WO2023122754A1 - Processes and intermediates for preparing gb13, gb22 and himgaline - Google Patents

Abstract

Provided herein are processes for the streamlined synthesis of Galbulimima alkaloids, such as himbadine, isolated from Galbulimima belgraveana and G. baccatta, trees endemic to the rainforests of Northern Australia and Papua New Guinea, as well as analogs thereof, such as GB13, GB16, GB22, and himgaline, and further including intermediates useful in the synthesis of these and related compounds.

Description

PROCESSES AND INTERMEDIATES FOR PREPARING GB13, GB22 AND HIMGALINE

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. provisional patent application No. 63/293,295, which was filed on December 23, 2021, and which is hereby incorporated by reference in its entirety.

GOVERNMENT SUPPORT

This invention was made with government support under grant number R35 GM122606 awarded by the National Institutes of Health and grant number CHE-1856747 awarded by the National Science Foundation. The government has certain rights in the invention.

FIELD OF INVENTION

This invention relates to processes for the syntheses of GB 13, GB22, himgaline, and himbadine, and intermediates useful in such syntheses.

BACKGROUND OF THE DISCLOSURE

The bark of Galbulimima belgraveana features as an analgesic and antipyretic in the traditional medicine of Papua New Guinea and as a hallucinogen and stimulant in its rituals.¹ The psychotropic principles remain unknown.² The alkaloid content in bark — a mixture of more than thirty congeners — varies unpredictably from 0.5% to only trace amounts,³ prompting numerous synthesis efforts. ^{Error! Bookmark not defined}. Previous syntheses of highly complex congeners like himgaline (1) have relied on iterative, stepwise installation of multiple methine stereocenters.^4-9

There is therefore a need for a more streamlined syntheses of these alkaloids.

SUMMARY OF THE DISCLOSURE

Some embodiments described herein provide a process for preparing a compound of Formula (12):

wherein R in Formula (12) is hydrogen or methyl; comprising the steps of:

Either

(A1) Silylating a compound of Formula (7)

followed by Simmons-Smith cyclopropropanation using Shi modification to form a compound of Formula (8)

(8); or

(A2) Converting methyl 2-chloro-6-methyl-nicotinate having the formula

to the compound of Formula (8);

(B) Cross-coupling the compound of Formula (8) with a compound of Formula (9)

wherein R in Formula (9) is methyl, to form a compound of Formula (10)

wherein R in Formula (10) is methyl; (C) cyclizing of the compound of Formula (10) in the presence of an acid to a compound of Formula (11)

wherein R is Formula (11) is hydrogen or methyl; and

(D) Hydrogenating the compound of Formula (11) to form the compound of Formula (12).

Some embodiments described herein also provide process for preparing a compound of Formula (2)

comprising the steps of:

(a) conducting a Benkeser reduction of the compound of Formula (12) prepared as described herein to form a compound of Formula (14)

(14); and

(b) hydrolyzing the compound of Formula (14) followed by basification to form the compound of Formula (2); wherein step (b) is performed either using the compound of Formula (14) formed in-situ or after isolation. Some embodiments described herein also provide a process for preparing a compound of Formula (1)

comprising converting the compound of Formula (2) prepared as described herein to the compound of Formula (1).

Some embodiments described herein provide a process for preparing a compound of Formula (3)

comprising converting the compound of Formula (12) prepared as described herein to the compound of Formula (3).

Some embodiments described herein also provide a process for preparing a compound of Formula (2)

comprising using the compound of formula (12)

wherein R in Formula (12) is H or methyl; or the compound of Formula (14)

(14); as an intermediate in preparing the compound of Formula (2).

Some embodiments described herein also provide a process for preparing a compound of Formula (1)

comprising using the compound of formula (12).

wherein R in Formula (12) is H or methyl; or the compound of Formula (14)

as an intermediate in preparing the compound of Formula (1).

Some embodiments described herein also provide a compound of formula (14A)

(14A), wherein R is C_1-6alkyl, which is optionally substituted with 1-3 substituents selected from the group consisting of halo, C_1-6alkyl, -OC_1-6alkyl, -OC_1-6alkyl-OC_1-6alkyl, and cyano.

Some embodiments described herein also provide a compound of formula (12)

(12), wherein R is alkyl, which is optionally substituted with 1-3 substituents selected from the group consisting of halo, C_1-6alkyl, -OC_1-6alkyl, -OC_1-6alkyl-OC_1-6alkyl, and cyano.

Some embodiments described herein also provide a compound of Formula (GB16)

Some embodiments described herein also provide a preparation of compound of Formula (GB16) from the compound of Formula (GB13) occurs according to the following scheme:

Some embodiments described herein also provide a process for preparing himbadine from the compound of Formula (14) according to the following scheme:

(14) himbadine

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows representative Galbulimima (GB) alkaloids and synthetic analysis, a, Chemical space related to GB alkaloids, b, Through-class retrosynthetic analysis relating GB alkaloids, c, a high FAT, low F_sp3 intermediate undergoes rapid attached ring scission, but can be formed under mild cross-coupling conditions.

Figure 2 shows that the failure of a Friedel-Crafts conjugate arylation leads to the development of the corresponding radical cross-coupling. ^a0.1 mmol bromobenzene, ^HH NMR yield, ^c(%yield of A), ^d0.25 mmol bromobenzene. ^ewith [Ir],

Figure 3 shows the scope and application of cross-coupling and stereoselective reduction in the systheses of GB22, GB13 and himgaline (Please confirm if this is a good legend for Figure 3). a. Endo -selective sp³-sp² cross-coupling: % isolated yield (enda.exo). b. A short synthesis of GB22, GB13 and himgaline via iterative, stereoselective reduction of multiple correlated carbons.

Figure 4 shows himgaline syntheses as walks through a chemical space parameterized by F_sp3 (#Csp3/Ctotai), Cm (mcbit) and molecular weight (Da). Figure 5 shows photos illustrating the experimental setup for photochemical reactions with tetralones.

Figure 6 is a ¹H NMR spectrum of crude product 14.

Figure 7 is ¹H NMR spectrum of crude himgaline.

Figure 8 is a ¹H NMR spectrum of crude GB 13 (a mixture of GB13 and 16-oxo- himgaline).

Figure 9 shows “natural” C10 configuration (convex-face protonation of Birch/ Benkeser radical anion) with different configurations at epimerizable C9/C15 positions.

Figure 10 shows “unatural” C10 configuration (concave-face protonation of Birch/ Benkeser radical anion) with different configurations at epimerizable C9/C16 positions.

Figure 11 shows relative energies of 15-oxo-himgaline diastereomers with different C9 and C15 configurations compared to the lowest energy diastereomer, which happens to be 16- oxo-himgaline itself. If the natural configuration of C10 is favored by Birch reduction and equilibration occurs under acidic conditions (which favor the aza-Michael ring-tautomer, 16- oxo-himgaline), then the natural configuration at C15 should be favored under equilibrating conditions.

Figure 12 shows the X-ray structure of compound 12b.

Figure 13 shows the X-ray structure of compound 12a.

Figure 14. A screen by PDSP of 45 common receptors identified himbadine as a high affinity ligand of sigmal (δ1) receptors (Ki = 14 nM). Sigma2 (δ2) receptors did not show significant ligation even at 10 pM himbadine.

DETAILED DESCRIPTION OF THE DISCLOSURE

Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning. All undefined technical and scientific terms used in this Application have the meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

As used herein, “a” or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

When a range of values is listed, it is intended to encompass each value and sub- range within the range. For example, “C_1-6alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C_1-6, C_1-5, C_1-4, C_1-3, C_1-2, C_2-6, C_2-5, C_2-4, C_2-3, C_3-6, C_3-5, C_3-4, C_4-6, C_4-5, and C_5-6 alkyl.

“Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C_1-20 alkyl”). In some embodiments, an alkyl group has 1 to 15 carbon atoms (“C_1-15 alkyl”). In some embodiments, an alkyl group has 1 to 14 carbon atoms (“C_1-14 alkyl”). In some embodiments, an alkyl group has 1 to 13 carbon atoms (“C_1-13 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 11 carbon atoms (“C_1-11 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C_1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C_1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C_1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C_1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“ C_1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C_1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C_1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C_1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“ C_1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“ C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C_2-6 alkyl”). Examples of C_1-6alkyl groups include methyl (C₁), ethyl (C2), n-propyl ( C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl ( C₄), sec-butyl (C₄), iso-butyl (C₄), n- pentyl ( C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl ( C₆). Additional examples of alkyl groups include n-heptyl (C7), n- octyl (C₈) and the like.

An alkyl groups may be optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted. In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a non-hydrogen substituent, and which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and/or non-hydrogen substituents which satisfy the valencies of the heteroatoms and results in the formation of a stable compound.

Exemplary non-hydrogen substituents may be selected from the group consisting of halogen, -CN, -NO₂, -N3, -SO₂H, -SO₃H, -OH, -OC_1-6alkyl, -OC_1-6alkyl-OC_1-6alkyl, -ON(C_1-6alkyl)₂, -N( C_1-6alkyl)₂, -N(OC_1-6alkyl)( C_1-6alkyl), -N(OH)(C_1-6alkyl), - NH(OH), -SH, -SC_1-6alkyl, -C(=O)(C_1-6alkyl), -CO₂H, -CO₂(C₁_₆ alkyl), -OC(=O)(C_1-6 alkyl), -OCO₂(C_1-6alkyl), -C(=O)NH₂, -C(=O)N(C_1-6alkyl)₂, -OC(=O)NH(C_1-6alkyl), - NHC(=O)( C_1-6alkyl), -N(C_1-6alkyl)C(=O)( C_1-6alkyl), -NHCO₂(C_1-6alkyl), - NHC(=O)N(C_1-6alkyl)₂, -NHC(=O)NH(C_1-6alkyl), -NHC(=O)NH₂, -C(=NH)O(C_1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC_1-6alkyl, -C(=NH)N(C_1-6alkyl)₂, - C(=NH)NH(C_1-6alkyl), -C(=NH)NH₂, -OC(=NH)N(C_1-6alkyl)₂, -OC(NH)NH(C_1-6alkyl), -OC(NH)NH₂, -NHC(NH)N(CI-6 alkyl)₂, -NHC(=NH)NH₂, -NHSO₂(C_1-6alkyl), - SO₂N(CIV, alkyl)₂, -SO₂NH(C_1-6alkyl), -SO₂NH₂, and -SO₂C_1-6alkyl.

“Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

Embodiments

Examples of embodiments of the present application include the following: Embodiment 1

A process for preparing a compound of Formula (12):

wherein R in Formula (12) is hydrogen or methyl; comprising the steps of:

Either

(Al) Silylating a compound of Formula (7)

followed by Simmons-Smith cyclopropropanation using Shi modification to form a compound of Formula (8)

(8); or

(A2) Converting methyl 2-chloro-6-methyl-nicotinate having the formula

to the compound of Formula (8);

(B) Cross-coupling the compound of Formula (8) with a compound of Formula (9)

wherein R in Formula (9) is methyl, to form a compound of Formula (10)

wherein R in Formula (10) is methyl;

(C) cyclizing of the compound of Formula (10) in the presence of an acid to a compound of Formula (11)

wherein R is Formula (11) is hydrogen or methyl; and

(D) Hydrogenating the compound of Formula (11) to form the compound of Formula (12).

Embodiment 2

The process of Embodiment 1, wherein in step (Al), the silylation is carried out in the presence of trimethyl silyl tritiate.

Embodiment 3

The process of Embodiment 1, wherein in step (Al), the cyclopropanation is carried out in the presence of CH₂I₂. Embodiment 4

The process of Embodiment 1, wherein in step (A2), the conversion of methyl 2- chloro-6-methyl-nicotinate to the compound of Formula (8) comprises the steps of: (A2-(i)) Converting methyl 2-chloro-6-methyl-ni cotinate to the compound of formula (SI- 37):

(SI-37);

(A2-(ii)) Converting the compound of Formula (SI-37) to the compound of Formula (SI-38):

(SI-38); and

(A-2-(iii)) Silylating the compound of Formula (SI-38) to the compound of Formula (8).

Embodiment 5

The process of any one of Embodiments 1-4, wherein in step (B), the cross-coupling is a nickel-catalyzed coupling.

Such nickel-catalyzed coupling reaction would be known to those of ordinary skill in the art. Examples include Ti(OiPr)4-enabled dual photoredox and nickel-catalyzed arylation/alkylation as described in the Varabyeva et al reference (Reference #23), as well as employing 2,4,6-tri(9H-carbazol-9-yl)-5-chloroisophthalonitrile (3CzClIPN) and/or 1, 2,3,5- tetrakis(carbazol-9-yl)-4,6-dicyanobenzene, 2,4,5,6-tetrakis(9J/-carbazol-9-yl)- isophthalonitrile (4CzIPN), 2,2’ -bipyridine (Bipy), and 2,6-lutidine and nickel dihalide (e.g., NiCl₂, NiBr₂).

Embodiment 6

The process of Embodiment 5, wherein in step (B), the nickel-catalyzed coupling is carried out in the presence of Nickel dihalide (e.g., NiBr₂), 2,4,6-tri(9H-carbazol-9-yl)-5- chloroisophthalonitrile (3CzClIPN) or 4CzlPN, 2,2’-bipyridine (Bipy), and 2,6-lutidine. Embodiment 7

The process of any one of Embodiments 1-6, wherein in step (C), the acid is a Lewis acid. Examples of preferred Lewis acids include, without limitation, AlCl₃, AlCl₃/1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), EtAlCl₂/HFIP, and Et₂AlCl/HFIP.

Embodiment 8

The process of any one of Embodiments 1-7, wherein in step (C), the acid comprises at least one selected from the group consisting of HC1, H₂SO₄, Bis(trifhioromethanesulfonyl)amine, triflic acid, AICL, AlCl₃/1,1,1,3,3,3-hexafhioro-2- propanol (HFIP), EtAlCl₂/HFIP, and Et₂AlCl/HFIP. Embodiment 9

The process of any one of Embodiments 1-8, wherein in step (C), the acid is a Lewis acid, and is Et₂AlCl/HFIP.

Embodiment 10

The process of any one of Embodiments 1-9, wherein in step (D), the hydrogenation is a rhodium -catalyzed hydrogenation. The characteristics and conditions for such hydrogenation will be well known to those of ordinary skill in the art.

Embodiment 11

The process of Embodiment 10, wherein in step (D), the rhodium-catalyzed hydrogenation is carried out in the presence of Rh/ALCh and hydrogen gas under high pressure. In one embodiment, the high pressure employed is about 300-1000 psi, and in one embodiment about 300-800 psi, and in one embodiment about 600 psi.

Embodiment 12

A process for preparing a compound of Formula (2)

comprising the steps of:

(a) conducting a Benkeser reduction of the compound of Formula (12) prepared according to any one of Embodiments 1-11 to form a compound of Formula (14)

(14); and

(b) hydrolyzing the compound of Formula (14) followed by basification to form the compound of Formula (2); wherein step (b) is performed either using the compound of Formula (14) formed in-situ or after isolation.

Methods of conducting Benkeser reduction will be well known to those of ordinary skill in the art. The method employs a metal, such as lithium and calcium in the presence of low molecular weight amines as the solvent and in part, as a source of protons. It is a modification of the Birch reduction that employs ammonia as the solvent, and offers the advantage that the reduction can be conducted at a temperature higher than the boiling point of ammonia (-33°C).

A modified Benkeser reduction using lithium and ethylenediamine (or analogs) in tetrahydrofuran has recently been reported (Burrows et al., Reference #37) and can be employed in the present invention.

Embodiment 13

The process of Embodiment 12, wherein in step (a), the Benkeser reduction is conducted in the presence of Li metal and an amine base.

Embodiment 14

A process for preparing a compound of Formula (1)

comprising converting the compound of Formula (2) prepared according to Embodiment 8 or 9 to the compound of Formula (1).

Embodiment 15

The process of Embodiment 14, comprising the steps of:

(i) converting the compound of Formula (2) under acidic conditions to a compound of Formula (15)

and

(ii) converting the compound of Formula (15) to the compound of Formula (1); wherein step (ii) is performed either using the compound of Formula (15) formed in-situ or after isolation.

Embodiment 16

The process of Embodiment 15, wherein step (ii) is performed after isolating the compound of Formula (15).

Embodiment 17

The process of Embodiment 15 or 16, wherein in step (ii), the compound of Formula (15) is treated with a hydride reductant to form the compound of Formula (1). Suitable hydride reductants would be well known to those ordinary skill in the art, and include such reagents as NaBH₄, lithium aliminum hydride, NaBH₃CN and NaBH(OAc)3. In a preferred embodiment, the hyride reductant is NaBH(OAc)3.

Embodiment 18

The process of Embodiment 17, wherein the hydride reductant is NaBH(OAc)3.

Embodiment 19

A process for preparing a compound of Formula (3)

15

SUBSTITUTE SHEET ( RULE 26)

comprising converting the compound of Formula (12) prepared according to any one of claims 1-7 to the compound of Formula (3).

Embodiment 20

The process of Embodiment 19, comprising the steps of:

(I) converting the compound of Formula (12) wherein R is methyl to the compound of Formula (12) wherein R is H; and

(II) converting the compound of Formula (12) wherein R is H to the compound of Formula

Embodiment 21

The process of Embodiment 20, wherein in step (I), the compound of Formula (12) wherein R is methyl is demethylated in the presence of BBr, to form the compound of Formula (12) wherein R is H; and wherein in step (II) the compound of Formula (12) wherein R is H is treated with formaldehyde (CH₂O) to form the compound of Formula (3).

