bromide ( ?)-8f (521 mg, 1.50 mmol, quant, yield) as colorless oil. The material was essentially pure and could be stored neat at -40 °C for several months with no signs of decomposition. (/?)-8f: R_f=0.85 (silica gel, EtOAc:hexanes 1 :10); [ a ] ²² = -26.5 (c= 1.0, CH₂C1₂); FT-IR (neat) v_max: 2954, 2937, 2912, 2875, 1468, 1457, 1414, 1364, 1351, 1236, 1203, 1147, 1139, 1122, 1083, 1053, 1005, 978, 936, 882, 822, 791, 740, 725, 686 cnT¹; Ή NMR (600 MHz, CDCb) ΰ 4.04 (ap t, J=6.9 Hz, 1 H), 4.00 (ABq, Δ5ΑΒ = 0.11 , /= 10.1 Hz, 2 H), 1.85-1.78 (m, 1 H), 1.85-1.78 (s, 3 H), 1.68-1.57 (m, 2 H), 1.41 (ddd, J= lj3.5, 10.9, 2.8 Hz, 1 H), 1.13 (s, 3 H), 1.09 (s, 3 H), 0.98 (t, /=7.9 Hz, 9 H), 0.64 (q, 7= 7.9Hz, 6 H) ppm; ¹³C NMR (151 MHz, CDCb) δ 139.5, 136.6, 71.4, 35.9, 35.3, 30.2, 29.4, 28.5, 28.1, 16.4, 7.1, 5.2 ppm; HRMS (CI) calcd for Ci₆H₃oBrOSi⁺ [ -H]⁺ 345.1244, found 345.1252.

{(3 ?)-2,6,6-Trimethyl-3-[(tripropylsilyl)oxy]cyclohex-l-en-l-yl}methanol [( ?)-S-16]: According to the procedure for the preparation of (R)-S-9 as described above, allylic alcohol (R)-S-S (397 mg, 2.00 mmol, l .O equiv) was reacted sequentially with tripropylsilyl chloride (686 ί, 617 mg, 3.20 mmol, 1.6 equiv) and DIBAL-H (5.40 mL, 1.0M solution in hexanes, 5.40 mmol, 2.7 equiv) to give product (/f)-S-16 (600mg, 1.84 mmol, 92% for two steps) as a colorless oil. (R)-S-16: Rf=0.40 (silica gel, EtOAc:hexanes 1:9); [ ] ² _D ² = -8.1 (c= 1.0, CH2CI2); FT-IR (neat) v_mia: 3452, 2954, 2925, 2868, 1454, 1408, 1374, 1364, 1352, 1332, 1204, 1148, 1139, 1123, 1084, 1053, 1028, 1005, 981, 935, 894, 884, 831, 819, 754, 739, 713, 695 cm-¹; Ή NMR (600MHz, CDCb) δ 4.14 (dd, 7= 11.4, 3.8 Hz, 1 H), 4.09 (dd, /= 11.4, 3.7 Hz, 1 H), 4.01 (ap t, /=5.9 Hz, 1 H), 1.84-1.74 (m, 1 H), 1.80 (s, 3 H), 1.65-1.58 (m, 2H), 1.45-1.32 (m, 7 H), 1.06 (s, 3 H), 1.02 (s, 3 H), 0.97 (t, =7.2Hz, 9 H), 0.70-0.55 (m, 6 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 140.3, 135.9, 71.2, 59.3, 35.5, 34.6, 29.6, 28.2, 27.9, 18.7, 17.3, 17.1, 16.1 ppm; HRMS (CI) calcd for Ci₉H₃₇0₂Si⁺ [M-H]⁺ 325.2557, found 325.2566.

{[(l ?)-3-(Bromomethyl)-2,4,4-trimethylcyclohex-2-en-l-yl]oxy}(tripropyl)silane [(R)-8g]: According to the procedure for the preparation of (R)-S as described above, (7?)-S-16 (490 mg, 1.50 mmol, l .O equiv) was reacted sequentially with MsCl (197 μ]_,, 292mg, 2.55 mmol, 1.7 equiv) and LiBr (457 mg, 5.25 mmol, 3.5 equiv) to give chiral allylic bromide (R)-Sg (584mg, 1.50 mmol, quant, yield) as colorless oil. The material was essentially pure and could be stored neat at -40 °C for several months with no signs of decomposition. (R)-Sg: R_f= 0.75 (silica gel, EtOAc:hexanes 1 : 10); [CC]_p = -24.5 (c= 1.0, CH₂C1₂); FT-IR (neat) v_max: 2954, 2924, 2867, 1454, 1407, 1374, 1364, 1351, 1333, 1203, 1148, 1139, 1122, 1084, 1052, 1028, 1006, 980, 935, 894, 883, 830, 818, 752, 739, 711, 697 cm-¹; ¾ NMR (600 MHz, CDC1₃) 54.05 (d, /= 10.2Hz, 1 H), 4.03 (ap t, J= 6.5 Hz, 1 H), 3.94 (d, 7=10.1 Hz, 1 H), 1.83-1.75 (m, 1 H), 1.78 (s, 3 H), 1.62-1.56 (m, 2H), 1.42-1.35 (m, 7 H), 1.13 (s, 3 H), 1.09 (s, 3 H), 0.97 (t, =7.2Hz, 9 H), 0.66-0.59 (m, 6 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 139.6, 136.5, 71.4, 35.9, 35.3, 30.2, 29.4, 28.6, 28.1, 18.7, 17.3, 17.1, 16.4 ppm; HRMS (CI) calcd for Ci₉H₃6BrOSi⁺ [ -H]⁺ 387.1713, found 387.1726.

{(3 ?)-2,6,6-Trimethyl-3-[(tributylsilyl)oxy]cyclohex-l-en-l-yl}methanol [(/?)-S-17]: According to the procedure for the preparation of (R)-S-9 as described above, allylic alcohol (R)-S-8 (397 mg, 2.00 mmol, l .O equiv) was reacted sequentially with tributylsilyl chloride (855 ί,, 751 mg, 3.20 mmol, 1.6 equiv) and DIBAL-H (5.40 mL, 1.0M solution in hexanes, 5.40 mmol, 2.7 equiv) to give product ( ?)-S-17 (634mg, 1.72 mmol, 86% for two steps) as a colorless oil. (/?)-S-17: R_f=0.45 (silica gel, EtOAc:hexanes 1 :9);

[a]_p = -8.1 (c= 1.0, CH2CI2); FT-IR (neat) v_max: 3455, 2956, 2922, 2873, 2855, 1465, 1409, 1375, 1365, 1351, 1342, 1296, 1252, 1198, 1139, 1148, 1139, 1123, 1079, 1052, 1028, 1007, 979, 964, 936, 888, 822, 789, 761, 733, 711, 695 cm^"1; >H NMR (600 MHz, CDCI3) δ 4.12 (ABq, A5AB = 0.048, J= 11.4HZ, 2H), 4.02 (ap t, 7=5.8 Hz, 1 H), 1.89-1.76 (m, 1 H), 1.80 (s, 3 H), 1.65-1.55 (m, 2H), 1.39-1.36 (m, 1 H), 1.36-1.29 (m, 12H), 1.06 (s, 3 H), 1.02 (s, 3 H), 0.92-0.86 (m, 9 H), 0.66-0.60 (m, 6 H) ppm; ¹³C NMR (151 MHz, CDCb) δ 140.3, 135.9, 71.2, 59.4, 35.5, 34.6, 29.6, 28.2, 27.9, 26.9, 25.7, 16.2, 14.2, 13.9 ppm; HRMS (CI) calcd for C22H₄30₂Si⁺ [ -H]⁺ 367.3027, found 367.3036.

{[(l/?)-3-(Bromomethyl)-2,4,4-trimethylcyclohex-2-en-l-yl]oxy}(tributyl)silane

According to the procedure for the preparation of (R)-8 as described above, ( ?)-S-17 (552 mg, 1.50 mmol, l .O equiv) was reacted sequentially with MsCl (197 ί-, 292mg, 2.55 mmol, 1.7 equiv) and LiBr (457 mg, 5.25 mmol, 3.5 equiv) to give chiral allylic bromide (/?)-8h (647 mg, 1.50 mmol, quant, yield) as colorless oil. The material was essentially pure and could be stored neat at -40 °C for several months with no signs of decomposition. (R)-Sh: R_f=0.70 (silica gel, EtOAc:hexanes 1:10); [a]^ =-18.1 (c= 1.0, CH2CI2); FT-IR (neat) v_max: 2956, 2921, 2871, 2856, 1465, 1409, 1376, 1364, 1351, 1341, 1296, 1251, 1198, 1139, 1147, 1139, 1122, 1079, 1050, 1027, 1006, 979, 963, 935, 887, 821, 789, 760, 731, 712, 694 cm^-1; >H NMR (600 MHz, CDCb) δ 4.03 (ap t, /= 7.0Hz, 1 H), 4.00 (ABq, ΔδΑΒ = 0.11, /= 10.1 Hz, 2H), 1.84-1.75 (m, 1 H), 1.78 (s, 3 H), 1.66-1.57 (m, 2H), 1.41 (ddd, 7= 13.5, 11.0, 2.7 Hz, 1 H), 1.35-1.30 (m, 12 H), 1.13 (s, 3 H), 1.09 (s, 3 H), 0.92- 0.87 (m, 9 H), 0.66-0.58 (m, 6 H) ppm; ¹³C NMR (151 MHz, CDC1₃) δ 139.6 136.5, 71.4, 35.9, 35.3, 30.3, 29.4, 28.6, 28.1, 26.9, 25.7, 16.5, 14.2, 13.9 ppm; HRMS (CI) calcd for C₂2H₄2BrOSi⁺ [ -H]⁺ 429.2183, found 429.2194.

Anthrones Svnthesis

S-18 S-19-S-23 S-24-S-28

S-19: R⁵ = Bn S-24: R⁵ = Bn

S-20: R⁵ = Me S-25: R⁵ = Me

S-21 : R⁵ = Allyl S-26: R⁵ = Allyl

S-22: R⁵ = 1-Naph-Me S-27: R⁵ = 1-Naph-Me

S-23: R⁵ = 4-CF,-Bn S-28: R⁵ = 4-CF₃-Bn

Compounds S-18, S-19, S-20, and cyclic anhydrides S-24 and S-25 were prepared following the reported procedure (Nicolaou et al, 2013; Nicolaou et al., 2014). The physical and spectroscopic data of those compounds matched those reported in the literature (Nicolaou et al, 2013; Nicolaou et al, 2014).

Ethyl 2-(allyloxy)-6-(2-ethoxy-2-oxoethyl)-4-methoxybenzoate (S-21): Following the reported procedure (Nicolaou et al, 2013; Nicolaou et al, 2014), S-21 was synthesized as follows. To a solution of compound S-18 (1.00 g, 3.50mmol, 1.0 equiv) in DMF (25 mL) at 25 °C were sequentially added K₂C0₃ (1.00 g, 7.00 mmol, 2.0 equiv) and allyl bromide (364 ί, 3.85 mmol, 1.1 equiv). The reaction mixture was stirred for 15 h, then diluted with H₂O (25 mL) and extracted with EtOAc (3 x50mL). The organic phase was dried over anhydrous Na₂SC¼, and concentrated under reduced pressure to give a crude oil, which was purified by flash column chromatography (silica gel, 2 →5%→10% EtOAc:hexanes) to give pure product S-21 (848 mg, 2.64 mmol, 75% yield) as a colorless oil. S-21: R_f= 0.30 (silica gel, EtOAc:hexanes 1 :4); FT-IR (neat) v_max: 2981, 1727, 1603, 1583, 1459, 1443, 1388, 1374, 1332, 1266, 1192, 1153, 1116, 1086, 1053, 992, 933, 835, 772, 683 cm-¹ ; Ή NMR (600 MHz, CDCb) δ 6.41-6.39 (m, 2 H), 6.00 (ddd, 7= 12.2, 10.6, 5.3 Hz, 1 H), 5.40 (ddd, 7= 17.3, 3.1, 1.6 Hz, 1 H), 5.25 (dd, 7= 10.6, 1.5 Hz, 1 H), 4.53 (ap dt, 7=4.9, 1.5 Hz, 2H), 4.33 (q, 7=7.1 Hz, 2H), 4.14 (q, 7=7.1 Hz, 2H), 3.80 (s, 3 H), 3.67 (s, 2H), 1.34 (t, 7= 7.1 Hz, 3 H), 1.24 (t, 7= 7.1 Hz, 3 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 170.9, 167.5, 161.6, 158.0, 135.2, 132.9, 117.5, 117.0, 107.9, 99.3, 69.7, 61.1, 61.0, 55.5, 39.7, 14.33, 14.28 ppm; HRMS (ESI) calcd for Ci7H₂₃06⁺ [ +H]⁺ 323.1489, found 323.1494.

8-(Allyloxy)-6-methoxy-l#-isochromene-l,3(4//)-dione (S-26): Following the reported procedure (Nicolaou et al, 2013; Nicolaou et al, 2014), S-26 was synthesized as follows. To a stirred solution of diester S-21 (806 mg, 2.50 mmol, l .O equiv) in EtOH (lOmL) was added a solution of NaOH (2.70 g, 68.0 mmol, 27 equiv) in water (7 mL) at 25 °C. The resulting mixture was heated to reflux for 15 h. EtOH was then removed under reduced pressure, and the remaining aqueous phase was acidified with 12 N aq. HCl to pH 1. The aqueous phase was extracted with EtOAc (3 30mL), and the combined organic phases were dried over anhydrous Na₂S0₄, filtered, and concentrated under reduced pressure to give the crude diacid as a white solid. To a stirred slurry of the so obtained diacid in toluene (6 mL) was added acetic anhydride (260 μΕ, 2.75 mmol, 1.1 equiv) via syringe, and the resulting mixture was heated to reflux for 1 h. The flask was then cooled in an ice bath, the solid product was filtered off, and the filter cake was washed with pentane. The solids were collected and dried to afford S-26 as light yellow crystals (546 mg, 2.2mmol, 88% yield for two steps). S-26: R_f= 0.25 (silica gel, EtOAc:hexanes 1 :4); m.p. = 115-116 °C (toluene); FT-IR (film) v_mai: 1786, 1742, 1603, 1583, 1388, 1374, 1332, 1272, 1223, 1198, 1175, 1152, 992, 933, 835, 772, 683 cm^"1; ¾ NMR (600 MHz, CDC1₃) δ 6.42 (d, /= 1.4 Hz, 1 H), 6.34 (s, 1 H), 6.05 (ddd, J= 15.5, 10.1, 4.7 Hz, 1 H), 5.60 (dd, J= 17.2, 1.0Hz, 1 H), 5.34 (dd, J= 10.6, 0.8 Hz, 1 H), 4.65 (d, J=4.6 Hz, 2H), 3.97 (s, 2H), 3.87 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCb) δ 165.8, 165.4, 162.9, 156.7, 138.8, 131.7, 118.3, 104.3, 103.7, 99.6, 69.8, 56.0, 35.5 ppm; HRMS (ESI) calcd for Ci₃Hi₂0₅Na⁺ [M+Na]⁺ 271.0577, found 271.0580.

Ethyl 2-(2-ethoxy-2-oxoethyl)-4-methoxy-6-(l-naphthylmethoxy)benzoate (S-22): According to the procedure described above for the preparation of S-21, compound S-18 (l .OOg, 3.50mmol, l .O equiv) was reacted with l-(bromomethyl)naphthalene (851 mg, 3.85 mmol, 1.1 equiv) to give product S-22 (1.23 g, 2.90 mmol, 83% yield) as a colorless oil. S-22: R_f= 0.20 (silica gel, EtOAc:hexanes 1 :4); FT-IR (neat) v_max: 2981, 1727, 1603, 1583, 1463, 1455, 1434, 1366, 1317, 1268, 1194, 1155, 1095, 1071, 1048, 1027, 1002, 961, 804, 776, 739, 678 cm-¹ ; ¾ NMR (600 MHz, CDCI3) δ 8.03 (d, 7= 8.2 Hz, 1 H), 7.90-7.81 (m, 2H), 7.61 (d, =6.8 Hz, 1 H), 7.55-7.49 (m, 2 H), 7.45 (dd, = 8.1, 7.2Hz, 1 H), 6.60 (d, 7=2.2Hz, 1 H), 6.46 (d, 7=2.2Hz, 1 H), 5.50 (s, 2 H), 4.19-4.11 (m, 4 H), 3.81 (s, 3 H), 3.70 (s, 2 H), 1.25 (t, J= 7.1 Hz, 3 H), 1.05 (t, J= 7.1 Hz, 3 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 171.0, 167.5, 161.7, 158.2, 135.5, 133.8, 132.1, 131.4 129.0, 128.8, 126.5, 126.3, 126.0, 125.4, 123.8, 117.2, 108.0, 99.5, 69.5, 61.06, 61.05, 55.6, 39.7, 14.3, 14.0 ppm; HRMS (ESI) calcd for C25H₂₇06⁺ [ +H] ⁺ 423.1802, found 423.1800.

6-Methoxy-8-(l-naphthylmethoxy)-l//-isochromene-l,3(4//)-dione (S-27): According to the procedure described above for the preparation of S-26, diester S-22 (1.06g, 2.50 mmol, l .O equiv) was reacted with NaOH (2.70 g, 68.0 mmol, 27 equiv) in water (7 mL), followed by AC2O (260 μΐ, 2.75 mmol, 1.1 equiv) to afford product S-27 as light yellow crystals (731 mg, 2.10mmol, 84% yield for two steps). S-27: R_f= 0.20 (silica gel, EtOAc:hexanes 1 :4); m.p. = 191-192 °C (toluene); FT-IR (film) v_max: 1780, 1733, 1609, 1585, 1350, 1334, 1273, 1224, 1196, 1177, 1148, 1002, 966, 802, 776, 739, 677 cm-¹ ; Ή NMR (600 MHz, DMSO-rfe) δ 8.21-8.16 (m, 1 H), 7.99-7.88 (m, 3 H), 7.55 (m, 3 H), 6.98 (s, 1 H), 6.59 (s, 1 H), 5.71 (s, 2 H), 4.17 (s, 2 H), 3.88 (s, 3 H) ppm; ¹³C NMR (151 MHz, DMSO-rf₆) δ 166.2, 165.3, 161.9, 157.0, 140.6, 133.1, 132.0, 130.5, 128.4, 128.3, 126.3, 126.0, 125.5, 125.4, 123.8, 104.6, 103.0, 99.4, 68.5, 56.0, 35.0 ppm; HRMS (ESI) calcd for C21H17 V [ +H]⁺ 349.1071, found 349.1074.

ethyl 2-(2-ethoxy-2-oxoethyl)-4-methoxy-6-{[4-(trifluoromethyl)benzyl]oxy}benzoate (S-23):

According to the procedure described above for the preparation of S-21, compound S-18 (l.OOg, 3.50mmol, l .O equiv) was reacted with l-(bromomethyl)-4-(trifluoromethyl)benzene (920mg, 3.85 mmol, 1.1 equiv) to give product S-23 (1.26 g, 2.86 mmol, 82% yield) as a colorless oil. S-23: R_f=0.30 (silica gel, EtOAc:hexanes 1 :4); FT-IR (neat) 2981 , 1729, 1603, 1583, 1463, 1456, 1434, 1367, 1320, 1317, 1268, 1194, 1156, 1095, 1071, 1048, 1027, 961, 844, 834, 738, 698 cm-¹ ; ¾ NMR (600 MHz, CDCI₃) δ 7.62 (d, 7=8.2Hz, 2H), 7.54 (d, 7=8.0 Hz, 2H), 6.45 (d, J=2.\ Hz, 1 H), 6.42 (d, 7=2.1 Hz, 1 H), 5.13 (s, 2H), 4.33 (q, 7=7.1 Hz, 2H), 4.15 (q, 7=7.1 Hz, 2H), 3.79 (s, 3 H), 3.70 (s, 2H), 1.30 (t, 7=7.1 Hz, 3 H), 1.25 (t, 7=7.1 Hz, 3 H) ppm; ¹³C NMR (151 MHz, CDCI₃) δ 170.9, 167.3, 161.7, 157.7, 140.8, 135.6, 130.21 (q, 7= 32.5 Hz), 127.2, 125.58 (q, 7=3.9 Hz), 124.22 (q, 7=272.1 Hz), 117.1, 108.3, 99.4, 69.9, 61.2, 61.1 , 55.6, 39.8, 14.29, 14.27 ppm; ¹⁹F NMR (282MHz, CDCI₃) δ -61.59 (s) ppm; HRMS (ESI) calcd for C22H24F3 [ +H]⁺ 441.1519, found 441.1522.

6-Methoxy-8-{[4-(trifluoromethyl)benzyl]oxy}-l//-isochromene-l,3(4//)-dione (S-28): Accordini to the procedure described above for the preparation of S-26, diester S-23 (1.12g, 2.50 mmol, l .O equiv) was reacted with NaOH (2.70 g, 68.0 mmol, 27 equiv) in water (7 mL), followed by AC2O (260 μΐ, 2.75 mmol, 1.1 equiv) to afford product S-28 as light yellow crystals (733 mg, 2.00 mmol, 80% yield for two steps). S-28: R_f=0.30 (silica gel, EtOAc:hexanes 1 :4); m.p. = 214-215 °C (toluene); FT-IR (film) v_max: 1781, 1755, 1733, 1605, 1580, 1442, 1346, 1324, 1270, 1236, 1201, 1158, 1112, 1066, 1017, 981, 954, 922, 844, 832, 774, 684 cm-¹; ¾ NMR (600 MHz, acetone-i e) δ 7.89 (d, 7=7.8 Hz, 2H), 7.77 (d, 7= 7.8 Hz, 2H), 6.77 (s, 1 H), 6.67 (s, 1 H), 5.44 (s, 2H), 4.20 (s, 2 H), 3.93 (s, 3 H) ppm; ¹³C NMR (151 MHz, acetone- ) 5 166.7, 166.5, 163.0, 157.8, 142.4, 141.30, 141.25, 130.1 (q, 7= 32.0Hz), 128.1, 126.2 (q, 7= 3.9Hz), 125.4 (q, 7=271.2 Hz), 105.7, 100.2, 70.3, 56.5, 35.8 ppm; ¹⁹F NMR (282 MHz, CDC1₃) δ -61.63 (s) ppm; HRMS (ESI) calcd for C18H14F3 [ +Na]⁺ 389.0607, found 389.0611.

Scheme 3. Anthrone Semi-Quinone Fragment 13 Synthesis

Hyd

4-(Diphenylmethoxy)phenol (S-29): Phenol S-29 was synthesized according to the reported procedure (Frlan et al., 2007). To a stirred suspension of hydroquinone (2.20 g, 20.0mmol, l.O equiv) and K2CO3 (1.38 g, 10.0 mmol, 0.5 equiv) in acetone (20 mL) under argon was added (bromomethylene)dibenzene (2.47 g, 10.0 mmol, 0.5 equiv). The mixture was heated to reflux for 15 h, filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 2%→5%→10% EtOAc:hexanes) furnished pure product S-29 (1.94 g, 7.00mmol, 70% yield) as a white solid. S-29: R_f= 0.50 (silica gel, EtOAc:hexanes 1 :9); m.p. = 106-108 °C (CH2CI2); FT-IR (film) v_max: 3356, 3029, 2923, 1505, 1452, 1260, 1208, 1100,1081, 1013, 916, 883, 823, 780, 740, 695 cnr¹ ; Ή NMR (600 MHz, CDCI3) 57.33-7.32 (m, 4 H), 7.26-7.23 (m, 4H), 7.19-7.16 (m, 2H), 6.73 (d, 7= 8.9Hz, 2H), 6.58 (d, 7=8.9 Hz, 2 H), 6.01 (s, 1 H), 4.43 (s, 1 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 152.6, 149.9, 141.7, 128.8, 127.9, 127.2, 117.7, 116.2, 83.0 ppm; HRMS (CI) calcd for Ci₉Hi₇02⁺ [ +H]⁺ 277.1229, found 277.1231.

4-(Diphenylmethoxy)-4-methoxycyclohexa-2,5-dien-l-one (S-30): Quinone S-30 was synthesized according to the reported procedure (Pelter and Elgendy, 1988). To a stirred solution of phenol S-29 (1.40g, 5.00 mmol, 1.0 equiv) in MeOH (50 mL) was added iodobenzene diacetate [PhI(OAc)2, 1.61 g, 5.00 mmol, 1.0 equiv] at 0 °C, and the resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by addition of saturated aq. NaHC0₃ (50 mL) and extracted with EtOAc (3 x 50mL). The combined organic phases were dried over anhydrous Na2SC>4, filtered, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 2%→5%→10% EtOAc:hexanes, 0.1% Et3N) to afford semi-quinone S-30 (1.47 g, 4.80mmol, 96% yield) as colorless oil. S-30: R_f=0.60 (silica gel, EtOAc:hexanes 1:9); FT-IR (neat) v_max: 3029, 2940, 2833, 1687, 1673, 1637, 1494, 1454, 1385, 1318, 1305, 1247, 1176, 1100, 1070, 1019, 973, 918, 856, 775, 743, 702 cm^"1 ; ¾ NMR (600 MHz, CDC1₃) Ή NMR (600 MHz, CDCI3) δ 7.38-7.30 (m, 8 H), 7.29-7.24 (m, 2H), 6.75 (d, 7= 10.2Hz, 2H), 6.15 (d, 7= 10.2 Hz, 2 H), 5.91 (s, l H), 3.38 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 185.5, 144.1, 142.7, 129.2, 128.6, 127.7, 126.9, 93.5, 76.5, 51.2 ppm; HRMS (CI) calcd for C₂oHn03⁺ [ -H]⁺ 305.1172, found 305.1184.