Embodiment 22

The process of Embodiment 21, wherein the compound of Formula (12) wherein R is H is treated with formaldehyde (CH₂O) to form the compound of Formula (3).

Embodiment 23

A process for preparing a compound of Formula (2)

comprising using the compound of formula (12)

wherein R in Formula (12) is H or methyl; or the compound of Formula (14)

(14); as an intermediate in preparing the compound of Formula (2).

Embodiment 24

A process for preparing a compound of Formula (1)

comprising using the compound of formula (12)

wherein R in Formula (12) is H or methyl; or the compound of Formula (14)

as an intermediate in preparing the compound of Formula (1).

Embodiment 25

A compound of formula

(14A), wherein R is C_1-6alkyl, which is optionally substituted with 1-3 substituents selected from the group consisting of halo, C_1-6alkyl, -OC_1-6alkyl, -OC_1-6alkyl-OC_1-6alkyl, and cyano.

Embodiment 26

A compound of formula

wherein R is alkyl, which is optionally substituted with 1-3 substituents selected from the group consisting of halo, C_1-6alkyl, -OC_1-6alkyl, -OC_1-6alkyl-OC_1-6alkyl, and cyano.

Preparation of compounds of formulae (14A) and (12) in embodiments 25 and 26 respectively, wherein R is a substituted C_1-6alkyl as set forth herein can be easily envisioned by those of ordinary skill in the art. For example, following the scheme in Figure 3b, one can prepare the compound of Formula (14A) wherein R is alkyl substituted with -OC_1-6alkyl, and specifically wherein R is -C₆H₁₂OMe by the following sequence of steps, starting with an analog of compound of Formula 9a/9b wherein R is -C₆H₁₂OMe:

Embodiment 27

A compound of Formula (GB16)

Embodiment 28

A process for preparing the compound of Formula (GB16) from the compound of Formula (GB13) occurs according to the following scheme:

Embodiment 29

A process for preparing himbadine from the compound of Formula (14) according to the following scheme:

14.2 nM

EXAMPLES

General Examples for the Processes and Compounds of the Invention

Extracts from Galbulimima belgraveana and baccata have yielded related alkaloids classified by connectivity between piperidine and decalin domains (Galbulimima alkaloids, classes I - IV, Figure la).^{Error! Bookmark not tlefinetl}- The simplest, class I GB alkaloid, himbacine (15 mcbits/atom),¹⁰ was found to antagonize muscarinic receptors Ml-5 (rhodopsin-like GPCRs, subfamily A18)^{11 12} and its enantiomeric series was developed into Vorapaxar, an antagonist of related GPCR PAR-1 (subfamily Al 5).¹³ Classes II-IV have not been well- developed towards biological goals,¹⁴ but the potential for development has attracted significant interest from the synthetic community. ^{Error! Bookmark not defined. Qg} alkaloid classes II and III have proved especially challenging to access (18-33 steps), although pioneering solutions have appeared (see SI for a full outline of each).^{Error! Bookmark not defined.-Error! Bookmark}

concise Syntheses by Movassaghi,¹ Sarpong^lv and Ma^{Error! Bookmark not defined}, obtained GB13 in 18-19 steps, and generated important data to aid our exploration. In search of a general strategy to access GB alkaloid chemical space, we targeted GB22 (3, Figure lb), a low-abundance class III alkaloid (1.8 ppm, milled bark) whose aromatic ring might allow rapid entry and diversification to complex congeners.¹⁵ In this design, high fraction aromatic (FAT) intermediate 5 containing 15 sp² atoms (11 mcbits/atom) might be reduced^{lv 16} to generate the 11 tetrahedral stereocenters in the complex alkaloid himgaline (1, 21 mcbits/atom). This is a classical strategy, represented by the earliest alkaloid synthesis — coniine in 1886 — in which reduction converted a simple aromatic to a high F_sp3 alkaloid, albeit with one stereocenter whose stereochemistry was not controlled.¹⁷ Success in himgaline would require relay of stereochemical configuration from the single stereocenter of 5 to nine prochiral carbons, including the concave-facing methine C-H bonds of GB13 (2). Although these hydrogens might epimerize to the concave face, the potential instability of extended enols and the existence of other low-energy configurations at ring junctions complicated our analysis of stereochemical equilibration (e.g. 9,10,15-epi-GB13 and 15-epi-GB13 are 2.6 kcal/mol and 1.3 kcal/mol lower in energy than GB13). Here we report unusually concise syntheses of GB22, GB13 and himgaline using an erafo-selective attached-ring cross-coupling and arene reduction that significantly reduce the synthetic burden compared to prior art.

Retrosynthetic analysis of GB22 (Figure lb) identified an embedded attached-ring system, which could be unmasked by pyridine hydrogenation^lv and intramolecular ketone arylation transforms. Despite the simplicity of 5, the most obvious disconnection — enone conjugate addition — fails. A direct Friedel -Crafts addition of 4 into the cyclohexadienone conjugate acid of 3 (Figure 2a)¹⁸ is prevented by preferential protonation of 4 and decomposition of 5 mediated by acids (see below). We thought that if the oxocarbenium ion were replaced with a P-keto carbon-centered radical, we might circumvent the Friedel-Crafts by interception of an arylnickel complex (Figure 2c).¹⁹ P-Keto radical formation has been implicated in the ring- opening of siloxy cyclopropanes by photoinduced electron transfer (PET) to 1,4- dicyanonaphthalene (DCN).²⁰ Inspired by the recent success of photoredox/Ni dual catalytic cross-coupling platforms,²¹ we considered a system in which a photoexcited catalyst might oxidatively cleave a siloxycyclopropane with erafo-selectivity, ^22,23,24 leading to arylnickel capture and reductive elimination. Typically, transition-metal catalyzed arylations of cyclopropanols and siloxycyclopropanols favor cleavage of the least hindered cyclopropane bond (path a, Figure 1c).²⁵ In contrast, this electron transfer arylation would provide the opposite regioselectivity (path b).

Early efforts to develop a dual catalytic endo- selective siloxycyclopropane arylation identified the Doyle-MacMillan dual catalyst system of [Ir{dF(CF3)ppy}2(dtbbpy)]PFe and Ni(dtbbpy)C12 as a good starting point (see Figure 2).²⁶ Yields of coupled product 6 proved dependent on heat removal by air circulation and difficult to reproduce without tight control of temperature (B-D, Figure 2, were major byproducts). Ultimately, the reaction setup was altered to accommodate the use of a water bath for temperature control and heating. In combination with organic dyes like 3CzClIPN and 4CzIPN, the reaction proved more reliable and offered shorter reaction times, lower costs and more flexibility over conditions.²⁷ Highly-polar solvents such as DMA and DMF were competent in this chemistry, but DMSO out-performed both. Additionally, carbonate bases were ineffective and phosphate bases proved inferior and less consistent than organic pyridine bases like 2,6- lutidine and 2-picoline. The yield of 6 decreased when we employed photocatalysts that had higher or lower oxidation potentials than 3CzClIPN. Finally, the reaction did not proceed in control reactions that excluded each of the reagents. These conditions were generally successful across a variety of siloxycyclopropanes and haloarenes. In all cases, the retrosynthetic disconnections using a conjugate addition transform would lead to a cyclohexadienone that exists as the phenol tautomer (B).

Neither electron-withdrawing nor electron-donating groups on the arene effected the efficiency of coupling and heterocycles coupled with efficiency (oxidant-sensitive arenes were problematic, however; see SI). The reaction translated from bromoarenes to 1- bromocyclohexene, albeit in reduced yield. Encouraged by the scope of this cross-coupling, especially with regard to heterocyclic substrates, we investigated entry into the synthesis of GB22 (Scheme 1). Ketone 7 is listed commercially and can be prepared in one step by condensation of 1,3-cyclopentanedione, methyl vinyl ketone, and ammonia.²⁸ Conversion to siloxycyclopropane 8 was carried out via silyl enol ether formation, followed by Simmons- Smith cyclopropanation using the Shi modification.²⁹ An alternative 3-step route to 8 from methyl 2-chloro-6-methyl-nicotinate was also developed to avoid the difficult purifications of the Simmons-Smith route. Cross-coupling with bromoarene 9a or 9b (2 steps from 1- naphthol)³⁰ occurred cleanly, after optimization to account for or/Ao-substitution that leads to steric crowding of the intermediate arylnickel. The higher yield of anisole 9b likely reflects the low bond dissociation enthalpy of C-H bonds in benzyl ether 9a.

The high FAT attached-ring intermediates 10a/b incorporated all the skeletal carbons of GB22, GB13 and himgaline, but the projected Friedel-Crafts arylation proved difficult. First, as suggested by positive Hammett parameters,³¹ dominant inductive effects disfavor attack by the meto-position of the phenolic ether. Koltunov found benzene itself to cyclize efficiently with 5-quinolol using triflic acid (F3CSO3H),^{Error! Error! Bookmark not} . ^de

^fined initial screens of strong Bronsted acids in our system delivered only small quantities of 4. Triflic acid instead competitively protonated 10a/b and effected a retro-Friedel-Crafts arylation to cleave the hard- won C-C bond and return quinolol 3 (see Figure 1 and SI). Typical Lewis acids like AlCh also did not yield 11 (see SI for a table of conditions). However, when inorganic aluminum Lewis acids were mixed with hexafluoroisopropanol (HFIP), tetracycle 4 was finally observed, albeit in low yield, along with 3. We suspect that an aluminum species such as Al[OCH(CF3)2]nCl_m might act as an efficient Lewis acid ³² or hydrogen-bonding catalyst. Minimization of strong Bronsted acidity (i.e. HC1 liberation) was accomplished by adding diethylaluminium chloride to HFIP, which quickly and exothermically evolved gas (likely ethane) to generate a new complex, tentatively assigned as A1[OCH(CF₃)₂]₂C1 and its aggregates. The mechanism of cyclization may involve acidification of HFIP, formation of a strong double hydrogen-bond donor bridged by aluminum, or formation of a strongly Lewis acidic complex.³³ HFIP alone³⁴ did not promote any reaction of 2. This procedure led to clean and reproducible cyclization of the acid-labile attached ring as either the parent phenol 4 (52%) or its methyl ether 11 (86%), depending on use of 10a (to 4) or 10b (to 11).

Both 4 and 11 could be hydrogenated over Rh/ALOs with exquisite stereocontrol to 12a/b (other diastereomers not detected), by analogy to related work on GB13 wherein a larger, pre- saturated decalin motif provided steric shielding. ^iv Here, the benzene nucleus was unaffected by rhodium -catalyzed hydrogenation, but despite its planarity, small size and ability to adsorb to metal surfaces,³⁵ it efficiently blocked the concave face of the pyridine ring. Whereas 12a could be TV-methylated (CH₂O (aq.), NaCNBHs) to GB22 directly, 12b required demethylation by BBrs (75%), resulting in one more operation than the benzyl ether series, but almost double the yield (16% vs. 29%, 3 vs. 4 steps). 'H- and ¹³C-NMR spectra of synthetic GB22 were identical to those reported by Lan and Mander.^{Error! Error! Bookmark not d}. ^efined

The next arene reduction benefited from retention of the methyl ether in 12b and probed the role of the piperidine ring in control of stereochemistry at the incipient decalone. Birch reduction (Li⁰ or Na° in NH3 (1)) and electrochemical reduction proved unsuccessful, but Benkeser reduction³⁶ (Li° in Mebfflz, THF/z-PrOH) was unique to effect clean reduction of the anisole. Proton source and metal were found to be important: MeOH, EtOH and LBuOH did not promote reduction, and neither was Na° effective. The recently reported Koide reduction³⁷ (Li°, ethylenediamine, THF) worked extremely well and yielded similar amounts of product to Li°/MeNH2 with greater operational ease. A single diastereomer and regioisomer predominated (14), resulting from intermolecular protonation of C10 from the convex face, despite the potential for intramolecular proton transfer to C9 from the piperidine N-H, modeled only 2.46A apart in 12a (X-ray). Minor byproduct pathways included demethylation (to 12a), over- reduction of the arene and ca. 10% of a regioisomer. Hydrolysis of 14 with 2M aqueous HC1, followed by basification (4M NaOH) led to GB13 in 71% yield, with each of the remaining methine stereocenters adopting the desired configuration. Only a single methine (C10) positioned its hydrogen to the convex face, whereas two new stereocenters (C9, Cl 5) derived from prochiral, planar carbons that projected hydrogens inward. This stereochemistry may reflect, in part, the thermodynamic preferences of ring-tautomer (aza-Michael product) 16-oxo- himgaline (15), which forms spontaneously under acidic conditions.¹¹ Whereas the decalin co- ring fusion of GB13 is calculated to be more stable by 1.3 kcal/mol, the trans-ring fusion of 16-oxo-himgaline is lower in energy by 2.7 kcal/mol. We speculate that the piperidine ammonium may deliver a proton internally to the enone y-carbon C9 since β,y to α,β-enone isomerization occurs under acidic conditions and an extended enol tautomer is occluded on its concave face by this ammonium (see 14 X-ray). The final stereogenic methine C-H was installed according to a one-step protocol, as first demonstrated in a 33-step synthesis of himgaline.¹¹¹ Thus, 9 prochiral carbons of high FAr intermediate 10b was converted in 3 steps to 9 new stereocenters (8 carbon, 1 nitrogen) by relay of increasing stereochemical information through simple reductions. To access pure GB13, 14 can be chromatographed to remove reduction byproducts prior to acid hydrolysis, but this is unnecessary for conversion to pure himgaline, resulting in a 7-9 step synthesis, depending on isolation of 14 and designation of official starting material (7 vs. cyclopentane- 1, 3-dione vs. methyl 2-chloro-6-methyl- nicotinate, see Figure 4).

Himgaline is constitutionally related to cross-coupled product 10b by these iterative additions of H2, excluding the (9-m ethyl embedded in starting material 9b. Since hydrogen atoms are typically omitted from complexity calculations,³⁸ the progression of high FAr intermediates to 100% F_sp3 (himgaline) is exclusively due to information carried by molecular topology (C-C, C-N, C-0 bonds) and chirality content. Here, the 260.16 mcbits^{Error! Bookmark not defined.} of ethyl 10b increase to 477.83 over 5 steps, or 43.5 mcbits per step. Visualized as a walk through chemical space^v (Figure 4), the synthesis begins proximal to commercial space (low molecular weight, low complexity and low F _sp3 /high FAT), converges early by cross- coupling and then rapidly reaches the high complexity, weight and F_sp3 of himgaline, typical of remote GB alkaloid space. In contrast, the shortest prior synthesis of himgaline (formal, racemic, 19 steps) varies 148.45 mcbits over 15 steps (9.9 mcbits per step) from the latest point of convergency. Each route allows its own unique exploration of different areas of chemical space. However, recognition that the key methine C-H stereocenters can be stereoselectively appended from prochiral sp² carbons of an aromatic himgaline core simplifies access to GB alkaloid space in a clear and quantifiable way. Whereas this analysis focuses on navigation to high complexity chemotypes, we anticipate that GB structural chemical space can be better parameterized to relate to the biological targets and relative potencies among family members. Given the structural similarity among the 25 Class II and III congeners, this approach is likely to prove general and finally provide a means to deconvolute the targets, functions and translational potential of the GB alkaloids. References

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Materials and methods

All reactions were carried out under positive pressure of argon unless otherwise noted. Glassware was oven-dried at 120 °C for a minimum of 12 hours, or flame-dried with a propane torch under vacuum (< 1 torr). Anhydrous dichloromethane (CH₂Cl₂ ) was distilled from calcium hydride (5% w/v) under positive pressure of nitrogen. Anhydrous tetrahydrofuran (THF) containing 250 ppm BHT (peroxide inhibitor) was purchased from MilliporeSigma / SigmaAldrich. Anhydrous toluene was obtained by passing the previously degassed solvent through an activated alumina column. Other commercially available solvents or reagents were used without further purification unless otherwise noted. Reactions were monitored by thin layer chromatography (TLC) using precoated silica gel plates from EMD Chemicals (TLC Silica gel 60 F254, 250 pm thickness). Flash column chromatography was performed over Silica gel 60 (particle size 0.04- 0.063 mm) from EMD Chemicals and activated neutral alumina (Brockmann I, 150 mesh) from Sigma- Aldrich. Room temperature or ambient temperature in Beckman Building, Lab 420 is 22 °C. Organic solvent from crude reaction mixtures and solutions of pure compounds was evaporated on a Buchi Rotavapor R3 (rotavap or rotovap, referred to in the experimental procedures).

Hexanes (ACS grade), ethyl acetate (ACS grade), diethyl ether (anhydrous ACS grade), dichloromethane (ACS grade), chloroform (ACS grade), and isopropanol (ACS grade) were purchased from Fisher Chemical and used without further purification. Anhydrous tetrahydrofuran, DMF, and acetonitrile were purchased from Sigma-Aldrich. Anhydrous DMSO was purchased from Acros Organics. Anhydrous ethanol was obtained from Pharmco- Aaper. [Ir{dF(CF3)ppy}2(dtbbpy)]PFe was prepared according to the procedure of Lowry et al.¹ Photocatalysts 3CzClIPN and 4CzIPN were prepared according to the procedure of Zeitler et al ² NiCl₂*glyme and IrCh’nHiO were purchased from Strem Chemicals. Commercially available substrates were used without further purification unless otherwise noted. The reactions were monitored by thin layer chromatography (TLC) using precoated silica gel plates from EMD Chemicals (TLC Silica gel 60 F254) or by LC/MS on an Agilent 6120 Quadrupole system with an ESI probe. Flash column chromatography was performed over Silica gel 60 (particle size 0.04-0.063 mm) from Fischer Scientific or Florsil® from Sigma Aldrich or Acros Organics. ¹H NMR and ¹³C NMR spectra were recorded on Bruker DPX-400, a Bruker DPX- 500 or Bruker DPX-600 equipped with cry oprobe, and the residual solvent peaks were used as internal standard (CDCl₃: 7.26 ppm ¹H NMR, 77.16 ppm, DMSO-d₆: 2.50 ppm ¹H NMR, 39.52 ppm, MeOH-tL: 3.31 ppm 'H NMR, 49.00 ppm ¹³C NMR;). NMR data is denoted with apparent multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, and combinations thereof.

Abbreviations:

3CzClIPN = 2,4,6-tri(9H-carbazol-9-yl)-5-chloroisophthalonitrile

4CzIPN = l,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene, 2,4,5,6-tetrakis(9Z7-carbazol- 9-yl)-isophthalonitrile

DMF = N,N-di methyl form am ide

DMSO = dimethylsulfoxide dtbbpy = 4,4'-di-tert-butyl-2,2'-dipyridyl

Bipy = 2,2’ -bipyridine

HFIP = l,l,l,3,3,3-hexafhioro-2-propanol

LED = light-emitting diode

NMR = nuclear magnetic resonance

TFA = 2,2,2-trifluoroacetic acid

THF = tetrahydrofuran

TMS = trimethyl silyl

OAc = acetate

Ac = acetyl

More detailed synthetic examples

Schemes of Present Invention

Synthesis of siloxycyclopropane substrates: General Procedure A.

Under an argon atomsphere, a flame dried round-bottom flask was charged with indanone starting material (1.0 equiv.) and diethyl ether (0.1 M in indanone), followed by Et°,N (3.0 - 4.0 equiv.). The solution was cooled to 0 °C in an ice water bath followed by dropwise addition of TMSOTf (1.2 equiv.). After stirring for 1 h at room temperature, 50 mL NH4CI (sat. aq.) was added and the aqueous layer extracted 3 times with 50 mL diethyl ether. The organic layer was washed with 100 mL brine (i.e. sat. aq. NaCl), dried with MgSCL, filtered through a short plug of Florisil® and concentrated under reduced pressure on a rotovap.

The resulting silyl enol ether was dissolved in CH₂Cl₂ (0.2 M) under an atmosphere of argon and cooled to 0 °C in an ice water bath followed by dropwise addition of Et₂Zn (2.0 equiv.). After stirring for 30 minutes at the same temperature, CH2I2 (2.0 equiv.) was added dropwise. The reaction was allowed to warm to ambient temperature (22 °C) and stir for 18 hours before addition of 100 mL NH4CI (sat. aq.). After extraction of the aqueous layer with 3 times 50 mL CH₂Cl₂, the combined organic layers were washed with 100 mL brine, dried over MgSO₄, filtered through a short Florisil® plug, and concentrated under reduced pressure on a rotovap.

Following General Procedure A using 1-indanone (6.608 g, 50.00 mmol) as substrate afforded the title compound SI-1 (7.59 g, 34.7 mmol, 69% over 2 steps).

Physical State: colorless oil

R_f= 0.50 (10% Et₂O/Hex)

'H NMR (600 MHz, CDCl₃) 6 7.39 (d, J= 7.5 Hz, 1H), 7.19 (t, J= 13 Hz, 1H), 7.15 - 7.08 (m, 2H), 3.22 (dd, J= 17.0, 6.4 Hz, 1H), 2.70 (d, J= 17.0 Hz, 1H), 1.99 (ddd, J= 10.3, 6.4, 4.6 Hz, 1H), 1.42 (ddd, J = 9.4, 5.1, 1.4 Hz, 1H), 0.49 - 0.32 (m, 1H), 0.11 (s, 9H).

¹³C NMR (151 MHz, CDCl₃) 6 146.81, 139.20, 126.52, 126.20, 125.48, 122.65, 68.25, 34.56, 24.02, 23.06, 1.08.

HRMS (ESI): Calc’d, for C₁oHuO [M-TMS+H⁺]: 147.0810; found: 147.0807

Following General Procedure A using 5-chloro- 1-indanone (1.67 g, 10.0 mmol) as substrate afforded the title compound SI-2 (1.84 g, 7.28 mmol, 73% over 2 steps) following purification by Florisil® column chromatography (hexanes/EtOAc = 1/0 to 99/1).

Physical State: pale-yellow oil.

R_f= 0.45 (10% Et₂O/Hex)

'H NMR (600 MHz, CDCl₃) 6 7.29 (d, J= 8.0 Hz, 1H), 7.18 - 7.13 (m, 1H), 7.07 (d, J= 1.9 Hz, 1H), 3.20 (dd, J= 17.2, 6.4 Hz, 1H), 2.68 (d, J= 17.2 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.42 (dd, J= 9.4, 5.2 Hz, 1H), 0.36 (t, J= 4.8 Hz, 1H), 0.10 (s, 9H).

¹³C NMR (151 MHz, CDCl₃) 6 145.49, 141.13, 132.03, 126.48, 125.71, 123.67, 67.71, 34.43, 24.21, 23.04, 1.04. HRMS (ESI): Calc’d, for C10H10CIO [M-TMS+H⁺]: 181.0420; found: 181.0419

Following General Procedure A using 5 -fluoro- 1 -indanone (0.950 g, 6.33 mmol) as substrate afforded the title compound SI-3 (0.90 g, 3.8 mmol, 60% over 2 steps).

Physical State: pale-yellow oil.

R_f= 0.45 (10% Et₂O/Hex)

'H NMR (600 MHz, CDCl₃) 6 7.30 (dd, J= 8.3, 5.3 Hz, 1H), 6.87 (td, J= 8.1, 2.7 Hz, 1H), 6.79 (dd, J= 9.0, 2.7 Hz, 1H), 3.21 (dd, J= 17.2, 6.4 Hz, 1H), 2.67 (d, J= 17.2 Hz, 1H), 2.00 (ddd, J= 9.4, 6.4, 4.3 Hz, 1H), 1.41 (dd, J= 9.4, 5.1 Hz, 1H), 0.37 (t, J= 4.8 Hz, 1H), 0.10 (s, 9H).

¹³C NMR (151 MHz, CDCl₃) 6 162.22 (d, J = 242.6 Hz), 142.45 (d, J = 2.4 Hz), 141.42 (d, J = 8.2 Hz), 123.49 (d, J = 8.9 Hz), 113.15 (d, J= 22.7 Hz), 112.50 (d, J= 22.5 Hz), 67.61, 34.51 (d, J= 2.8 Hz), 24.26, 22.99, 1.05.

HRMS (ESI): Calc’d, for C10H10FO [M-TMS+H⁺]: 165.0716; found: 165.0711

Following General Procedure A using 6-methyl-l -indanone (0.600 g, 4.10 mmol) as substrate afforded the title compound SI-4 (0.60 g, 2.58 mmol, 63% over 2 steps).

Physical State: pale-yellow oil.

Rf= 0.85 (1 : 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃) 6 7.19 (d, J= 1.7 Hz, 1H), 6.98 (d, J= 7.6 Hz, 1H), 6.94 (dd, J = 7.6, 1.7 Hz, 1H), 3.17 (dd, J= 16.8, 6.4 Hz, 1H), 2.64 (d, J= 16.8 Hz, 1H), 2.35 (s, 3H), 1.98 (ddd, J= 9.5, 6.4, 4.4 Hz, 1H), 1.40 (dd, J = 9.4, 5.0 Hz, 1H), 0.36 (t, J = 4.7 Hz, 1H), 0.11 (s, 11H).

¹³C NMR (151 MHz, CDCl₃) 6 146.93, 136.14, 135.80, 127.35, 125.18, 123.30, 68.12, 34.12, 24.29, 23.10, 21.49, 1.10.

HRMS (ESI): Calc’d, for C11H13O [M-TMS+H⁺]: 161.0966; found: 161.0966

Following General Procedure A using 4-methyl-l -indanone (1.5 g, 10.0 mmol) as substrate afforded the title compound SI-5 (2.00 g, 2.0 mmol, 86% over 2 steps).

Physical State: pale-yellow oil.

Rf= 0.85 (1 : 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃) 6 7.24 (d, J= 7.5 Hz, 1H), 7.12 (t, J= 7.5 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 3.10 (dd, J= 17.0, 6.4 Hz, 1H), 2.62 (d, J= 17.0 Hz, 1H), 2.19 (s, 3H), 2.02 (ddd, J= 9.3, 6.3, 4.3 Hz, 1H), 1.42 (dd, J= 9.4, 5.0 Hz, 1H), 0.37 (t, J= 4.7 Hz, 1H), 0.12 (s, 9H). ¹³C NMR (151 MHz, CDCl₃) 6 146.51, 137.86, 134.63, 127.41, 126.48, 120.10, 68.42, 33.53, 23.99, 223.08, 18.61, 1.10.

HRMS (ESI): Calc’d, for C11H13O [M-TMS+H⁺]: 161.0966; found: 161.0962

Following General Procedure A using 6-methoxy-l -indanone (1.6 g, 10.0 mmol) as substrate afforded the title compound SI-6 (1.60 g, 6.4 mmol, 64% over 2 steps).

Physical State: pale-yellow oil.

R/= 0.80 (1 : 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃) 6 6.98 (dd, J= 8.2, 1.2 Hz, 1H), 6.96 (d, J= 2.5 Hz, 1H), 6.68 (dd, J = 8.2, 2.5 Hz, 1H), 3.80 (s, 3H), 3.17 - 3.08 (m, 1H), 2.62 (d, J= 16.5 Hz, 1H), 2.01 (ddd, J= 9.5, 6.3, 4.4 Hz, 1H), 1.40 (dd, J= 9.3, 5.0 Hz, 1H), 0.38 (t, J = 4.7 Hz, 1H), 0.11 (s, 9H). ¹³C NMR (151 MHZ, CDCl₃) 6 158.75, 148.36, 130.92, 126.04, 112.58, 108.19, 68.17, 55.56, 33.68, 24.84, 23.12, 1.08.

HRMS (ESI): Calc’d, for C₁₁H₁₃O₂ [M-TMS+H⁺]: 177.0916; found: 177.0713

Following General Procedure A using 3 -methyl- 1 -indanone (1.5 g, 10.3 mmol) as substrate afforded the title compound SI-7 (1.60 g, 7.3 mmol, 71% over 2 steps) as a 1.7: 1.0 mixture of diastereomers.

Physical State: pale-yellow oil.

Rf= 0.85 (1 : 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃) 6 7.40 - 7.37 (m, 1H), 7.35 (dd, J= 7.2, 1.5 Hz, 0.6H), 7.22 - 7.13 (m, 3.2H), 7.13 - 7.10 (m, 1H), 7.06 - 7.03 (m, 0.6H), 3.62 (p, J= 6.8 Hz, 0.6H), 2.83 (q, J= 7.2 Hz, 1H), 2.01 (ddd, J= 9.5, 6.2, 4.4 Hz, 0.6H), 1.86 (dd, J= 9.3, 4.3 Hz, 1H), 1.41 (dd, J= 9.4, 5.0 Hz, 1H), 1.31 (d, J = 7.2 Hz, 3H), 1.23 - 1.18 (m, 2.4H), 0.42 (t, J= 4.8 Hz, 0.6H), 0.38 (t, J= 4.7 Hz, 1H), 0.12 (s, 9H), 0.11 (s, 5.4H).

¹³C NMR (151 MHz, CDCl₃, major) 8 145 92, 144.51, 126.38, 126.30, 124.65, 122.32, 67.25, 41.67, 31.71, 24.42, 22.58, 1.20.

¹³C NMR (151 MHz, CDCl₃, minor) 8 146.57, 143.49, 126.59, 126.20, 124.13, 122.31, 67.08, 38.36, 29.19, 19.14, 15.63, 0.96.

HRMS (ESI): Calc’d, for C11H13O [M-TMS+H⁺]: 161.0966; found: 161.0963

Following General Procedure A using 6, 7- Dihydrocyclopentafb] pyridin-5-one (1.5 g, 10.3 mmol) as substrate afforded the title compound SI-8 (141 mg, 0.64 mmol, 22% over 2 steps) following purification by Florisil® column chromatography (hexanes/EtOAc = 1/0 to 4/1).

Physical State: yellow-brown oil.

R_f= 0.25 (20% Et₂O/Hex)

'H NMR (600 MHz, CDC13) 8 8.34 (dd, J = 4.9, 1.7 Hz, 1H), 7.66 (dd, J = 7.6, 1.6 Hz, 1H), 7.09 (dd, J = 8.0, 5.4 Hz, 1H), 3.33 (dd, J = 17.8, 6.6 Hz, 1H), 2.83 (d, J = 17.9 Hz, 1H), 2.05 (ddd, J = 9.4, 6.6, 4.5 Hz, 1H), 1.48 (dd, J = 9.4, 5.4 Hz, 1H), 0.45 - 0.39 (m, 1H), 0.11 (s, 9H). ¹³C NMR (151 MHz, CDC13) 6 160.95, 147.94, 140.26, 130.32, 121.11, 65.90, 36.89, 22.86, 22.32, 1.03. HRMS (ESI): Calc’d, for C11H13O [M-TMS+H⁺]: 220.1158; found: 220.1154

Following General Procedure A using l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (0.348 g, 2.0 mmol) as substrate afforded the title compound 21 (259 mg, 1.0 mmol, 50% over 2 steps) following purification by Florisil® column chromatography (hexanes/Et₂O = 1/0 to 19/1).

Physical State: white solid.

R_f= 0.42 (5% Et₂O/Hex)

¹H NMR (600 MHz, CDCl₃) 6 6.82 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 4.58 (ddd, J = 9.3, 8.0, 1.3 Hz, 2H), 3.42 - 3.23 (m, 2H), 3.16 (dd, J = 16.6, 6.4 Hz, 1H), 2.63 (d, J = 16.5 Hz, 1H), 2.02 (ddd, J = 9.2, 6.3, 4.4 Hz, 1H), 1.39 (dd, J = 9.4, 5.1 Hz, 1H), 0.44 (t, J = 4.7 Hz, 1H), 0.09 (s, 9H).

¹³C NMR (151 MHz, CDCl₃) 6 159.63, 143.19, 130.80, 124.35, 121.65, 107.30, 71.72, 67.91, 33.84, 28.38, 24.26, 22.96, 0.83.

HRMS (ESI): Calc’d, for C11H13O [M-TMS+H⁺]: 189.0916; found: 189.0912.

Optimization of tetralone synthesis

Solvent Screen:

Entry Solvent Yield of SI-11 (%)

ausing 2,6-lutidine as base. Base Screen:

2 2,6-lutidine 70

10 3-picoline 46

12 ditertbutyl pyridine 21

ditertbutyl methylpyridine

14 collidine 51

Entry Deviation Yield of SI-11 (%) 16) 65

<5

4 pyridine as base, ligand <5

no reaction

10 bromobenzene as limiting 73 Photocatalyst and Reaction Setup

(%yield) refers to minor exo-cross coupling product

5. Synthesis of P-Substituted Tetralones: General Procedure B

A flame-dried test tube was charged with NiCl₂.6H₂O (0.2 equiv.), 3CzC1IPN (0.07 equiv.), dtbbpy (0.2 equiv.) and, if solid, aryl or vinyl bromide (1.0 equiv.). The contents were then placed under an atmosphere of argon before being dissolved in dry DMSO (0.1 M in aryl or vinyl bromide). 2,6-Lutidine (2.0 equiv.) and, if an oil, bromide coupling partner (1.0 equiv.) were added to the solution followed by siloxycyclopropane (1.8 equiv.). At this point the solution was sparged with argon for 30 minutes before being sealed with Teflon® and electrical tape (see Figure 5). The reaction tube was placed into a water bath at 45 °C and irradiated with a blue Kessil lamp; up to six reactions could be run at one time. After 36 hours, EtOAc was added, and the reaction tube was cooled to 0 °C before addition of water (the addition of water generated heat). The aqueous layer was extracted three times with 3 mL EtOAc, and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure on a rotovap.

Crude reaction mixtures were generally purified by silica gel column chromatography followed by an additional preparative TLC purification to remove impurities with very similar Rf (napthol and uncoupled tetralone byproducts). Specifications are made for each reaction. In most cases, the product was isolated as an inseparable mixture of regioisomers. NMR peak reports are based on the mixture because several peaks overlap. ¹³C NMR peak reports for each regioisomer could be deconvoluted more easily and are therefore reported with separate entries.

Synthesis and characterization data for tetralones o-

coup ng product

Following General Procedure B using bromobenzene (1.0 equiv., 26 μL, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv., 100 μL, 0.45 mmol) afforded a mixture (6.4: 1.0) of the title compound SI-11 and its regioisomer (42 mg, 0.19 mmol, 76% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes :Et₂O) and preparative TLC (3:2 hexanes:Et₂O) to remove minor naphthol impurities. The ³H and ¹³C NMR signals of the minor regioisomer were identical to those previously reported.³

Physical State: white solid.