Scheme 4. Synthesis of Anthrones 7, 7i-7p

S-24: R⁵ = Bn S-31 R⁵ = Bn, R⁶ = Me 7: R⁵ = Bn, R⁶ = Me

S-25: R⁵ = Me S-32 R⁵ = Me, R⁶ = Me 7i: R⁵ = Me, R⁶ = Me

S-26: R⁵ = Allyl S-33 R⁵ = Allyl, R⁶ = Me 7j: R⁵ = Allyl, R⁶ = Me

S-27: R⁵ = 1-Naph-Me S-34 R⁵ = 1-Naph-Me, R⁶ 7k: R⁵ = 1-Naph-Me, R⁶ = Me S-28: R⁵ = 4-CF₃-Bn S-35 R⁵ = 4-CF₃-Bn, R⁶ = 71: R⁵ = 4-CF₃-Bn, R⁶ = Me

S-36 R⁵ = Bn, R⁶ = Bn 7m: R⁵ = Bn, R⁶ = Bn

S-37 R⁵ = Bn, R⁶ = DiPh-Me 7n R⁵ = Bn, R⁶ = DiPh-Me

S-38 R⁵ = Allyl, R⁶ = Bn 7o R⁵ = Allyl, R⁶ = Bn

S-39 R5 = 4-CF₃-Bn, R⁵ = Bn 7p R5 = 4-CF₃-Bn, R⁶ = Bn

Anthrones 7 and 7i were prepared following the previously reported procedure (Nicolaou et aZ., 2013; Nicolaou et al, 2014). The physical and spectroscopic data of these compounds matched those previously reported (Nicolaou et al, 2013; Nicolaou et al, 2014).

l-(Allyloxy)-8-hydroxy-3,5-dimethoxyanthracen-9(10//)-one (7j): Anthrone 7j was synthesized according to the reported procedure (Nicolaou et al, 2013; Nicolaou et al, 2014). 4,4-Dimethoxycyclohexa- 2,5-dien-l-one³⁵ (463 mg, 3.00 mmol, 3.0 equiv) was dissolved in MeCN (6 mL), and DBU (450 μί, 3.00 mmol, 3.0 equiv) was added. Separately, cyclic anhydride S-26 (248 mg, l .OO mmol, l .O equiv) was slurried in MeCN (6 mL) and added to the quinone solution at 25 °C over 0.5 h using a syringe pump with constant agitation. After the addition was complete, the mixture was heated to 65 °C for 18 h. The dark mixture was then cooled to 25 °C and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5%→10%→20%→25%→30% EtOAc:hexanes, 0.1 % Et₃N) gave the BCD tricycle S-33 (143 mg, 400 μπιοι, 40% yield) as yellow solid. The obtained BCD tricycle S-33 was dissolved in CH2CI2 (4 mL) at 25 °C and freshly crystallized CSA (1.9 mg, 8.0 μιηο1, 0.02 equiv) was added. The resulting solution was stirred for 30 min and the reaction was quenched by addition of saturated aq. NaHCCb (4mL). The layers were separated, and the organic phase was dried over anhydrous Na2SC , filtered, and concentrated under reduced pressure to give essentially pure anthrone 7j (130mg, 400 μηιοΐ, quant, yield) as an orange solid. 7j: R_f=0.20 (silica gel, EtOAc:hexanes 3:7); m.p. = 145-146 °C (CH2CI2); FT-IR (film) v™*: 2925, 2840, 1636, 1600, 1476, 1435, 1387, 1351, 1329, 1269, 1230, 1196, 1173, 1115, 1091, 1071, 1058, 1026, 963, 931, 853, 818, 785, 735, 665 cnr H NMR (600MHz, CDCb) δ 12.95 (s, l H), 6.96 (d, 7= 8.9 Hz, 1 H), 6.79 (d, 7= 8.8 Hz, 1 H), 6.45 (s, I H), 6.34 (s, I H), 6.11 (ddt, 7= 17.0, 10.1, 4.7 Hz, I H), 5.67 (ddd, 7= 17.2, 1.8, 1.8 Hz, I H), 5.36 (ddd, 7= 11.0, 1.4, 1.4Hz, 1 H), 4.63 (d, 7= 3.3 Hz, 2H), 4.05 (s, 2H), 3.82 (s, 3 H), 3.81 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCb) 5 188.8, 164.1, 162.2, 156.3, 147.7, 146.3, 132.5, 127.4, 117.9, 117.5, 116.7, 114.8, 114.5, 104.7, 99.1, 69.6, 56.0, 55.5, 29.0 ppm; HRMS (ESI) calcd for Ci₉Hi80₅Na⁺ [ +Na]⁺ 349.1046, found 349.1052.

8-Hydroxy-3,5-dimethoxy-l-(l-naphthylmethoxy)anthracen-9(10//)-one (7k): Anthrone 7k was synthesized according to the procedure described above for the preparation of 7j. 4,4-Dimethoxy-cyclohexa- 2,5-dienone (Frlan et al, 2007) (463 mg, 3.00 mmol, 3.0 equiv) was reacted with S-27 (426 mg, l .OO mmol, l .O equiv) to give the BCD tricycle S-34 (206 mg, 450μπιο1, 45% yield) as yellow solid. The obtained BCD tricycle S-34 was reacted with CSA (2.1 mg, 9.0 μιηοΐ, 0.02 equiv) to give essentially pure anthrone 7k ( 192 mg, 450μιηο1, quant, yield) as an orange solid. 7k: R_f= 0.30 (silica gel, EtOAc:hexanes 3:7); m.p. = 172-173 °C (CH2CI2); FT-IR (film) v_max: 2925, 2838, 1636, 1600, 1475, 1432, 1393, 1352, 1329, 1268, 1230, 1195, 1173, 1115, 1101, 1063, 1026, 961, 932, 853, 819, 800, 773, 732 cm ; ¾ NMR (600 MHz, CDCb) δ 13.04 (s, 1 H), 8.09 (d, 7= 8.2 Hz, 1 H), 8.02 (d, 7=6.8 Hz, 1 H), 7.89 (d, 7=7.8 Hz, 1 H), 7.83 (d, 7= 8.1 Hz, 1 H), 7.60-7.47 (m, 3 H), 7.02 (d, 7= 8.9Hz, I H), 6.86 (d, 7= 8.8 Hz, I H), 6.56 (s, I H), 6.52 (s, I H), 5.68 (s, 2H), 4.15 (s, 2 H), 3.85 (s, 3 H), 3.81 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCb) δ 188.9, 164.2, 162.2, 156.5, 147.9, 146.4, 133.7, 131.9, 130.7, 128.9, 128.5, 127.5, 126.4, 125.9, 125.8, 125.5, 123.2, 117.7, 117.0, 115.3, 114.7, 105.0, 99.9, 69.3, 56.1, 55.6, 29.1 ppm; HRMS (ESI) calcd for C27H₂20₅Na⁺ [M+Na]⁺ 449.1359, found 449.1361.

8-Hydroxy-3,5-dimethoxy-l-{[4-(trifluoromethyl)benz l]oxy}anthracen-9(10//)-one (71):

Anthrone 71 was synthesized according to the procedure described above for the preparation of 7j. 4,4- Dimethoxy-cyclohexa-2,5-dienone (Frlan et al, 2007) (463 mg, 3.00 mmol, 3.0 equiv) was reacted with S-28 (366 mg, 1.00 mmol, l .Oequiv) to give the BCD tricycle S-35 (200 mg, 420 μιηο1, 42% yield) as yellow solid. The obtained BCD tricycle S-35 was reacted with CSA (2.0 mg, 8.4 μιηο1, 0.02 equiv) to give essentially pure anthrone 71 (187 mg, 420 μιηο1, quant, yield) as an orange solid. 71: R_f=0.40 (silica gel, EtOAc:hexanes 3:7); m.p. = 165-166 °C (CH₂C1₂); FT-IR (film) v_max: 2926, 2842, 1637, 1602, 1585, 1476, 1437, 1421, 1382, 1325, 1269, 1230, 1196, 1164, 1120, 1099, 1066, 1027, 1019, 991, 961, 932, 855, 825, 782, 734,722, 666 cnT¹; ¾ NMR (600MHz, CDCb) δ 12.97 (s, I H), 7.76 (d, 7= 8.0Hz, 2H), 7.67 (d, 7= 8.0Hz, 2H), 7.02 (d, 7= 8.9 Hz, 1 H), 6.85 (d, 7= 8.9Hz, I H), 6.51 (s, I H), 6.39 (d, /= 1.7Hz, I H), 5.21 (s, 2 H), 4.13 (s, 2H), 3.84 (s, 3 H), 3.82 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCb) δ 188.8, 164.2, 161.7, 156.5, 147.8, 146.5 140.8, 130.0 (q, 7=32.4 Hz), 126.8, 125.7 (q, 7= 3.3 Hz), 124.3 (q, 7=272.0Hz), 117.6, 117.0, 115.1, 114.7, 113.9, 105.1, 99.5, 69.8, 56.1, 55.6, 29.1 ppm; ¹⁹F NMR (282MHz, CDC1₃) δ -61.54 (s) ppm; HRMS (ESI) calcd for C24Hi9F₃0₅Na⁺ [M+Na]⁺ 467.1077, found 467.1077.

OBn

OBn O OH

7m l,5-Bis(benzyloxy)-8-hydroxy-3-methoxyanthracen-9(10/7)-one (7m): Anthrone 7m was synthesized according to the procedure described above for the preparation of 7j. 4-(Benzyloxy)-4- methoxycyclohexa-2,5-dienone (Frlan et al, 2007) (691 mg, 3.00 mmol, 3.0 equiv) was reacted with S-24³⁰ (298 mg, l .OOmmol, l.O equiv) to give the BCD tricycle S-36 (233 mg, 480 μπιο1, 48% yield) as yellow solid. The obtained BCD tricycle S-36 was reacted with CSA (2.3 mg, 9.6 μηιο1, 0.02 equiv) to give essentially pure anthrone 7m (106 mg, 235 μηιο1, 49%) and 7 (89.2mg, 235 μηιο1, 49%) as orange solids. 7m: R_f=0.45 (silica gel, EtOAc:hexanes 3:7); m.p. = 89-90 °C (CH2CI2); FT-IR (film) v_mm: 2925, 2854, 1633, 1597, 1582, 1498, 1462, 1435, 1384, 1350, 1325, 1266, 1226, 1196, 1165, 1096, 1055, 1025, 991, 963, 905, 868, 814, 735, 696, 656 cm ; ¾ NMR (600 MHz, CDCb) δ 13.08 (s, I H), 7.61 (d, 7=7.5 Hz, 2H), 7.53-7.30 (m, 8 H), 7.10 (d, 7=8.9 Hz, I H), 6.85 (d, 7= 8.9Hz, I H), 6.53 (s, I H), 6.47 (s, I H), 5.26 (s, 2 H), 5.09 (s, 2H), 4.22 (s, 2H), 3.83 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCb) 5 189.0, 164.4, 162.4, 156.9, 147.1, 146.4, 137.4, 136.8, 128.9, 128.3, 128.1 , 128.0, 127.7, 126.9, 118.8, 117.9, 115.4, 114.9, 105.1, 100.0, 71.2, 70.9, 55.8, 29.3 ppm; HRMS (ESI) calcd for C29H₂₄0₅Na⁺ [M+Na]⁺ 475.1516, found 467.1517.

l-(Benzyloxy)-5-(diphenylmethoxy)-8-hydroxy-3-methoxyanthracen-9(10/ )-one (7n): Anthrone 7n was synthesized according to the procedure described above for the preparation of 7j. 4-(Diphenylmethoxy)- 4-methoxycyclohexa-2,5-dien-l-one (S-30, 919 mg, 3.00mmol, 3.0 equiv) was reacted with S-24³⁰ (298 mg, 1.00 mmol, l .O equiv) to give the BCD tricycle S-37 (233 mg, 400 μπιο1, 40%) as yellow solid. The obtained BCD tricycle S-37 was reacted with CSA (1.9 mg, 8.0 μπιοι, 0.02 equiv) to give crude anthrone 7n (lOOmg, 192μηιο1, 48% yield) and 7 (71.5 mg, 192 μιηηιο1, 48% yield) as orange solids. 7n: R_f= 0.40 (silica gel, EtOAc:hexanes 3:7); m.p. =72-74 °C (CH₂C1₂); FT-IR (film) v_max: 2925, 2852, 1664, 1629, 1597, 1509, 1495, 1465, 1454, 1438, 1384, 1361, 1324, 1283, 1259, 1228, 1165, 1082, 1065, 1016, 966, 882, 863, 830, 818, 802, 760, 736, 697 cm-¹ ; ¾ NMR (600 MHz, CDC1₃) δ 13.08 (s, 1 H), 7.55 (d, 7= 7.6 Hz, 2H), 7.40 (m, 3 H), 7.36- 7.31 (m, 6 H), 7.26 (m, 2H), 6.92 (d, 7=9.0 Hz, 1 H), 6.73 (d, 7= 1.9 Hz, 2H), 6.68 (d, 7=9.0Hz, 1 H), 6.48 (s, 1 H), 6.43 (s, 1 H), 6.15 (s, 1 H), 5.21 (s, 2H), 4.22 (s, 2 H), 3.78 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDC ) δ 188.8, 164.3, 162.2, 156.9, 146.2, 143.9, 141.5, 136.7, 128.8, 128.7, 128.6, 128.1, 128.0, 127.0, 126.8, 120.5, 117.7, 116.2, 114.9, 105.0, 99.8, 82.6, 70.8, 55.7, 29.4 ppm; HRMS (ESI) calcd for C₃5H₂80₅Na⁺ [ +Na]⁺ 551.1829, found 551.1830.

l-(Allyloxy)-5-(benzyloxy)-8-hydroxy-3-methoxyanthracen-9(10//)-one (7o): Anthrone 7o was synthesized according to the procedure described above for the preparation of 7j. 4-(Benzyloxy)-4- methoxycyclohexa-2,5-dienone (Frlan et al, 2007) (691 mg, 3.00 mmol, 3.0 equiv) was reacted with S-26 (248 mg, l .OOmmol, l .O equiv) to give the BCD tricycle S-38 (200mg, 460 μπιο1 , 46% yield) as yellow solid. The obtained BCD tricycle S-38 was reacted with CSA (2.2 mg, 9.2 μιηο1, 0.02 equiv) to give essentially pure anthrone 7o (90mg, 225 μηιοΐ , 49% yield) and 7j (73 mg, 225 μιηοΐ , 49% yield) as orange solids. 7o: R_f=0.40 (silica gel, EtOAc:hexanes 3:7); m.p. = 118-119 °C (CH₂CI₂); FT-IR (film) v_max: 2924, 2854, 1634, 1597, 1582, 1474, 1462, 1454, 1384, 1369, 1351, 1326, 1266, 1227, 1195, 1167, 1114, 1089, 1053, 1025, 992, 969, 930, 868, 815, 754, 737, 697, 666 cm^"1; ¾ NMR (600 MHz, CDCI3) δ 13.02 (s, 1 H), 7.49-7.37 (m, 5 H), 7.09 (d, 7=8.9 Hz, 1 H), 6.83 (d, 7= 8.9 Hz, 1 H), 6.53 (s, 1 H), 6.43 (s, 1 H), 6.13 (ddt, 7= 17.1, 10.4, 4.8 Hz, 1 H), 5.67 (ddd, 7= 17.2, 1.6, 1.6 Hz, 1 H), 5.37 (ddd, 7= 10.7, 1.5, 1.5 Hz, 1 H), 5.08 (s, 2 H), 4.70-4.68 (m, 2H), 4.20 (s, 2H), 3.86 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 188.8, 164.2, 162.3, 156.7, 146.9, 146.2, 137.2, 132.4, 128.7,128.6, 128.1, 127.5, 118.6, 118.0,116.1, 114.7, 104.7, 99.4, 71.0, 69.7, 55.6, 29.7, 29.1 ppm; HRMS (ESI) calcd for C25H₂₂0₅Na⁺ [ +Na]⁺ 425.1359, found 425.1363.

5-(Benzyloxy)-8-hydroxy-3-methoxy-l-{[4-(trifluoromethyl)benzyl]oxy}anthracen-9(10//)-one (7p): Anthrone 7p was synthesized according to the procedure described above for the preparation of 7j. 4- (Benzyloxy)-4-methoxycyclohexa-2,5-dienone (Frlan et al, 2007) (691 mg, 3.00 mmol, 3.0 equiv) was reacted with S-28 (366 mg, 1.00 mmol, l.O equiv) to give the BCD tricycle S-39 (232 mg, 420 μπιο1, 42% yield) as yellow solid. The obtained BCD tricycle S-39 was reacted with CSA (2.0 mg, 8.4 ιηο1, 0.02 equiv) to give essentially pure anthrone 7p (108 mg, 206 μιηο1, 49% yield) and 71 (92.0mg, 206 μιηο1, 49% yield) as orange solids. 7p: R_f = 0.50 (silica gel, EtOAc:hexanes 3:7); m.p. = 95-96 °C (CH₂C1₂); FT-IR (film) v_max: 2952, 2923, 2854, 1634, 1599, 1586, 1454, 1421, 1380, 1369, 1352, 1323, 1266, 1228, 1196, 1163, 1119, 1098, 1065, 1018, 992, 964, 941, 825, 737, 697, 664 cm-' ; Ή NMR (600 MHz, CDC1₃) δ 13.03 (s, 1 H), 7.72-7.62 (m, 4H), 7.50- 7.35 (m, 5 H), 7.10 (d, /= 8.8 Hz, 1 H), 6.85 (d, /= 8.6Hz, 1 H), 6.55 (s, 1 H), 6.43 (s, 1 H), 5.26 (s, 2H), 5.09 (s, 2H), 4.22 (s, 2H), 3.85 (s, 3 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 188.7, 164.2, 161.7, 156.7, 146.9, 146.4, 140.7, 137.1, 129.9 (q, 7=32.2Hz), 128.7, 128.1, 127.8, 127.5, 126.8, 125.6 (q, /= 3.6Hz), 124.2 (q, J=271.8 Hz), 118.7, 117.6, 116.0, 114.8, 104.9, 99.7, 70.9, 69.8, 55.6, 29.1 ppm; ¹⁹F NMR (282MHz, CDCI3) δ -61.54 (s) ppm; HRMS (ESI) calcd for C3oH₂3F₃05Na⁺ [M+Na]⁺ 543.1390, found 543.1386.

Scheme 5. and PTC15

7, 7i-7p (R)-[8, 8a-8h] 6, 6a-6p

General procedure for the asymmetric alkylation: To a stirred mixture of anthrone [(7, 7i-7p),

ΙΟΟμπιοΙ, 1.0 equiv], allylic bromide { (R)-[S, 8a-8h]; Ι ΙΟ μπιοΙ, 1.1 equiv} and PTC15 (Ι .ΟΟ μιηοΙ, 1 mol%, 0.01 equiv) in (CH₂)₂C1₂ (0.9 mL) under argon, was added 40% aq. Cs₂C0₃ solution (0.3 mL) dropwise at -30 ^CC. The reaction mixture was stirred vigorously and then allowed to warm to -20 °C. Stirring was continued at this temperature for 72 h. The mixture was then quenched by addition of H₂0 (10 mL) and extracted with CH₂C1₂ (lOmL). The organic phase was washed with brine and dried over anhydrous Na₂S04 and concentrated under reduced pressure. Purification of the residue by flash column chromatography on silica gel (2%→5%→10% EtOAc:hexanes) gave the alkylated anthrones (6, 6a-6p) as yellow products. General procedure for the preparation of racemic alkylated anthrones: To a solution of anthrone [(7, 7i-7p), ΙΟΟμηιοΙ, 1.0 equiv], allylic bromide { (R)-[S, 8a-8h]; 110 mol, 1.1 equiv} in DMF (1 mL) under argon, was added Na2C0₃ (10.6 mg, l .OOmmol, lO equiv), The reaction mixture was shielded from light and stirred vigorously for 1 h in the dark. The reaction was quenched by addition of water (10 mL) and diluted with EtOAc (lOmL). The aqueous phase was extracted with EtOAc (2x lOmL), and the combined organic phases were washed with brine (20 mL), dried over anhydrous Na^SC , filtered, and concentrated under reduced pressure to give a crude oil, which was purified by flash column chromatography on silica gel (2%→5%→10% EtO Ac:hexanes) to give the racemic alkylated anthrones (6, 6a-6p) as yellow products.

(105)-l-(Benzyloxy)-10-[(3-{[ter/-butyl(dimethyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en-l- yl)methyl]-8-hydroxy-3,5-dimethoxyanthracen-9(10/7)-one [enantioenriched (10S,14/f)-6]: yellow foam, 46.3 mg, 72.0 μιηο1, 72% yield, 95:5 dr. the diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 7.01 min for (10/?,14/f)-6; 8.05 min for (105,14/i)-

6. Enantioenriched (105,14 ?)-6: [<X]_p ⁼+94.7 (c= 1.0, CH2Q2); all other physical and spectroscopic data of this compound matched those mentioned above.

(105)-l-(Benzyloxy)-10-{[(3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en-l- yl]methyl}-8-hydroxy-3,5-dimethoxyanthracen-9(10/7)-one [enantioenriched 6a] : yellow solid, 59.8 mg, 78.0 μιηο1, 78% yield, 91 :9 dr. the diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 5.99 min for (10R,14 ?)-6a; 7.30 min for (10S,14tf)-6a.

Crystalization from hexanes/fPrOH 19: 1 gave crystals (> 99: 1 dr) suitable for X-ray crystallographic analysis, which revealed its absolute configuration for the chiral alkylated anthrones as shown below (FIG. 2).

Enantioenriched 6a: R_f=0.40 (silica gel, EtOAc:hexanes 1 :4); [αβ² =+69.5 (c= 1.0, CH₂C1₂, > 99: 1 dr); m.p. = 165-166 °C (hexanes/iPrOH 19: 1)); FT-IR (film) v_max: 2934, 2857, 1637, 1599, 1585, 1568, 1474, 1429, 1385, 1352, 1329, 1297, 1267, 1228, 1196, 1166, 1148, 1104, 1077, 1035, 999, 978, 968, 935, 881, 856, 822, 792, 766, 739, 702, 659 cm^"1 ; This compound exhibited broad NMR signals (both in H NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; >H NMR (600 MHz, CDC1₃) δ 12.69 (s, 1 H, major), 12.67 (s, 1 H, minor), 7.73 (d, 7=6.3 Hz, 2H, minor), 7.69 (d, 7=6.4 Hz, 2H, major), 7.58 (d, 7=7.5 Hz, 2H, major + minor), 7.49-7.34 (m, 8 H, major + minor), 7.30 (ap t, 7=7.3 Hz, 1 H, major + minor), 7.06 (d, 7=9.0Hz, 1 H, major + minor), 6.87 (d, 7= 8.9Hz, 1 H, major + minor), 6.47 (b, 1 H, minor), 6.45 (b, 1 H, major), 5.27 (ABq, Δ5_ΑΒ =0.065, 7= 12.5 Hz, 2 H, major + minor), 4.65 (b, 1 H, major + minor), 4.59 (b, 1 H, minor), 4.02-3.58 (m, 4 H, major + minor), 3.88 (s, 3 H, major + minor), 2.65 (d, 7= 12.4 Hz, 1 H, major + minor), 2.10-0.02 (m, 15 H, major + minor), 1.08 (s, 9 H, major), 1.05 (s, 9H, minor) ppm; ¹³C NMR (151 MHz, CDCI3)* δ 188.59 (major), 188.55 (minor), 163.74 (major), 163.64 (minor), 162.0 (major + minor), 156.30 (major), 156.25 (minor), 150.09 (b, major + minor), 147.72 (major + minor), 136.70 (major + minor), 136.24 (major + minor), 136.18 (major + minor), 135.3 (minor), 135.0 (major), 134.9 (major + minor), 134.1 (major + minor), 133.4 (major + minor), 129.77 (minor), 129.72 (major), 129.65 (minor), 129.57 (major), 128.72 (major + minor), 127.8 (major + minor), 127.7 (major), 127.6 (minor), 127.5 (major + minor), 1 17.80 (major + minor), 117.74 (major + minor), 1 15.13 (major + minor), 1 15.10 (major + minor), 107.1 (b, major + minor), 99.8 (major + minor), 73.6 (b, major + minor), 70.8 (major + minor), 56.08 (minor), 56.03 (major), 55.65 (major), 55.48 (minor), 41.14 (b, major + minor), 39.1 (b, major + minor), 35.94 (major + minor), 29.27 (major + minor), 28.65 (major + minor), 27.42 (major + minor), 26.70 (major + minor), 19.62 (major + minor) ppm; HRMS (ESI) calcd for C49H₅40₆SiNa⁺ [M+Na]⁺ 789.3582 found 789.3575. *Due to signal broadening, not aU the ¹³C signals could be identified.

(105)-l-(Benzyloxy)-10-{[(3R)-3-{[(2,3-dimethylbutan-2-yl)(dimethyl)silyl]oxy}-2,6,6- trimethylcyclohex-l-en-l-yl]methyl}-8-hydroxy-3,5-dimethoxyanthracen-9(10//)-one [enantioenriched 6b]: yellow foam, 49.7 mg, 74.0 μηιο1, 74% yield, 95:5 dr. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 5.52 min for (10/f,14fl)-6b, 6.19 min for (10S,14R)-6b. Enantioenriched 6b: R_f=0.55 (silica gel, EtOAc:hexanes 1 :4); [ f^ = +81.6 (c= 1.0, CH₂C1₂); FT-IR

(film) v_mas: 2956, 2865, 1639, 1600, 1585, 1569, 1475, 1433, 1384, 1353, 1329, 1297, 1267, 1229, 1196, 1 171, 1 148, 1102, 1077, 1033, 1003, 980, 968, 935, 882, 856, 829, 775 737, 696 cm^"1; This compound exhibited broad NMR signals (both in Ή NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600MHz, CDCI₃) δ 12.68 (s, 1 H, major), 12.67 (s, 1 H, minor), 7.57 (d, 7=7.4Hz, 2H, major + minor), 7.39 (ap t, 7=7.6Hz, 2H, major + minor), 7.30 (ap t, 7= 7.4Hz, 1 H, major + minor), 7.05 (d, 7= 9. OHz, 1 H, major + minor), 6.86 (d, 7= 8.9 Hz, 1 H, major + minor), 6.44 (d, 7=2.2Hz, 2 H, major), 6.43 (d, 7= 2.2Hz, 2H, minor), 6.38 (b, 1 H, major), 6.29 (b, 1 H, minor), 5.26 (ABq, Δ5_ΑΒ = 0.072, 7= 12.6 Hz, 2H, major + minor), 4.62 (b, 1 H, major + minor), 3.95 (b, 1 H, major + minor), 3.89 (s, 3 H, major + minor), 3.82 (s, 3 H, major + minor), 2.68 (d, /= l 1.3 Hz, 1 H, major + minor), 1.99-0.82 (m, 14 H, major + minor), 0.94-0.83 (m, 13 H, major + minor), 0.14 (s, 3 H, major), 0.12 (s, 3 H, major), 0.09 (s, 3 H, minor) 0.07 (s, 3 H, minor) ppm; ¹³C NMR (151 MHz, CDCI₃)* 188.63 (major), 188.58 (minor), 163.75 (major), 163.67 (minor), 162.1 (major + minor), 156.30 (major + minor), 150.2 (b, major + minor), 147.74 (major + minor), 136.71 (major + minor), 133.52 (major + minor), 128.73 (major + minor), 127.83 (major + minor), 126.8 (major + minor), 117.82 (major + minor), 117.75 (major + minor), 115.11 (major + minor), 115.08 (major + minor), 107.17 (major + minor), 99.84 (major + minor), 72.5 (b, major + minor), 70.8 (major + minor), 56.14 (minor), 56.07 (major), 55.70 (major), 55.59 (minor), 41.30 (b, major + minor), 38.85 (b, major + minor), 36.33 (b, major + minor), 35.96 (major + minor), 34.02 (major + minor), 29.76 (major + minor), 29.17 (b, major + minor), 25.51 (major + minor), 25.11 (major + minor), 20.38 (major + minor), 20.32 (major + minor), 18.77 (major + minor), 18.73 (major + minor), -1.73 (major), -1.87 (minor), -2.52 (major + minor) ppm; HRMS (ESI) calcd for C4iH540eSiNa⁺ [ +Na]⁺ 693.3582, found 693.3583. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-10-{[(3R)-3-{[Benzyl(dimethyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en-l-yl]methyl}-l-

(benzyloxy)-8-hydroxy-3,5-dimethoxyanthracen-9(10//)-one [enantioenriched 6c]: yellow foam, 46.0 mg, 68.0 μιηο1, 68% yield, 88: 12 dr. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 4.31 min for (10 ?,14/?)-6c, 5.26 min for (10S,14ff)-6c.