Rf= 0.60 (1 : 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃) 6 8.09 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.7 Hz, 0.2H), 7.57 (t, J = 7.5, 0.2H), 7.52 (td, J = 7.5, 1.4 Hz, 1H), 7.41-7.35 (m, 3.4H), 7.33 - 7.27 (m, 4.4H), 7.25 - 7.22 (m, 0.4H), 3.51 - 3.44 (m, 1H), 3.41 (dd, J = 14.0, 4.3 Hz, 0.2H), 3.26 - 3.14 (m, 2.2H), 3.04 - 2.96 (m, 1.2H), 2.90 - 2.82 (m, 1.2H), 2.68 (dd, J = 14.0, 10.5 Hz, 0.2H).

¹³C NMR (151 MHz, CDCl₃, major) 8 197.88, 143.56, 143.50, 133.91, 129.02, 128.98, 128.92, 127.33, 127.11, 127.07, 126.81, 46.09, 41.24, 37.81.

¹³C NMR (151 MHz, CDCl₃, minor) 8 207.92, 153.75, 139.77, 136.67, 134.93, 132.23, 128.65, 127.55, 126.71, 126.47, 124.14, 49.05, 37.11, 32.31.

HRMS (ESI): Calc’d, for C₁₆H₁₅O [M+H⁺]: 223.1123; found: 223.1124

Following General Procedure B using 4-bromodibenzothiophene (1.0 equiv., 66 mg, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv., 100 μL, 0.45 mmol) afforded a mixture (4.3: 1.0) of the title compound SI-12 and its regioisomer (39 mg, 0.12 mmol, 47% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes:Et₂O) and preparative TLC (toluene, two passes) to remove minor naphthol impurities. Physical State: white solid.

R_f= 0.25 (20% Et₂O/Hex) 'H NMR (600 MHz, CDCl₃) 6 8.20-8.13 (m, 2.19H), 8.09 (d, J= 7.81 Hz, 1H), 8.06 (d, J = 7.83 Hz, 0.23H), 7.89-7.81 (m, 1.42H), 7.59-7.31 (m, 7.71H), 7.31 (d, J= 7.59 Hz, 1H), 3.83 - 3.76 (m, 1H), 3.69 (dd, J = 14.5, 4.4 Hz, 0.23H), 3.42 - 3.33 (m, 2H), 3.31 (ddd, J= 10.6, 8.0, 4.1 Hz, 0.24H), 3.21 - 3.13 (m, 1.23H), 3.06 (dd, J= 16.6, 12.8 Hz, 1H), 2.97 - 2.88 (m, 0.45H).

13C NMR (151 MHz, CDCl₃, major) 8 197.55, 143.31, 138.92, 138.72, 137.76, 136.34, 136.11, 134.05, 132.25, 129.09, 127.48, 127.26, 127.08, 125.31, 124.72, 123.46, 122.94, 121.90, 120.49, 44.58, 40.64, 36.03.

13C NMR (151 MHz, CDCl₃, minor) 8 207.62, 153.67, 139.84, 136.61, 136.21, 136.07, 135.02, 134.35, 127.62, 126.93, 126.78, 126.73, 125.06, 124.64, 124.23, 122.98, 120.03, 44.58, 40.64, 36.03.

HRMS (ESI): Calc’d, for C₁₁H₁₃O [M+H⁺]: 329.1000; found: 329.1003

Following General Procedure B using 1 -bromocyclohexene (1.0 equiv., 40 mg, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv., 100 μL, 0.45 mmol) afforded a mixture (6.2: 1.0) of the title compound SI-13 and its regioisomer (22 mg, 0.10 mmol, 39% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes :Et₂O) and preparative TLC (7:3 hexanes:Et₂O) to remove minor impurities.

Physical State: colorless oil.

R_f= 0.55 (20% Et₂O/Hex)

'H NMR (600 MHz, CDCl₃) 8 8.02 (d, J= 8.02, 9.25 Hz, 1H), 7.75 (d, J= 7.71 Hz, 0.16H), 7.58 (td, J= 7.45, 1.22 Hz, 0.16H), 7.49 - 7.44 (m, 1.16H), 7.36 (t, J = 7.45 Hz, 0.16H), 7.31 (t, J= 7.58 Hz, 1H), 7.25 (s, 0.5H), 5.54 (s, 1H), 5.47 (s, 0.16H), 3.22 (dd, J = 18.04, 8.51 Hz, 0.16H), 3.01 - 2.92 (m, 2H), 2.86 - 2.81 (m, 0.32H), 2.78 - 2.65 (m, 2.32H), 2.56 (dd, J = 16.07, 12.54 Hz, 1H), 2.04 - 2.02 (m, 4.64H), 1.68 - 1.55 (m, 5H).

¹³C NMR (151 MHz, CDCl₃, major) 8 198.78, 143.99, 138.96, 133.54, 132.20, 128.89, 127.04, 126.66, 121.71, 44.15, 42.62, 35.15, 26.45, 25.21, 22.92, 22.51.

¹³C NMR (151 MHz, CDCl₃, minor) 8 209.03, 153.94, 136.66, 135.52, 134.69, 127.29, 126.61, 123.93, 123.08, 45.64, 39.97, 32.36, 28.19, 25.32, 22.48.

HRMS (ESI): Calc’d, for C₁₆H₁₉O [M+H⁺]: 227.1436; found: 227.1440

Following General Procedure B using 4-bromobenzenetrifluoride (1.0 equiv., 35 μL, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv., 100 μL, 0.45 mmol) afforded a mixture (6.7: 1.0) of the title compound SI-14 and its regioisomer (52 mg, 0.18 mmol, 71% yield) following purification by column chromatography (gradient elution, hexanes to 6: 1 hexanes:Et₂O) and preparative TLC (toluene) to remove minor impurities.

Physical State: white solid.

R_f= 0.30 (20% Et₂O/Hex)

'H NMR (600 MHz, CDCl₃) 6 8.09 (d, J= 7.83 Hz, 1H), 7.79 (d, J= 7.71 Hz, 0.15H), 7.63 (d, J= 8.35 Hz, 2H), 7.59 (t, J = 7.45 Hz, 0.15H), 7.56 - 7.52 (m, 1.3H), 7.43 - 7.36 (m, 3.75), 7.29 (d, J= 7.58 Hz, 1H), 3.54 (m, 1H), 3.43 (dd, J= 14.3, 4.50 Hz, 0.15H), 3.23 (m, 2.15H), 3.02 (m, 1.15H), 2.84 (m, 1.30H).

¹³C NMR, ¹⁹F decoupled (100 MHz, CDCl₃, major) 8 197 16, 147 43, 142 89, 134 13, 132.14, 129.38, 128.99, 127.46, 127.34, 127.28, 125.94, 45.70, 41.05, 37.42.

¹³C NMR, ¹⁹F decoupled (100 MHz, CDCl₃, minor) 8 207 34, 153 45, 143 92, 136 50, 135.17, 132.14, 129.50, 129.38, 127.76, 126.74, 125.63, 48.66, 36.83, 32.22.

HRMS (ESI): Calc’d, for C₁₇H₁₄F₃O [M+H⁺]: 291.0997; found: 291.0998

Following General Procedure B using (Z)-2-bromo-2-butene (1.0 equiv., 26 μL, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv., 100 μL, 0.45 mmol) afforded a mixture (5.9:1) of the title compound SI-15 and its regioisomer (15 mg, 0.07 mmol, 29% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes :Et₂O) and preparative TLC (3:2 Et₂O:hexanes) to remove minor impurities.

Physical State: white solid.

R_f= 0.50 (20% Et₂O/Hex) 1H NMR (600 MHz, CDCl₃) 8 8.03 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.6 Hz, 0.15H), 7.58 (t, J = 8.2 Hz, 0.15H), 7.49 - 7.44 (m, 1.15H), 7.36 (t, J = 7.4 Hz, 0.15H), 7.31 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 5.12 (d, J = 9.0 Hz, 1.15H), 3.27 (dd, J = 17.2, 8.0 Hz, 0.15H), 3.14 - 3.05 (m, 1H), 2.93 (dd, J = 17.2, 5.3 Hz, 1H), 2.80 (dd, J = 16.2, 10.7 Hz, 2H), 2.75 - 2.67 (m, 1.15H), 2.64 - 2.58 (m, 0.15H), 2.42 (dd, J = 16.7, 12.1 Hz, 1H), 2.30 - 2.20 (m, 0.15H), 1.72 (s, 3H), 1.69 (s, 0.45H), 1.66 (s, 3H), 1.64 (s, 0.45H).

¹³C NMR (151 MHz, CDCl₃, major) 8 198.40, 143.79, 133.67, 133.16, 132.44, 129.06, 127.12, 126.82, 124.01, 77.37, 77.16, 76.95, 45.70, 36.64, 34.90, 25.85, 18.12.

¹³C NMR (151 MHz, CDCl₃, minor) 8 208.78, 154.07, 137.00, 134.77, 134.05, 127.41, 126.72, 121.16, 47.72, 32.32, 29.77, 25.95, 18.08.

HRMS (ESI): Calc’d, for C₁₄H₁₇O [M+H⁺]: 201.1279; found: 201.1281

Following General Procedure B using l-bromo-4-tert-butylbenzene (1.0 equiv., 43 μL, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv., 100 μL, 0.45 mmol) afforded a mixture (5.0: 1.0) of the title compound SI-16 and its regioisomer (50 mg, 0.18 mmol, 72% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes:Et₂O) and preparative TLC (1 : 1 Et₂O:hexanes) to remove minor impurities.

Physical State: white solid.

R_f= 0.45 (20% Et₂O/Hex)

'H NMR (600 MHz, CDCl₃) 6 8.10 (d, J = 7.83 Hz, 1H), 7.80 (d, J= 7.71 Hz, 0.20H), 7.58 (t, J= 6.74 Hz, 0.20H), 7.52 (t, J = 7.45 Hz, 1H), 7.42 - 7.33 (m, 4H), 7.29 (d, J = 7.71 Hz, 1H), 7.25 (s, 1H), 7.20 (d, J= 8.35 Hz, 0.40H), 3.45 (ddd, J= 13.61, 10.47, 3.60 Hz, 1H), 3.39 (dd, J = 14.13, 4.24 Hz, 0.20H), 3.24 - 3.16 (m, 2.40H), 3.03 - 2.97 (m, 1.20H), 2.91 - 2.82 (m, 1.20H), 2.62 (dd, J = 14.00, 10.66 Hz, 0.20H), 1.35, (s, 9H), 1.33 (s, 1.8H).

¹³C NMR (151 MHz, CDCl₃, major) 8 198.06, 149.96, 143.64, 140.54, 133.85, 132.26, 128.98, 127.31, 127.01, 126.46, 125.77, 46.13, 40.71, 37.87, 34.58, 31.48.

¹³C NMR (151 MHz, CDCl₃, minor) 8 208.06, 153.83, 149.26, 136.71, 136.70, 134.88, 128.65, 127.51, 126.71, 125.53, 124.15, 49.13, 36.67, 34.51, 32.50, 31.50.

HRMS (ESI): Calc’d, for C₂₀H₂₃O [M+H⁺]: 279.1749; found: 297.1753

Following General Procedure B using l-bromo-4-tert-butylbenzene (1.0 equiv., 43 μL, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv, 100 μL, 0.45 mmol) afforded a mixture (5.0: 1.0) of the title compound SI-17 and its regioisomer (45 mg, 0.17 mmol, 70% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes:Et₂O) and preparative TLC (toluene, two passes) to remove minor naphthol impurities. Physical State: white solid.

R_f= 0.30 (20% Et₂O/Hex)

'H NMR (600 MHz, CDCl₃) 6 8.08 (d, J= 7.83 Hz, 1H), 7.77 (d, J= 7.71 Hz, 0.20H), 7.58 (t, J= 6.74 Hz, 0.20H), 7.52 (t, J = 7.45, 1H), 7.41 - 7.33 (m, 3.40H), 7.29 - 7.23 (m, 3.80H), 7.17 (d, J= 8.35 Hz, 0.40H), 3.45 (dddd, J = 13.10, 9.76, 5.97, 3.53 Hz, 1H), 3.33 (dd, J = 14.13, 4.50 Hz, 0.20H), 3.18 (m, 2.20H), 2.95 (m, 1.20H), 2.81 (m, 1.20H), 2.70 (dd, J = 14.32, 9.70 Hz, 0.20H).

¹³C NMR (151 MHz, CDCl₃, major) 8 197.45, 143.12, 141.99, 134.03, 132.83, 132.17, 130.42, 129.07, 128.22, 127.41, 127.23, 45.97, 40.66, 37.68.

¹³C NMR (151 MHz, CDCl₃, minor) 8 207.59, 153.58, 138.15, 136.61, 135.07, 132.31, 128.98, 128.78, 127.67, 126.73, 124.20, 45.97, 40.66, 37.68.

HRMS (ESI): Calc’d, for C₁₆H₁₄C₁₀ [M+H⁺]: 257.0733; found: 257.0736

Following General Procedure B using bromobenzene (1.0 equiv., 26 μL, 0.25 mmol) and siloxycyclopropane SI-8 (1.8 equiv., 99 mg, 0.45 mmol) afforded the title compound SI-18 (24 mg, 0.11 mmol, 42% yield) following purification by column chromatography (gradient elution, 1.5: 1 to 0.4: 1 hexanes :EtO Ac) and preparative TLC (4: 1 EtOAc: hexanes) to remove minor impurities.

Physical State: white solid.

R_f= 0.25 (40% EtOAc/Hex) Hl NMR (600 MHz, CDCl₃) 6 8.73 (dd, J = 4.82, 1.88 Hz, 1H), 8.32 (dd, J= 7.92, 1.87 Hz, 1H), 7.38 (t, J = 7.64 Hz, 2H), 7.34 - 7.28 (m, 4H), 3.54 (tt, J = 12.55, 4.02 Hz, 1H), 3.47 - 3.35 (m, 2H), 3.02 (ddd, J = 16.70, 3.86, 1.92 Hz, 1H), 2.90 (dd, J = 16.68, 12.94 Hz, 1H).

¹³C NMR (151 MHz, CDCl₃) 6 197.34, 162.78, 154.04, 142.79, 135.16, 129.04, 127.77, 127.28, 126.81, 122.63, 45.67, 40.38, 39.82.

HRMS (ESI): Calc’d, for C₁₅H₁₄NO [M+H⁺]: 224.1075; found: 224.1078

Following General Procedure B using bromobenzene (1.0 equiv., 26 μL, 0.25 mmol) and siloxycyclopropane SI-10 (1.8 equiv., 105 mg, 0.45 mmol) afforded the title compound SI-19 (20 mg, 0.09 mmol, 34% yield) following purification by column chromatography (gradient elution, hexanes to 1 : 1 hexanes:EtOAc) and preparative TLC (1.5: 1 EtOAc: hexanes, two passes) to remove minor naphthol impurities.

Physical State: white solid.

R_f= 0.30 (40% EtOAc/Hex)

'H NMR (600 MHz, CDCl₃) 6 8.21 (d, J= 7.96 Hz, 1H), 7.36 (t, J= 7.64 Hz, 2H), 7.30 - 7.27 (m, 3H), 7.18 (d, J = 7.96, 1H), 3.52 (tt, J = 12.46, 3.98 Hz, 1H), 3.42 (dd, J= 16.95, 4.37 Hz, 1H), 3.32 (dd, J= 16.95, 11.56 Hz, 1H), 2.99 (ddd, J= 16.63, 3.84, 1.86 Hz, 1H), 2.86 (dd, J = 16.62, 12.86 Hz, 1H), 2.62 (s, 3H).

¹³C NMR (151 MHz, CDC13) 8 197.17, 163.92, 162.33, 142.89, 135.49, 128.98, 127.18, 126.78, 125.48, 122.47, 45.62, 40.25, 39.80, 25.12.

HRMS (ESI): Calc’d, for C₁₆H₁₆NO [M+H⁺]: 238.1232; found: 238.1234

Following General Procedure B using A-(3-bromo-5-fluorophenyl) acetamide (1.0 equiv., 58 mg, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv, 100 μL, 0.45 mmol) afforded a mixture (5.6: 1.0) of the title compound SI-20 and its regioisomer (44 mg, 0.15 mmol, 59% yield) following purification by column chromatography (gradient elution, 1 : 1 to 4: 1 EtOAc: hexanes) and preparative TLC (EtOAc) to remove minor naphthol impurities.

Physical State: pale yellow solid.

R_f= 0.35 (30% EtOAc/Hex)

'H NMR (600 MHz, CDCl₃) 6 8.04 (d, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.73 (d, J = 7.7 Hz, 0.2H), 7.55 (t, J= 8.0 Hz, 0.2H), 7.52 - 7.44 (m, 2.2H), 7.39 (d, J= 7.7 Hz, 0.2H), 7.33 (q, J = 6.9 Hz, 1.2H), 7.28 - 7.23 (m, 1.2H), 7.18 - 7.10 (m, 2.2H), 7.04 (dd, J= 8.2, 2.1 Hz, 0.2H), 3.68 (tt, J= 11.8, 4.3 Hz, 1H), 3.29 (dd, J = 14.1, 4.8 Hz, 0.2H), 3.23 - 3.08 (m, 2.2H), 3.02 - 2.94 (m, 0.2H), 2.93 - 2.79 (m, 2.2H), 2.70 (dd, J= 14.1, 9.9 Hz, 0.2H), 2.16 (s, 3H), 2.15 (s, 0.6H).

¹³C NMR (151 MHz, CDCl₃, major) 8 197.77, 168.69, 160.70 (d, J = 245.3 Hz), 143.32, 138.20 (d, J= 11.2 Hz), 133.95, 131.97, 128.93, 127.75 (d, J = 5.8 Hz), 127.23, 127.05, 125.68 (d, J= 14.5 Hz), 115.37 (d, J= 3.1 Hz), 107.83 (d, J= 27.6 Hz), 44.51, 36.05, 34.49, 24.55.

¹³C NMR (151 MHz, CDCl₃, minor) 8 207.80, 168.63, 161.12 (d, J = 244.6 Hz), 153.65, 136.37, 137.93, 135.01, 131.14 (d, J = 6.0 Hz), 127.51, 126.66, 123.99, 121.98, 115.24, 107.39, 47.99, 32.15, 29.67, 24.55.

HRMS (ESI): Calc’d, for C₁sHnFNCh [M+H⁺]: 298.1243; found: 298.1248

Following General Procedure B using bromobenzene (1.0 equiv, 26 μL, 0.25 mmol) and siloxycyclopropane SI-4 (1.8 equiv, 118 μL, 0.45 mmol) afforded a mixture (7.5:1) of the title compound SI-21 and its regioisomer (33 mg, 0.14 mmol, 56% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes :Et₂O) and preparative TLC (1 :1 CH₂C₁₂:toluene) to remove minor naphthol impurities.

Physical State: colorless oil.

R/= 0.40 (3: 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃) 6 7.92 - 7.87 (m, 1H), 7.58 (s, 0.1H), 7.37 (t, J= 7.6 Hz, 2.1H), 7.33 (dd, J= 7.8, 2.0 Hz, 1.1H), 7.32 - 7.27 (m, 3.1H), 7.25 - 7.20 (m, 0.2H), 7.18 (d, J= 7.7 Hz, 1H), 3.48 - 3.41 (m, 1H), 3.39 (dd, J= 14.0, 4.3 Hz, 0.1H), 3.21 - 3.09 (m, 2.1H), 3.03 - 2.93 (m, 1.1H), 2.83 (dd, J= 16.6, 13.2 Hz, 1.1H), 2.66 (dd, J= 14.0, 10.5 Hz, 0.1H), 2.40 (s, 0.3H), 2.39 (s, 3H). ¹³C NMR (151 MHz, CDCl₃, major) 8 198.23, 143.71, 140.68, 136.82, 134.91, 132.04, 128.92, 127.46, 127.09, 126.86, 126.45, 46.16, 41.42, 37.47, 21.13.

¹³C NMR (151 MHz, CDCl₃, minor) 8 208.10, 151.14, 139.91, 137.51, 136.85, 136.23, 129.06, 128.65, 126.40, 124.10, 49.44, 37.21, 31.97, 21.25.

HRMS (APCI): Calc’d, for C17H17O [M+H⁺]: 237.1279; found: 237.1284

Following General Procedure B using bromobenzene (1.0 equiv., 27.1 μL, 0.25 mmol) and siloxycyclopropane SI-3 (1.8 equiv., 107 μL, 0.45 mmol) afforded a mixture (4.7: 1.0) of the title compound SI-22 and its regioisomer (55 mg, 0.23 mmol, 92% yield) following purification by column chromatography (gradient elution, 19: 1 hexanes:Et₂O to 9: 1 hexanes:Et₂O) and preparative TLC (2: 1 hexanes:Et₂O) to remove minor impurities.

Physical State: colorless oil.

Rf= 0.25 (9: 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃) 8 8.11 (dd, J= 8.1, 6.0 Hz, 1H), 7.78 (dd, J= 8.3, 5.3 Hz, 0.2H), 7.40 - 7.35 (m, 2H), 7.29 (d, J= 7.6 Hz, 3.4H), 7.23 (dd, J= 7.8, 2.8 Hz, 0.6H), 7.10 - 7.00 (m, 1H), 6.96 (dd, J= 9.1, 2.5 Hz, 1H), 3.47 (tt, J= 12.0, 4.2 Hz, 1H), 3.38 (dd, J= 14.0, 4.4 Hz, 0.2H), 3.27 - 3.12 (m, 2.2H), 3.03 (ddt, J = 12.0, 8.2, 4.2 Hz, 0.2H), 2.96 (ddd, J= 16.7, 3.8, 1.9 Hz, 1H), 2.83 (dd, J= 16.8, 13.1 Hz, 1.2H), 2.69 (dd, J= 14.0, 10.3 Hz, 0.2H).

¹³C NMR (151 MHz, CDCl₃, major) 8 196.35, 166.07 (d, J = 255.97 Hz), 146.52 (d, J= 9.4 Hz), 143.13, 130.45 (d, J= 9.9 Hz), 128.99, 128.94 (d, J=2.8 Hz), 127.26, 126.79, 115.34 (d, J= 21.5 Hz), 114.77 d, (J= 22.1 Hz), 45.81, 41.10, 37.85.

¹³C NMR (151 MHz, CDCl₃, minor) 8 205.98, 167.40 (d, J= 256.5 Hz), 156.63 (d, J= 10.0 Hz), 139.45, 133.09 (d, J= 2.2 Hz), 129.03, 128.71, 126.59, 126.43 (d, J= 10.5 Hz), 115.90 (d, J= 23.8 Hz), 113.30 (d, J= 22.1 Hz), 49.26, 37.08, 32.20.

HRMS (APCI): Calc’d, for C₁₆H₁₃FO [M-TMS+H⁺]: 241.1029; found: 241.1035

Following General Procedure B using bromobenzene (1.0 equiv., 26 μL, 0.25 mmol) and siloxycyclopropane SI-2 (1.8 equiv., 118 μL, 0.45 mmol) afforded a mixture (5.0: 1.0) of the title compound SI-23 and its regioisomer (33 mg, 0.14 mmol, 56% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes :Et₂O) and preparative TLC (1 : 1 CHjCl 2 Toluene) to remove minor naphthol impurities.

Physical State: clear oil.

Rf= 0.25 (9: 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃) 6 8.02 (d, J= 8.4 Hz, 1H), 7.70 (d, J= 8.2 Hz, 0.2H), 7.40 - 7.35 (m, 2.2H), 7.33 (dd, J= 8.5, 2.1 Hz, 1.2H), 7.29 (p, J= 3.1 Hz, 4.4H), 7.25 - 7.21 (m, 0.4H), 3.46 (ddt, J= 12.8, 11.2, 4.3 Hz, 1H), 3.37 (dd, J= 14.0, 4.4 Hz, 0.2H), 3.24 - 3.11 (m, 2.4H), 3.02 (ddd, J= 10.2, 8.0, 4.1 Hz, 0.2H), 2.97 (ddd, J= 16.8, 3.8, 1.9 Hz, 1H), 2.84 (dd, J= 16.7, 13.0 Hz, 1.2H), 2.69 (dd, J= 14.1, 10.2 Hz, 0.2H).

¹³C NMR (151 MHz, CDCl₃, major) 8 196.74, 145.03, 143.08, 140.17, 130.70, 129.01, 128.87, 128.72, 127.63, 127.29, 126.79, 45.86, 41.02, 37.57.

¹³C NMR (151 MHz, CDCl₃, minor) 8 206.41, 155.19, 141.20, 139.37, 135.14, 128.87, 128.72, 128.40, 126.90, 126.62, 125.27, 49.14, 37.04, 31.98. : 257.0733; found: 257.0738

Following General Procedure B using 2-bromo-5-fluoropyridine (1.0 equiv., 44 mg, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv, 100 μL, 0.45 mmol) afforded the title compound SI-24 (30 mg, 0.12 mmol, 49% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes:EtOAc) and preparative TLC (1 :3 acetone Toluene) to remove minor naphthol impurities.

Physical State: colorless oil.

Rf= 0.5 (1 :3 acetone:toluene)

'H NMR (600 MHz, CDCl₃) 6 8.42 (d, J = 3.0 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.27 (d, 1H), 7.22 (dd, J = 8.6, 4.4 Hz, 1H), 3.62 (tt, J = 11.8, 4.2 Hz, 1H), 3.36 (dd, J = 16.2, 11.2 Hz, 1H), 3.24 - 3.16 (m, 1H), 3.02 (dd, J = 16.8, 12.2 Hz, 1H), 2.97 - 2.88 (m, 1H). ¹³C NMR (151 MHz, CDCl₃) 6 197.62, 158.48 (d, J = 254.87 Hz), 157.97 (d, J = 3.87 Hz), 143.02, 137.72 (d, J = 23.21 Hz), 133.94, 132.18, 129.01, 127.21, 127.05, 123.54 (d, J = 18.24 Hz), 122.50 (d, J = 3.87), 44.59, 42.29, 36.14.

HRMS (APCI): Calc’d, for C15H12FNO [M+H⁺]: 242.0981; found: 242.0988

Following General Procedure B using 4-bromo-3 -fluoroaniline (1.0 equiv., 48 mg, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv., 100 μL, 0.45 mmol) afforded a mixture (6.7:1) of the title compound SI-25 and its regioisomer (22 mg, 0.09 mmol, 34% yield) following purification by column chromatography (gradient elution, hexanes to 1 : 1 hexanes:EtOAc) and preparative TLC (3:7 Et₂O:toluene) to remove minor naphthol impurities.

Physical State: brown solid.

Rf= 0.15 (1 : 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃, major) 8 1HNMR (600 MHz, CDC13) 8 8.07 (d, J = 7.8 Hz, 1H), 7.51 (td, J = 7.5, 1.5 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 6.93 (dd, J = 12.1, 2.0 Hz, 1H), 6.86 (dd, J = 8.2, 2.0 Hz, 1H), 6.76 (t, J = 8.6 Hz, 1H), 3.34 (tdt, J = 9.5, 6.2, 3.7 Hz, 1H), 3.13 (d, J = 9.9 Hz, 2H), 2.96 - 2.89 (m, 1H), 2.75 (dd, J = 16.6, 13.1 Hz, 1H).

¹³C NMR (151 MHz, CDCl₃, major) 8 197.90, 151.72 (d, J = 238.8 Hz), 143.42, 134.49 (d, J = 5.8 Hz), 133.93, 133.28 (d, J = 13.1 Hz), 132.20, 128.98, 127.32, 127.07, 122.66 (d, J = 3.3 Hz), 117.19 (d, J = 4.4 Hz), 113.67 (d, J = 18.8 Hz), 46.28, 40.28, 37.95.

¹³C NMR (151 MHz, CDCl₃, minor) 8 207.96, 153.78, 136.69, 134.95, 130.38, 127.55, 126.71, 124.93 (d, J = 3.3 Hz), 124.12, 117.12 (d, J = 3.9 Hz), 115.81 (d, J = 18.2 Hz), 49.08, 36.10, 32.15.

HRMS (APCI): Calc’d, for C14H13FNO [M+H⁺]: 256.1138; found: 256.1141

Following General Procedure B using 4-bromo- 1,1’ -biphenyl (1.0 equiv., 58 mg, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv, 100 μL, 0.45 mmol) afforded a mixture (5.0: 1.0) of the title compound SI-26 and its regioisomer (56 mg, 0.19 mmol, 75% yield) following purification by column chromatography (gradient elution, 19: 1 hexanes :Et₂0 to 9: 1 hexanes:Et₂O) and preparative TLC (2: 1 hexanes:Et₂O) to remove minor impurities.

Physical State: white solid.

Rf= 0.25 (9: 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃) 6 8.12 (d, J= 7.8 Hz, 1H), 7.82 (d, J= 7.7 Hz, 0.2H), 7.63 - 7.57 (m, 4.2H), 7.54 (ddd, J= 11.5, 6.0, 2.2 Hz, 1.2H), 7.45 (q, J= 8.2 Hz, 2.2H), 7.42 - 7.30 (m, 5.2H), 3.52 (ddt, J= 13.8, 10.7, 4.4 Hz, 1H), 3.45 (dd, J= 14.0, 4.4 Hz, 0.2H), 3.31 - 3.20 (m, 2.4H), 3.10 - 2.99 (m, 1.2H), 2.94 - 2.84 (m, 1.2H), 2.74 (dd, J= 14.0, 10.4 Hz, 0.2H).

¹³C NMR (151 MHz, CDCl₃, major) 8 197.81, 143.44, 142.60, 140.81, 140.07, 133.94, 132.25, 129.00, 128.92, 127.61, 127.42, 127.36, 127.25, 127.16, 127.11, 46.07, 40.90, 37.79.

¹³C NMR (151 MHz, CDCl₃, minor) 8 207.88, 153.75, 140.96, 139.40, 138.86, 136.67, 134.96, 129.45, 128.87, 127.58, 127.28, 127.11, 127.09, 126.73, 124.17, 49.01, 36.74, 32.37.

HRMS (APCI): Calc’d, for C₂₂H₁₈O [M+H⁺]: 299.1436; found: 299.144

Following General Procedure B using l-(4-bromo-2-chlorophenyl)ethan-l-one (1.0 equiv., 58 mg, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv, 100 μL, 0.45 mmol) afforded a mixture (6.7: 1.0) of the title compound SI-27 and its regioisomer (41 mg, 0.14 mmol, 55% yield) following purification by column chromatography (9: 1 hexanes:Et₂O) and preparative TLC (2: 1 hexanes:Et₂O) to remove minor impurities.

Physical State: white solid.

R/= 0.30 (1 : 1 hexanes: Et₂O)

'H NMR (600 MHz, CDCl₃) 8 8.07 (dd, J= 7.9, 1.5 Hz, 1H), 7.77 (d, J= 7.7 Hz, 0.2H), 7.58 (td, J= 7.5, 1.2 Hz, 0.2H), 7.52 (td, J= 7.5, 1.5 Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.44 - 7.31 (m, 3.6H), 7.28 (d, J = 7.6 Hz, 1.2H), 3.52 - 3.44 (m, 1H), 3.34 (dd, J = 14.2, 4.5 Hz, 0.2H), 3.24 - 3.13 (m, 2.4H), 3.01 - 2.91 (m, 1.2H), 2.80 (dd, J= 16.6, 13.0 Hz, 1.2H), 2.73 (dd, J= 14.2, 9.9 Hz, 0.2H), 2.66 (s, 3H), 2.63 (s, 0.6H).

13C NMR (151 MHz, CDCl₃, major) 8 200.51, 196.86, 142.66, 142.54, 139.50, 134.02, 131.96, 131.04, 130.37, 129.88, 128.86, 127.84, 127.32, 127.22, 45.62, 40.40, 37.27, 30.87. 13C NMR (151 MHz, CDCl₃, minor) 8 207.12, 200.60, 153.28, 139.09, 138.80, 136.66, 135.06, 132.59, 130.81, 129.86, 129.66, 127.64, 126.63, 124.09, 48.43, 36.10, 32.09, 30.89. HRMS (APCI): Calc’d, for C₁₈H₁₅ClO₂ [M+H⁺]: 299.0839; found: 299.0838

Following General Procedure B using 5-bromoindole (1.0 equiv., 83 mg, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv., 100 μL, 0.45 mmol) afforded a mixture (5.0:1) of the title compound SI-28 and its regioisomer (24 mg, 0.09 mmol, 37% yield) following purification by column chromatography (gradient elution, hexanes to 3: 1 hexanes :Et₂0) and preparative TLC (CH₂Cl₂ ) to remove minor tetralone impurities.

Physical State: white solid

R_f= 0.50 (CH2CI2)

'H NMR (600 MHz, CDCl₃) 6 8.26 (s, 1H), 8.20 (s, 0.2H), 8.11 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.6 Hz, 0.2H), 7.57 (m, 1.2H), 7.52 (t, J = 7.5 Hz, 1H), 7.42 - 7.34 (m, 2.4H), 7.33 (d, J = 8.3 Hz, 0.2H), 7.30 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 2.9 Hz, 1H), 7.20 (t, J = 2.8 Hz, 0.2H), 7.15 (dd, J = 8.4, 1.7 Hz, 1H), 7.10 (dd, J = 8.3, 1.7 Hz, 0.2H), 6.55 (s, 1H), 6.51 (s, 0.2H), 3.56 (ddt, J = 15.5, 12.8, 4.1 Hz, 1H), 3.51 (dd, J = 14.0, 4.3 Hz, 0.2H), 3.34 - 3.20 (m, 2H), 3.15 (dd, J = 17.1, 7.7 Hz, 0.2H), 3.09 - 3.02 (m, 1.2H), 2.92 (dd, J = 16.6, 13.3 Hz, 1.2H), 2.77 (dd, J = 14.0, 10.4 Hz, 0.2H).

¹³C NMR (151 MHz, CDCl₃, major) 8 198.59, 144.01, 135.25, 134.98, 133.86, 132.33, 129.03, 128.23, 127.31, 126.95, 124.97, 121.28, 118.35, 111.42, 102.66, 46.93, 41.47, 38.63.

¹³C NMR (151 MHz, CDCl₃, minor) 8 208.56, 154.09, 136.81, 134.75, 131.03, 128.21, 127.45, 126.75, 126.53, 124.64, 124.11, 123.38, 120.74, 111.20, 102.44, 46.93, 41.47, 38.63. HRMS (APCI): Calc’d, for C₂₆H₁₉NO₂ [M+H⁺]: 262.1232; found: 262.1242.