Enantioenriched 6c: R_f=0.48 (silica gel, EtOAc:hexanes 1 :4); [θ¾ =+78.6 (c= 1.0, CH2CI2); FT-IR (film) v_max: 2936, 2863, 1637, 1600, 1584, 1568, 1492, 1475, 1453, 1432, 1384, 1353, 1330, 1297, 1268, 1230, 1207, 1167, 1102, 1058, 1033, 1002, 980, 968, 935, 882, 835, 763, 738, 698 cm^"1; This compound exhibited broad NMR signals (both in Ή NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600 MHz, CDCI₃) δ 12.73 (s, 1 H, minor), 12.68 (s, 1 H, major), 7.57 (d, 7=7.5 Hz, 2 H, major + minor), 7.39 (dd, 7= 15.3, 7.7Hz, 2H, major + minor), 7.30 (ap t, 7=7.5 Hz, 1 H, major + minor), 7.24-7.20 (m, 2H, major + minor), 7.09-7.03 (m, 3 H, major + minor), 6.86 (d, 7= 8.9 Hz, 1 H, major + minor), 6.47 (s, 1 H, minor), 6.45 (s, 1 H, major), 6.38 (b, 1 H, major), 6.27 (b, 1 H, minor), 5.25 (ABq, Δ5ΑΒ = 0.073, 7= 12.5 Hz, 2H, major + minor), 4.64 (b, 1 H, major), 4.55 (b, 1 H, minor), 3.96 (b, 1 H, major + minor), 3.91 (s, 3 H, minor), 3.89 (s, 3 H, major), 3.82 (s, 3 H, minor), 3.80 (s, 3 H, major), 2.69 (b, 1 H, major + minor), 2.16-0.56 (m, 17 H, major + minor), 0.14 (s, 3 H, minor), 0.09 (s, 3 H, major), 0.05 (s, 3 H, major), 0.02 (s, 3 H, minor) ppm; ¹ C NMR (151 MHz, CDCI3)* 188.59 (major), 188.56 (minor), 163.78 (major), 163.73 (minor), 161.94 (major + minor), 156.35 (minor), 156.30 (major), 147.76 (major), 147.67 (minor), 139.43 (minor), 139.25 (major), 136.72 (minor), 136.70 (major), 133.35 (major + minor), 128.72 (major + minor), 128.56 (minor), 128.53 (major), 128.38 (major), 128.30 (minor), 127.81 (major + minor), 126.79 (major + minor), 117.78 (major + minor), 117.75 (major), 117.71 (minor), 115.19 (major + minor), 115.14 (major), 115.01 (minor), 106.51 (major + minor), 100.33 (major + minor), 72.5 (b, major + minor), 70.8 (major + minor), 64.6 (major + minor), 56.10 (minor), 56.03 (major), 55.72 (major), 55.50 (minor), 40.8 (b, major + minor), 35.91 (minor), 35.84 (major), 31.06 (major + minor), 29.55 (major), 29.36 (minor), 28.9 (minor), 28.64 (major), 27.58 (major + minor), 25.51 (major + minor), -1.54 (major + minor), -1.57 (major), -1.68 (minor) ppm; HRMS (ESI) calcd for C₄2H₄₈06SiNa⁺ [M+Na]⁺ 699.3112, found 699.3109. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l-(Benzyloxy)-10-{[(3R)-3-{[l,l,l,3,3,3-hexamethyl-2-(trimethylsilyl)trisilan-2-yl]oxy}- 2,6,6-trimethylcyclohex-l-en-l-yl]methyl}-8-hydroxy-3,5-dimethoxyanthracen-9(10//)-one

[enantioenriched 6d]: yellow foam, 42.6 mg, 55.0 πιο1, 55% yield, 95:5 dr. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/ZPrOH: 98/2, 220 nm): 4.02 min for (10R,14/?)-6d, 4.82 min for (105,14R)-6d.

Enantioenriched 6d: R_f=0.45 (silica gel, EtOAc:hexanes 1 :4); [a]_p = +82.9 (c= 1.0, CH₂C1₂); FT-IR (film) Vmax: 2946, 2895, 1638, 1600, 1585, 1570, 1475, 1453, 1433, 1385, 1328, 1298, 1267, 1243, 1228, 1170, 1102, 1062, 1033, 999, 972, 834, 739, 694 cm-¹; This compound exhibited broad NMR signals (both in H NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond, ¾ NMR (600 MHz, CDC1₃) δ 12.69 (s, 1 H, minor), 12.67 (s, 1 H, major), 7.57 (d, 7=7.4Hz, 2H, major + minor), 7.39 (ap t, 7=7.6Hz, 2H, major + minor), 7.30 (ap t, 7=7.4Hz, I H, major + minor), 7.05 (d, 7=9.0 Hz, I H, major + minor), 6.86 (d, 7=8.9 Hz, 1 H, major + minor), 6.45 (d, 7=2.0Hz, 1 H, minor), 6.44 (d, 7=2.0 Hz, 1 H, major), 6.36 (b, 1 H, major), 6.29 (b, 1 H, minor), 5.25 (ABq, Δ5ΑΒ = 0.073, 7= 12.6Hz, 1 H, major + minor), 4.62 (b, 1 H, , major + minor), 3.90 (s, 3 H, minor), 3.89 (s, 3 H, major), 3.83 (s, 3 H, minor), 3.81 (s, 3 H, major), 3.67 (b, 1 H, major + minor), 2.64 (d, 7= 11.4Hz, 1 H, major + minor), 1.95-0.75 (m, 14H, major + minor), 0.21 (s, 27H, major), 0.19 (s, 27 H, minor) ppm; ¹³C NMR (151 MHz, CDC1₃)* δ 187.60 (major), 187.57 (minor), 162.8 (major + minor), 161.1 (major + minor), 155.3 (major + minor), 149.1 (b, major + minor), 146.8 (major + minor), 135.73 (minor), 135.71 (minor), 132.3 (major + minor), 127.7 (major + minor), 126.8 (major + minor), 125.8 (major + minor), 116.8 (major + minor), 116.74 (major), 116.69 (minor), 114.2 (major + minor), 114.1 (major + minor), 105.9 (b, major + minor), 98.8 (b, major + minor), 69.9 (major + minor), 55.1 (major + minor), 54.7 (major), 54.5 (minor), 40.1 (b, major + minor), 35.0 (major + minor), 28.9 (major + minor), 28.2 (major + minor), 27.7 (major + minor), -0.1 (major + minor) ppm; HRMS (ESI) calcd for C₄₂H₆20₆Si₄Na⁺ [M+Na]⁺ 797.3516, found 797.3518. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l-(Benzyloxy)-8-hydroxy-3,5-dimethoxy-10-({(3/f)-2,6,6-trimethyl-3- [(triisopropylsilyl)oxy]cyclohex-l-en-l-yl}methyl)anthracen-9(10//)-one [enantioenriched 6e]: yellow foam, 51.4 mg, 75.0 μmol, 75% yield, 92:8 dr. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 5.74 min for (10/?,14/?)-6e, 6.45 min (10S,14/?)-

6e.

Enantioenriched 6e: R_f=0.52 (silica gel, EtOAc:hexanes 1 :4); [a]^ =+90.6 (c= 1.0, CH₂C1₂); FT-IR

(film) v_max: 2941, 2865, 1637, 1600, 1584, 1569, 1472, 1433, 1384, 1350,1329, 1297, 1267, 1229, 1170, 1102, 1054, 1054, 1042, 1033, 1003, 967, 934, 883, 824, 737, 677 era ¹: This compound exhibited broad NMR signals (both in H NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600MHz, CDCI₃) 5 12.68 (s, 1 H, major), 12.65 (s, 1 H, minor), 7.56 (d, 7=7.5 Hz, 2H, major + minor), 7.39 (ap t, 7=7.4Hz, 2H, major + minor), 7.30 (ap t, 7= 7.4Hz, 1 H, major + minor), 7.06 (d, 7= 8.9Hz, 1 H, major + minor), 6.86 (d, 7= 8.9Hz, 1 H, major + minor), 6.44 (s, 1 H, major), 6.42 (s, 1 H, minor), 6.40 (b, 1 H, major), 6.31 (b, 1 H, minor), 5.26 (ABq, Δ5ΑΒ =0.067, 7= 10.6 HZ, 2H, major + minor), 4.65 (b, 1 H, major), 4.60 (b, 1 H, minor), 4.14 (b, 1 H, major), 4.04 (b, 1 H, minor), 3.90 (s, 3 H, major + minor), 3.82 (s, 3 H, major + minor), 2.69 (b, 1 H, major + minor), 2.16-0.55 (m, 14H, major + minor), 1.10 (s, 18 H, major + minor), 1.05 (s, 3 H, major + minor) ppm; ¹³C NMR (151 MHz, CDCI3)* ¹³C NMR (151 MHz, CDCI3) δ 188.62 (major), 188.58 (minor), 163.74 (major), 163.67 (minor), 162.01 (major), 161.88 (minor), 156.31 (major), 156.28 (minor), 150.2 (b, major + minor), 147.73 (major), 147.66 (minor), 136.7 (major + minor), 133.5 (major + minor), 128.7 (major + minor), 127.8 (major + minor), 126.78 (major), 126.75 (minor), 117.8 (major + minor), 117.73 (major), 117.70 (minor), 115.1 (major + minor), 107.0 (major), 106.4 (minor), 100.0 (b, major + minor), 72.8 (b, major + minor), 70.8 (major + minor), 56.1 (major + minor), 55.7 (major), 55.6 (minor), 40.9 (b, major + minor), 39.0 (b, major + minor), 35.9 (major + minor), 29.9 (major + minor), 29.1 (minor), 29.0 (major), 18.54 (major), 18.50 (minor), 18.47 (major), 18.44 (minor), 17.84 (major + minor), 13.0 (major), 12.98 (minor), 12.4 (major + minor) ppm; HRMS (ESI) calcd for C42H₅60₆SiNa⁺ [ +Na]⁺ 707.3738, found 707.3742. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l-(Benzyloxy)-8-hydroxy-3,5-dimethoxy-10-({(3 i)-2,6,6-trimethyl-3- [(triethylsilyl)oxy]cyclohex-l-en-l-yl}methyl)anthracen-9(10 /)-one [enantioenriched 6f]: yellow foam, 49.5 mg, 77.0 μιηοΐ, 77% yield, 93:7 dr. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C , flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 4.74 min for (10/?,14/f)-6f, 5.50 min for (10S,14/?)-6f.

Enantioenriched 6f: R_f=0.56 (silica gel, EtOAc:hexanes 1:4); [af = + 87.1 (c = 1.0, CH₂C1₂); FT-IR (film) v_max: 2954, 2936, 2875, 1637, 1600, 1584, 1568, 1475, 1432, 1384, 1353,1329, 1296, 1267, 1230, 1171, 1102, 1075, 1060, 1033, 1002, 967, 934, 880, 825, 738, 696 cm^"1; This compound exhibited broad NMR signals (both in H NMR and ¹ C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600MHz, CDCI₃) δ 12.72 (s, 1 H, minor), 12.68 (s, 1 H, major), 7.56 (d, 7=7.5 Hz, 2H, major + minor), 7.39 (ap t, 7=7.5 Hz, 2H, major + minor), 7.30 (ap t, 7= 7.2Hz, 1 H, major + minor), 7.05 (d, 7= 8.9Hz, 1 H, major + minor), 6.86 (d, 7= 8.9 Hz, 1 H, major + minor), 6.47 (s, 1 H, minor), 6.44 (s, 1 H, major), 6.40 (b, 1 H, major), 6.29 (b, 1 H, minor), 5.25 (ABq, Δ5_ΑΒ = 0.068, 7= 12.6 Hz, 2H, major + minor), 4.65 (b, 1 H, major), 4.57 (b, 1 H, minor), 3.96 (b, 1 H, 4.65 (b, 1 H, major + minor), 3.89 (s, 3 H, major + minor), 3.86 (s, 3 H, major), 3.82 (s, 3 H, minor), 2.70 (b, 1 H, major + minor), 2.05-0.79 (m, 14 H, major + minor), 0.98 (t, 7= 5.9 Hz, 9 H , major + minor) 0.61 (q, 7=7.8 Hz, 6 H, major + minor) ppm; ¹ C NMR (151 MHz, CDCI₃)* δ 188.62 (major), 188.57 (minor), 163.7 (major + minor), 161.9 (major + minor), 156.3 (major + minor), 147.75 (major), 147.69 (minor), 136.7 (major + minor), 133.5 (major + minor), 128.7 (major + minor), 127.8 (major + minor), 126.8 (major + minor), 117.8 (major + minor), 117.6 (major + minor), 115.2 (major + minor), 115.1 (major + minor), 106.4 (b, major + minor), 100.5 (b, major + minor), 72.3 (b, major + minor), 70.8 (major + minor), 56.10 (minor), 56.05 (major), 55.8 (major), 55.62 (minor), 55.40.9 (b, major + minor), 35.91 (minor), 35.86 (major), 29.78 (major), 29.65 (minor), 28.9 (minor), 28.8 (major), 7.13 (major), 7.09 (minor), 5.22 (major), 5.13 (minor) ppm; HRMS (ESI) calcd for C₃₉H₅o0₆Si a⁺ [M+Na]⁺ 665.3269, found 665.3268. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l-(Benzyloxy)-8-hydroxy-3,5-dimethoxy-10-({(3/i)-2,6,6-trimethyl-3- [(tripropylsilyl)oxy]cyclohex-l-en-l-yl}methyl)anthracen-9(10/f)-one [enantioenriched 6g]: yellow foam, 50.0 mg, 73.0pmol, 73% yield, 89: 11 dr. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 4.31 min for (10R,14fi)-6g, 5.26 min for (105,14 ?)-6g.

Enantioenriched 6g: R_f=0.54 (silica gel, EtOAc:hexanes 1:4); [o]^ = + 82.2 (c= 1.0, CH₂C1₂); FT-IR (film) v_max: 2953, 2926, 2867, 1637, 1600, 1584, 1569, 1475, 1432, 1384, 1353,1329, 1297, 1229, 1205, 1171, 1102, 1033, 1003, 967, 934, 856, 798, 749, 695 cm-' ; This compound exhibited broad NMR signals (both in Ή NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600 MHz, CDC1₃) δ 12.73 (s, 1 H, minor), 12.68 (s, 1 H, major), 7.57 (d, 7=7.3 Hz, 2H, major + minor), 7.39 (ap t, 7=7.6Hz, 2H, major + minor), 7.30 (ap t, 7=7.4Hz, 1 H, major + minor), 7.05 (d, 7= 8.9 Hz, 1 H, major + minor), 6.86 (d, 7=9.0 Hz, 1 H, major + minor), 6.46-6.43 (m, 1 H, major + minor), 6.39 (b, 1 H, major), 6.29 (b, 1 H, minor), 5.30-5.20 (m, 2H, major + minor), 4.65 (b, 1 H, major), 4.56 (b, 1 H, minor), 3.96 (b, 1 H, major + minor), 3.90 (s, 3 H, major + minor), 3.85 (s, 3 H, major + minor), 2.69 (b, 1 H, major + minor), 2.12-0.68 (m, 14 H, major + minor), 1.44-1.34 (m, 6 H, major + minor), 1.03-0.94 (m, 9 H, major + minor), 0.64-0.53 (m, 6 H, major + minor) ppm; ¹³C NMR (151 MHz, CDCI3)* δ 188.62 (major), 188.56 (minor), 163.8 (major + minor), 161.9 (major), 161.8 (minor), 156.3 (major + minor), 150.3 (b, major + minor), 147.8 (major), 147.7 (minor), 136.7 (major + minor), 133.5 (major + minor), 128.7 (major + minor), 127.8 (major + minor), 126.8 (major + minor), 117.76 (major + minor), 117.74 (major + minor), 115.2 (major + minor), 115.1 (major + minor), 106.3 (b, major + minor), 100.3 (b, major + minor), 72.4 (b, major + minor), 70.8 (major + minor), 56.10 (minor), 56.05 (major), 55.7 (b, major), 55.6 (minor), 40.9 (b, major + minor), 35.91 (minor), 35.86 (major), 29.8 (major), 29.7 (minor), 28.89 (minor), 28.86 (major), 18.8 (major + minor), 17.36 (major), 17.27 (minor) 17.09 (major), 17.02 (minor) ppm; HRMS (ESI) calcd for C₄2H₅606SiNa⁺ [M+Na]⁺ 707.3738, found 707.3737. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l-(Benzyloxy)-8-hydroxy-3,5-dimethoxy-10-({(3 ?)-2,6,6-trimethyl-3- [(tributylsilyl)oxy]cyclohex-l-en-l-yl}methyl)anthracen-9(10//)-one [enantioenriched 6h]: yellow foam, 50.9 mg, 70.0 ιηοΐ, 70% yield, 89: 11 dr. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 4.00 min for (10tf,14/?)-6h, 4.69 min for (105,14 ?)-6h.

Enantioenriched 6h: R_f=0.50 (silica gel, EtOAc:hexanes 1:4); [a]^² = + 77.0 (c= 1.0, CH₂C1₂); FT-IR (film) v_max: 2955, 2923, 2870, 2857, 1637, 1600, 1569, 1475, 1383, 1352,1329, 1297, 1229, 1205, 1197, 1171, 1102, 1178, 1054, 1002, 966, 934, 887, 856, 790, 765, 695 cm^"1; This compound exhibited broad NMR signals (both in H NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600MHz, CDCI3) δ 12.73 (s, 1 H, minor), 12.68 (s, 1 H, major), 7.57 (d, 7=7.3 Hz, 2H, major + minor), 7.39 (ap t, 7=7.6 Hz, 2H, major + minor), 7.30 (ap t, 7= 7.4Hz, 1 H, major + minor), 7.05 (d, 7= 8.9Hz, 1 H, major + minor), 6.86 (d, 7=9.0Hz, 1 H, major + minor), 6.45 (d, 7=2.0Hz, 1 H, major + minor), 6.39 (b, 1 H, major), 5.29 (b, 1 H, minor), 5.25 (ABq, Δ5ΑΒ =0.070, 7= 12.8 Hz, 1 H, major + minor), 4.65 (b, 1 H, major), 4.56 (b, 1 H, minor), 3.96 (b, 1 H, major + minor), 3.90 (s, 3 H, major + minor), 3.85 (s, 3 H, major + minor), 2.69 (b, 1 H, major + minor), 2.22-0.68 (m, 14 H, major + minor), 1.39-1.26 (m, 12 H, major + minor), 0.91 (t, 7= 7.2 Hz, 9 H, major + minor), 0.65-0.55 (m, 6 H, major + minor) ppm; ¹³C NMR (151 MHz, CDCI3)* δ 188.62 (major), 188.57 (minor), 163.8 (major + minor), 161.92 (major), 161.86 (minor), 156.3 (major + minor), 150.3 (b, major + minor), 147.8 (major), 147.7 (minor), 136.7 (major + minor), 133.5 (major + minor), 128.7 (major + minor), 127.8 (major + minor), 126.8 (major + minor), 117.76 (major + minor), 117.74 (major), 117.72 (minor), 115.2 (major + minor), 115.1 (major + minor), 106.3 (b, major + minor), 100.5 (b, major + minor), 72.3 (b, major + minor), 70.8 (major + minor), 56.09 (minor), 56.06 (major), 55.76 (b, major), 55.59 (minor), 40.9 (b, major + minor), 35.93 (minor), 35.88 (major), 29.8 (major), 29.7 (minor), 28.91 (minor), 28.87 (major), 26.9 (major), 26.7 (minor), 25.7 (major), 25.6 (minor), 14.9 (minor), 14.2 (major), 14.1 (minor), 13.9 (major) ppm; HRMS (ESI) calcd for C45H₆20₆Si a⁺ [M+Na]⁺ 749.4208, found 749.4216. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l-(Benzyloxy)-10-{[(3R)-3-{[(2,3-dimethylbutan-2-yl)(dimethyl)silyl]oxy}-2,6,6- trimethylcyclohex-l-en-l-yl]methyl}-8-hydroxy-3,5-dimethoxyanthracen-9(10//)-one [enantioenriched 6b]: yellow foam, 49.7 mg, 74.0 mmol, 74% yield, 95:5 dr. The diastereomenc ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 inL/min, hexanes/iPrOH: 98/2, 220 nm): 5.59 min for (10«,14/?)-6b, 6.49 min for (105,14 ?)-6b. Enantioenriched 6b: R_f=0.55 (silica gel, EtOAc:hexanes 1 :4); [αβ² =+82.0 (c= 1.0, CH2CI2); all other physical and spectroscopic data of this compound matched those mentioned above.

(105)-10-{[(3/?)-3-{[(2,3-Dimethylbutan-2-yl)(dimethyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en- l-yl]methyl}-8-hydroxy-l,3,5-trimethoxyanthracen-9(10/7)-one [enantioenriched 6i] : yellow foam, 42.8 mg, 72.0 mmol, 72% yield, 90.4:9.6 dr. The diastereomeric ratio was determined by HPLC after benzylation of the alkylated anthrone 6i (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 90/10, 220 nm): 5.51 min for benzylated (10ff,14/?)-6i, 7.04 min for benzylated (10S,14R)-6i.

Enantioenriched 6i: R_f= 0.30 (silica gel, EtOAc:hexanes 1 :4); [a]²² =+52.3 (c= 1.0, CH2CI2); FT-IR (film) v_max: 2957, 2930, 2869, 1726, 1638, 1600, 1571, 1468, 1378, 1355, 1330, 1286, 1268, 1229, 1200, 1163, 1147, 1121, 1104, 1075, 1034, 1003, 965, 935, 883, 831, 767, 741 cm^"1; This compound exhibited broad NMR signals (both in H NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; H NMR (600MHz, CDCI₃) δ 12.53 (s, 1 H, major), 12.51 (s, 1 H, minor), 7.04 (d, 7=9.0Hz, 1 H, major + minor), 6.84 (d, 7= 8.9Hz, I H, major + minor), 6.42 (d, 7=2.1 Hz, 1 H, major), 6.40 (d, 7=2.3 Hz, I H, minor), 6.38 (b, I H, major), 6.30 (b, I H, minor), 4.62 (b, I H, major + minor), 3.99-3.93 (m, I H, major + minor), 3.95 (s, 3 H, major), 3.94 (s, 3 H, minor), 3.892 (s, 3 H, minor), 3.886 (s, 3 H, major), 3.874 (s, 3 H, major), 3.868 (s, 3 H, minor), 2.68 (d, 7= 13.1 Hz, I H, major + minor), 2.02-0.80 (m, 14 H, major + minor), 0.94-0.83 (m, 13 H, major + minor), 0.14 (s, 3 H, major), 0.13 (s, 3 H, major), 0.10 (s, 3 H, minor), 0.08 (s, 3 H, minor) ppm; ¹³C NMR (151 MHz, CDCI₃) δ 188.78 (major), 188.74 (minor), 164.01 (major), 163.92 (minor), 163.31 (major), 163.19 (minor), 156.26 (major), 156.24 (minor), 150.4 (b, major + minor), 147.72 (major), 147.64 (minor), 133.7 (minor), 133.5 (major), 117.9 (major), 117.8 (minor), 117.69 (minor), 117.67 (major), 115.1 (major + minor), 114.5 (major + minor), 106.6 (major), 106.1 (minor), 98.2 (minor), 98.0 (major), 72.6 (b, major + minor), 56.3 (major + minor), 56.13 (minor), 56.05 (major), 55.8 (major), 55.6 (minor), 41.3 (b, major), 40.8 (b, minor), 39.1 (b, major + minor) 36.3 (major + minor), 36.0 (major + minor), 34.0 (major), 33.9 (minor), 29.8 (major), 29.7 (minor), 29.2 (major), 29.1 (minor), 25.11 (major), 25.07 (minor), 20.4 (major + minor), 20.3 (major + minor), 18.8 (major + minor), 18.7 (major + minor), -1.7 (major), -1.8 (minor), -2.5 (major + minor) ppm; HRMS (ESI) calcd for C₃5H₅o0₆SiNa⁺ [M+Na]⁺ 617.3269, found 617.3265. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l-(AUyloxy)-10-{[(3R)-3-{[(2,3-dimethylbutan-2-yl)(dimethyl)silyl]oxy}-2,6,6- trimethylcyclohex-l-en-l-yl]methyl}-8-hydroxy-3,5-dimethoxyanthracen-9(10 /)-one [enantioenriched 6j]: yellow foam, 46.6mg, 75.0 pmol, 75% yield, 93:7 dr. The diastereomeric ratio was determined by HPLC after benzylation of the alkylated anthrone 6j (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/i^'PrOH: 98/2, 220 nm): 6.03 min for benzylated (10 ?,14fl)-6j, 7.89 min for benzylated (105,14/f)-6j. Enantioenriched 6j: Rf= 0.36 (silica gel, EtOAc:hexanes 1 :4); [a]^ =+89.8 (c= 1.0, CH2CI2); FT-IR (film) v_max: 2955, 2935,

2865, 1638, 1600, 1568, 1475, 1435, 1353, 1328, 1297, 1267, 1228, 1197, 1173, 1149, 1117, 1099, 1077, 1052, 1042, 1033, 1002, 966, 934, 883, 830, 766, 670 cm-¹ ; This compound exhibited broad NMR signals (both in ¾ NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600 MHz, CDCI₃) δ 12.61 (s, I H, major), 12.59 (s, I H, minor), 7.04 (d, 7=9.0Hz, I H, major + minor), 6.84 (d, 7= 8.9Hz, I H, major + minor), 6.41 (d, 7=2.0Hz, I H, major), 6.39 (d, 7=2.2Hz, I H, minor), 6.38 (b, I H, major), 6.29 (b, 1 H, minor), 6.16-6.05 (m, 1 H, major + minor), 5.63 (ap dq, 7= 17.3, 1.7 Hz, 1 H, major + minor), 5.35 (ap dq, 7= 10.7, 1.6 Hz, 1 H, major + minor), 4.75-4.68 (m, 1 H, major + minor), 4.67-4.49 (m, 2H, major + minor), 3.96 (b, 1 H, major + minor), 3.893 (s, 3 H, minor), 3.887 (s, 3 H, major), 3.857 (s, 3 H, major + minor), 2.68 (d, 7= 13.1 Hz, I H, major + minor), 2.02-0.80 (m, 14H, major + minor), 0.94-0.83 (m, 13 H, major + minor), 0.14 (s, 3 H, major), 0.13 (s, 3 H, major), 0.10 (s, 3 H, minor), 0.08 (s, 3 H, minor) ppm; ¹³C NMR (151 MHz, CDCI3)* δ 188.63 (major), 188.58 (minor), 163.77 (major), 163.68 (minor), 162.13 (major), 162.00 (minor), 156.27 (major), 156.24 (minor), 150.2 (b, major + minor), 147.71 (major), 147.63 (minor), 133.5 (major + minor), 132.53 (major + minor), 117.91 (major + minor), 117.8 (major + minor), 117.74 (major), 117.68 (minor), 115.1 (major + minor), 114.9 (major + minor), 106.9 (major), 106.4 (minor), 99.4 (b, major + minor), 72.6 (b, major + minor), 69.8 (major + minor), 56.12 (minor), 56.05 (major), 55.72 (major), 55.59 (minor), 41.3 (b, major + minor), 38.9 (b, major + minor) 36.3 (b, major + minor), 36.0 (major + minor), 34.0 (major), 33.9 (minor), 29.8 (major), 29.7 (minor), 29.13 (major), 29.07 (minor), 25.11 (major), 25.07 (minor), 20.4 (major + minor), 20.3 (major + minor), 18.77 (major + minor), 18.73 (major + minor), -1.72 (major), -1.82 (minor), -2.52 (major + minor) ppm; HRMS (ESI) calcd for C37H₅20₆SiNa⁺ [M+Na]⁺ 643.3425, found 643.3424. *Due to signal broadening, not all the ¹³C signals could be identified.