Following General Procedure B using bromobenzene (1.0 equiv, 27 μL, 0.25 mmol) and siloxycyclopropane SI-9 (1.8 equiv., 117 mg, 0.45 mmol) afforded a mixture (5.8: 1) of the title compound SI-29 and its regioisomer (31 mg, 0.12 mmol, 46% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes :Et₂0) and preparative TLC (1 :1 CH₂C12:toluene) to remove minor tetral one impurities.

Physical State: white solid.

Rf= 0.30 (4: 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃, major) 8 7.36 (t, J= 7.5 Hz, 2H), 7.31 - 7.27 (m, 3H), 7.06 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 4.63 (t, J= 8.9 Hz, 2H), 3.61 (td, J = 8.8, 3.2 Hz, 2H), 3.42 (dtd, J= 12.1, 7.9, 3.7 Hz, 1H), 3.13 (d, J= 8.0 Hz, 2H), 2.94 (dd, J= 16.7, 3.7 Hz, 1H), 2.81 (dd, J= 16.7, 13.2 Hz, 1H).

¹³C NMR (151 MHz, CDCl₃, major) 8 199.06, 159.87, 143.71, 135.48, 129.00, 128.87, 128.63, 128.52, 127.04, 126.81, 114.44, 72.27, 46.81, 41.49, 37.55, 31.49.

¹³C NMR (151 MHz, CDCl₃, minor) 8 208.27, 160.46, 145.60, 139.90, 133.04, 129.16, 128.35, 126.44, 125.63, 124.25, 115.93, 72.47, 49.88, 37.22, 31.99, 28.58.

HRMS (APCI): Calc’d, for C₁₈H₁₆O₂ [M+H⁺]: 265.1229; found: 265.1231

Following General Procedure B using bromobenzene (1.0 equiv., 26 μL, 0.25 mmol) and siloxycyclopropane SI-6 (1.8 equiv, 112 μL, 0.45 mmol) afforded a mixture (3.3: 1.0) of the title compound SI-30 and its regioisomer (40 mg, 0.16 mmol, 63% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes :Et₂O) and preparative TLC (1 : 1 CH₂Cl₂:toluene x 3) to remove minor impurities.

Physical State: white solid.

R_f= 0.4 (1 : 1 CH₂C12:toluene)

'H NMR (600 MHz, CDCl₃) 8 7.56 (d, J= 2.8 Hz, 1H), 7.37 (t, J= 7.6 Hz, 2H), 7.33 - 7.28 (m, 3H), 7.28 - 7.15 (m, 4H), 7.10 (dd, J= 8.4, 2.9 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 1H), 3.48 - 3.37 (m, 1.3H), 3.19 - 3.12 (m, 2H), 3.09 (dd, J= 16.6, 7.6 Hz, 0.3H), 3.02 (ddt, J= 11.5, 7.8, 4.0 Hz, 0.3H), 2.99 - 2.94 (m, 1H), 2.86 - 2.76 (m, 1.3H), 2.67 (dd, J= 14.0, 10.4 Hz, 0.3H).

¹³C NMR (151 MHz, CDCl₃, major) 8 197.74, 158.59, 143.53, 136.03, 132.94, 130.08, 128.79, 126.98, 126.73, 122.15, 109.13, 55.56, 45.78, 41.38, 36.94.

¹³C NMR (151 MHz, CDCl₃, minor) 207.84, 159.45, 146.50, 139.71, 137.69, 128.92, 128.54, 127.32, 126.36, 124.27, 105.13, 55.62, 55.56, 49.75, 31.52. HRMS (APCI): Calc’d, for C17H16O2 [M+H⁺]: 253.1229; found: 253.1233

Following General Procedure B using bromobenzene (1.0 equiv., 26 μL, 0.25 mmol) and siloxy cyclopropane SI-7 (1.8 equiv., 105 mg, 0.45 mmol) as substrate afforded a mixture (7.7: 1 + minor diastereomers) of the title compound SI-31 and its regioisomer (41 mg, 0.17 mmol, 69% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes:Et₂O) and preparative TLC (19: 1 toluene: acetone) to remove minor tetralone impurities.

Physical State: clear oil.

Rf= 0.85 (1 : 1 hexanes:Et₂O)

³H NMR (600 MHz, CDCl₃) 6 8.09 (dd, J= 7.8, 1.5 Hz, 1H), 7.75 (d, J = 7.7 Hz, 0.12H), 7.62

- 7.53 (m, 1.12H), 7.44 (d, J= 7.7 Hz, 1.12H), 7.41 - 7.28 (m, 4.24H), 7.24 (dd, J= 8.8, 7.3 Hz, 2.48H), 3.38 (dd, J= 13.9, 4.36 Hz, .2), 3.36 - 3.29 (m, 1H), 3.18 - 3.08 (m, 1.12H), 3.00

- 2.89 (m, 2H), 2.75 (dd, J= 13.9, 9.7 Hz, 0.12H), 2.54 (dt, J= 9.4, 4.4 Hz, 0.12H), 1.30 (d, J = 6.9 Hz, 3H), 1.13 (d, J= 7.1 Hz, 0.36H).

¹³C NMR (151 MHz, CDCl₃, major) 8 197.69, 147.52, 143.28, 134.16, 132.12, 128.86, 127.59, 127.51, 127.18, 127.01, 126.73, 48.28, 45.35, 39.15, 19.13.

¹³C NMR (151 MHz, CDCl₃, minor) 8 207.22, 158.41, 139.78, 135.86, 135.09, 129.21, 128.64, 128.53, 126.47, 125.15, 123.82, 57.98, 38.92, 36.36, 20.20. : 237.1279; found: 237.1282

Following General Procedure B using bromobenzene (1.0 equiv, 26 μL, 0.25 mmol) and siloxycyclopropane SI-5 (1.8 equiv., 112 μL, 0.45 mmol) afforded a mixture (5.9: 1.0) of the title compound SI-32 and its regioisomer (36 mg, 0.15 mmol, 61% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes :Et₂O) and preparative TLC (1 : 1 hexanes: Et₂O) to remove minor impurities.

Physical State: white solid. Rf= 0.85 (1 : 1 hexanes:Et₂0)

'H NMR (600 MHz, CDCl₃) 6 7.99 (d, J= 7.8 Hz, 1H), 7.64 (d, J= 7.6 Hz, 0.2H), 7.40 (t, J = 7.6 Hz, 3.2H), 7.34 (d, J= 6.9 Hz, 2.2H), 7.33 - 7.29 (m, 1.4H), 7.29 - 7.25 (m, 1.4H), 7.25 - 7.23 (m, 0.2H), 3.48 - 3.38 (m, 1.2H), 3.22 (dd, J= 16.8, 4.3 Hz, 1H), 3.08 (dd, J= 17.0, 7.8 Hz, 0.2H), 3.02 (ddt, J= 11.8, 7.8, 3.9 Hz, 0.2H), 2.99 - 2.92 (m, 2H), 2.87 (dd, J= 16.1, 13.6 Hz, 1H), 2.72 (dd, J= 17.0, 3.8 Hz, 0.2H), 2.66 (dd, J= 14.1, 10.5 Hz, 0.2H), 2.33 (s, 3H), 2.30 (s, 0.6H).

¹³C NMR (151 MHz, CDCl₃, major) 8 198.27, 143.87, 141.84, 136.53, 135.31, 132.42, 128.95, 127.15, 126.88, 126.49, 125.20, 45.39, 40.71, 35.01, 19.68.

¹³C NMR (151 MHz, CDCl₃, minor) 8 208.27, 152.76, 139.89, 136.44, 135.92, 135.38, 129.00, 128.67, 127.76, 126.48, 121.51, 48.96, 37.20, 31.17, 17.93.

HRMS (APCI): Calc’d, for C17H17O [M+H⁺]: 237.1279; found: 237.1283

Following General Procedure B using 5-bromo-l,3-benzodioxole (1.0 equiv., 50 mg, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv, 100.0 μL, 0.45 mmol) afforded a mixture (5.6: 1.0) of the title compound SI-33 and its regioisomer (49.0 mg, 0.18 mmol, 74% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes:Et₂O) and preparative TLC (9: 1 toluene: isopropanol) to remove minor impurities.

Physical State: white solid.

Rf= 0.55 (9: 1 toluene: isopropanol)

Hl NMR (600 MHz, CDCl₃) 8 8.07 (dd, J= 7.9, 1.5 Hz, 1H), 7.77 (d, J = 7.6 Hz, 0.18H), 7.57 (td, J= 7.4, 1.2 Hz, 0.18H), 7.51 (td, J= 7.5, 1.5 Hz, 1H), 7.41 (d, J= 7.6 Hz, 0.18H), 7.38 - 7.32 (m, 1.18H), 7.27 (d, J = 7.7 Hz, 1H), 6.79 (dd, J= 4.9, 3.0 Hz, 2H), 6.76 - 6.71 (m, 1.36H), 6.68 (dd, J= 8.0, 1.7 Hz, 0.18H), 3.43 - 3.32 (m, 1H), 3.29 (dd, J= 14.1, 4.4 Hz, 0.18H), 3.20 - 3.11 (m, 2.36H), 2.99 - 2.90 (m, 1.18H), 2.86 (dd, J= 17.1, 4.2 Hz, 0.18H), 2.77 (dd, J = 16.6, 13.2 Hz, 1H), 2.62 (dd, J= 14.1, 10.2 Hz, 0.18H).

¹³C NMR (151 MHz, CDCl₃, major) 8 197.72, 147.92, 146.43, 143.31, 137.52, 133.81, 132.10, 128.86, 127.23, 126.98, 119.70, 108.46, 107.13, 101.07, 46.31, 40.92, 37.99.

¹³C NMR (151 MHz, CDCl₃, minor) 8 207.76, 153.65, 147.73, 146.08, 136.58, 134.84, 133.35, 127.45, 126.61, 124.05, 121.86, 109.26, 108.25, 100.89, 49.11, 36.68, 32.05. HRMS (APCI): Calc’d, for C₁₇H₁₅O₃ [M+H⁺]: 267.1021; found: 267.1025

Following General Procedure B using 2-(4-bromophenyl)ethan-l-ol (1.0 equiv., 35 μL, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv., 100 μL, 0.45 mmol) afforded a mixture (3.2: 1.0) of the title compound SI-34 and its regioisomer. Purification by column chromatography (gradient elution, 19: 1 hexanes:Et₂O to 4: 1 hexanes:Et₂O) and preparative TLC (3% isopropanol in 1 :4 toluene:CH₂Cl₂) yielded a mixture of product isomers (5.0: 1.0) in 89% yield (59 mg, 0.22 mmol).

Physical State: clear oil.

Rf= 0.45 (3% isopropanol in 1 :4 toluene:CH₂Cl₂)

'H NMR (600 MHz, CDCl₃) 6 8.08 (d, J= 7.8 Hz, 1H), 7.78 (d, J= 7.7 Hz, 0.2H), 7.61 - 7.55 (m, 0.2H), 7.54 - 7.48 (m, 1H), 7.42 - 7.32 (m, 1.8H), 7.31 - 7.14 (m, 5.4H), 3.87 (h, J= 6.0 Hz, 2.4H), 3.45 (tt, J= 13.6, 4.4 Hz, 1H), 3.36 (dd, J = 14.0, 4.4 Hz, 0.2H), 3.25 - 3.13 (m, 2.2H), 3.02 - 2.91 (m, 1.4H), 2.91 - 2.78 (m, 3.4H), 2.65 (dd, J= 14.0, 10.4 Hz, 0.2H).

¹³C NMR (151 MHz, CDCl₃, major) 8 197.98, 143.51, 141.74, 137.38, 133.94, 132.23, 129.56, 128.99, 127.34, 127.08, 127.04, 63.74, 46.12, 40.88, 38.87, 37.84.

¹³C NMR (151 MHz, CDCl₃, minor) 8 208.02, 153.77, 137.89, 136.62, 134.96, 132.40, 129.32, 129.26, 127.57, 126.72, 124.17, 63.77, 49.06, 36.75, 32.37, 29.83.

HRMS (APCI): Calc’d, for C₁₈H₁₆O₂ [M+H⁺]: 265.1229; found: 265.1234

Following the procedure for synthesis of compound 10a using 5- bromo-8-methoxy-l, 2, 3, 4- tetrahydronaphthalene (1.0 equiv., 60 mg, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv., 100 μL, 0.45 mmol) afforded a mixture (2.6: 1.0) of the title compound SI-35 and its regioisomer. Purification by column chromatography (gradient elution, 1 :0 hexanes:Et₂O to 4: 1 hexanes:Et₂O) and preparative TLC (4: 1 toluene: acetone) yielded a mixture of product isomers (3.3: 1.0) in 67% yield (51 mg, 0.17 mmol).

Physical State: white solid. Rf= 0.25 (4: 1 hexanes:Et₂O)

'H NMR (600 MHz, CDCl₃) 8 8.10 (d, J = 7.85 Hz, 1H), 7.80 (d, J= 7.63 Hz, 0.3H), 7.59 (dd, J= 8.10, 6.79 Hz, 0.3H), 7.51 (td, J= 8.10, 6.79, 1H), 7.43 (d, J= 7.66, 0.3H), 7.44- 7.35 (m, 1.3H), 7.28 (d, J= 7.61 Hz, 1H), 7.14 (d, J= 8.48 Hz, 1H), 7.0 (d, J= 8.22 Hz, 0.3H), 6.74 (d, J= 8.48, 1H), 6.66 (d, J= 8.22 Hz, 0.3H), 3.83 (s, 3H), 3.82 (s, 0.9H), 3.64 (tt, J= 13.10, 3.79 Hz, 1H), 3.38 (dd, J= 14.60, 4.04 Hz, 0.3H), 3.24 - 3.14 (m, 1.3H), 3.08 - 3.02 (m, 1H), 3.00 (ddt, J= 11.63, 7.82, 3.97 Hz, 0.3H), 2.89 - 2.69 (m, 8H), 2.49 (dd, J= 14.43, 10.94 Hz, 0.3H), 1.78 (m, 5.2H).

¹³C NMR (151 MHz, CDCl₃, major) 8 198.56, 156.18, 144.06, 135.87, 133.80, 133.62, 128.95, 127.35, 127.00, 126.75, 126.45, 122.77, 107.07, 55.36, 46.27, 37.71, 35.82, 26.43, 23.84, 23.03, 22.25.

¹³C NMR (151 MHz, CDCl₃, minor) 8 208.45, 156.12, 153.87, 136.88, 136.69, 134.87, 129.78, 127.53, 126.56, 126.45, 124.15, 106.67, 55.34, 47.66, 33.90, 32.89, 26.94, 23.75, 22.99, 22.41.

HRMS (APCI): Calc’d, for C₂₁H₂₃O₂ [M+H⁺]: 307.1698; found: 307.1700

Following General Procedure B using 2-bromotoluene (1.0 equiv., 44 mg, 0.25 mmol) and siloxycyclopropane SI-1 (1.8 equiv, 100 μL, 0.45 mmol) afforded a mixture (4.0: 1.0) of the title compound SI-36 and its regioisomer (27 mg, 0.11 mmol, 45% yield) following purification by column chromatography (gradient elution, hexanes to 4: 1 hexanes:Et₂O).

Physical State: colorless oil.

Rf= 0.80 (4: 1 hexanes:EtOAc)

1H NMR (600 MHz, CDCl₃) 5 8.11 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.7 Hz, 0.24H), 7.60 (d, J = 7.4 Hz, 0.24H), 7.53 (t, J = 7.4 Hz, 1H), 7.43 (d, J = 7.6 Hz, 0.24H), 7.37 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 2.4 Hz, 0.5H), 7.25 (d, J = 7.6 Hz, 1H), 7.23 - 7.14 (m, 2H), 3.69 (tt, J = 13.0, 3.9 Hz, 1H), 3.22 (dd, J = 16.1, 12.1 Hz, 1H), 3.13 - 3.07 (m, 1H), 2.93 - 2.80 (m, 2H), 2.38 (s, 0.75H), 2.37 (s, 3H).

¹³C NMR (151 MHz, CDCl₃, major) 8 198.08, 143.69, 141.43, 135.46, 133.80, 132.12, 130.84, 128.86, 127.30, 127.00, 126.75, 126.53, 125.13, 45.61, 36.99 (2C), 19.40.

¹³C NMR (151 MHz, CDCl₃, minor) 8 208.02, 153.63, 138.00, 136.52, 136.45, 134.85, 130.48, 128.98, 127.49, 126.63, 126.49, 126.02, 124.09, 47.55, 34.48, 32.64, 19.59. HRMS (APCI): Calc’d, for C₁₄H₁₂O₂ [M+H⁺]: 237.1279; found: 237.1287

4. Syntheses of GB22, GB13 and himgaline

₇ SI-10

Compound SI-10: To a flame-dried flask were added 7 (294 mg, 2.00 mmol), anhydrous CH₂Cl₂ (8 mL), and Et₃N (1.11 mL, 8.00 mmol) under argon. To the stirred mixture was added TMSOTf (722 μL, 4.00 mmol) at 0 °C over 5 min. After stirring for 1 hour at 22 °C, the reaction was cooled to 0 °C and quenched with cold sat. aq. NH₄CI. The aqueous layer was extracted with CH₂Cl₂ and the organic layer was washed with cold brine, dried over Na₂SO₄ and quickly purified by chromatography on a Florisil®-packed column (hexanes/ether = 1/0 to 5/1) to give SI-10 (365 mg, 1.66 mmol, 83%).

Physical State: yellow oil.