(10S)-10-{[(3R)-3-{[(2,3-Dimethylbutan-2-yl)(dimethyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en- l-yl]methyl}-8-hydroxy-3,5-dimethoxy-l-(l-naphthylmethoxy)anthracen-9(10//)-one [enantioenriched 6k]: yellow foam, 50.5 mg, 70.0 ιηο1, 70% yield, 92:8 dr. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 4.29 min for (10R,14/?)-6k, 5.18 min for (10S,14fl)-6k.

Enantioenriched 6k: R_f=0.43 (silica gel, EtOAc:hexanes 1 :4); [α β² = +66.6 (c= 1.0, CH₂C1₂); FT-IR

(film) v_max: 2955, 2928, 2863, 1637, 1600, 1568, 1474, 1433, 1355, 1328, 1298, 1267, 1229, 1197, 1174, 1149, 1105, 1078, 1052, 1043, 1033, 1002, 967, 934, 883, 853, 830, 794, 771, 739 cm^"1; This compound exhibited broad NMR signals (both in Ή NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600 MHz, CDC1₃) δ 12.66 (s, 1 H, major), 12.64 (s, 1 H, minor), 8.12-8.06 (m, 1 H, major + minor), 7.95 (d, 7=6.9 Hz, 1 H, major + minor), 7.89 (d, 7=7.5 Hz, 1 H, major + minor), 7.82 (d, 7= 8.2Hz, 1 H, major + minor), 7.57-7.48 (m, 3 H, major + minor), 7.06 (d, 7=9. OHz, 1 H, major + minor), 6.86 (d, 7=9. OHz, 1 H, major + minor), 6.55 (d, 7= 2.3Hz, 1 H, major), 6.53 (d, 7=2.3 Hz, 1 H, minor), 6.40 (b, 1 H, major), 6.31 (b, 1 H, minor), 5.77 (d, 7= 12.9 Hz, 1 H, major + minor), 5.66 (d, 7= 12.9 Hz, 1 H, major + minor), 4.63 (b, 1 H, major + minor), 3.95 (s, 1 H, major + minor), 3.90 (s, 3 H , major + minor), 3.81 (s, 3 H, major + minor), 2.70 (d, 7= 11.0 Hz, 1 H, major + minor), 2.02-0.80 (m, 14H, major + minor), 0.94-0.83 (m, 13 H, major + minor), 0.14 (s, 3 H, major), 0.12 (s, 3 H, major), 0.09 (s, 3 H, minor), 0.07 (s, 3 H, minor) ppm; ¹³C NMR (151 MHz, CDCI3) )* δ 188.61 (major), 188.56 (minor), 163.75 (major), 163.66 (minor), 162.02 (major), 161.91 (minor), 156.30 (major), 156.27 (minor), 150.24 (b, major + minor), 147.74 (major), 147.67 (minor), 133.7 (major + minor), 132.5 (major + minor), 131.9 (major + minor), 130.8 (major + minor), 129.6 (major + minor), 128.9 (major + minor), 128.5 (major + minor), 126.4 (major + minor), 125.9 (major + minor), 125.8 (major + minor), 125.5 (major + minor), 123.2 (major + minor), 117.8 (major + minor), 117.77 (major), 117.74 (minor), 115.2 (major + minor), 115.1 (major + minor), 107.2 (major), 106.7 (minor), 100.1 (b, major + minor), 72.6 (b, major + minor), 69.4 (major + minor), 56.15 (minor), 56.08 (major), 55.73 (major), 55.60 (minor), 41.3 (b, major + minor), 39.0 (b, major + minor) 36.4 (b, major + minor), 36.0 (major + minor), 34.0 (major), 33.9 (minor), 29.85 (major), 29.80 (minor), 29.77 (major), 29.68 (minor), 29.13 (b, major + minor), 25.11 (major), 25.07 (minor), 20.4 (major + minor), 20.33 (major), 20.29 (minor), 18.77 (major + minor), 18.73 (major + minor), -1.72 (major), -1.82 (minor), -2.52 (major + minor) ppm; HRMS (ESI) calcd for C45H₅60₆SiNa⁺ [ +Na]⁺ 743.3738, found 743.3739. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-10-{[(3R)-3-{[(2,3-Dimethylbutan-2-yl)(dimethyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en- l-yl]methyl}-8-hydroxy-3,5-dimethoxy-l-{[4-(trifluoromethyl)benzyl]oxy}anthracen-9(10/T)-⁽ ne

[enantioenriched 61]: yellow foam, 56.2 mg, 76.0 ιηο1, 76% yield, 98:2 dr. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/ZPrOH: 98/2, 220 nm): 5.86 min for (10R,14ff)-61, 6.51 min for (105,14/f)-61. Enantioenriched 61: R_f=0.48 (silica gel, EtOAc:hexanes 1 :4); [a]^ =+70.3 (c= 1.0, CH₂C1₂); FT-IR

(film) v_max: 2956, 2936, 2865, 1637, 1601, 1585, 1568, 1474, 1436, 1379, 1354, 1324, 1267, 1228, 1197, 1165, 1125, 1103, 1066, 1034, 1019, 1004, 934, 882, 827, 766 cm⁴ ; This compound exhibited broad NMR signals (both in H NMR and ¹ C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600MHz, CDCI₃) δ 12.62 (s, 1 H, major), 12.61 (s, 1 H, minor), 7.73 (d, J= 8.1 Hz, 2H, major + minor), 7.67 (d, 7= 8.2Hz, 2H, major + minor), 7.07 (d, 7=9.0Hz, 1 H, major + minor), 6.87 (d, 7=9.0Hz, 1 H, major + minor), 6.42 (s, 1 H, major + minor), 6.40 (b, 1 H, major), 6.32 (b, 1 H, minor), 5.32 (d, J= 13.1 Hz, 1 H, major + minor), 5.24 (d, J= 13.1 Hz, 1 H, major + minor), 4.64 (b, 1 H, , major + minor), 3.96 (b, 1 H, major + minor), 3.90 (s, 3 H, major + minor), 3.85 (s, 3 H, major + minor), 2.70 (d, J= 11.7 Hz, 1 H, major + minor), 2.02-0.80 (m, 14H, major + minor), 0.93-0.80 (m, 13 H, major + minor), 0.14 (s, 3 H, major), 0.12 (s, 3 H, major), 0.09 (s, 3 H, minor), 0.07 (s, 3 H, minor) ppm; ¹³C NMR (151 MHz, CDC1₃)* δ 188.66 (major), 188.61 (minor), 163.78 (major), 163.69 (minor), 161.56 (major + minor), 156.31 (major), 156.28 (minor), 150.45 (b, major + minor), 147.76 (major), 147.67 (minor), 140.8 (major + minor), 133.5 (major + minor), 130.05 (q, J=32.6 Hz, major + minor), 126.9 (major + minor), 125.70 (q, = 3.6Hz, major + minor), 124.31 (q, 7=272.3 Hz, major + minor), 117.95 (major), 117.85 (minor), 117.68 (major + minor), 115.2 (major + minor), 115.1 (major + minor), 107.3 (major), 106.7 (minor), 99.8 (major + minor), 72.6 (b, major + minor), 70.0 (major + minor), 56.13 (minor), 56.08 (major), 55.79 (major), 55.66 (minor), 41.3 (b, major + minor), 38.9 (b, major + minor) 36.3 (b, major + minor), 36.0 (major + minor), 34.0 (major), 33.9 (minor), 29.85 (major), 29.80 (minor), 29.77 (major), 29.68 (minor), 29.18 (b, major + minor), 25.1 1 (major), 25.06 (minor), 20.37 (major + minor), 20.31 (major + minor), 18.77 (major + minor), 18.73 (major + minor), -1.72 (major), -1.82 (minor), -2.52 (major + minor) ppm; ¹⁹F NMR (282MHz, CDCI3) δ -61.51 ppm; HRMS (ESI) calcd for C₄2H53F₃06SiNa⁺ [M+Na]⁺ 761.3456, found 761.3463. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l,5-Bis(benzyloxy)-10-{[(3 ?)-3-{[(2,3-dimethylbutan-2-yl)(dimethyl)silyl]oxy}-2,6,6- trimethylcyclohex-l-en-l-yl]methyl}-8-hydroxy-3-methoxyanthracen-9(10 )-one [enantioenriched 6m]: yellow foam, 58.3 mg, 78.0 pmol, 78% yield, 99.0:1.0 dr. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 6.27 min for (10 ?,14 f)-6m, 7.21 min for (105,14/?)-6m.

Enantioenriched 6m: R_f= 0.55 (silica gel, EtOAc:hexanes 1 :4); [af^ =+61.8 (c= 1.0, CH2CI2); FT-IR (film) v_max: 2956, 2929, 2869, 1727, 1637, 1600, 1584, 1569, 1465, 1434, 1380, 1353, 1328, 1286, 1262, 1229, 1 168, 1 148, 1123, 1101, 1075, 1042, 1033, 1003, 968, 936, 883, 831, 774, 739, 696 cm-¹; This compound exhibited broad NMR signals (both in Ή NMR and ¹³C NMR) due to hindered bond rotation of the newly- formed C-C bond; ¾ NMR (600 MHz, CDCI₃) δ 12.72 (s, 1 H, major + minor), 7.56 (d, 7=7.6 Hz, 2 H, major + minor), 7.45 (d, 7= 7.0 Hz, 2H, major + minor), 7.41-7.37 (m, 4H, major + minor), 7.35 (t, 7= 7.5 Hz, 1 H, major + minor), 7.30 (t, 7=7.4 Hz, 1 H, major + minor), 7.12 (d, 7=9.0Hz, 1 H, minor), 7.1 1 (d, 7=9.0Hz, 1 H, major), 6.84 (d, 7=9.0Hz, 1 H, major + minor), 6.43 (d, 7= 2.2Hz, 1 H, major), 6.42 (d, 7=2.2 Hz, 1 H, minor), 6.31 (b, 1 H, major), 6.21 (b, 1 H, minor), 5.25 (ABq, Δ5ΑΒ = 0.070, 7= 12.6 HZ, 2H, minor), 5.11 (ABq, Δ5ΑΒ = 0.046, 7=11.1 Hz, 2H, major), 4.59 (b, 1 H , major + minor), 3.86 (b, 1 H, major + minor), 3.81 (s, 3 H, major), 3.80 (s, 3 H, minor), 2.72 (d, 7= 12.9Hz, 1 H, major + minor), 2.00-0.80 (m, 14 H, major + minor), 0.93- 0.80 (m, 13 H, major + minor), 0.083 (s, 3 H, major), 0.075 (s, 3 H, major), 0.07 (s, 3 H, minor), 0.05 (s, 3 H, minor) ppm; ¹³C NMR (151 MHz, CDCb)* δ 188.62 (major), 188.57 (minor), 163.68 (major), 163.57 (minor), 161.98 (major + minor), 156.54 (major), 156.49 (minor), 150.03 (b, major + minor), 146.93 (major), 146.87 (minor), 136.89 (major), 136.84 (minor), 136.74 (minor), 136.71 (major), 134.1 (major + minor), 128.72 (major), 128.69 (minor), 128.67 (major), 128.65 (minor), 128.58 (major + minor), 128.39 (minor), 128.34 (major), 127.8 (major + minor), 126.79 (major), 126.77 (minor), 1 19.26 (major), 119.06 (minor), 1 17.8 (major + minor), 1 15.18 (major + minor), 1 15.14 (major + minor), 107.2 (major), 106.8 (minor), 99.98 (major + minor), 72.7 (b, major + minor), 71.73 (major), 71.66 (minor), 70.81 (major + minor), 55.71 (major), 55.55 (minor), 41.14 (b, major + minor), 38.9 (b, major + minor) 36.5 (b, major + minor), 35.85 (major), 35.78 (minor), 34.0

(major), 33.9 (minor), 31.73 (major + minor), 29.85 (major), 29.80 (minor), 29.75 (major + minor), 29.21 (b, major + minor), 25.51 (major + minor) 25.1 1 (major), 25.05 (minor), 22.80 (major + minor) 20.38 (major + minor), 20.29 (major + minor), 18.78 (major + minor), 18.72 (major + minor), -1.74 (major), -1.86 (minor), -2.56 (minor), -2.61 (major) ppm; HRMS (ESI) calcd for C₄₇i½06SiNa⁺ [ +Na]⁺ 769.3895, found 769.3895. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l-(Benzyloxy)-10-{[(3R)-3-{[(2,3-dimethylbutan-2-yl)(dimethyl)silyl]oxy}-2,6,6- trimethylcyclohex-l-en-l-yl]methyl}-5-(diphenylmethoxy)-8-hydroxy-3-methoxyanthracen-9(10//)-one

[enantioenriched 6n]: yellow foam, 49.4 mg, 60.0 pmol, 60% yield, > 99: 1 dr. The diastereomeric ratio was determined by HPLC after benzylation of the alkylated anthrone 6n (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/i^'PrOH: 90/10, 220 nm): 7.41 min for benzylated (10/?,14fl)-6n, 10.39 min for benzylated (105,14 ?)-6n. Enantioenriched 6n: R_f=0.45 (silica gel, EtOAc:hexanes 1 :4); [a]²² = +38.2 (c= 1.0, CH₂C1₂); FT-IR

(film) v_max: 2956, 2926, 2866, 1726, 1636, 1599, 1583, 1569, 1468, 1433, 1379, 1352, 1327, 1287, 1254, 1228, 1206, 1197, 1168, 1121, 1100, 1076, 1042, 1033, 1022, 1002, 969, 915, 882, 831, 777, 764, 740, 697 cm-' ; This compound exhibited broad NMR signals (both in ¾ NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600 MHz, CDC1₃) δ 12.70 (s, 1 H, major + minor), 7.55 (d, 7= 7.5 Hz, 2 H, major + minor), 7.44 (d, =7.2Hz, 2H, major + minor), 7.43-7.37 (m, 4H, major + minor), 7.36-7.26 (m, 7 H, major + minor), 6.91 (d, J=9.1 Hz, 1 H, major + minor), 6.70 (d, /=9.0Hz, 1 H, major + minor), 6.43 (d, /=2.1 Hz, 1 H, major), 6.43 (d, /=2.1 Hz, 1 H, minor), 6.25 (b, 1 H, major + minor), 6.21 (s, 1 H, major + minor), 5.25 (ABq, Δ5ΑΒ = 0.073, 7= 12.6Hz, 2H, major + minor), 4.59 (b, 1 H, major + minor), 3.84 (b, 1 H, major + minor), 3.80 (s, 3 H, major + minor), 2.79 (d, 7= 12.6 Hz, 1 H, major + minor), 2.10-0.70 (m, 14H, major + minor), 0.95-0.85 (m, 7 H, major + minor), 0.82 (s, 6 H, major + minor), 0.07 (s, 6H, major + minor) ppm; ¹³C NMR (151 MHz, CDCI₃)* δ 188.62 (major + minor), 163.63 (major + minor), 161.92 (major + minor), 156.56 (major + minor), 156.52 (major + minor), 146.34 (major + minor), 140.73 (b, major + minor), 140.61 (major + minor), 136.7 (major + minor), 134.3 (major + minor), 128.8 (major + minor), 128.72 (major + minor), 128.66 (major + minor), 128.6 (major + minor), 128.1 (major + minor), 128.0 (major + minor), 127.9 (major + minor), 127.8 (major + minor), 127.7 (major + minor), 126.79 (major + minor), 126.76 (major + minor), 120.9 (major + minor), 117.76 (minor), 117.73 (major), 115.2 (major + minor), 107.2 (major + minor), 100.04 (major + minor), 83.7 (major + minor), 70.8 (major + minor), 55.7 (major + minor), 35.8 (major + minor), 35.7 (major + minor), 34.0 (major + minor), 29.9 (major + minor), 29.8 (major + minor), 29.5 (major + minor), 25.1 (major), 25.0 (minor), 20.4 (major + minor), 20.3 (major + minor), 18.8 (major + minor), 18.7 (major + minor), -1.7 (major + minor), -2.6 (major + minor) ppm; HRMS (ESI) calcd for C53H₆2C>6Si a⁺ [ +Na]⁺ 845.4208, found 845.4208. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-l-(AUyloxy)-5-(benzyloxy)-10-{[(3R)-3-{[(2,3-dimethylbutan-2-yl)(dimethyl)silyl]oxy}- 2,6,6-trimethylcyclohex-l-en-l-yl]methyl}-8-hydroxy-3-methoxyanthracen-9(10//)-one [enantioenriched 6o]: yellow foam, 51.6 mg, 74.0 μιηο1, 74% yield, 99:1 dr. The diastereomeric ratio was determined by HPLC after benzylation of the alkylated anthrone 6o (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/ZPrOH: 90/10, 220 nm): 7.06 min for benzylated (10/f ,14 ?)-6o, 9.75 min for benzylated (105,14/?)-6o. Enantioenriched

6o: R_f= 0.52 (silica gel, EtOAc:hexanes 1 :4); [θ¾² = +66.9 (c= 1.0, CH₂C1₂); FT-IR (film) v_max: 2956, 2925, 2868, 1726, 1637, 1599, 1583, 1568, 1464, 1435, 1377, 1353, 1326, 1283, 1261, 1227, 1197, 1169, 1119, 1096, 1074, 1041, 1027, 1001, 981, 967, 934, 882, 830, 775, 739, 696, 667 cirr¹ ; This compound exhibited broad NMR signals (both in Ή NMR and ¹³C NMR) due to hindered bond rotation of the newly-formed C-C bond; ¾ NMR (600MHz, CDC1₃) δ 12.65 (s, 1 H, major + minor), 7.44 (d, 7=6.9Hz, 2H, major + minor), 7.38 (ap t, 7=7.2Hz, 2H, major + minor), 7.34 (ap t, 7=7.2Hz, 1 H, major + minor), 7.10 (d, 7=9. OHz, 1 H, major + minor), 6.82 (d, 7=9.0Hz, 1 H, major + minor), 6.40 (d, 7=2.1 Hz, 1 H, major), 6.38 (d, 7=2.1 Hz, 1 H, minor), 6.31 (b, 1 H, major), 6.21 (b, 1 H, minor), 6.10 (ap ddt, 7= 17.2, 10.5, 4.7 Hz, 1 H, major + minor), 5.63 (dd, 7= 17.2, 1.5 Hz, 1 H, major + minor), 5.35 (dd, 7= 10.7, 1.5 Hz, 1 H, major + minor), 5.10 (dd, 7= 18.2, 11.1 Hz, 2H, major + minor). 4.63 (ddd, 7= 13.4, 7.3, 5.2 Hz, 2H, major + minor), 4.60 (b, 1 H , major + minor), 3.87 (b, 1 H, major + minor), 3.84 (s, 3 H, major), 3.83 (s, 3 H, minor), 2.71 (d, 7= 12.2 Hz, 1 H, major + minor), 1.99- 0.65 (m, 14H, major + minor), 0.95-0.85 (m, 7 H, major + minor), 0.82 (s, 6 H, major), 0.72 (s, 6H, minor), 0.09 (s, 6 H, major), 0.07 (s, 6 H, minor) ppm; ¹³C NMR (151 MHz, CDCI₃)* δ 188.61 (major + minor), 171.28 (major + minor), 163.73 (major + minor), 162.07 (major + minor), 156.50 (major + minor), 150.06 (b, major + minor), 146.91 (major + minor), 136.9 (major + minor), 134.1(major + minor), 132.5 (major + minor), 128.7 (major + minor), 128.6 (major + minor), 128.3 (major + minor), 119.2 (major + minor), 117.9 (major + minor), 117.8 (major + minor), 115.2 (major + minor), 115.0 (major + minor), 106.9 (major + minor), 99.6 (major + minor), 72.7 (b, major + minor), 71.7 (major + minor), 69.8 (major + minor), 60.5 (major + minor), 55.7 (major + minor), 41.1 (b, major + minor), 39.0 (b, major + minor), 36.5 (b, major + minor), 35.85 (major), 35.77 (minor), 34.0 (major + minor), 29.84 (major + minor), 29.75 (major + minor), 29.2 (major + minor), 25.1 (major), 25.0 (minor), 20.4 (major + minor), 20.3 (major + minor), 18.8 (major + minor), 18.7 (major + minor), 14.3 (major + minor), -1.7 (major + minor), -2.6 (major + minor) ppm; HRMS (ESI) calcd for C₄₃H560eSiNa⁺ [ +Na]⁺ 719.3738, found 719.3734. *Due to signal broadening, not all the ¹³C signals could be identified.

(105)-5-(Benzyloxy)-10-{[(3R)-3-{[(2,3-dimeth lbutan-2- l)(dimeth l)silyl]oxy}-2,6,6- trimethylcyclohex -en-l-yl]methyl}-8-hydroxy-3-methoxy-l-{[4-

(trifluoromethyl)benzyl]oxy}anthracen-9(10/ )-one [enantioenriched 6p]: yellow foam, 61.1 mg, 75.0μιηο1, 75% yield, > 99: 1 dr. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/ZPrOH: 98/2, 220 nm): 5.79 min for (10R,14 ?)-6p, 6.45 min for (10S,14R)-6p. Enantioenriched 6p: R_f=0.60 (silica gel, EtOA hexanes 1:4); [a]p =+48.0 (c= 1.0, CH₂C1₂); FT-IR (film) 2957, 2927, 2869, 1727, 1637, 1601, 1584, 1568, 1465, 1435, 1379, 1353, 1325, 1286, 1265, 1229, 1197, 1166, 1125, 1102, 1067, 1042, 1033, 1022, 1004, 969, 936, 882, 830, 775, 741, 696, 670 cm^"1 ; This compound exhibited broad NMR signals (both in Ή NMR and ¹³C NMR) due to hindered bond rotation of the newly- formed C-C bond; ¾ NMR (600 MHz, CDCb) δ 12.65 (s, 1 H, major + minor), 7.70 (dd, 7=36.9, 8.2Hz, 4H, major + minor), 7.48-7.32 (m, 5 H), 7.12 (d, 7= 9.0Hz, 1 H, major + minor), 6.85 (d, 7=9.0Hz, 1 H, major + minor), 6.41 (d, 7= 2.1 Hz, 1 H, major), 6.39 (d, 7= 2.1 Hz, 1 H, minor), 6.34 (b, 1 H, major), 6.24 (b, 1 H, minor), 5.28 (ABq, A5AB = 0.082, 7= 13.1 HZ, 2H, minor), 5.11 (ABq, Δ5ΑΒ = 0.048, 7= 11.1 HZ, 2H, major), 4.62 (b, 1 H, major + minor), 3.87 (b, 1 H, major + minor), 3.83 (s, 3 H, major), 3.81 (s, 3 H, minor), 2.73 (d, 7= 12.3 Hz, 1 H, major + minor), 1.95-0.60 (m, 14H, major + minor), 0.95-0.87 (m, 7 H, major + minor), 0.84 (s, 6 H, major), 0.80 (s, 6 H, minor), 0.08 (s, 3 H, major + minor), 0.07 (s, 3 H, major), 0.06 (s, 6 H, minor) ppm; ¹³C NMR (151 MHz, CDC1₃)* δ 188.65 (major + minor), 163.7 (major + minor), 161.5 (major + minor), 156.6 (major + minor), 147.0 (major + minor), 140.8 (major + minor), 136.8 (major + minor), 134.1 (major + minor), 130.05 (q, 7=32.4Hz, major + minor), 128.7 (major + minor), 128.6 (major + minor), 128.4 (major + minor), 126.9 (major + minor), 125.71 (q, 7= 3.5 Hz), 124.31 (q, 7=271.8 Hz), 119.4 (major + minor), 117.7 (major + minor), 115.3 (major + minor), 115.1 (major + minor), 107.3 (major + minor), 99.9 (major + minor), 71.7 (major + minor), 70.0 (major + minor), 56.1 (major + minor), 55.8 (major + minor), 41.1 (b, major + minor), 36.5 (b, major + minor), 35.9 (major + minor), 34.0 (major + minor), 29.9 (major + minor), 29.8 (major + minor), 25.1 (major + minor), 20.4 (major + minor), 20.3 (major + minor), 18.8 (major + minor), 18.7 (major + minor), 14.3 (major + minor), -1.7 (major + minor), -2.6 (major + minor) ppm; ¹⁹F NMR (282 MHz, CDCI3) δ -61.51 ppm; HRMS (ESI) calcd for C48H₅70₆SiNa⁺ [ +Na]⁺ 837.3769, found 837.3768. *Due to signal broadening, not all the ¹³C signals could be identified.