Rf= 0.50 (5: 1 hexanes :EtO Ac)

'H NMR (600 MHz, CDCl₃) 6 7.49 (d, J= 7.7 Hz, 1H), 7.04 (d, J= 7.7 Hz, 1H), 5.42 (t, J = 2.4 Hz, 1H), 3.36 (d, J= 2.4 Hz, 2H), 2.59 (s, 3H), 0.30 (s, 9H).

¹³C NMR (151 MHz, CDCl₃) 6 163.94, 154.65, 152.09, 132.48, 125.75, 120.54, 105.20, 77.37, 77.16, 76.95, 36.55, 24.36, 0.13.

HRMS (ESI): Calc’d, for C₁₂H₁₈NOSi [M+H⁺]: 220.1158; found: 220.1161.

Note: Compound 7 was prepared by a modified procedure of the report⁴ using 1 : 1 toluene/i- PrOH instead of toluene alone. This modification reduced formation of an undesired regioisomer of 5 which was difficult to remove by silica gel chromatography. The reported yield of 55% could not be achieved; highly pure (>95% purity) 7 was obtained in 15% yield.

Compound 8; To a flame dried flask were added anhydrous CH₂Cl₂ (8.0 mL) and Et₂Zn (1.0 M in n-hexane, 4.0 mmol, 4.0 mL) at 0 °C under argon. To the stirred solution was added TFA (4.00 mmol, 306 μL, in 4 mL of CH₂Cl₂ ) slowly using syringe pump (4.0 mL/h) at 0 °C. After stirring for 15 min at the same temperature, the reaction flask was covered with aluminum foil to exclude light. CH₂I₂ (4.00 mmol, 322 μL, in 4.0 mL of CH₂Cl₂ ) was added slowly using a syringe pump (5.0 mL/h) at 0 °C and allowed to stir for 30 min at the same temperature. To the solution was added SI-10 (364 mg, 1.66 mmol, in 4.0 mL of CH2CI2) over 10 min at 0 °C. After stirring for 3 h at 22 °C, the reaction was quenched with ice and cold sat. aq. NH4CI. The aqueous layer was extracted with CH₂Cl₂ . The organic layer was washed with cold brine, dried over Na₂SO₄ and concentrated under reduced pressure. The crude material was quickly purified by Florisil® column chromatography (hexanes/EtOAc = 1/0 to 10/1) to give 8 (303 mg, 1.30 mmol, 78%).

Physical State: pale-yellow oil.

Rf= 0.37 (hexanes/EtOAc = 2/1)

'H NMR (600 MHz, CDCl₃) 67.55 (d, J= 7.8 Hz, 1H), 6.95 (d, J= 7.8 Hz, 1H), 3.29 (dd, J = 17.8, 6.5 Hz, 1H), 2.78 (d, J= 17.8 Hz, 1H), 2.51 (s, 3H), 2.01 (ddd, J= 9.6, 6.4, 4.5 Hz, 1H), 1.45 (dd, J= 9.5, 4.5 Hz, 1H), 0.40 (dd, J= 5.0, 5.0, 1H), 0.10 (s, 9H).

¹³C NMR (151 MHz, CDCl₃) 6 160.44, 156.73, 137.24, 130.70, 120.58, 65.91, 36.96, 24.26, 22.95, 22.31, 1.07.

HRMS (ESI): Calc’d, for C₁₃H₂₀NOSi [M+H⁺]: 234.1314; found: 234.1314.

Note: The product was used for the next reaction immediately or dissolved in benzene and stored at -24 ⁰C.

An alternative route to 8 began from 6-chloro-2-methyl-nicotinic acid ($1 ,9/g from Combi- Blocks) or its methyl ester (ca. $14.4/g or $14.2/g from eNovation or Combi-Blocks)

Methyl 6-chloro-2-methyl-nicotinate: To a stirred solution of 6-chloro-2-methyl-nicotinic acid (10.0 g, 58.3 mmol, 1 equiv.) in DMF (120 mL) was added K₂CO₃ (21.9 g, 159 mmol, 2.7 equiv.). Once gas evolution ceased, Mel (4.4 mL, 69.9 mmol, 1.2 equiv.) was added. The mixture was stirred at room temperature overnight. The reaction was diluted with water and extracted with EtOAc (200 mL) three times. The combined organic layers were washed with 5% LiCl in water (100 mL) five times to remove DMF, dried over Na₂SO₄, and concentrated to afford the title compound (7.72 g, 41.6 mmol, 71%).

Physical State: chocolate-brown solid.

Rf. 0.40 (20% Et₂O /hexanes) ¹H NMR (600 MHz, CDCl₃) 6 8.07 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 3.93 (s, 3H), 2.58 (s, 3H).

¹³C NMR (151 MHz, CDCl₃) 6 165.14, 162.63, 149.54, 140.83, 123.59, 121.82, 52.80, 24.46.

HRMS (ESI): Calc’d, for C₈H₉ClNO₂ [M+H⁺]: 186.0322; found: 186.0318.

methyl 6-chlon>2-methyl-nicotinate

Compound SI-37: To a flame dried flask equipped with a stir bar was added CS₂CO₃ (42.1 g, 129.3 mmol, 3 equiv.) allyl pinacol boronate (16.2 mL, 86.2 mmol, 2 equiv.), methyl 6-chloro- 2-methyl-nicotinate (8.0 g, 43.1 mmol, 1 equiv.), and 1,4-dioxane (300 mL). The reaction suffered from poor conversion and long reaction times if the base was not ground with mortar and pestle and flame dried prior to use. The reaction mixture was sparged with argon for roughly 5 minutes at which point Pd(dppf)C12* CH₂Cl₂ (880 mg, 1.1 mmol, 2.5 mol%) was added, and the orange-red reaction mixture was sparged with argon for an additional 5 minutes. A reflux condenser with argon balloon on top was attached to the flask and the reaction was heated to 100 °C and refluxed for 75 minutes before LCMS analysis showed it was complete. Once complete, water was added and extracted with EtOAc (200 mL) 3 times. The combined organic layers were washed with brine, dried over Na₂SO₄, and purified by silica column chromatography (0-30% Et₂O/hexanes) to yield SI-37 (6.7 g, 34.94 mmol, 81%).

Physical State: pale-yellow solid.

Rf. 0.43 (20% Et₂O/hexanes)

'H NMR (600 MHz, CDCl₃) 6 8.06 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.07 (ddt, J = 16.8, 10.1, 6.5 Hz, 1H), 5.08 - 5.02 (m, 2H), 3.94 (dt, J = 6.5, 1.7 Hz, 2H), 3.88 (s, 3H), 2.56 (s, 3H).

¹³C NMR (151 MHz, CDCl₃) 6 167.01, 161.75, 160.57, 139.02, 136.14, 122.48, 120.86, 115.97, 52.19, 41.52, 24.82.

HRMS (ESI): Calc’d, for C11H14NO2 [M+H⁺]: 192.1025; found: 192.1026.

SI-37 SI-38 Compound SI-38: To a flame dried flask equipped with a stir bar were added SI-37 (1.711 g, 8.947 mmol) and dry THF (15.4 mL). To the stirred mixture was added Ti(O'Pr)4 (5.43 mL, 17.9 mmol, 2 equiv.) at room temperature. The mixture was cooled to 0 °C and 1.8 M n- BuMgCl in Et₂O (24.85 mL, 5 equiv.) was added via syringe pump at 4 mL/h. The reaction mixture was maintained at 0 °C during addition of the Grignard reagent. Once the Grignard reagent addition was complete (ca. 6 h), the reaction mixture, still at 0 °C, was diluted with 28 mL of Et₂O and quenched with 8 mL of water. Upon quenching, the mixture was stirred for an additional hour at which point it was filtered through Celite using EtOAc and concentrated to yield SI-38 as a pale-yellow solid (1.25 g, 7.8 mmol, 87%). Crude material was commonly of high enough purity to forgo any additional purification although it could be recrystallized via slow evaporation from EtOAc. Crude product could also be triturated with Et₂O to remove minor impurities.

Physical State: pale yellow solid.

Rf. 0.30 (10% MeOH/CH₂Cl₂)

'H NMR (600 MHz, CDCl₃) 6 7.60 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 3.97 (s, 1H), 3.21 (dd, J = 18.0, 6.7 Hz, 1H), 2.72 (d, J = 18.0 Hz, 1H), 2.47 (s, 3H), 1.98 (ddd, J = 9.4, 6.5, 4.4 Hz, 1H), 1.54 (dd, J = 9.4, 5.4 Hz, 1H), 0.44 (t, J = 4.9 Hz, 1H).

¹³C NMR (151 MHz, CDCl₃) 6 160.95, 156.65, 137.06, 130.59, 120.77, 64.89, 36.79, 24.02, 23.32, 23.15.

HRMS (ESI): Calc’d, for C10H12NO [M+H⁺]: 162.0919; found: 162.0915.

Compound 8 via SI-38: To a flame dried flask equipped with a stir bar were added SI-38 (3.0 g, 19 mmol, 1 equiv.) and dry CH₂Cl₂ (30 mL). Imidazole (2.5 g, 37 mmol, 2 equiv) was added at room temperature and the reaction mixture was cooled to 0 °C before adding freshly distilled TMSC1 (4.3 mL, 33 mmol, 1.8 equiv.). The ice bath was removed, and the reaction was stirred at room temperature for about 2 hours. At this time, a small aliquot was removed, washed with brine, concentrated and an NMR was taken to determine completion, as both LCMS and TLC analysis showed cyclopropanol even at 100% conversion. Once complete, the reaction was washed with ice cold brine, dried over Na₂SO₄ and concentrated. The crude oil was filtered through Florisil® with Et₂O to yield 8 (4.3 g, 100%). ¹H NMR and ¹³C NMR spectra matched the values of previously synthesized 8. Physical State: pale-yellow oil.

Rf= 0.37 (hexanes/EtOAc = 2/1)

'H NMR (600 MHz, CDCl₃) 67.55 (d, J= 7.8 Hz, 1H), 6.95 (d, J= 7.8 Hz, 1H), 3.29 (dd, J = 17.8, 6.5 Hz, 1H), 2.78 (d, J= 17.8 Hz, 1H), 2.51 (s, 3H), 2.01 (ddd, J= 9.6, 6.4, 4.5 Hz, 1H), 1.45 (dd, J= 9.5, 4.5 Hz, 1H), 0.40 (dd, J= 5.0, 5.0, 1H), 0.10 (s, 9H).

¹³C NMR (151 MHz, CDCl₃) 6 160.44, 156.73, 137.24, 130.70, 120.58, 65.91, 36.96, 24.26, 22.95, 22.31, 1.07.

HRMS (ESI): Calc’d, for C₁₃H₂₀NOSi [M+H⁺]: 234.1314; found: 234.1314.

Compound 9a: To a stirred solution of 4-bromo-5,6,7,8-tetrahydronaphthalen-l-ol⁵ (700 mg, 3.08 mmol) in DMF (7 mL) was added NaH (60% in oil, 250 mg, 6.2 mmol) at 0 °C under Ar. After stirring for 30 minutes, benzyl bromide (0.549 mL, 4.62 mmol) was added. After stirring for 4.5 h at room temperature, the reaction mixture was quenched with a mixture of MeOH and water. The aqueous layer was extracted with ether (3 x 25 mL). The organic layer was washed with NaHCO, (sat. aq.), NH₄CI (sat. aq.), and brine, dried over Na₂SO₄ and concentrated under reduced pressure on a rotovap. The crude product was purified by silica gel column chromatography (hexane s/EtO Ac = 1/0 to 20/1) to give 9a (915 mg, 2.88 mmol, 94%). 'H NMR and ¹³C NMR spectra were consistent with the literature values.⁶

Physical State: colorless oil.

Rf= 0.44 (hexanes)

'H NMR (600 MHz, CDCl₃) 66 7.44 - 7.38 (m, 4H), 7.35 - 7.31 (m, 2H), 6.63 (d, J= 8.7 Hz, 1H), 5.05 (s, 2H), 2.76 - 2.72 (m, 4H), 1.82 - 1.73 (m, 4H).

¹³C NMR (151 MHz, CDCl₃6 155.72, 137.62, 137.31, 129.44, 129.26, 128.68, 127.97, 127.19, 116.87, 109.97, 70.03, 30.76, 24.07, 22.99, 22.28.

HRMS (ESI): Calc’d, for C₂₇H₂₉BrO [M+H⁺]: 317.0541; found: 317.0542.

Compound 10a: A flame-dried test tube was charged with siloxycyclopropane 8 (0.45 mmol, 105 mg, 1.8 equiv.), NiBn (0.08 mmol, 16 mg, 0.3 equiv.), 3CzClIPN (0.02 mmol, 15 mg, 0.09 equiv.), bipy (0.08 mmol, 12 mg, 0.3 equiv.), and 9a (0.25 mmol, 79 mg, 1.0 equiv.). The contents were then placed under an atmosphere of argon before being dissolved in dry DMSO (0.25 mL, 1 M) and 2,6-lutidine (0.50 mmol, 58 μL, 2.0 equiv.). At this point the reaction was sparged with argon for 30 minutes before being sealed with Teflon® and electrical tape (see photos). The reaction vessel was placed into a water bath maintained at 45 °C and, once the reaction became homogeneous, irradiated with a blue Kessil lamp. After 36 hours, 1 mL each of EtOAc, water, and brine were added. The aqueous layer was extracted three times with EtOAc (2 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexanes/ethyl acetate 1/0 to 1/1) to give 10a (33.2 mg, 0.08 mmol, 33%) as a white solid. ¹H NMR (600 MHz, CDCl₃) 8 8.22 (d, J = 8.0 Hz, 1H), 7.46 - 7.44 (m, 2H), 7.41 - 7.38 (m, 2H), 7.34 - 7.31 (m, 1H), 7.17 (d, J= 8.0 Hz, 1H), 7.09 (d, J= 8.4 Hz, 1H), 6.78 (d, J= 8.5 Hz, 1H), 5.07 (s, 2H), 3.67 (dddd, J= 11.2, 8.3, 5.7, 5.7 Hz, 1H), 3.31 - 3.21 (m, 2H), 2.89 - 2.70 (m, 6H), 2.61 (s, 3H), 1.80 - 1.76 (m, 4H).

¹³C NMR (151 MHz, CDCl₃) 6 197.91, 163.88, 162.99, 155.43, 137.68, 136.16, 135.42, 133.33, 128.66, 127.88, 127.24, 125.40, 122.76, 122.36, 108.43, 69.83, 45.75, 40.38, 34.77, 26.47, 25.23, 24.07, 23.04, 22.28.

Rf 0.44 (hexanes/EtOAc = 2/1)

HRMS: m/z (ESI): Calcd. for C27H28NO2 [M+H]: 398.2120; found: 398.2119.

Compound 4: To a stirred solution of Et₂AlCl (1.0 mmol in 2.0 mL of toluene) was added HFIP (0.42 mL, 4.0 mmol) dropwise over 1 min at 0 °C under argon to give an orange solution. After stirring for 10 min at room temperature (the solution color became brown), 10a (79.5 mg, 0.200 mmol) was added and the reaction mixture was warmed to 80 °C. After stirring overnight (19 h) at 80 °C, the reaction was cooled to room temperature and MeOH (1 mL), Rochelle salt (sat. aq.) (2 mL), NaHCOs (sat. aq.) (5 mL) were added and stirred for 5 min at room temperature. The aqueous layer was extracted with EtOAc (10 mL) three times. The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and filtered. Silica gel (ca. 1 g) was added, and the organic solvent was removed under reduced pressure. The crude product absorbed in silica-gel was purified by silica gel column chromatography (CH₂Cl₂ /EA = 1/0 to 2/1) to give 2 (32.0 mg, 0.104 mmol, 52%) as a white solid.

'H NMR (500 MHz, DMSO-d₆ ) 6 8.89 (s, 1H), 7.66 (d, J= 7.9 Hz, 1H), 6.92 (d, J= 7.9 Hz, 1H), 6.40 (s, 1H), 5.90 (s, 1H), 3.48 (br dd, J= 4.3, 4.3 Hz, 1H), 3.12 (br dd, J= 17.6, 4.7 Hz, 1H), 2.72 (br dd, J= 16.6, 5.5 Hz, 1H), 2.62 - 2.54 (m, 2H), 2.43 - 2.41 (m, 1H), 2.32 - 2.27 (m, 1H), 2.29 (s, 3H), 2.05 (d, J= 9.7 Hz, 1H), 1.73 - 1.62 (m, 4H).

¹³C NMR (126 MHz, DMSO-d₆ ) 6 155.60, 154.22, 153.48, 149.24, 140.01, 133.02, 130.66, 129.19, 122.09, 120.32, 103.48, 79.17, 48.79, 36.69, 34.85, 26.16, 23.96, 23.69, 22.84, 22.77. R/ 0.20 (hexanes/EtOAc = 1/1)

HRMS: m/z (ESI): Calcd. for C20H22NO2 [M+H]: 308.1651; found: 308.1649.

Entry Conditions³ 4 (%)^b 3 (%)^b

. . overnight; isolated yield.

Compound 12a: To a stirred solution of 4 (62 mg, 0.20 mmol) in THF (4 mL) and EtOH (4 mL) was added Rh/Al (5% for Rh, 62 mg, 15 mol%) and the reaction mixture was stirred vigorously under H2 (600 psi) for 39 h. The reaction mixture was filtered through C₆lite®, washed with THF (100 mL), then concentrated under reduced pressure on a rotovap. The crude product was purified by Florsil® (CH₂Cl₂/MeOH = 1/0 to 0/1) to give 12 (51 mg, 0.16 mmol, 81%) as a colorless oil.