Enantioselective Total Synthesis and Absolute Configuration of (-)-Viridicatumtoxin B Scheme 14. E icatumtoxin B [(-)-!] and Its

Note: to avoid confusion, the numbering on (6S,UR)-6, (6S,15R)-4 and (-)-9 in this Scheme is based on the viridicatumtoxin numbering, as opposed to the carbon numbering of compound (10S,14R)-6 (see Table 3), which is the same compound as (6S,17R)-6, but numbered based on the anthrone numbering.

(105)-l-(Benzyloxy)-10-{[(3R)-3-{[fert-butyl(dimethyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en-l- yl]methyl}-8-hydroxy-3,5-dimethoxyanthracen-9(10/7)-one [(65,17/?)-6]: To a stirred mixture of anthrone 7 (3.01 g, 8.00 mmol, l .O equiv), allylic bromide (R)-8 (3.06 g, 8.80mmol, l. l equiv) and PTC15 (22.0mg, 40.0 μπιοΐ, 0.5 mol%, 0.005 equiv) in (CH₂)₂Cl2 (80mL) under argon, was added 50% aq. KOH solution (24 mL) dropwise at -30 °C. The reaction mixture was stirred vigorously at -30 °C for 240 h (10 days). The mixture was then quenched by addition of water (150 mL) and extracted with CH2CI2 (3 X 150mL). The organic phase was washed with brine (100 mL) and dried over anhydrous Na₂S0₄. Evaporation of solvents and purification of the residue by flash column chromatography on silica gel (10% EtOAc:hexanes) gave chiral alkylated anthrone (65,17R)-6 (3.70g, 5.76 mmol, 72% yield, 95:5 dr) as a yellow foam. Compound (6S,17R)-6 is the same as (105,14 ?)-6, which is numbered based on the viridicatumtoxin numbering. The diastereomeric ratio was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/ZPrOH: 98/2, 220 nm): 7.01 min for (6R,17R)-6; 8.05 min for (6S,17/?)-6. The physical and spectroscopic data of this compound matched those mentioned obove of (10S,14/?)-6.

(2/?,10b5)-5-(Benzyloxy)-7-hydroxy-3,10-dimethoxy-2',6^,,6'-trimethyl-l,10b-dihydro-6H- spiro[aceanthrylene-2,r-cyclohex[2]en]-6-one [(65,15 ?)-4]: Chiral alkylated anthrone (6S,17R)-6 (3.70 g, 5.76 mmol, l .O equiv) was dissolved in CH₂CI₂ (360 mL) and cooled to -78 °C. A freshly prepared solution of BF₃- Et₂0 (2.90 mL of a 0.1 M solution in CH₂CI₂, 290 μιηο1, 0.05 equiv) was added dropwise, and the reaction mixture was slowly warmed to 0 °C and stirred at this temperature for 0.5 h. The reaction was quenched by addition saturated aq. NaHCC>3 solution (200 mL), and the phases were separated. The aqueous phase was extracted with CH₂CI₂ (200mL), and the combined organic layers were dried over a₂S0₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 5%→10% EtOAc:hexanes) to give chiral BCDEF spirocycle (6S,15ff)-4 (2.18 g, 4.26 mmol, 74% yield, 95:5 er) as a yellow foam. The enantiomeric ratio was determined by HPLC (Chiralcel OD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 90/10, 220 nm): 6.56 min for (6R,15S)-4; 7.78 min for (6S,15tf)-4.

After recrystallization from hexanes:CH2Cb (50: 1), yellow crystals were obtained with 99.2:0.8 er (91% yield). (65,15/?)-4: R_f= 0.50 (silica gel, EtOAc:hexanes 1:4); [ ] =+65.7 (c= 1.0, CH2CI2, 99.2:0.8 er); m.p. = 157-158 °C [dec, hexanes:CH₂Ci2 50:1)]; FT-IR (film) v_max: 2939, 2917, 2838, 1633, 1598, 1568, 1472, 1441, 1383, 1328, 1301, 1270, 1257, 1220, 1200, 1139, 1106, 1034, 1001, 924, 867, 824, 790, 770, 735, 705, 696 cm-¹ ; ¾ NMR (600 MHz, CDCI₃) δ 13.14 (s, 1 H), 7.60 (d, 7=7.4Hz, 2H), 7.42 (ap t, J=7.6 Hz, 2H), 7.33 (ap t, 7=7.4Hz, l H), 7.06 (d, /=9.0Hz, 1 H), 6.86 (d, 7=9.0 Hz, 1 H), 6.40 (s, 1 H), 5.43 (d, J=3.5 Hz, 1 H), 5.37 (d, J= 12.4Hz, 1 H), 5.28 (d, J= 12. Hz, 1 H), 4.40 (dd, /= 11.8, 7.5 Hz, 1 H), 3.81 (s, 3 H), 3.75 (s, 3 H), 3.14 (dd, J= 13.7, 7.5 Hz, 1 H), 2.26-2.15 (m, 2H), 2.02 (dd, J= 14.3, 8.9 Hz, 1 H), 1.95 (ap td, J= 12.5, 6.1 Hz, 1 H), 1.38 (dd, 7= 13.1, 6.0Hz, 1 H), 1.27 (s, 3 H), 1.00 (s, 3 H), 0.96 (s, 3 H), 0.92 (s, l H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 189.0, 162.1, 161.2, 157.4, 155.4, 149.3, 138.3, 136.9, 131.1, 128.8, 128.0, 127.0, 124.1, 121.3, 119.3, 118.1, 115.7, 112.8, 97.0, 71.6, 58.8, 56.6, 55.2, 44.9, 41.7, 38.8, 34.9, 27.8, 25.8, 24.9, 23.1, 20.5 ppm; HRMS (ESI) calcd for C₃₃H₃₄0₅Na⁺ [M+Na]⁺ 533.2298, found 533.2304.

(-1-9

(2 ?)-5-(Benzyloxy)-7-h droxy-3,10-dimethoxy-2',6',6'-trimethyl-6 /-spiro[aceanthrylene-2, - cyclohex[2]en]-6-one f(-)-9] (Nicolaou ef al, 2013; Nicolaou et al, 2014): Spirocycle (6S,15tf)-4 (2.00 g, 3.92 mmol, l .O equiv) was dissolved in MeOH:CH2Ci2 (1:1, 80 mL), and the solution was cooled to 0 °C. Freshly prepared Phl(0 Ac)2³⁷ (1.51 g, 4.69 mmol, 1.2 equiv) was added and the reaction mixture was stirred for 30 min at 0 °C and 30 min at 25 °C. The reaction was quenched by addition of saturated aq. NaHCCb (200 mL) and was extracted with EtOAc (2 x 200 mL). The combined organic phases were washed with brine (100 mL), dried over Na₂S0₄, and concentrated under reduced pressure. The so-obtained crude ketal was dissolved in CH2CI2 (80 mL), and freshly crystallized CSA (63.0 mg, 270 ιηο1, 0.07 equiv) was added at 0 °C. The reaction mixture was stirred at 0 °C for 5 minutes and was then quenched by addition of saturated aq. NaHCOs (lOOmL). The layers were separated, and the organic phase was dried over Na₂S0₄, filtered, and concentrated under reduced pressure to give the crude product (-)-9. Flash column chromatography (silica gel, 2% EtOAc: toluene) gave intermediate (-)-9 (1.61 g, 3.16 mmol, 81% for two steps, > 99: 1 er) as a red solid. The enantiomeric ratio was determined by HPLC (Chiralcel OD-H, 25 °C, flow rate: 1 mL/min, hexanes/ZPrOH: 90/10, 220 nm): 8.63 min for (-)-9 [(155)-9], 9.14 min for (+)-9 [(15R)-9].

(-)-9: R_f=0.70 (silica gel, EtOAc:hexanes 1 :9); [a]²² =-130 (c=0.05, CH2CI2); m.p. = 199-200 °C (CH2CI2); FT-IR (film) v_mas : 2936, 2324, 2162, 2050, 1981, 1625, 1574, 1479, 1442, 1429, 1384, 1363, 1331, 1311, 1259, 1238, 1222, 1180, 1163, 1128, 1029, 931, 874, 829, 806, 735, 716, 696 cm-¹; ¾ NMR (CDCI3, 600 MHz) δ 13.98 (s, 1 H), 7.65-7.63 (m, 2H), 7.60 (s, 1 H), 7.45-7.41 (m, 2 H), 7.34 (m, 1 H), 7.20 (d, 7=6.0Hz, 1 H), 7.00 (d, y=6.0Hz, 1 H), 6.44 (s, 1 H), 5.74 (bs, 1 H), 5.38 (d, 7= 12.8 Hz, 1 H, AB system), 5.35 (d, /= 12.8 Hz, 1 H, AB system), 3.97 (s, 3 H), 3.81 (s, 3 H), 2.31-2.22 (m, 2H), 1.90 (ddd, 7= 12.9, 5.6, 5.6 Hz, 1 H), 1.66 (ddd, /= 12.9, .5, 6.5 Hz, 1 H), 1.14 (s, 3 H), 0.85 (s, 6 H) ppm; ¹³C NMR (CDCI3, 151 MHz) 5 188.5, 161.2, 159.8, 157.9, 152.4, 151.6, 150.4, 136.9, 131.7, 130.6, 128.8, 128.0, 126.9, 124.6, 124.1, 120.2, 118.1, 117.4, 116.8, 110.3, 96.0, 71.4, 66.9, 56.2, 55.5, 37.0, 35.8, 27.1, 26.8, 23.2, 19.8 ppm; HRMS (ESI) calcd for C₃₃H₃₂0₅Na⁺ [M+Na]⁺ 531.2142, found 531.2146.

(2/f)-5-(Benzyloxy)-3,10-dimethoxy-2',6',6'-trimethyl-6-oxo-6 /-spiro[aceanthrylene-2, - cyclohex[2]en]-7-yl4-bromobenzoate (-)-ll: To a stirred solution of quinomethide (-)-9 (15.3 mg, 30.0 μπιο1, l .O equiv) in CH₂CI₂ (2mL) was added 4-bromobenzoyl chloride 10 (32.9 mg, 150 μηιο1, 5 equiv), 4- dimethylaminopyridine (DMAP, 36.7 mg, 300 mol, lO equiv) and triethylamine (EkN, 126 μί, 91.1 mg, 900μιηο1, 30 equiv). The reaction mixture was stirred at 25 °C for 6 h before the reaction was quenched by addition of saturated aq. NaHCC solution (5 mL) and extracted with CH₂CI₂ (2 5 mL). The combined organic phases were dried over Na2S04, and concentrated under reduced pressure. Flash column chromatography (silica gel, 5% EtOAc:hexanes) gave protected p-bromobenzoate (-)-ll (19.7 mg, 28.5 μιηοΐ, 95% yield) as a yellow solid. Crystalization from CF Ck/hexanes 1 :4 gave crystals suitable for X-ray crystallographic analysis, which revealed its absolute configuration as shown below (FIG. 4).

(-)-ll: R_f=0.60 (silica gel, EtOAc:hexanes 1 :9); [a]" =-87 (c=0.1, CH2CI2); m.p. = 220-221 ^CC (CH₂Cl₂/hexanes 1 :4); FT-IR (film) v_max: 2960, 2923, 2854, 1736, 1647, 1616, 1581, 1497, 1484, 1462, 1442, 1423, 1396, 1384, 1361, 1332, 1273, 1240, 1222, 1172, 1142, 1123, 1075, 1021, 1011, 918, 871, 843, 807, 775, 741, 697, 676 cm^"1 ; ¾ NMR (600 MHz, CDCI₃) δ 8.21 (d, 7= 8.4Hz, 2H), 7.69 (d, /= 8.4Hz, 2H), 7.61 (s, 1 H), 7.46 (d, 7=7.5 Hz, 2H), 7.28-7.24 (m, 1 H), 7.22-7.15 (m, 4H), 6.42 (s, 1 H), 5.75-5.73 (m, 1 H), 5.17- 5.12 (m, 2H), 4.05 (s, 3 H), 3.83 (s, 3 H), 2.30-2.26 (m, 2H), 1.95-1.88 (m, 1 H), 1.71-1.64 (m, 1 H), 1.16 (d, J= 1.0Hz, 3 H), 0.86 (s, 6 H) ppm; ¹³C NMR (151 MHz, CDCI3) δ 181.0, 166.1, 160.6, 159.1, 156.3, 152.2, 150.5, 144.7, 137.1, 132.4, 131.9, 131.8, 130.1, 130.0, 128.4, 128.1, 127.6, 126.9, 125.5, 124.4, 124.0, 123.8, 122.8, 113.8, 112.2, 97.1, 71.6, 66.8, 56.1, 55.5, 37.0, 35.9, 27.1, 26.8, 23.3, 19.9 ppm; HRMS (ESI) calcd for C4oH₃₅Br06Na⁺ [M+Na] ⁺ 713.1509, found 713.1511.

Scheme 15. Total Synthesis of Enantiopure (-)-Viridicatumtoxin B [(-)-l]

(- 14 (drca. 4:1) (+)-13 (dr ca. 4:1) |d) Ni(acac)₂ (cat.),

H-23 [H-1] [(-)-viridicatumtoxin B]

(2/?)-5-(Benzyloxy)-3,10,10-trimethoxy-2',6',6'-trimethyl-6//-spiro[aceanthrylene-2, - cyclohex[2]ene]-6,7(10ff)-dione (-)-12 (Nicolaou et al, 2013; Nicolaou et al, 2014): Quinomethide (-)-9 (1.31 g, 2.55 mmol, l .O equiv) was dissolved in a mixture of CThCbMeOH (1 :10; 55 mL), and freshly prepared PhI(OAc)₂ (Sharefkin and Saltzman., 1963) (1.00 g, 3.10 mmol, 1.2 equiv) was added with stirring at 25 °C. The reaction mixture was stirred at that temperature for 1.5 h and was then quenched by addition of saturated aq. NaHC03 (50 mL). The resulting mixture was diluted with water (lOOmL) and extracted with CH2CI2 (lOOmL). The organic layer was dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, 10% acetone in toluene, 0.1% Et3N) to give diketone ketal (-)-12 (1.19 g, 2.20mmol, 86% yield) as a yellow solid. (-)-12: R_f=0.15 (silica gel, acetone:toluene 1 :9);

[a]_p =-132 (c=0.1, CH2CI2); m.p. = 194-195 °C (dec, CH2CI2); FT-IR (film) v_mm: 2937, 2835, 1681, 1618,

1582, 1456, 1435, 1373, 1328, 1282, 1224, 1094, 1082, 1067, 846, 733 cm^"1 ; ¾ NMR (CDCI3, 600 MHz) δ 7.83 (s, 1 H), 7.65-7.62 (m, 2H), 7.43-7.39 (m, 2 H), 7.32 (m, 1 H), 6.64 (d, J= 10.4Hz, 1 H), 6.59 (d, J= 10.4 Hz, 1 H), 6.43 (s, 1 H), 5.76 (bs, 1 H), 5.30 (d, J= 12.0 Hz, 1 H, AB system), 5.26 (d, J= 12.0Hz, 1 H, AB system), 3.82 (s, 3 H), 3.26 (s, 3 H), 3.17 (s, 3 H), 2.28-2.23 (m, 2 H), 1.94 (ddd, 7= 13.1, 6.3, 6.3 Hz, 1 H), 1.61 (m, 1 H), 1.13 (bs, 3 H), 0.88 (s, 3 H), 0.82 (s, 3 H) ppm; ¹³C NMR (CDCl₃, 151 MHz) δ 183.3, 179.6, 161.6, 160.6, 159.2, 148.4, 147.1, 140.9, 136.7, 135.2, 130.5, 130.1, 130.0, 128.7, 127.9, 127.1, 125.0, 123.5, 112.2, 96.7, 96.5, 71.1, 68.6, 56.0, 51.7, 51.6, 37.5, 35.5, 27.1, 26.9, 23.1 , 19.9 ppm; HRMS (ESI) calcd for C34H₃40₆Na⁺ [ +Na]⁺ 561.2248, found 561.2249.

2-(Trimethylsilyl)ethyl (l ?,12'R,12a' f)-5',9'-bis(benzyloxy)-7'-hydroxy-3',13',13'-trimethoxy- 2,6,6-trimethyl-6',8'-dioxo-8',12',12a',13'-tetrahydro-6'fl-spiro[cyclohex-2-ene-l,2'-cyclo- penta[6,7]tetraceno[2,3-i/][l,2]oxazole]-12'-carboxylate (+)-13 (ca. 4: 1 mixture of C15-C4/C4a diastereomers): To a stired solution of pentacycle 12 (l .OO g, 1.84mmol, l.Oequiv), potassium ferf-butoxide (fBuOK, 248 mg, 2.24 mmol, 1.2 equiv) and PTC-14 (9.80mg, 18.4 μmol, O.Ol equiv) in toluene (18 mL) at -78 °C under argon was added dropwise a solution of phenyl ester isoxazole 5 (Nicolaou et al, 2013; Nicolaou et al, 2014) (920mg, 2.04 mmol, l . l equiv) in toluene (18 mL). The resulting solution was then warmed to -50 °C and stirred at that temperature for 48 h. Then, the reaction was quenched by addition of saturated aq. NH₄CI solution (40 mL). The phases were separated, and the organic phase was dried over Ν¾8(¾, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, 2%→5% acetone in toluene) to give product 13 (1.47g, 1.62mmol, 88% yield, dr ca. 4:1) as a yellow foam.

13: R_f= 0.60 (silica gel, EtOAc:hexanes 3:7); [ f^ =+153 (c=0.1 , CH₂Ch); FT-IR (film) v_max: 2952, 1737, 1656, 1618, 1582, 1511, 1489, 1454, 1385, 1366, 1308, 1250, 1223, 1157, 1054, 1025, 932, 859, 838, 736, 696 cm-¹; ¾ NMR (C₆D₆, 600MHz) δ 16.73 (bs, 1 H, major + minor), 7.70-7.64 (m, 2 H, major + minor), 7.61 (s, 1 H, minor), 7.58 (s, 1 H, major), 7.39-7.35 (m, 2 H, major + minor), 7.21-7.02 (m, 6 H, major + minor), 6.24 (bs, 1 H, minor), 6.23 (bs, 1 H, major), 5.72 (bs, 1 H, minor), 5.69 (bs, 1 H, major), 5.19-5.17 (m, 2 H, major + minor), 5.06-5.01 (m, 2 H, major + minor), 4.73 (d, /= 10.0Hz, 1 H, major), 4.72 (m, 1 H, minor), 4.42-4.26 (m, 2 H, major + minor), 4.22 (d, /= 10.0Hz, 1 H, major), 4.20 (d, J= 10.0Hz, 1 H, minor), 3.23 (s, 3 H, major), 3.22 (s, 3 H, minor), 3.13 (s, 3 H, major), 3.09 (s, 3 H, minor), 3.03 (s, 3 H, minor), 2.97 (s, 3 H, major), 2.26- 2.18 (m, 1 H, major + minor), 2.14-2.07 (m, 1 H, major + minor), 1.96 (ddd, /= 13.2, 6.6, 6.6 Hz, 1 H, major), 1.89 (ddd, J= 13.2, 6.7, 6,7Hz, 1 H, minor), 1.47 (ap ddd, J= 13.2, 6.7, 6.7 Hz, 2 H, major + minor), 1.23 (bs, 3 H, minor), 1.17 (bs, 3 H, major), 1.01 (ap t, J=8.5 Hz, 2 H, major + minor), 0.99 (ap t, J= 8.5 Hz, 2 H, major + minor), 0.91 (s, 3 H, major), 0.90 (s, 3 H, minor), 0.87 (s, 3 H, major), 0.82 (s, 3 H, minor), -0.09 (s, 9 H, major), -0.11 (s, 9 H, minor) ppm; ¹³C NMR (C₆D₆, 151 MHz) δ 181.4 (major), 181.3 (minor), 178.8 (major), 178.4 (minor), 175.5 (major), 175.4 (minor), 171.6 (minor), 171.5 (major), 169.2 (major), 169.1 (minor), 168.4 (major + minor), 161.0 (minor), 160.5 (major), 159.2 (minor), 159.0 (major), 157.4 (major), 157.3 (minor), 148.7 (minor), 148.5 (major), 140.13 (minor), 140.06 (major), 137.40 (minor), 137.35 (major), 135.9 (major + minor), 134.8 (minor), 134.7 (major), 132.5 (major), 132.4 (minor), 130.7 (minor), 130.6 (major), 128.9 (major + minor)*, 128.7 (major)*, 128.6 (minor)*, 128.56 (minor)*, 128.47 (major)*, 127.32 (minor), 127.25 (major), 125.15 (minor), 125.12 (major), 123.5 (minor), 123.3 (major), 113.3 (major), 113.2 (minor), 106.3 (major + minor), 103.29 (major), 103.26 (minor), 102.6 (major), 102.5 (minor), 97.8 (minor), 97.4 (major), 72.3 (major + minor), 71.6 (minor), 71.4 (major), 68.40 (minor), 68.35 (major), 64.8 (major + minor), 54.98 (major + minor), 54.2 (major), 53.7 (minor), 52.8 (minor), 52.5 (major), 40.69 (minor), 40.65 (major), 40.2 (major + minor), 37.7 (major), 37.5 (minor), 35.8 (major + minor), 27.21 (major), 27.14 (minor), 27.14 (minor), 27.06 (major), 23.4 (major + minor), 20.3 (minor), 20.2 (major), 17.4 (major + minor), -1.66 (major), -1.67 (minor) ppm; HRMS (ESI) calcd for C₅2H₅5NOiiSiNa⁺ [M+Na]⁺ 920.3437, found 920.3428. *Due to overlapping ¹³C chemical shifts of diastereomers, these signals could not be assigned with accuracy.

(l/^,12a^,/^)■5^9'-Bis(benz lox )-7^,-h drox -3 13 13^,■trimethox -2,6,6-trimeth l-12a^,,13^,- dihydro-6'H-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-i/][l,2]oxazole]-6',8'(12'//)-dione (-)-14 (ca. 4: l mixture of CI 5-C4a diastereomers) [Nicolaou et al, 2013; Nicolaou et al, 2014]: A solution of Teoc-heptacycle (+)-13 (1.60g, 1.80mmol, l.Oequiv, dr ca. 4: 1) and NH₄F (1.35 g, 35.5 mmol, 20 equiv) in THF (200 mL) was degassed three times with argon at -78 °C, and the reaction flask was shielded from light using aluminum foil. A freshly prepared solution of tetra-n-butylammonium fluoride (18.0mL, 1 M solution in THF, 18.0 mmol, 10 equiv, prepared from TBAF 3H₂O) was added in one portion at -78 °C. The reaction mixture was warmed to 25 °C and stirred for 10 minutes. The reaction was then quenched by addition of brine (120 mL) and extracted with EtOAc (120mL). The layers were separated, and the organic phase was washed with water (3 x lOOmL), dried over a2S04, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, 2%→5% acetone in toluene) to give heptacycle (-)-14 (1.17g,

1.57 mmol, 87% yield, dr ca. 4: 1) as an orange foam. (-)-14: R_f=0.50 (silica gel, acetone: toluene 1 :9); [<¾]p =- 24 (c=0.05, CH2CI2); FT-IR (film) v_max: 2956, 2927, 2855, 1711, 1653, 1618, 1582, 1509, 1455, 1365, 1311, 1258, 1219, 1157, 1075, 1052, 1027, 912, 814, 736, 697 cm-¹; Ή NMR (CDCI₃, 600 MHz) δ 15.60 (s, 1 H, major), 15.59 (s, 1 H, minor), 7.72 (s, 1 H, major), 7.70 (s, 1 H, minor), 7.61-7.57 (m, 2H, major + minor), 7.52- 7.49 (m, 2H, major + minor), 7.41-7.36 (m, 4H, major + minor), 7.35-7.29 (m, 2H, major + minor), 6.45 (s, 1 H, minor), 6.44 (s, 1 H, major), 5.77 (bs, 1 H, minor), 5.76 (bs, 1 H, major), 5.40 (s, 2 H, major + minor), 5.35- 5.25 (m, 2H, major + minor), 3.91 (dd, 7= 11.0, 8.3 Hz, 1 H, major), 3.86 (dd, 7= 11.0, 8.5 Hz, 1 H, minor), 3.80 (s, 3 H, minor), 3.79 (s, 3 H, major), 3.45 (s, 3 H, major), 3.40 (s, 3 H, minor), 3.44-3.43 (m, 1 H, minor), 3.41- 3.39 (m, 1 H, major), 3.34 (s, 3 H, minor), 3.27 (s, 3 H, major), 3.02-2.94 (m, 2H, major + minor), 2.26 (bs, 2H, major + minor), 1.99 (ap dt, 7= 13.2, 6.5 Hz, 1 H, major + minor), 1.62 (bs, 1 H, major + minor), 1.55 (ap dt, 7= 12.9, 6.3 Hz, 1 H, major + minor), 1.13 (s, 3 H, minor), 1.09 (s, 3 H, major), 0.93 (s, 3 H, major), 0.88 (s, 3 H, minor), 0.79 (s, 3 H, major), 0.77 (s, 3 H, minor) ppm; ¹³C NMR (CDCI₃, 151 MHz) δ 182.1 (major), 182.0 (minor), 180.1 (major), 179.8 (minor), 179.1 (major + minor), 170.0 (major + minor), 168.1 (major + minor), 160.7 (minor), 160.3 (major), 159.41 (major), 159.37 (minor), 159.2 (minor), 159.1 (major), 148.2 (minor), 148.1 (major), 141.17 (minor), 141.15 (major), 136.80 (major + minor), 135.46 (major + minor), 132.84 (major + minor), 132.61 (major), 132.56 (minor), 130.0 (major + minor), 128.8 (major + minor)*, 128.7 (major + minor)*, 128.6 (major + minor)*, 128.41 (major)*, 128.35 (minor)*, 127.9 (major + minor)*, 127.2 (minor), 127.1 (major), 125.4 (minor), 125.2 (major), 123.4 (minor), 123.2 (major), 112.3 (major), 112.2 (minor), 105.7 (major + minor), 103.43 (major), 103.38 (minor), 102.17 (major), 102.15 (minor), 97.2 (minor), 97.0 (major), 72.4 (major + minor), 71.40 (minor), 71.36 (major), 68.4 (minor), 68.3 (major), 55.6 (minor), 55.5 (major), 53.5 (major), 53.0 (minor), 52.9 (minor), 52.6 (major), 37.8 (major), 37.6 (minor), 37.0 (minor), 36.9 (major), 35.64 (major), 35.60 (minor), 27.3 (minor), 27.2 (major), 26.9 (minor), 26.8 (major), 23.12 (major + minor), 20.5 (major + minor), 20.0 (major + minor) ppm; HRMS (ESI) calcd for C46H₄₃ C>9 a⁺ [ +Na]⁺ 776.2830, found 776.2857. *Due to overlapping ¹³C chemical shifts of diastereomers, these signals could not be assigned with accuracy.

(l/?,7a'S,12a7?)-5 9'-Bis(benzyloxy^

dihydro-6^-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-d][l,2]oxazole]-6^,,7^,,8^,(7a^,i7,12^,7i)- trione (-)-15 (ca 4:1 mixture of C15-C4a/C12a diastereomers): To a stirred solution of substrate (-)-14 (250mg, 330 mol, l .O equiv, dr ca. 4:1) in THF (25 mL) under argon was added a solution of Ni(acac)₂ (17.0mg, 66.0 μmol, 0.20 equiv) in THF (2mL), stired for five minutes at 25 °C, and then cooled to -78 °C. DMDO³⁸ (-0.08 M solution in acetone, 13.0mL, -0.990 mmol, 3.0 equiv) was added dropwise at -78 °C and further stirred at this temperature for 3 h. The reaction was then quenched by addition of dimethylsulfide (1.0 mL), and the mixture was stirred at -78 °C for 15 minutes. Saturated aq. NH₄CI solution (15 mL) was added, and the mixture was allowed to warm to 25 °C and then diluted with water (20 mL) and extracted with EtO Ac (3 x 20 mL). The layers were separated, and the organic phase was washed with water (20 mL) and brine (20 mL), dried over a2S04, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 3%→5%→10% acetone in toluene) gave the hydroxylated product (-)-15 (131 mg, 172 μπιο1, 52% yield, 72% yield brsm, dr ca. 4: 1) as an orange powder and recovered starting material (-)-14 (70.2 mg,

92.9 μπιο1, 28% yield). 15: R_f = 0.25 (silica gel, acetone:toluene 1 :9); [a]²² =-116 (c = 0.2, CH2CI2); FT-IR (film) w 3425, 2931, 2850, 1719, 1618, 1582, 1514, 1488, 1455, 1366, 1313, 1259, 1224, 1132, 1103, 1055, 991, 829, 735, 696 cm^"1 ; ¾ NMR (CDCb, 600 MHz) δ 7.864 (s, 1 H, major), 7.857 (s, 1 H, minor), 7.61-7.57 (m, 2 H, major + minor), 7.44-7.29 (m, 8 H, major + minor), 6.452 (s, 1 H, major), 6.446 (s, 1 H, minor), 5.79 (bs, 1 H, major + minor), 5.29-5.20 (m, 4H, major + minor), 5.04 (bs, 1 H, major + minor), 3.82 (s, 6 H, major + minor), 3.44 (s, 3 H, minor), 3.41 (s, 3 H, major), 3.39 (dd, 7 = 9.3, 6.2 Hz, 1 H, major + minor), 3.25 (s, 3 H, major), 3.16 (s, 3 H, minor), 3.24-3.19 (m, 1 H, major + minor), 2.94 (dd, /= 19.1, 6.4Hz, 1 H, minor), 2.89 (dd, / = 19.1, 6.3 Hz, 1 H, major), 2.28 (bs, 2H, major + minor), 1.91 (ap dt, 7= 12.8, 6.1 Hz, 1 H, major + minor), 1.61 (ap dt, J= 13.4, 6.7 Hz, 1 H, major + minor), 1.10 (s, 3 H, major + minor), 0.85 (bs, 6 H, minor), 0.84 (s, 3 H, major), 0.83 (s, 3 H, major + minor) ppm; ¹³C NMR (CDCI3, 151 MHz) δ 191.7 (major), 191.5 (minor), 184.00 (minor), 183.96 (major), 180.04 (major), 180.00 (minor), 177.5 (minor), 177.3 (major), 167.80 (major + minor), 162.93 (minor), 162.86 (major), 160.84 (major), 160.70 (minor), 159.5 (major), 159.4 (minor), 148.6 (major), 148.5 (minor), 146.7 (major), 146.6 (minor), 136.5 (major + minor), 135.0 (major + minor), 132.5 (major), 132.4 (minor), 132.2 (major + minor), 130.1 (major), 129.9 (minor), 128.7 (major + minor)*, 128.6 (major + minor)*, 128.5 (major)*, 128.3 (minor)*, 128.18 (minor)*, 128.15 (major)*, 127.9 (major + minor)*, 127.0 (major + minor)*, 125.4 (minor), 125.2 (major), 123.5 (major), 123.4 (minor), 111.62 (major), 111.57 (minor), 106.33 (minor), 106.30 (major), 102.43 (major), 102.41 (minor), 96.9 (major), 96.7 (minor), 80.6 (minor), 80.5 (major), 72.43 (minor), 72.41 (major), 71.3 (major), 71.2 (minor), 68.50 (minor), 68.46 (major), 55.57 (major), 55.55 (minor), 51.9 (major), 51.7 (minor), 49.41 (major), 49.36 (minor), 44.4 (major + minor), 37.8 (major), 37.7 (minor), 35.8 (major), 35.6 (minor), 27.0 (major + minor), 26.90 (major), 26.87 (minor), 23.1 (major + minor), 22.63 (minor), 22.56 (major), 20.0 (major), 19.9 (minor) ppm; HRMS (ESI) calcd for C46H₄₃NOioNa⁺ [M+Na]⁺ 792.2779, found 792.2787. *Due to overlapping ¹³C chemical shifts of diastereomers, these signals could not be assigned with accuracy.

(l/?,7a'5,12a'S)-5',9'-Bis(benzyloxy)-6^7a'-dihydroxy-3^13',13'-trimethoxy-2,6,6-trimethyl- 12a',13'-dihydro- //-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-i ][l,2]oxazole]- Τ,$'(7Ά'Η,ΜΗ)- dione (+)-16 and (l/?,7a^,/?,12a^,/?)-5^,,9'-bis(benzyloxy)-6^,,7a^,-dihydroxy-3^,,13^,,13'- trimethoxy-2,6,6-trimethyl 2a^l3'-dihydro- //-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3- rf][l,2]oxazole]-7',8^,(7a'//,12^, )-dione (-)-17 (Nicolaou et al, 2013; Nicolaou et al., 2014): A solution of hydroxyl compound (-)-15 (450 mg, 584 μηιο1, 1.0 equiv, dr ca. 4:1) in THF (32mL) at -78 °C was added dropwise a solution of NaCNB¾ (148 mg, 2.35 mmol, 4.0 equiv) in THF (8 mL). The reaction mixture was stirred at -78 °C for 1.5 h, then quenched by addition of saturated aq. NH₄CI solution (20 mL) and allowed to warm to 25 °C. The mixture was diluted with water (40 mL) and extracted with EtOAc (3 x40 mL). The combined organic phases were dried over Na2S04, filtered, and concentrated under reduced presure. The crude material was then purified by preparative TLC (silica gel, 10% acetone in toluene) to give naphthol (-)-17 (224mg, 280 μιηο1, 48% yield) and its disteroisomer (+)-16 (56.0mg, 70.0μιηο1, 12%· yield) as yellow powders.

(l/?,7a'S,12a'S)-5',9'-Bis(benzyloxy)-6^7a'-d^

12a',13'-dihydro- //-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-i ][l,2]oxazole]-7',8'-

(7a'H,12'fl)-dione (+)-16: R_f=0.50 (silica gel, acetone: toluene 1 :4); [ ]^² = +103 (c=0.2, CH2CI2); FT-IR (film) v_mai: 3400, 2940, 2921, 1717, 1593, 1514, 1485, 1448, 1408, 1370, 1345, 1306, 1235, 1219, 1130, 1104, 1048, 998, 904, 820, 735, 696 cm^"1 ; H NMR (CDCI3, 600 MHz) δ 15.54 (s, 1 H), 7.60-7.57 (m, 2H), 7.49- 7.47 (m, 2 H), 7.42-7.30 (m, 6 H), 6.65 (s, 1 H), 5.70 (s, 1 H), 5.51 (bs, 1 H), 5.33 (s, 2H), 5.30 (s, 2H), 3.84 (s, 3 H), 3.82 (d, 7= 18.0Hz, 1 H), 3.44 (s, 3 H), 3.35 (dd, 7= 10.0, 7.3 Hz, 1 H), 3.16 (dd, 7= 19.0, 7.5 Hz, 1 H), 3.13 (s, 3 H), 2.97 (d, J= 18.3 Hz, l H), 2.87 (dd, 7= 19.0, 10.0Hz, l H), 2.26-2.21 (m, l H), 2.08-2.02 (m, 1 H), 1.84 (ap td, 7= 12.4, 6.0Hz, I H), 1.51 (s, 3 H), 1.34 (dd, 7= 12.6, 5.5Hz, I H), 0.88 (s, 3 H), 0.43 (s, 3 H) ppm; ¹³C NMR (CDCI3, 151 MHz) δ 193.4, 184.3, 179.2, 168.9, 168.0, 159.5, 159.3, 148.2, 137.2, 136.6, 135.14, 135.12, 128.8, 128.62, 128.60, 128.3, 128.0, 126.9, 123.5, 122.9, 121.3, 108.8, 107.3, 106.5, 102.5, 98.2, 78.4, 72.4, 71.6, 58.5, 55.5, 50.5, 48.0, 45.1, 43.4, 38.6, 34.1, 25.7, 24.01, 23.99, 23.0, 21.1 ppm; HRMS (ESI) calcd for C₄6H₄5NOioNa⁺ [M+Na]⁺ 794.2936, found 794.2955.

(l ?,7a' ?,12a' ?)-5',9'-Bis(benz lo )-6 7a'-dih drox -3 13 13'-trimethox -2,6,6-trimeth l- 12a',13'-dihydro-l'i/-spiro[cyclohex-2-ene-l,2^l-cyclopenta[6,7]tetraceno[2,3-i ][l,2]oxazole]-

7^,,8'(7a^,//,12'H)-dione (-)-17: R_f = 0.60 (silica gel, acetone:toluene 1 :4); [ ] =-70 (c= 0.2, CH2CI2); FT-IR (film) 3409, 2939, 1715, 1592, 1514, 1484, 1448, 1407, 1344, 1307, 1219, 1131, 1105, 1049, 994, 905, 735, 696 cm-¹; ¾ NMR (CDCI3, 600 MHz) δ 15.39 (s, 1 H), 7.62-7.56 (m, 2H), 7.49-7.45 (m, 2H), 7.42-7.39 (m, 2H), 7.38-7.30 (m, 4H), 6.66 (s, 1 H), 5.62 (bs, I H), 5.49 (bs, 1 H), 5.35-5.28 (m, 4H), 3.84 (s, 3 H), 3.49 (d, 7= 18.8 Hz, I H), 3.38-3.31 (m, 1 H), 3.35 (s, 3 H), 3.34 (s, 3 H), 3.16 (d, 7= 18.8 Hz, 1 H), 3.09 (dd, 7= 18.8, 7.4Hz, 1 H), 2.84 (dd, 7= 18.8, 8.4 Hz, 1 H), 2.25-2.21 (m, 1 H), 2.09-2.02 (m, 1 H), 1.79 (ddd, 7= 12.3, 12.3, 6.2Hz, I H), 1.45 (s, 3 H), 1.36 (dd, 7= 12.3, 5.9Hz, I H), 0.94 (s, 3 H), 0.48 (s, 3 H) ppm; ¹³C NMR (CDCI₃, 151 MHz) δ 193.9, 184.3, 179.3, 168.4, 168.0, 159.5, 159.3, 148.3, 137.4, 136.5, 135.2, 134.5, 128.8, 128.60, 128.55, 128.2, 128.0, 126.9, 123.6, 123.2, 120.8, 109.0, 107.7, 106.3, 102.4, 98.1, 78.3, 72.4, 71.5, 58.5, 55.5, 51.2, 48.2, 45.1, 43.8, 38.1, 34.2, 25.8, 24.7, 23.5, 23.0, 21.1 ppm; HRMS (ESI) calcd for C₄6H45NOioNa⁺ [ +Na]⁺ 794.2936, found 794.2954.

(lR,7a' ?,12a' ?)-5'^'-Bis(benzyloxy)-6 7a'-dihydroxy-3'-methoxy-2,6,6-trimethyl-12',12a'- dihydro-l'H-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-i/][l,2]oxazole]-7',8',13'(7a'ir⁾- trione (-)-18 (Nicolaou et al, 2013; Nicolaou et al, 2014): To a solution of ketal (-)-17 (155 mg, 201 μηιοΐ, l .O equiv) in THF (15 mL) was added 2 N aq. HC1 (1.6 mL). The reaction mixture was stirred at 25 °C for 5 h and was then diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic phase was washed with water (50 mL) and brine (50 mL), and then dried over Na2S0₄, filtered, and concentrated under reduced pressure to give analytically pure triketone (-)-18 (145 mg, 201 μκιοΐ, quant, yield) as a yellow foam. (-)-18: R_f=0.70 (silica gel, EtOAc:hexanes 2:3); [ \ =-27 (c= 0.1, CH₂C1₂); FT-IR (film) v_max: 3448, 2962, 2918, 1696, 1609, 1585, 1513, 1481, 1446, 1402, 1344, 1327, 1292, 1258, 1199, 1158, 1132, 1108, 1037, 908, 825, 731, 696 cm^"1; ¾ NMR (CDC1₃, 600 MHz) δ 13.91 (s, 1 H), 7.62-7.59 (m, 2H), 7.46-7.42 (m, 2H), 7.41-7.39 (m, 2H), 7.36 (m, 1 H), 7.34-7.28 (m, 3 H), 6.77 (s, 1 H), 5.49 (bs, 1 H), 5.33 (s, 2H), 5.29 (d, 7 = 12.0Hz, 1 H, AB system), 5.26 (d, 7= 12.0Hz, 1 H, AB system), 4.94 (s, 1 H), 3.89-3.82 (m, 5 H), 3.66 (d, 7=20.0 Hz, 1 H), 3.33 (dd, 7= 17.3, 4.8 Hz, 1 H), 3.15 (d, 7=20.0Hz, 1 H), 2.19 (m, 1 H), 2.03 (m, 1 H), 1.80 (ddd, 7= 12.7, 12.7, 6.2Hz, 1 H), 1.45 (s, 3 H), 1.30 (dd, 7= 12.7, 5.6Hz, 1 H), 0.88 (s, 3 H), 0.30 (s, 3 H) ppm; ¹³C NMR (CDCI3, 151 MHz) δ 195.5, 192.0, 184.8, 181.7, 168.1, 164.6, 159.4, 159.1, 147.7, 142.3, 136.2, 136.1, 135.0, 128.8, 128.6, 128.5, 128.24, 128.21, 127.2, 127.0, 121.8, 121.4, 110.2, 107.8, 105.3, 100.2, 78.5, 72.4, 71.7, 59.6, 55.6, 53.0, 45.5, 38.4, 34.0, 25.4, 24.2, 22.9, 20.9, 20.7 ppm; HRMS (ESI) calcd for C44H3₉N0₉Na⁺ [ +Na]⁺ 748.2517, found 748.2531.

(l/f,7a'5,8'5,12a' ?)-5',9'-bis(benz loxy)-6',7a',8'-trihydroxy-3'-methoxy-2,6,6-trimethyl- 7a',8',12',12a'-tetrahydro- //-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-rf][l,2]oxazole]- 7',13'-dione (-)-19 (Nicolaou et al, 2013; Nicolaou et al, 2014): To a solution of triketone (-)-18 (98.0mg, 135 μηιο1, l.O equiv) in anhydrous EtO Ac: acetone (1 :1, lOmL) at 25 °C was added sodium triacetoxyborohydride (34.1 mg, 162 μιηοΐ, 1.2 equiv) and the solution was warmed to 40 °C for 2 h. The reaction mixture was then allowed to cool to 25 °C, diluted with water (20 mL) and extracted with EtO Ac (20 mL). The organic phase was washed with water (lO mL) and brine (lOmL), dried over Na2SC , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, 10% acetone in toluene) to give diol (-)-19 (45.2mg, 62.1 μιηοΐ, 46%) as a yellow foam. (-)-19: R_f = 0.50 (silica gel, EtOAc:hexanes 3:7);

[a]p =-5 (c= 0.1, CH2CI2); FT-IR (film) v_max: 3475, 2961, 2920, 2855, 1693, 1662, 1586, 1512, 1483, 1446,

1403, 1341, 1293, 1260, 1199, 1162, 1132, 1113, 1036, 908, 732, 696 cirT¹; Ή NMR (CDCI3, 600 MHz) 5 14.41 (s, 1 H), 7.62-7.60 (m, 2 H), 7.46-7.43 (m, 2H), 7.40-7.31 (m, 6 H), 6.73 (s, 1 H), 5.49 (bs, 1 H), 5.36 (d, 7= 12.1 Hz, 1 H, AB system), 5.33 (d, 7= 12.1 Hz, 1 H, AB system), 5.27 (d, 7= 11.7 Hz, 1 H, AB system), 5.23 (d, 7= 11.7 Hz, 1 H, AB system), 4.59 (d, 7= 3.9Hz, 1 H), 4.17 (s, 1 H), 3.85 (s, 3 H), 3.82 (d, 7= 17.6 Hz, 1 H), 3.67 (d, 7=6.9 Hz, 1 H), 3.54 (d, 7= 19.5 Hz, 1 H), 3.24 (d, 7= 19.5 Hz, 1 H), 2.92 (dd, 7= 17.6, 6.9 Hz, 1 H), 2.19 (m, 1 H), 2.03 (m, 1 H), 1.82 (ddd, 7= 12.7, 12.7, 6.0Hz, 1 H), 1.68 (d, 7= 3.9Hz, 1 H), 1.46 (s, 3 H), 1.29 (dd, 7= 12.7, 6.0Hz, 1 H), 0.87 (s, 3 H), 0.31 (s, 3 H) ppm; ¹³C NMR (CDCI3, 151 MHz) 5201.1, 193.0, 169.6, 169.3, 164.8, 159.4, 159.3, 148.0, 138.8, 136.5, 136.4, 135.7, 128.9, 128.72, 128.68, 128.5, 128.2, 127.1, 126.5, 124.2, 121.5, 110.0, 109.9, 103.8, 99.5, 77.1, 71.8, 71.7, 68.5, 59.6, 55.6, 50.5, 44.9, 38.5, 34.0, 25.5, 24.2, 23.0, 21.0, 18.7 ppm; HRMS (ESI) calcd for C44H₄iN0₉Na⁺ [M+Na]⁺ 750.2674, found 750.2696.

(l ?,7a'5,8'R 2a'R)-5',9'-Bis(benzyloxy)-8'-{[fert-butyl(dimethyl)silyl]oxy}-6',7a'-dihydroxy-3'- methoxy-2,6,6-trimethyl-7a',8',12',12a'-tetrahydro- //-spiro[cyclohex-2-ene-l,2'-cyclo- penta[6,7]tetraceno[2,3-d][l,2]oxazole]-7',13'-dione (+)-20 (Nicolaou et al, 2013; Nicolaou et al, 2014): To a stirred solution of diol (-)-19 (28.0 mg, 38.0 μηιοΐ, 1.0 equiv) in CH2CI2 (2.8 mL) was added freshly distilled 2,6-lutidine (70.0 μί, 570 μηιο1, 15 equiv). The reaction mixture was cooled to 0 °C, and freshly distilled TBSOTf (85.0 380 μιηο1, 10 equiv) was added. The reaction mixture was allowed to warm to 25 °C and stirred for 15 minutes. Three additional portions of 2,6-lutidine (70μί, each) and TBSOTf (85 μί, each) were added to the reaction flask in 15 minute intervals (0°C to 25 °C) and the mixture was stirred for an additional 1 h at 25 °C. The reaction was then quenched by addition of saturated aq. NaHC0₃ solution (5 mL) (vigorous bubbling) and extracted with CH2CI2 (2 5 mL). The combined organic phasess were dried over Na₂S0₄, filtered, and concentrated under reduced pressure. Residual volatiles were then azeotropically removed with toluene (twice). The crude material was then purified by preparative TLC (silica gel, 5% acetone in toluene) to give the TBS-ether (+)-20 (24.2mg, 28.9 mmol, 76%) as a yellow foam. (+)-20: R_f =0.40 (silica gel, 5% acetone in toluene); [a]²² =+68 (c=0.1, CH2CI2); FT-IR (film) v_max: 3479, 2927, 2856, 1697, 1656, 1605, 1589, 1510, 1473, 1448, 1405, 1343, 1295, 1260, 1205, 1166, 1135, 1082, 1048, 838, 779, 736, 697 cm-¹ ; 'H NMR (CDC1₃, 600 MHz) δ 14.53 (s, 1 H), 7.61-7.57 (m, 2 H), 7.44-7.39 (m, 4H), 7.37-7.31 (m, 4 H), 6.72 (s, 1 H), 5.49 (bs, 1 H), 5.35 (d, 7= 12.1 Hz, 1 H, AB system), 5.32 (d, J= 12.1 Hz, 1 H, AB system), 5.28 (d, J= 11.5 Hz, 1 H, AB system), 5.21 (d, 7= 11.5 Hz, 1 H, AB system), 4.56 (s, 1 H), 4.02 (bs, 1 H), 3.91 (d, J= 17.9 Hz, 1 H), 3.84 (s, 3 H), 3.59 (d, 7=7.4 Hz, 1 H), 3.56 (d, /= 19.9 Hz, 1 H), 3.22 (d, 7= 19.9 Hz, 1 H), 2.86 (dd, 7= 17.9, 7.4Hz, 1 H), 2.19 (m, 1 H), 2.03 (m, 1 H), 1.84 (m, 1 H), 1.44 (s, 3 H), 1.27 (m, 1 H), 0.89 (s, 3 H), 0.33 (s, 3 H), 0.31 (s, 9 H), -0.26 (s, 3 H), -0.53 (s, 3 H) ppm; ¹³C NMR (CDCI3, 151 MHz) δ 202.2, 191.8, 169.5, 169.4, 165.1, 159.3, 159.2, 147.9, 138.5, 136.6, 136.4, 135.5, 129.0, 128.8, 128.7, 128.6, 128.1, 127.1, 126.4, 124.5, 121.4, 110.4, 109.7, 104.5, 99.8, 77.8, 71.9, 71.8, 69.2, 59.6, 55.5, 50.2, 45.1, 38.5, 34.0, 25.5, 25.2, 24.2, 23.0, 20.9, 18.4, 17.7, -5.47, -5.50 ppm; HRMS (ESI) calcd for C₅oH₅₅N09SiNa⁺ [ +Na]⁺ 864.3538, found 864.3553.

(l f,7a' ^,8'/^,12a'S)-5 9'-Bis(benz lox )-8'-{[ter but l(dimeth l)sil l]ox }-6 7a l2 '- trihydroxy-3'-methoxy-2,6,6-trimethyl-7a',8',12',12a'-tetrahydro- //-spiro[cyclohex-2-ene-l,2'-cyclo- penta[6,7]tetraceno[2,3-i/][l,2]oxazole]-7',13'-dione (+)-21 (Nicolaou et al, 2013; Nicolaou et al, 2014): A solution of TBS-ether (+)-20 (22 mg, 0.026 mmol, l .O equiv) in THF (0.4 mL) was cooled to -78 °C, and KHMDS solution (1 M in THF, 88 μί, 88 μηιοΐ, 3.4equiv) was added dropwise. After stirring for 1 h at -78 °C, freshly prepared recrystallized Davis oxaziridine (Vishwakarma et al, 1988) (26 mg, ΙΟΟ πιοΙ, 3.9 equiv) in THF (0.15 mL) was added, and the mixture was stirred for 2 h at -78 °C. Then, the reaction was quenched by addition of MeOH (0.2 mL), followed by dimethyl sulfide (0.1 mL) and saturated aq. NH₄CI solution (2.0 mL). The mixture was extracted with CH2CI2 (3 x 10 mL), and the combined organic layers were dried over MgSC , filtered, and concentrated under reduced pressure. Purification by preparative TLC (silica gel, 5% acetone in toluene), gave product (+)-21 (7.2 mg, 8.3 μιηοΐ, 32% yield, 55% yield brsm) as an orange foam and recovered contaminated starting material (+)-20, which was purified by a second preparative TLC with 1.25% acetone in

CH2CI2 [(+)-20, 9.2mg, Π μΓηοΙ, 42% yield]. (+)-21: R_f=0.40 (silica gel, acetone:toluene 1 :9); [0¾ =+27

(c= 0.1, CH2CI2); FT-IR (film) v_max: 3460, 2921, 2856, 1702, 1606, 1588, 1509, 1473, 1447, 1403, 1340, 1320, 1267, 1205, 1136, 1050, 910, 838, 780, 734, 696 cirT¹ ; H NMR (CDCI3, 600 MHz) δ 14.09 (s, 1 H), 7.59-7.57 (m, 2 H), 7.45-7.39 (m, 4 H), 7.38-7.33 (m, 4H), 6.72 (s, 1 H), 5.50 (bs, 1 H), 5.36 (d, /= 12.4 Hz, 1 H, AB system), 5.33 (d, J= 12.4 Hz, 1 H, AB system), 5.28 (d, J= 11. Hz, 1 H, AB system), 5.20 (d, J= 11.4 Hz, 1 H, AB system), 4.62 (s, 1 H), 4.29 (s, 1 H), 4.15 (d, /= 17.6 Hz, 1 H), 3.84 (s, 3 H), 3.55 (d, = 19.4Hz, l H), 3.22 (d, J= 19.4Hz, 1 H), 3.00 (s, 1 H), 2.68 (d, J= 17.6 Hz, 1 H), 2.19 (m, 1 H), 2.03 (m, 1 H), 1.84 (m, 1 H), 1.46 (s, 3 H), 1.28 (m, 1 H), 0.88 (s, 3 H), 0.35 (s, 3 H), 0.32 (s, 9 H), -0.26 (s, 3 H), -0.54 (s, 3 H) ppm; ¹³C NMR (CDCI₃, 151 MHz) 5200.8, 190.2, 169.7, 169.1, 164.2, 159.2, 159.1, 147.8, 140.4, 136.6, 136.4, 135.4, 129.1, 128.81, 128.76, 128.6, 128.1, 127.1, 126.5, 123.2, 121.4, 110.6, 109.8, 104.3, 100.1, 80.8, 77.5, 72.0, 71.8, 68.5, 59.7, 55.5, 44.9, 38.6, 34.0, 28.7, 25.4, 25.2, 24.2, 23.0, 20.9, 17.7, -5.4, -5.6 ppm; HRMS (ESI) calcd for C₅oH₅5NOioSiNa⁺ [M+Na]⁺ 880.3487, found 880.3528.

(l ?,7a' ?,8'S,12a'S)-5^9'-Bis(benzyloxy)-6^7a^8',12a'-tetrahydroxy-3'-methoxy-2,6,6-trimethyl- 7a',8',12^,,12a^,-tetrahydro- //-spiro[cyclohex-2-ene-l,2^,-cyclopenta[6,7]tetraceno[2,3-rf][l,2]oxazole]- 7',13'-dione (-)-22 (l ?,7a' f,8'S,12a'5,13'5)-5',9^,-bis(benzyloxy)-6',7a',12a',13'-tetrahydroxy-3'- methoxy-2,6,6-trimethyl- ,7a',8',12',12a',13'-hexahydro-7'H-spiro[cyclohex-2-ene-l,2'- [ll,14]dioxa[10]aza[8,13]epoxycyclopenta[6,7]tetraceno[2,3-rf][l,2]oxazol]-7'-one (-)-22' (Nicolaou et al, 2013; Nicolaou et al, 2014): Diol (+)-21 (8.3 mg, 9.7 μιηοΐ, l .O equiv) was dissolved in MeCN (0.3 mL) in a plastic vial and cooled to 0 °C. HF- pyridine (70% HF in pyridine, 16 lh) was added, and the mixture was warmed to 55 °C. After 2 h, 8 h, and 14 h, an additional portion of HF 'pyridine (70% HF in pyridine, 40 [lL each; 0 to 55 °C) was added. After 20 h the reaction mixture was allowed to cool to 25 °C, diluted with EtOAc (4 mL), and carefully quenched by addition of saturated aq. NaHCC solution (4 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 x 15 mL). The combined organic phases were dried over MgSC filtered, and concentrated under reduced pressure. Purification by preparative TLC (silica gel, 20% acetone in toluene) afforded triol (-)-22/(-)-22' (5.2 mg, 7.0 μιηοΐ, 72% yield) as a yellow foam. *(-)-

22/(-)-22': R_f = 0.40 (silica gel, acetone:toluene 1 :9); [α ² =-42 (c=0.1, CH₂C1₂); FT-IR (film) v_max: 3460,

2923, 1698, 1590, 1513, 1483, 1448, 1403, 1341, 1323, 1264, 1205, 1 134, 1044, 816, 738, 697 cm-¹; 'H NMR (CDCI3, 600MHz, 298 K) 514.02 (bs, 1 H), 7.61-7.58 (m, 2H), 7.46-7.28 (m, 8 H), 6.73 (s, 1 H), 5.50 (bs, 1 H), 5.34 (d, J= 12.1 Hz, 1 H, AB system), 5.31 (d, / = 12.1 Hz, 1 H, AB system), 5.35-5.12 (m, 2 H), 5.10-2.80 (m, 5 H), 3.85 (s, 3 H), 2.76 (d, J= 17.3 Hz, 1 H), 2.19 (m, 1 H), 2.03 (m, 1 H), 1.83 (m, 1 H), 1.47 (s, 3 H), 1.29 (m, 1 H), 0.88 (s, 3 H), 0.37 (bs, 3 H) ppm; ¹³C NMR (151 MHz, CDCI3, 298 K) 5 199.7, 171.2, 169.2, 159.4 (b), 159.2, 147.7, 136.4, 136.1, 135.6, 128.7, 128.6, 128.5, 128.3, 127.1, 126.9, 121.6, 1 10.0, 99.8, 71.7, 71.6, 59.7, 55.5, 44.5, 38.5, 33.9, 33.5, 31.9, 29.6, 29.5, 29.4, 29.2, 29.1, 25.4, 24.7, 24.1, 22.8, 22.7, 21.1 ppm; HRMS (ESI) calcd for C44H₄iNOioNa⁺ [M+Na]⁺ 766.2623, found 766.2640. * Without wishing to be bound by any theory, it is believed that the hydroxy ketone 22 exists in equilibrium with its cyclic hemiacetal isomer 22'. At T = 298 K, slow interconversion between these two species is observed in CDCI3, which results in broad signals in the ¾ and ¹³C NMR spectra. Due to signal broadening, not all the ¾ and ¹³C signals could be identified with accuracy (Nicolaou et al, 2013; Nicolaou et al, 2014).

(l/?,7a7 2a'S)-5\9'-Bis(benzyloxy)-6\7a\12a^

dihydro-r//-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-d][l,2]oxazole]-7',8',13'(7a'//)- trione (-)-23 (Nicolaou et al, 2013; Nicolaou et al, 2014): A solution of triol (-)-22/(-)-22' (5.0 mg, 6.7 μιηοΐ, l .O equiv) in (Qt Ck (DCE, 360 μΐ,) was cooled to 0 °C, and Dess-Martin periodinane⁴⁰ (0.3 M solution in CH2CI2, 27 μί, 3.4 mg, 8.1 μπιοΐ, 1.2 equiv) was added. After stirring for 30 minutes at 0 °C, the mixture was allowed to warm up to 25 °C and stirred for 1.5 h. Then, the reaction mixture was warmed up to 50 °C, and one additional portion of Dess-Martin periodinane (0.3 M solution in CH2CI2, 14 μί, 1.7mg, 4.1 μηιοΐ, 0.6 equiv, 0 to 50 °C) was added after 1 h. After 2 h at 50 °C, TLC analysis indicated complete conversion. The reaction mixture was allowed to cool to 25 °C, and then quenched by addition of saturated aq. NaHC03:saturated aq. Na2S203 solution (1 : 1, 5 mL). The phases were separated, and the aqueous phase was extracted with CH2CI2 (2 x5 mL). The combined organic phases were washed with brine (5 mL), dried over MgSC , filtered, and concentrated under reduced pressure. Purification by preparative TLC (silica gel, 5% acetone in CH2CI2) afforded triketone (-)-23 (4.1 mg, 5.5 μταοΐ, 82% yield) as a yellow powder. (-)-23: Rf=0.50 (silica gel, acetone:toluene 1 :9); [α]£ =-107 (c=0.1, CH₂C1₂), FT-IR (film) v_milx: 3451, 2919, 1715, 1613, 1586, 1516, 1485, 1447, 1403, 1342, 1274, 1203, 1186, 1140, 1091, 1027, 965, 737, 696 cm-'; H NMR (CD2CI2, 600 MHz) δ 14.11 (s, 1 H), 7.61-7.58 (m, 2 H), 7.54-7.42 (m, 2H), 7.47-7.39 (m, 5 H), 7.36 (m, 1 H), 6.85 (s, l H), 5.54 (bs, 1 H), 5.37 (s, 2H), 5.35-5.30 (m, 2 H), 4.63 (s, l H), 4.29 (s, 1 H), 4.05 (d, /= 18.9 Hz, 1 H), 3.90 (s, 3 H), 3.42 (d, J= 18.4Hz, 1 H), 3.16 (d, J= 18.4 Hz, 1 H), 3.06 (d, /= 19.8 Hz, 1 H), 2.24 (m, l H), 2.09 (m, 1 H), 1.89 1.89 (ap td, 7= 11.8, 5.7 Hz, 1 H), 1.49 (s, 3 H), 1.40 (dd, J = 12.9, 5.7Hz, 1 H), 0.94 (s, 3 H), 0.46 (s, 3 H) ppm; ¹³C NMR (CD2CI2, 151 MHz) δ 194.9, 194.7, 185.1, 179.1, 167.9, 166.8, 160.5, 159.9, 147.9, 143.7, 136.7, 136.4, 135.5, 129.2, 129.06, 129.05, 128.97, 128.5, 127.54, 127.47, 122.1, 118.2, 110.4, 108.6, 106.4, 100.7, 83.9, 81.0, 73.1, 72.0, 60.3, 56.0, 44.5, 38.7, 34.8, 34.4, 25.6, 24.4, 23.3, 20.9 ppm; HRMS (ESI) calcd for C₄₄H₃9NOioNa⁺ [M+Na]⁺ 764.2466, found 764.2489.

(l ?,7a' ? 1a'5)-5\6\7a^,,10\lla'-Pentahydroxy-3'-methoxy-2,6,6-trimethyl-7\8\12'-trioxo- 7\7a 8 ll^lla 12'-hexahydro ^-spiro[cyclohex-2-ene-l,2'-cyclopenta[i/e]tetracene]-9'-carboxamide [Synthetic (-)-viridicatumtoxin B, (-)-l] (Nicolaou et al, 2013; Nicolaou et al, 2014): Triketone R-23 (4.0 mg, 5.4 μιηοΐ, l.O equiv) was dissolved in anhydrous l,4-dioxane:MeOH (1 : 1, 1.0 mL) under argon and Pd black (2.8 mg, 26.5 μπιοΐ, 4.9 equiv) was added. The suspension was degassed, placed under a hydrogen atmosphere, and stirred for 10 minutes at 25 °C, after which time the hydrogen balloon was removed, the flask was flushed with argon and the suspension was filtered (Celite^®; MeOH:CH2Cb 1 :9). The resulting solution was concentrated under reduced pressure to give crude product [(-)-l] (4.2 mg). This product was purified by reverse-phase preparative HPLC (Shimazu HPLC, Atlantis prep T3 OBD column, 16 x 150 mm, 5 μιη particle size, 5 mL/min, 85% MeCN in H₂0 + 0.07% TFA buffer, λ=220 nm: t= 10.643 mm) to provide pure (-)- viridicatumtoxin B [(-)-l, 2.9 mg, 5.1 μιηοΐ, 96%] as a yellow powder, (-)-l: R_f=0.10 (silica gel,

MeOH:CH₂Ci2 1 :9); [a]²² =-116 (c= 0.1, EtOH), FT-IR (film) 3423, 2921, 2855, 1623, 1587, 1491,

1449, 1400, 1260, 1190, 1142, 1089, 798 cm-¹ ; ¾ NMR (CDCb, 600 MHz) δ 17.89 (s, 1 H), 14.72 (s, 1 H), 9.20 (s, 1 H), 8.74 (s, 1 H), 6.80 (s, 1 H), 6.02 (bs, 1 H), 5.53 (bs, 1 H), 4.03 (d, J= 19.8 Hz, 1 H), 3.90 (s, 3 H), 3.11 (d, 7= 18.8 Hz, 1 H), 3.04 (d, J- 19.8 Hz, 1 H), 2.81 (d, /= 18.8 Hz, 1 H), 2.22 (m, 1 H), 2.07 (m, 1 H), 1.86 (m, 1 H), 1.46 (s, 3 H), 1.40 (m, 1 H), 0.93 (s, 3 H), 0.46 (s, 3 H) ppm; ¹³C NMR (CDCb, 151 MHz) δ 195.2, 194.3, 192.8, 188.8, 173.0, 165.4, 161.3, 158.4, 146.4, 144.8, 135.8, 127.3, 122.0, 117.1, 107.3, 106.9, 102.6, 99.7, 80.7, 77.7, 60.6, 55.8, 44.6, 42.1, 38.5, 34.2, 25.6, 24.5, 23.0, 20.9 ppm; HRMS (ESI) calcd for C₃oH₂9NOioNa⁺ [ +Na]⁺ 586.1584, found 586.1681. Enantioselective Total Synthesis and Absolute Configuration of (+)-Viridicatumtoxin B

Scheme 16. Enantioselective Synthesis of the BCDEF Fragment (6R,15S)-4 of (+)-Viridicatumtoxin B and Its Absolute Configuration

Note: to avoid confusion, the numbering on (6R, 175)-6, (6/?,15S)-4 and (+)-9 in this Scheme is based on the viridicatumtoxin numbering, as opposed to the carbon numbering of compound (10/?,145)-6, which is the same compound (65,17/?)-6, but numbered based on the anthrone numbering.

(10/?)-l-(Benzyloxy)-10-{[(3R)-3-{[teri-butyl(dimethyl)silyl]oxy}-2,6,6-trimethylcyclohex-l-en-l- yl]methyl}-8-hydroxy-3,5-dimethoxyanthracen-9(10 /)-one [(6R,17S)-6\: To a stirred mixture of anthrone 7 (6.02g, 16.0mmol, l .O equiv), allylic bromide (5)-8 (6.12 g, 17.6 mmol, l .l equiv) and PTC17 (44.0mg, 80.0 μmol, 0.005 equiv) in (Cl^teCk (160mL) under argon, was added 50% aq. KOH (48 mL) dropwise at -30 °C. The reaction mixture was stirred vigorously at -30 °C for 240 h (10 days). The mixture was then quenched by addition of water (300 mL) and extracted with CH2CI2 (3 x 300 mL). The organic phase was washed with brine, dried over anhydrous a2S04, and concentrated under reduced pressure. Purification of the residue by flash column chromatography on silica gel (10% EtOAc:hexanes) gave chiral alkylated anthrone (6R,17S)- 6 (6.49g, 11.7 mmol, 73% yield, 95:5 dr) as a yellow foam. Compound (6 ?,175)-6 is the same as (10 f,145)-6, the latter is numbered based on the anthrone numbering. The diastereomeric ratio of the product (6R,175)-6 was determined by HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 98/2, 220 nm): 5.36 min for (6R,nS)-6; 9.66 min for (65,175)-6. (see below).

This material was enriched by crystallization from hexanes [precipitating crystals were racemic (17S)- 6 while the mother liquor contained the enriched (6R,17S)-6 (5.91 g, 10.6 mmol, 91% yield, > 99: 1 dr) (see below). (6R,17S)-6: [ f^ =-95.1 (c= 1.0, CH2CI2 95:5 dr). The other physical and spectroscopic data of this compound matched those mentioned above for (10R,14S)-6.

(25,10b/?)-5-(Benzyloxy)-7-hydroxy-3,10-dimethoxy-2',6^,,6'-trimethyl-l,10b-dihydro-6//- spiro[aceanthrylene-2,l'-cyclohex[2]en]-6-one [(6/f,15S)-4]: Chiral alkylated anthrone (6fl,17S)-6 (5.00 g, 7.78 mmol, l .O equiv) was dissolved in CH2CI2 (500 mL) and cooled to -78 °C. A freshly prepared solution of BF3^#OEt2 (3.9 mL of a 0.1 M in CH2CI2, 390 ηιο1, 0.05 equiv) was added dropwise, and the reaction mixture was slowly warmed to 0 °C and stirred at this temperature for 0.5 h. The reaction was quenched by addition of saturated aq. NaHC0₃ solution (300 mL), and the phases were separated. The aqueous phase was extracted with CH2CI2 (300 mL), and the combined organic layers were dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 5%→10% EtOAc:hexanes) to give chiral BCDEF spirocycle (6R,155)-4 (3.02 g, 5.91 mmol, 76% yield, 99.2:0.8 er) as a yellow foam. The enantiomeric ratio was determined by HPLC (Chiralcel OD-H, 25 °C, flow rate: 1 mL/min, hexanes/iPrOH: 90/10, 220 nm): 7.29 min for (6fl,15S)-4; 9.79 min for (65,15/f)-4. (see below). (6/f,15S)-4:

=-64.8 (c= 1.0, CH2CI2, 99.2:0.8 er). The other physical and spectroscopic data of this compound were identical to those mentioned above for compound (65,15 ?)-4.

(25)-5-(Benz lox )-7-hydroxy-3 0-dimethoxy-2',6',6'-trimethyl-6 /-spiro[aceanthrylene-2, - cyclohex[2]en]-6-one (+)-9: Spirocycle (6R,15S)-4 (3.00g, 5.88 mmol, l .O equiv) was dissolved in MeOH:CH₂Cl₂ (1: 1, 120 mL), and the solution was cooled to 0 °C. Freshly prepared PhI(OAc)₂ ³⁷ (2.27 g, 7.05 mmol, 1.2 equiv) was added and the reaction mixture was stirred for 30 minutes at 0 °C and for 30 additional minutes at 25 °C. The reaction was quenched by addition of saturated aq. NaHC0₃ (300 mL) and extracted with EtOAc (2 x300mL). The combined organic phases were washed with brine (150 mL), dried over Na₂S0₄, and concentrated under reduced pressure. The so-obtained crude ketal was dissolved in CH₂C1₂ (120 mL), and freshly crystallized CS A (95.0 mg, 0.410 mmol, 0.07 equiv) was added at 0 °C. The reaction mixture was stirred at 0 °C for 5 minutes and was then quenched by addition of saturated aq. NaHCC solution (100 mL). The layers were separated, and the organic phase was dried over Na₂S0₄, filtered, and concentrated under reduced pressure to give crude product (+)-9. Flash column chromatography (silica gel, 2% EtOAc:toluene) gave pure intermediate (+)-9 (2.39 g, 4.70mmol, 80% yield for two steps) as ared solid. Compound (+)-9 is the enantiomer of compound (-)-9, The enantiomeric ratio was determined by HPLC (Chiralcel OD-H, 25 °C, flow rate: 1 mL/min, hexanes/ZPrOH: 90/10, 220 nm): 9.07 min for (-)-9 [(15S)-9], 9.65 min for (15/f)-24., 9.14 min for (+)-9 [(15/0-9]. (+)-9: [a]²² =+132 (c= 0.05, CH₂C1₂); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (-)-9.

(25)-5-(Benzyloxy)-3,10-dimethoxy-2',6',6'-trimethyl-6-oxo-6/ -spiro[aceanthrylene-2, - cyclohex[2]en] -7-yl 4-bromobenzoate (+)-l 1 : To a solution of quinomethide (+)-9 (20 mg, 39 pmol, 1.0 equiv) in CH2CI2 (3 mL) was added 4-bromobenzoyl chloride 10 (44 mg, 0.20 mmol, 5 equiv), 4- dimethylaminopyridine (DMAP, 48 mg, 0.39 mmol, lOequiv) and triethylamine (E13N, 170pL, 120mg, 1.2 mmol, 30 equiv). The reaction mixture was stirred at 25 °C for 6 h before it was quenched by addition of saturated aq. NaHC0₃ solution (6 mL) and extracted with CH₂C1₂ (2 x6 mL) . The combined organic phases were dried over Na₂S0₄, and concentrated under reduced pressure. Flash column chromatography (silica gel, 5% EtOAc:hexanes) gave protected p-bromobenzoate (+)-ll (26 mg, 37 ηιο1, 95% yield) as a yellow solid. Crystalization from CFbCk/hexanes 1 :4 gave crystals suitable for X-ray crystallographic analysis, which revealed its absolute configuration as shown below (FIG. 6).

(+)-ll: [0C]p =+88 (c= 0.1, CH₂C1₂); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (-)-ll. Scheme 17. Total Synthesis of Enantio ure (+)-Viridicatumtoxin B [(+)-!]

(+)-23 [(⁺)-¹] [(+)viridicatumtoxin B]

(25)-5-(Benzyloxy)-3,10,10-trimethoxy-2',6',6'-trimeth l-6/ -spiro[aceanthrylene-2, - cyclohex[2]ene]-6,7(10 /)-dione (+)-12 (Nicolaou et al, 2013; Nicolaou et al, 2014): Quinomethide (+)-9 (2. lOg, 4.13 mmol, l .O equiv) was dissolved in a mixture of CthCb MeOH (1 :10; 88 mL), and freshly prepared PhI(OAc)2³⁷ (l -60g, 4.96 mmol, 1.2 equiv) was added. The reaction mixture was stirred at 25 °C for 1.5 h and was then quenched by addition of saturated aq. NaHCC solution (80 mL). The mixture was diluted with water and extracted with CH2CI2 (160mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, 10% acetone in toluene, 0.1 % L¾N) to give diketone ketal (+)-12 (1.99g, 3.68 mmol, 89% yield) as a yellow solid. (+)-12: [CC] ² = +138 (c=0.1, CH2CI2); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (-)-12.

2-(Trimethylsilyl)ethyl (15,12^,5,12a^,5)-5^,,9^,-bis(benzyloxy)-7^,-hydroxy-3',13^,,13^,-trimethoxy- 2,6,6-trimethyl-6^8'-dioxo-8',12',12a',13'-tetrahydro-6' /-spiro[cyclohex-2-ene-l,2'- cyclopenta[6,7]tetraceno[2,3-rf][l,2]oxazole]-12'-carboxylate (-)-13 (ca. 4:1 mixture of C15-C4/C4a diastereomers): To a solution of pentacycle (+)-12 (1.50g, 2.76 mmol, l .O equiv), potassium ferf-butoxide (372 mg, 3.31 mmol, 1.2 equiv) and PTC-14 (14.7 mg, 27.6 μιηο1, 0.01 equiv) in toluene (28 mL) under argon was added dropwise a solution of phenyl ester isoxazole 5^j0 (1.38 g, 3.04 mmol, 1.1 equiv) in toluene (28 mL) at -78 °C, and the resulting solution was then warmed to -50 °C and stirred at this temperature for 48 h. Then, the reaction was quenched by addition of saturated aq. NH₄CI solution (60 mL). The phases were separated, and the organic phase was dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, 2%→5% acetone in toluene) to give product (-)-13 (2.18 g,

2.40 mmol, 87% yield, dr ca. 4: 1) as a yellow foam. (-)-13: [a =-157 (c=0.1, CH2CI2); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (+)-13. OBn 0 OH 0 ^L

(+)-14 (dr ca. 4:1)

(1 ,12a^,S)-5 9^,-Bis(benzylox )-7^,-hydrox -3 13 13^,-trimethoxy-2,6,6-trimethyl-12a^,,13^,- dihydro-6'/ -spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-d][l,2]oxazole]-6',8'(12'/ )-dione (+)-14 (ca. 4:1 mixture of C15-C4a diastereomers) [Nicolaou et al, 2013; Nicolaou et al, 2014]: A solution of Teoc-heptacycle (-)-13 (2.00g, 2.23 mmol, 1.0 equiv, d.r. ca. 4:1) and N¾F (1.69 g, 44.6mmol, 20 equiv) in THF (250 mL) was degassed three times with argon at -78 °C, and the reaction flask was shielded from light using aluminum foil. A freshly prepared solution of tetra-n-butylammonium fluoride (22.3 mL, 1 M solution in THF, 22.3 mmol, 10 equiv, prepared from TBAF 3H₂O) was added in one portion at -78 °C. The reaction mixture was warmed to 25 °C and stirred for 10 minutes. The reaction was then quenched by addition of brine (150mL) and extracted with EtOAc (150mL). The layers were separated, and the organic phase was washed with water (3 x 120mL), dried over Na₂S0₄, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, 2%→5% acetone in toluene) to give heptacycle (+)-14

(1.42g, 1.90mmol, 85% yield, dr ca. 4:1) as an orange foam. (+)-14: [αβ² =+26 (c=0.05, CH₂C1₂); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (-)-

14.

(15,7a^,12a^,S)-5^9^,-Bis(benzyloxy)-7a^,-hydroxy-3\13^13^,-trimethoxy-2,6,6-trimethyl-12a^,,13'- dihydro-6'H-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-ifl[l,2]oxazole]-6',7',8'(7a'//,12' /)- trione (+)-15 (ca. 4:1 mixture of C15-C4a C12a diastereomers): To a stirred solution of compound (+)-14 (l -60g, 2.11 mmol, 1.0 equiv, dr ca. 4:1) in THF (lOOmL) under argon was added a solution of Ni(acac)2 (109 mg, 0.424 mmol, 0.2 equiv) in THF (10 mL). The resulting mixture was stired for five minutes at 25 °C, and then cooled to -78 °C. DMDO (Murray and Singh, 1997) (-0.08 M solution in acetone , 80 mL, -6.33 mmol, 3.0 equiv) was added dropwise at -78 °C. The reaction mixture was stired at -78 °C for 3 h, and then quenched by addition of dimethylsulfide (5.0 mL, 4.20 g, 68.0 mmol, 32 equiv), and the mixture was stirred at -78 °C for 15 minutes. Saturated aq. NH₄CI solution (TOOmL) was added, and the mixture was allowed to warm to 25 °C. The resulting mixture was diluted with water (150 mL) and extracted with EtOAc (3 x lOOmL). The layers were separated, and the organic phase was washed with water (250 mL) and brine (250 mL), dried over N ₂S04, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 3%→5%→10% acetone in toluene) gave the hydroxylated product (+)-15 (840 mg, 1.09 mmol, 52% yield, 72% yield brsm, dr ca. 4: 1) as an orange powder, and recovered starting material (+)-14 (448 mg, 591 μιηοΐ, 30% yield). (+)-15: [( ]p = +116.5 (c=0.2, CH2CI2); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound

(15,7a^,/^,12a^,/^)-5 9^,-Bis(benz lox )-6 7a^,-dih drox -3 13 13^, rimethox -2,6,6-trimeth l- 12a',13'-dihydro-l'i/-spiro[cyclohex-2-ene-l,2^l-cyclopenta[6,7]tetraceno[2,3-ii][l,2]oxazole]-

7',8^,(7a^,#,12'H)-dione (-)-16 and (15,7a^,S,12a^,5)-5^, _?9^,-bis(benzyloxy)-6^,,7a^,-dihydroxy-3^,,13^,,13'- trimethoxy-2,6,6 rimethyl 2a',13'-dihydro- /-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3- <fl[l,2]oxazole]-7',8'(7a'ff,1277)-dione (+)-17 (Nicolaou et al, 2013; Nicolaou et al, 2014): To a solution of alcohol (+)-15 (770mg, l .OO mmol, 1.0 equiv, dr ca. 4: 1) in THF (50 mL) at -78 °C was added dropwise a solution of NaCNBH3 (252mg, 4.00 mmol, 4.0 equiv) in THF (12mL). The reaction mixture was stirred at -78 °C for 1.5 h, then quenched by addition of saturated aq. NH4CI solution (30 mL) and allowed to warm to 25 °C. The mixture was diluted with water (50 mL) and extracted with EtO Ac (3 x50mL). The combined organic phases were dried over Na2SC , filtered, and concentrated under reduced pressure. The crude material was purified by preparative TLC (silica gel, 10% acetone in toluene) to give naphthol (+)-17 (376 mg, 0.470 mmol, 47% yield) and its diasteroisomer (-)-16 (96.0 mg, 0.120 mmol, 12% yield) both as yellow powders.

(15,7a 7?,12a '/?)-5',9'-Bis(benzyloxy)-6^,,7a'-dihydroxy-3',13',13'-trimethoxy-2,6,6-trimethyl- 12a',13'-dihydro- //-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-J][l,2]oxazole]-

7',8'(7a7/,12'H)-dione (-)-16: [OC]^² =-101 (c=0.2, CH₂C1₂); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (+)-16.

(15,7a'5,12a'5)-5',9'-Bis(benzyloxy)-6^7a'-dihydroxy-3',13',13'-trimethoxy-2,6,6-trimethyl- 12a',13'-dihydro- //-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-i ][l,2]oxazole]-7',8'-

(7a'#,12'H)-dione (+)-17: [CC]_Q = +71 (c=0.2, CH2CI2); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (-)-17.

(15,7a'S,12a'5)-5\9^,-Bis(benzyloxy)-6\7a'-dihydroxy-3'-methoxy-2,6,6-trimethyl-12',12a'- dihydro-l'H-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-i/][l,2]oxazole]-7',8',13'(7a'ir⁾- trione (+)-18 (Nicolaou et al., 2013; Nicolaou et al, 2014): To a stirred solution of ketal (+)-17 (230mg, 290 pmol, 1.0 equiv) in THF (23 mL) was added 2 N aq. HCl (2.5 mL). The reaction mixture was stirred at 25 °C for 5 h and was then diluted with water (50 mL) and extracted with EtOAc (100 mL). The organic phase was washed with water (100 mL) and brine (100 mL), and then dried over Na2S04, filtered, and concentrated under reduced pressure to give essentially pure triketone (+)-18 (210mg, 290 pmol, quant, yield) as a yellow foam.

(+)-18: [0t]p =+28 (c=0.1, CH2Q2); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (-)-18.

(15,7a^,R,8^,R,12a^,5)-5',9^,-Bis(benzyloxy)-6^,,7a',8^,-trihydroxy-3^,-methoxy-2,6,6-trimethyl- 7a',8',12',12a'-tetrahydro- /-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-rf][l,2]oxazole]- 7',13'-dione (+)-19 (Nicolaou et al, 2013; Nicolaou et al, 2014): To a stirred solution of triketone (+)-18 (196 mg, 280 pmol, l.O equiv) in anhydrous EtOAc:acetone (1 : 1, 20 mL) at 25 °C was added sodium triacetoxyborohydride (68.0 mg, 336 pmol, 1.2 equiv) and the solution was warmed to 40 °C for 2 h. The reaction mixture was then allowed to cool to 25 °C, diluted with water (30 mL) and extracted with EtOAc (30 mL). The organic phase was washed with water (20 mL) and brine (20 mL), dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, 10% acetone in toluene) to give dihydroxy naphthol (+)-19 (92.2 mg, 126 μηιο1, 47% yield) as a yellow foam. (+)-19: [(¾ =+6 (c=0.1,

CH2CI2); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (-)-19.

(15,7a^,8'R,12a^,5)-5^9^,-Bis(benzyloxy)-8^,-{[fert-butyl(dimethyl)silyl]oxy}-6^,,7a'-dihydroxy-3'- methoxy-2,6,6-trimethyl-7a',8',12',12a'-tetrahydro- -spiro[cyclohex-2-ene-l,2'-cyclopenta- [6,7]tetraceno[2,3-i ][l,2]oxazole]-7',13'-dione (-)-20 (Nicolaou et al, 2013; Nicolaou et al, 2014): To a stirred solution of dihydroxy naphthol (+)-19 (65.5 mg, 90.0 μιηο1, l .O equiv) in CH2Q2 (3.3 mL) was added freshly distilled 2,6-lutidine (160 μί, 1.35 mmol, 15 equiv). The reaction mixture was cooled to 0 °C, and freshly distilled TBSOTf (200 ] L, 900 μιηοΐ, 10 equiv) was added. The reaction mixture was allowed to warm to 25 °C and stirred for 15 minutes. Three additional portions of 2,6-lutidine (160 μΐ_^, each) and TBSOTf (200 μΐ_^, each) were added to the reaction flask in 15 minute intervals (0 °C to 25 °C) and the mixture was stirred for an additional 1 h at 25 °C. The reaction was then quenched by addition of saturated aq. NaHC0₃ solution (10 mL) (vigorous bubbling) and extracted with CH2CI2 (2 x l0mL). The combined organic phases were dried over Na₂S0₄, filtered, and concentrated under reduced pressure. Residual volatiles were azeotropically removed with toluene (twice). The crude material was then purified by preparative TLC (silica gel, 5% acetone in toluene) to give TBS-ether (-)-20 (57.3 mg, 68.2 μιηο1, 75% yield) as a yellow foam. (-)-20: [a]^ =-67 (c=0.1, CH2CI2); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (+)-20.

(15,7a'S,8^,/?,12a^,R)-5^9^,-Bis(benzyloxy)-8^,-{[ter^butyl(dimethyl)silyl]oxy}-6^,,7a',12a'- trihydroxy-3'-methoxy-2,6,6 rimethyl-7a',8',12',12a'-tetrahydro- //-spiro[cyclohex-2-ene-l,2'-cyclo- penta[6,7]tetraceno[2,3-i/][l,2]oxazole]-7',13'-dione (-)-21 (Nicolaou et al, 2013; Nicolaou et al, 2014): A solution of TBS-ether (-)-20 (66.5 mg, 79.0 μηιο1, l .O equiv) in THF (1.4mL) was cooled to-78 °C, and KHMDS solution (1 M in THF, 270 μί, 270μιηο1, 3.4 equiv) was added dropwise. After stirring for 1 h at -78 °C, freshly prepared recrystallized Davis oxaziridine (Vishwakarma et al, 1988) (80.0mg, 312 μmol, 3.9 equiv) in THF (0.4 mL) was added and the mixture was stirred for 2 h at -78 °C. The reaction was quenched by addition of MeOH (0.3 mL), followed by dimethyl sulfide (0.2 mL) and saturated aq. NH₄CI solution (3.0 mL). The mixture was extracted with CH2CI2 (3 20mL) and the combined organic layers were dried over MgSC , filtered, and concentrated under reduced pressure. Purification by preparative TLC (silica gel, 5% acetone in toluene, then 1.25% acetone in CH2CI2 for the recovered starting material and 5% acetone in CH2CI2 for the product) afforded dihydroxy naphthol (-)-21 (20.3 mg, 23.7 μιηο1, 30% yield, 51 % yield brsm) as an orange foam and recovered starting material (-)-20 (27.5 mg, 32.0 μιηο1, 41 % yield). (-)-21: [0C]_p =-28 (c= 0.1, CH2CI2); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (+)-21.

(15,7a'5,8'/?,12a' ?)-5',9'-Bis(benzyloxy)-6',7a',8',12a'-tetrahydroxy-3'-methoxy-2,6,6-trimethyl- 7a',8',12',12a'-tetrahydro- //-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-rf][l,2]oxazole]- 7',13'-dione (+)-22/(15,7a'5,8'/?,12a ?,13'/?)-5',9'-bis(benzyloxy)-6',7a',12a',13'-tetrahydroxy-3'- methoxy-2,6,6-trimethyl-r,7a',8',12',12a',13'-hexahydro-7'i -spiro[cyclohex-2-ene-l,2'- [ll,14]dioxa[10]aza[8,13]epoxycyclopenta[6,7]tetraceno[2,3-rf][l,2]oxazol]-7'-one (+)-22' (Nicolaou et al, 2013; Nicolaou et al, 2014): Dihydroxy naphthol (-)-21 (11.7 mg, 13.6 μηιο1, l .O equiv) was dissolved in MeCN (0.4 mL) in a plastic vial and cooled to 0 °C. HF' pyridine (70% HF in pyridine, 0.02 mL) was added while stirring and the mixture was warmed to 55 °C. After 2 h, 8 h, and 14 h, an additional portion of HF' pyridine (70% HF in pyridine, 0.05 mL each ; 0 to 55 °C) was added. After 20 h the reaction mixture was allowed to cool to 25 °C, diluted with EtOAc (5 mL), and carefully quenched by addition of saturated aq. NaHCC>3 solution (5 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 x 15 mL). The combined organic phases were dried over MgSCU, filtered, and concentrated under reduced pressure. Purification by preparative TLC (silica gel, 20% acetone in toluene) afforded triol (+)-22/(+)-22'

(7.5 mg, ΙΟ μπιοΙ, 74% yield) as a yellow foam. [O]^ = +44 (c=0.1, CH2CI2); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (-)-22/(-)-22'.

(15,7a^,S,12a^,R)-5^9^,-Bis(benzyloxy)-6^7a\12a^,-trihydroxy-3^,-methoxy-2,6,6-trimethyl-12^,,12a'- dihydro-r//-spiro[cyclohex-2-ene-l,2'-cyclopenta[6,7]tetraceno[2,3-ifl[l,2]oxazole]-7',8',13'(7a' /)- trione (+)-23 (Nicolaou et al, 2013; Nicolaou et al, 2014): To a stirred solution of triol (+)-22/(+)-22' (7.1 mg, 9.5 μmol, 1.0 equiv) in DCE (0.5 mL) that was cooled to 0 °C was added Dess-Martin periodinane (Dess et al, 1983) (0.3 M solution in CH2CI2, 37 μΐ,, 4.6 mg, 11 μιηοΐ, 1.2 equiv). After stirring for 30 min at 0 °C, the mixture was stirred at 25 °C for 1.5 h. The reaction mixture was then warmed up to 50 °C, and one additional portion of Dess-Martin periodinane (0.3 M solution in CH2CI2, 19 ί, 2.4 mg, 5.5 ιηο1, 0.6 equiv, 0 °C to 50 °C) was added after 1 h. After 2 h at 50 °C, TLC analysis indicated complete conversion. The reaction mixture was allowed to cool to 25 °C, and the reaction was then quenched by addition of saturated aq. NaHC0₃:saturated aq. Na2S20₃ solution (1 :1, lOmL). The phases were separated, and the aqueous phase was extracted with CH2CI2 (2 x lOmL). The combined organic phases were washed with brine (lO mL), dried over MgS0₄, filtered, and concentrated under reduced pressure. Purification by preparative TLC (silica gel, 5% acetone in CH2CI2) afforded triketone (+)-23 (5.9 mg, 8.0 μιηο1, 83% yield) as a yellow powder. (+)-23: [θ ² =+108 (c=0.1, CH2CI2); all other physical and spectroscopic data of this compound were identical to those mentioned above for compound (-)-23.

(15,7a'S,lla'R)-5 ,6\7a\10\lla'-Pentahydroxy-3'-methoxy-2,6,6 rimethyl-7\8^12'-trioxo- 7\7a 8 ll^lla 12'-hexahydro ^-spiro[cyclohex-2-ene^,2'-cyclopenta[i/e]tetracene]-9'-carboxamide {synthetic (+)-viridicatumtoxin B [(+)-l]} (Nicolaou et al, 2013; Nicolaou et al., 2014): Triketone (+)-23 (5.3 mg, 7.1 μιηοΐ, l .O equiv) was dissolved in anhydrous 1 ,4-dioxane:MeOH (1 :1, 1.2 mL) under argon and Pd black (3.7 mg, 35 μπιο1, 4.9 equiv) was added. The suspension was degassed, placed under a hydrogen atmosphere, and stirred for 10 minutes at 25 °C, after which time the hydrogen was removed by flushing the flask with argon. The suspension was then filtered (Celite^®; MeOH:CH2Ci2 1 :9), and concentrated under reduced pressure to give crude triketone (+)-viridicatumtoxin B [(+)-l, 5.6 mg]. This product was purified by reverse-phase preparative HPLC (Shimazu HPLC, Atlantis prep T3 OBD column, 16 x 150 mm, 5 μιη particle size, 5 mL/min, 85% MeCN in H₂0 + 0.07% TFA buffer, λ=220 nm: t= 10.642 min) to provide pure (+)- viridicatumtoxin B [(+)-l, 3.8 mg, 6.8 μπιοΐ, 95% yield] as a yellow powder. (+)-l: [d]^ =+118 (c=0.1, EtOH); all other physical and spectroscopic data of this compound were identical to those mentioned above for (-)- viridicatumtoxin B [(-)-l].

All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims. VI. References

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Claims

WHAT IS CLAIMED IS:

1. A compound of the formula:

wherein:

Ri and Ri ' are each independently hydrogen, hydroxy, alkoxy(c<8), substituted alkoxy(c<8), acyloxy(c<8), or substituted acyloxv(c<8); ^or Ri and Ri ' are taken together and are oxo;

R3 is hydrogen or a group of the formula: -Y-R7, wherein:

Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R7 is hydrogen, amino, alkylamino,c<8), substituted alkylamino(c<8), dialkylamino(c<i2), substituted dialkylamin0(c<i2), heterocycloalkyl₍c<i2), or substituted heterocycloalkyl(c<i2);

R4 is hydroxy, oxo, alkoxy(c<8), or substituted alkoxy(c<8); and

R5 and R6 are each independently hydrogen, alky¾c<8), or substituted alkyl(c<8); provided that when R2 is hydrogen and R3 is hydrogen or methyl, then Ri is not methoxy or Ri

or a pharmaceutically acceptable salt thereof.

The compound of claim 1 further defined as:

wherein: Ri and Ri ' are each independently alkoxy(c<8), substituted alkoxy(c<8), acyloxy(c<8), or substituted acyloxy(c<8);

R3 is hydrogen or a group of the formula: -Y-R7, wherein:

Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R4 is hydroxy, oxo, alkoxy(c<8), or substituted alkoxy(c<8); and

R5 and R6 are each independently hydrogen, alkyl<c<8), or substituted alkyl(c<8); or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 further defined as:

wherein:

Ri and Ri ' are each independently hydrogen, hydroxy, alkoxy(c<8), substituted alkoxy(c<8), acyloxy(c<8), or substituted acyloxy(c<8); or R i and Ri ' are taken together and are oxo;

R3 is hydrogen or a group of the formula: -Y-R7, wherein:

Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R7 is hydrogen, amino, alkylamino(c 8), substituted alkylamino(c<8), dialkylamino(c<i2), substituted dialkylamino(c<i2), heterocycloalkyl(c<i2), or substituted heterocycloalkyl(c<i2);

R4 is hydroxy, oxo, alkoxy(c<8), or substituted alkoxy(c<8); and

R5 and R6 are each independently hydrogen,

or substituted alkyl(c<8); larmaceutically acceptable salt thereof.

4. The compound of claim 1 further defined as:

wherein:

Ri and Ri ' are each independently hydrogen, hydroxy, alkoxy(c<8), substituted alkoxy(c<8), acyloxy(c<8), or substituted acyloxy(c<8); or Ri and Ri ' are taken together and are oxo;

R2 is hydrogen, amino, alkylamino(c<8), substituted alkylamino(c<8), dia]kylamino(c<i2), or substituted dialkylamino(c<i2);

R3 is a group of the formula: -Y-R7, wherein:

Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R7 is hydrogen, amino, alkylamino₍c<8), substituted alkylamino(c<8), dialkylamino(c<i2), substituted dialkylamino(c<i2), heterocycloalkyl(c<i2), or substituted heterocycloalkyl(c<i2);

R4 is hydroxy, oxo, alkoxy(c<8), or substituted alkoxy(c<8); and

R5 and R6 are each independently hydrogen, alkyl<c<8), or substituted alkyl(c<8); provided that when R2 is hydrogen and R3 is methyl, then Ri is not methoxy or Ri and Ri' are not oxo;

or a pharmaceutically acceptable salt thereof.

5. The compound of either claim 1 or claim 4 further defined as:

wherein:

R3 is a group of the formula: -Y-R7, wherein: Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

R7 is amino, alkylamino(c<8), substituted alkylamino(c<8), dialkylamino(c<i2), substituted dialkylamino(c<i2), heterocycloalkyl(c<i2), or substituted heterocycloalkyl(c<i2);

R4 is hydroxy, oxo, alkoxy(c<8), or substituted alkoxy(c<8); and

R5 and R6 are each independently hydrogen, alkyl(c<8), or substituted alkyl(c<8); or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 and 3-5, wherein Ri and Ri ' are taken together and are oxo.

7. The compound according to any one of claims 1-5, wherein Ri is alkoxy(c<6) or substituted alkoxy(c<6).

8. The compound according to any one of claims 1 and 3-5, wherein Ri is hydrogen.

9. The compound according to any one of claims 1-5, wherein Ri ' is alkoxy(c<6) or substituted alkoxy(c<6).

10. The compound according to any one of claims 1 and 3-5, wherein Ri ' is hydrogen.

11. The compound according to any one of claims 1 , 2, 4, and 5, wherein R2 is hydrogen.

12. The compound according to any one of claims 1-5, wherein R2 is dialkylamino(c<8) or substituted dialkylaminO(c<8).

13. The compound according to any one of claims 1-3, wherein R3 is hydrogen.

14. The compound according to any one of claims 1-5, wherein R3 is -Y-R7, wherein:

Y is alkanediyl(c<8) or substituted alkanediyl(c<8); and

15. The compound of claim 14, wherein Y is alkanediyl(c<6) or substituted alkanediyl(c<6).

16. The compound of claim 14, wherein R7 is dialkylamino(c<i2) or substituted dialkylamino(c<i2).

17. The compound of claim 14, wherein R7 is heterocycloalkyl(c<i2) or substituted heterocycloalkyl(c<i2).

18. The compound according to any one of claims 1-5, wherein R4 is hydroxy.

19. The compound according to any one of claims 1-5, wherein R4 is oxo.

20. The compound according to any one of claims 1-5, wherein R5 is hydrogen.

21. The compound according to any one of claims 1-5, wherein R6 is hydrogen.

22. The compound according to any one of claims 1-5, wherein the compound is present as greater than 80% of a single stereoisomer.

23. The compound of claim 22, wherein the compound is present as greater than 90% of a single stereoisomer.

24. The compound of claim 23, wherein the compound is present as greater than 95% of a single stereoisomer.

25. The compound according to any one of claims 1-5 further defined as:

harmaceutically acceptable salt thereof.

A compound of the formula:

or a pharmaceutically acceptable salt thereof;

27. The compound of claim 26, wherein the compound is present as at least 90% of the depicted stereoisomer.

28. The compound of claim 27, wherein the compound is present as at least 95% of the depicted stereoisomer.

29. A pharmaceutical composition comprising:

(A) a compound according to any one of claims 1-28; and

(B) an excipient.

30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in cremes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion.

31. The pharmaceutical composition of either claim 29 or claim 30, wherein the pharmaceutical composition is formulated as a unit dose.

32. A method of treating a disease or disorder comprising administering a pharmaceutically effective amount of a compound or composition according to any one of claims 1-31.

33. The method of claim 32, wherein the disease or disorder is a microbial infection.

34. The method of either claim 32 or claim 33, wherein the microbial infection is a bacterial infection.

35. The method according to any one of claims 32-34, wherein the infection is by a Gram-positive or Gram- negative bacteria.

36. The method according to any one of claims 32-35, wherein the disease is a bacteria infection by Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Acinetobacter baumannii, Escherichia coli, Acinetobacter calcoaceticus, Staphycococcus epidermidis, Pseudomonas aeruginosa, Klebsiella aerogenes, Candida albicans, Salmonella typhinurium, Streptococcus pneumoniae, Micrococcus luteus, Bacillus cerues, or Bacillus subtilis.

37. The method of claim 36, wherein the disease is a bacteria infection by Staphylococcus aureus 503, Staphylococcus aureus 209, Staphylococcus aureus RN420, methicillin-resistant Staphylococcus aureus CCARM 3167, methicillin-resistant Staphylococcus aureus 371, methicillin-resistant Staphylococcus aureus CCARM 3506, quinolone-resistant Staphylococcus aureus CCARM 3505, quino lone-resistant Staphylococcus aureus CCARM 3519, Bacillus subtilis KCTC 1021, Bacillus cerues KCTC 1661, Micrococcus luteus KCTC 1056, Streptococcus pneumoniae KCTC 3932, Streptococcus pneumoniae KCTC 5412, Enterococcus faecium 501, Enterococcus faecium KCTC 3122, Enterococcus faecalis 5613, Enterococcus faecalis KCTC 5191, Enterococcus faecalis KCTC 3511, Staphycococcus epidermidis KCTC 3958, Salmonella typhinurium KCTC 1926, Acinetobacter calcoaceticus KCTC 2357, Escherichia coli CCARM 1358, Escherichia coli KCTC 1682, Pseudomonas aeruginosa KCTC 2004, Pseudomonas aeruginosa KCTC 2742, Klebsiella aerogenes KCTC 2619, Acinetobacter baumannii AB210, or Candida albicans KCTC 7535.

38. The method according to any one of claim 34-37, wherein the bacteria is a drug -resistant bacteria.

39. The method according to any one of claims 32-38 further comprising administering a second therapeutic agent.

40. The method of claim 39, wherein the second therapeutic agent is an antibiotic.

41. The method of either claim 39 or claim 40, wherein the second therapeutic agent is a tetracycline antibiotic.

42. The method according to any one of claims 39-41, wherein the second therapeutic agent is viridicatumtoxin A, viridicatumtoxin B, vancomycin, tetracycline, spirohexaline, minocycline, tigecycline, doxycycline, a β-lactam antibiotic, an aminoglycoside antibiotic, a sulfonamide antibiotic, a macrolide antibiotic, a glycopeptide antibioitic, an ansamycin antibiotic, an oxazolidinone antibiotic, a quinolone antibiotic, a streptogramin antibiotic, or a lipopeptide antibiotic.

43. The method of either claim 32 or claim 33, wherein the microbial infection is a viral infection.

44. The method according to any one of claims 32, 33, and 43, wherein the virus is a poxvirus.

45. The method of claim 44, wherein the poxvirus is variola virus, vaccinia virus, or molluscum contagiosum.

46. The method according to any one of claims 32, 33, and 43-45 further comprising administering a second therapeutic agent.

47. The method of claim 46, wherein the second therapeutic agent is an interferon or antiviral compound.

48. The method of claim 32, wherein the disease or disorder is cancer.

49. The method of either claim 32 or claim 48, wherein the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

50. The method of either claim 32 or claim 48, wherein the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, gastrointestinal tract, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid.

51. The method according to any one of claims 32 or 48-50 further comprising administering a second therapeutic agent.

52. The method of claim 51, wherein the second therapeutic agent is a second chemotherapeutic agent, radiotherapy, immunotherapy, or surgery.

53. A method of inhibiting the activity of a bacterial ribosome for the treatment of a disease or disorder comprising administering a compound or composition according to any one of claims 1-31.

54. A method of inhibiting the activity of a bacterial UPP synthase for the treatment of a disease or disorder comprising administering a compound or composition according to any one of claims 1-31.

wherein:

Ri , R2, and R3 are each independently hydrogen, alkyl(c<g), substituted alkyl(c<g), cycloalkyl(c<8), or substituted cycloalkyl(c<8);

R4 is hydroxy, alkylsilyloxy(c<i 8), substituted alkylsilyloxy(c<i8), alkylarylsilyloxy(c<i 8), substituted alkylarylsilyloxy(c<i8), alkylaralkylsilyloxy^'(c<i8), substituted alkylaralkylsilyloxy(c<i8), or -OR_a, wherein:

R_a is a hydroxy protecting group;

R5, R6, R7, and Rs are each independently hydroxy, alkoxy(c<i2), substituted alkoxy(c<i2), alkenyloxy(c<i2), substituted alkenyloxy(c<i2), alkynyloxy(c<i2), substituted alkynyloxy(c<i2), aryloxy(c≤i2), substituted aryloxy(c<i2), aralkoxy(c≤i2), substituted aralkoxv(c<i2), or -ORb, wherein:

Rb is a hydroxy protecting group;

Xi is 0 or NRc, wherein:

Rc is hydrogen, alkyl(c<i 8), or substituted alkyl(c<8);

comprising reacting a compound of the formula:

wherein:

R5, Re, R7, and Rs are as defined above;

with a compound of the formula:

wherien:

R5, Re, R7, and Rs are as defined above;

Yi is a leaving group;

in the presence of a phase transfer catalyst and a base under conditions sufficient to cause a reaction. The method of claim 55, wherein the phase transfer catalyst is a compound of the formula:

wherein:

Rio and Rn are each independently alkyl(c<i8), alkenyl(c≤i8), aryl(c<i8), aralkyl(c<i8), or a substituted version of any of these groups;

R12 is hydrogen, hydroxy, alkoxy(c<i2), substituted alkoxy(c<i2), acyloxy(c<i2), substituted acyloxy(c<i2), aralkyl(c<i2), or substituted aralkyl(c<i2);

X2 is a monovalent anion; and

n is 1 , 2, or 3.

The method of claim 56, wherein the phase transfer catalyst is a compound of the formula

58. The method according to any one of claims 55-57, wherein the base is a metal carbonate.

59. The method of claim 58, wherein the base is cesium carbonate.

60. The method according to any one of claims 55-57, wherein the method comprises adding the base as a solution in water.

61. The method of claim 60, wherein the base as a solution in water comprises 20% to about 60% base. 62. The method of claim 61 , wherein the base as a solution in water comprises 40% base.

63. The method according to any one of claims 55-57, wherein the method comprises adding from about 5 equivalents to about 25 equivalents of the base relative to the compound of formula III.

64. The method of claim 63, wherein the method comprises adding about 10 equivalents of the base. 65. The method according to any one of claims 55-57, wherein the method comprises adding from about 1.0 equivalents to about 5 equivalents of the compound of formula IV relative to the compound of formula III.

66. The method of claim 65, wherein the method comprises adding about 1.1 equivalents of the

compound of formula IV.

67. The method according to any one of claims 55-57, wherein the method comprises adding from about 0.1 mol% to about 20 mol% of the phase transfer catalyst.

68. The method of claim 67, wherein the method comprises adding from about 0.1 mol% to about 5 mol% of the phase transfer catalyst.

69. The method according to any one of claims 55-57, wherein the method further comprises an organic solvent.

70. The method of claim 69, wherein the organic solvent is a haloalkane(c<8).

71. The method of claim 70, wherein the organic solvent is dichloroethane or methylene chloride. 72. The method according to any one of claims 55-57, wherein the method further comprises reacting at a temperature from about -80 °C to about 25 °C.

73. The method of claim 72, wherein the temperature is from about -40 °C to about 0 °C.

74. The method according to any one of claims 55-57, wherein the method comprises reacting for a time period from about 6 hours to about 1 week.

75. The method of claim 74, wherein the time period is about 1 day to about 4 days.

76. The method according to any one of claims 55-57, wherein the method further comprises reacting the compound of formula II with a fluoride source to produce a compound of formula:

wherein:

R5, R6, R7, and Rs are each independently hydroxy, alkoxy(c<i2), substituted alkoxy(c<i2), alkenyloxy(c<i2), substituted alkenyloxy(c<i2), alkynyloxy(c<i2), substituted alkynyloxy(c<i2), aryloxy(c<i2), substituted aryloxy(c<i2), aralkoxy(c<i2), substituted aralkoxy(c<i2), or -ORb, wherein:

Rb is a hydroxy protecting group;

Xi is 0 or NRc, wherein:

R_c is hydrogen, alkyl(c<i 8), or substituted alkyl(c<8);

or a salt thereof.

The method according to any one of claims 55-76, further comprising a purification step.