R/ 0.46 (7N NH₃ in MeOH/CH₂Cl₂ = 1/4)

Hl NMR (600 MHz, MeOD-d₄) 6 6.69 (s, 1H), 3.17 - 3.15 (m, 1H), 3.05 (br dd, J= 5.8, 5.8 Hz, 1H), 2.72 - 2.60 (m, 4H), 2.55 - 2.52 (br m, 1H), 2.33 - 2.25 (m, 2H), 2.09 (ddd, J= 14.1, 7.1, 2.6 Hz, 1H), 2.04 - 2.02 (m, 1H), 1.81 (d, J = 9.6 Hz, 1H), 1.79 - 1.72 (m, 5H), 1.50 - 1.43 (m, 1H), 1.29 - 1.09 (m, 3H), 0.62 (d, J= 6.4 Hz, 3H).

¹³C NMR (151 MHz, MeOD-d₄) 6 155.60, 146.13, 134.90, 134.04, 124.51, 108.99, 81.45, 57.04, 55.58, 52.20, 43.10, 37.79, 35.39, 29.31, 26.87, 24.54, 24.20, 24.01, 23.90, 22.39. HRMS (ESI): Calcd. for C₂₀H₂₈NO₂ [M+H]: 314.2120; found: 314.2128.

GB22 (3): To a stirred solution of 12a (50 mg, 0.16 mmol) in MeOH/AcOH (2.0 / 0.2 mL) were added aq. formaldehyde (ca. 10 wt%, 1.0 mL) and NaBH₃CN (10 mg, 0.160 mmol) at room temperature. The reaction was monitored by LCMS to determine conversion. After stirring for 1 h, NaBH₃CN (10 mg, 0.16 mmol) was added and stirring continued for another hour. NaBH₃CN (10.0 mg, 0.160 mmol) was then added to the stirring mixture. Ater 1 h, the reaction was quenched with aq. HC1 (2 N, 0.5 mL) at 0 °C and stirred for 1 h at room temperature. NH₃ (aq., 28%) was added to reach ca. pH 10, and the organic layer was extracted with EtOAc (10 mL) four times. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure on a rotovap. The crude material was purified by Florsil® (CH2CI2/7N NH₃ in MeOH; gradient from 1/0 to 5/1) to give 1 (41 mg, 0.126 mmol, 79%) as a white solid. The ³H NMR and ¹³C NMR were consistent with the values of the isolated natural product.⁷

R/ 0.47 (7N NH₃ in MeOH/CH₂Cl₂ = 1/9)

¹H NMR (600 MHz, CDCl₃) 6 6.51 (s, 1H), 3.15 - 3.13 (m, 1H), 2.77 (br s, 1H), 2.71 - 2.66 (m, 1H), 2.64 - 2.55 (m, 3H), 2.23-2.20 (br m, 1H), 2.18 (br d, J= 9.5 Hz, 1H), 2.07 (br s, 1H), 2.04 - 2.02 (m, 1H), 1.99 - 1.94 (m, 1H), 1.95 (s, 3H), 1.82 - 1.73 (m, 4H), 1.70 - 1.68 (br m, 1H), 1.47 - 1.39 (m, 3H), 1.37 - 1.33 (m, 1H), 0.77 (d, J= 6.3 Hz, 3H).

¹³C NMR (151 MHz, CDCl₃) 6 152.04, 145.18, 137.44, 132.08, 121.78, 106.79, 82.14, 60.38, 55.85, 51.30, 43.88, 39.00, 34.94, 30.78, 29.24, 26.09, 23.33, 22.90, 22.78, 21.32, 20.51.

HRMS (ESI): Calcd. for C21H29NO2 [M+H]: 328.2277; found: 328.2278.

Compound 9b: To a stirred solution of 4-bromo-5,6,7,8-tetrahydronaphthalen-l-ol⁵ (5.5 g, 24.2 mmol) in THF (60 mL) was added NaH (60% in oil, 1.2 g, 48.4 mmol) at 0 °C under Ar. After stirring for 30 minutes, methyl iodide (2.3 mL, 36.3 mmol) was added. After stirring for 4.5 h at room temperature, the reaction was quenched with a mixture of MeOH and water (approx. 10 mL of each). The aqueous layer was extracted with ether (three times 50 mL). The organic layer was washed with NaHCO₃ (sat. aq.), NH4CI (sat. aq.), and brine (100 mL each), then dried over Na₂SO₄ and concentrated under reduced pressure on a rotovap. The crude product was purified by silica gel column chromatography (hexanes/Et₂O = 1/0 to 20/1) to give 9b (4.96 g, 20.6 mmol, 85%) as a white solid.

Physical State: white solid.

Rf. 0.50 (10% Et₂O/hexanes)

'H NMR (600 MHz, CDCl₃) 67.33 (d, J= 8.6 Hz, 1H), 6.56 (d, J= 8.7 Hz, 1H), 3.80 (s, 3H), 2.68 (dt, J= 43.0, 6.4 Hz, 4H), 1.81 - 1.71 (m, 4H).

¹³C NMR (151 MHz, CDC13) 6 156.51, 137.27, 129.33, 128.69, 116.44, 108.43, 55.44, 30.60, 23.72, 22.86, 22.16.

HRMS (ESI): Calc’d, for C₁₁H₁₄BrO [M+H⁺]: 241.0228; found: 241.0221.

Compound 10b: A flame-dried test tube was charged with siloxycyclopropane 8 (0.45 mmol, 105 mg, 1.8 equiv.), NiBn (0.075 mmol, 16 mg, 0.3 equiv.), 4CzIPN (0.018 mmol, 14 mg, 0.07 equiv.), bipy (0.075 mmol, 12 mg, 0.3 equiv.), and 9b (0.25 mmol, 60 mg, 1.0 equiv.). The contents were then placed under an atmosphere of argon before being dissolved in dry DMSO (0.5 mL, IM) and 2,6-lutidine (0.5 mmol, 58 μL, 2.0 equiv). At this point the reaction was sparged with argon for 30 minutes before being sealed with Teflon® and electrical tape (see photos). The reaction was placed into a water bath maintained at 45 °C and irradiated with a blue Kessil lamp. After 36 hours, 1 mL each of EtOAc, water, and brine were added. The aqueous layer was extracted three times with 2 mL EtOAc, and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure on a rotovap. The crude product was purified by silica-gel column chromatography (hexanes/EA 1/0 to 1/1) to give 3 (46 mg, 0.14 mmol, 57%) as a white solid.

Physical State: white solid.

Rf. 0.40 (40% EA/hexanes)

'H NMR (600 MHz, CDCl₃) 6 8.24 (d, J= 7.9 Hz, 1H), 7.20 (d, J= 7.9 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.72 (d, J= 8.5 Hz, 1H), 3.82 (d, J= 1.1 Hz, 3H), 3.67 (tt, J= 12.2, 4.5 Hz, 1H), 3.38 - 3.22 (m, 2H), 2.90 - 2.66 (m, 6H), 2.64 (s, 3H), 1.80 - 1.72 (m, 4H).

¹³C NMR (151 MHz, CDC13) 8 197.51, 163.47, 162.62, 156.16, 135.83, 132.77, 126.72, 125.43, 122.64, 122.44, 107.00, 77.27, 77.05, 76.84, 55.23, 45.60, 39.91, 34.55, 26.30, 24.81, 23.71, 22.89, 22.14.

HRMS (ESI): Calc’d. For C₂₁H₂₄NO₂ [M+H⁺]: 322.1807; found: 322.1808.

Optimization of 8 + 9b a 10b:

Compound 11: To a stirred solution of Et₂AlC1 (2.5 mmol in 2.5 mL of toluene) was added HFIP (1.05 mL, 10 mmol) dropwise over 1 min at 0 °C under Ar to give an orange solution. After stirring for 10 min at room temperature (the solution became a more intense orange color), 3 (161 mg, 0.5 mmol) was added and the mixture was warmed to 80 °C. After stirring overnight (19 h) at 80 °C, the reaction was cooled to ambient temperature and MeOH (1 mL), Rochelle salt (sat. aq.) and NaHCO₃ (sat. aq.) were added. After stirring this mixture for 5 minutes at room temperature, the aqueous layer was extracted with EtOAc three times (10 mL). The combined organic layers were washed with brine, dried over Na₂SO₄ and filtered. Silica- gel (ca. 1 g) was added and the organic solvent was removed under reduced pressure. The crude product absorbed in silica gel was purified by column chromatography (hexanes/EA 10/1 to 1/1) to give 11 (138 mg, 0.420 mmol, 86%) as a white solid.

Physical State: white solid.

R/: 0.20 (50% EA/hexanes)

'H NMR (600 MHz, CDCl₃) 67.80 (d, J= 7.8 Hz, 1H), 6.91 (d, J= 7.8 Hz, 1H), 6.57 (s, 1H), 3.74 (s, 3H), 3.64 - 3.59 (m, 1H), 3.27 (dd, J= 17.5, 4.6 Hz, 1H), 2.85 - 2.76 (m, 2H), 2.67 - 2.58 (m, 1H), 2.56 (t, J= 5.1 Hz, 2H), 2.45 (ddd, J = 9.6, 5.4, 1.5 Hz, 1H), 2.42 (s, 3H), 2.29 (d, J= 9.1 Hz, 1H), 1.80 - 1.72 (m, 4H).

¹³C NMR (151 MHz, CDCl₃) 6 157.01, 156.45, 153.31, 147.60, 138.29, 133.84, 132.21, 129.11, 125.37, 120.76, 98.33, 80.51, 55.47, 49.64, 36.26, 35.17, 26.44, 24.01, 23.56, 22.70, 22.56.

HRMS (ESI): Calc’d, for C₂₁H₂₄NO₂ [M+H⁺]: 322.1807; found: 322.1813.

Compound 12b: To a stirred solution of 11 (130 mg, 0.40 mmol) in THF (1 mL) and EtOH (1 mL) was added Rh/Al (5% for Rh, 109 mg, 10 mol%). The mixture was vigorously stirred under H2 (600 psi) for 39 h. The reaction mixture was filtered through C₆lite®, washed with THF, then concentrated under reduced pressure. The crude product was dissolved in a 1 : 1 mixture of diethyl etherhexanes (3 mL) and the solvent was evaporated to afford a white solid. The solid was filtered and dried to give 7 (165 mg, 0.163 mmol, 95%) as a white solid.

Physical State: white solid.

R/ 0.4 (9: 1 CH₂C₁₂:7N NH₃ in MeOH)

'H NMR (600 MHz, CDCl₃) 6 6.75 (s, 1H), 3.83 (s, 3H), 3.19 (m, 2H), 2.72 - 2.57 (m, 4H), 2.52 (d, J = 16.6 Hz, 1H), 2.36 (bs, 1H), 2.31 (ddd, J = 9.6, 5.5, 2.3 Hz, 1H), 2.11 (ddd, J = 4.1, 7.3, 2.8 Hz, 1H), 2.06 (m, 1H), 1.89 (d, J = 9.50 Hz, 1H), 1.83-1.69 (m, 5H), 1.50 (ddd, J = 19.9, 14.2, 5.8 Hz, 1H), 1.20-1.14 (m, 1H), 1.13-1.04 (m, 1H), 0.62 (d, J= 6.3 Hz, 3H). ¹³C NMR (151 MHz, CDC13) 6 156.99, 144.81, 135.27, 133.59, 125.77, 103.12, 81.17, 57.18, 55.86, 54.41, 51.24, 41.76, 36.78, 34.97, 28.75, 25.86, 23.52, 23.29, 22.72, 22.62, 22.57. HRMS (ESI): Calc’d, for C₂₁H₃₀NO [M+H⁺]: 328.2277; found: 328.2268.

Compound 12a via compound 12b: To a stirred solution of 12b (15 mg, 0.046 mmol) in CH₂Cl₂ (0.65 mL) at 0 °C was added a 1 M solution of BBr₃ in heptane (0.27 mL). The ice bath was removed, and the reaction was stirred for 5 hours at room temperature until completion according to TLC, at which point it was cooled to -78 ^°C and quenched with MeOH. The mixture was basified with 50% NH₄₀H/H₂₀ solution to ca. pH 9. The aqueous layer was extracted with CH₂Cl₂ three times (3 mL), the combined organics washed with brine, and dried over Na₂SO₄. The crude product was purified by Florsil® column chromatography (0-50% 7M NH₃ in MeOH/ CH2CI2) to give 12 (11 mg, 0.035 mmol, 75%). ¹H NMR and ¹³C NMR spectra matched the values of previously synthesized 12a.

R/ 0.46 (7N NH₃ in MeOH/CH₂Cl₂ = 1/4)

Hl NMR (600 MHz, MeOD-d₄) 6 6.69 (s, 1H), 3.17 - 3.15 (m, 1H), 3.05 (br dd, J= 5.8, 5.8 Hz, 1H), 2.72 - 2.60 (m, 4H), 2.55 - 2.52 (br m, 1H), 2.33 - 2.25 (m, 2H), 2.09 (ddd, J= 14.1, 7.1, 2.6 Hz, 1H), 2.04 - 2.02 (m, 1H), 1.81 (d, J= 9.6 Hz, 1H), 1.79 - 1.72 (m, 5H), 1.50 - 1.43 (m, 1H), 1.29 - 1.09 (m, 3H), 0.62 (d, J= 6.4 Hz, 3H).

¹³C NMR (151 MHz, MeOD-d₄) 6 155.60, 146.13, 134.90, 134.04, 124.51, 108.99, 81.45, 57.04, 55.58, 52.20, 43.10, 37.79, 35.39, 29.31, 26.87, 24.54, 24.20, 24.01, 23.90, 22.39. HRMS: m/z (ESI): Calcd. for C20H28NO2 [M+H]: 314.2120; found: 314.2128.

Compound 14: To a stirred solution of 800 μL THF, 400 μL 'PrOH, and 12b (20 mg, 0.061 mmol) was added methylamine gas via metal needle, which condensed to liquid against the glass reaction vessel, held at approximately -15 °C using an ice and NaCl bath. Methylamine gas was either released from a pressurized cylinder (lecture bottle) or, due to the difficulty of acquiring replacement cylinders, could be generated by basification of MeNEh’HCl. Approximately 6 grams of MeNH₂’HCl were dissolved in a minimal amount of water (ca. 10 mL). The solution was slowly dripped into a round bottom flask that contained 10 grams of NaOH and was equipped with an outlet hose connected to a column of Drierite that fed into the reaction mixture via flexible needle. The -15 °C reaction vessel was itself vented to a gas outlet running to an oil bubbler to monitor gas production. The outlet of the bubbler fed into the baffle of a well-ventilated fume hood. After approximately 1-2 mL of MeNH₂ (g) was condensed to liquid in the vessel, 4 thin 2 mg slivers of lithium metal (rinsed with dry hexanes) were added to the solution of 12b in THF/i-PrOH/MeNH₂ (1). Once the reaction turned deep blue, the reaction was monitored by LCMS by sampling small aliquots, which we quenched in methanol. It was difficult to completely avoid overreduction (m/z = 302) as well as methyl deprotection to the corresponding phenol 12a (m/z = 314), so frequent sampling was important. If the reaction stalled, more lithium was added in small chunks (1-5 mg). Any recovered starting material could be isolated and recycled. Once the reaction was mostly complete, it was quenched with a minimal amount of water (ca. 0.5 mL) and the MeNH₂ was allowed to evaporate slowly over the course of a few hours. After bubbling had ceased and the reaction mixture became a thick paste, about 1 mL of water was added and the aqueous layer was extracted 5 times with 2 mL CH₂Cl₂ . The organic layer was dried over Na₂SO₄ and purified by preparative TLC. The silica plate was deactivated with 2% Et₃N/ CH₂Cl₂ and allowed to dry completely before loading the sample, which was eluted with 12 mL Et₃N, 88 mL toluene, and 100 mL CH₂Cl₂to afford 14 (10 mg, 0.03 mmol, 49%).

Alternatively, recent work by Burrows et al.⁶ offered a simpler procedure and improved impurity profile without the need to freebase MeNH₂.HCl and condense the resulting gas. Unlike the Benkeser conditions above, this procedure completely consumed 12b and the only products detected were the enol ether 14 and an over-reduced byproduct (m/z = 302).

To a stirred solution of 12b (9 mg, 0.03 mmol) in THF (300 μL), ethylenediamine (30 μL) and Z-BuOH (2 drops), was added lithium metal rinsed with hexanes (6 mg, 0.86 mmol, 6 eq.). Once the reaction turned pale blue, the reaction was monitored every 15 minutes by LCMS. Upon completion (90 minutes), the reaction was quenched with water (1 mL) and extracted 5 times with CH₂Cl₂ . Drying over Na₂SO₄ and filtration yielded crude product 14 (49% combined yield of regioisomers by ¹H NMR in CDCL using 10 μL 1,2-di chlorobenzene as internal standard).

'H NMR (600 MHz, C₆D₆) 6 3.32 (s, 3H), 3.25 (d, J = 14.26 Hz, 1H), 3.20 (t, J= 6.3 Hz, 1H), 3.07-3.00 (m, 1H), 2.67 (dp, J = 12.2, 4.2 Hz, 1H), 2.55-2.48 (m, 1H), 2.44-2.39 (m, 1H), 2.34 - 2.31 (m, 1H), 2.22-2.18 (m, 1H), 1.93-1.84 (m, 3H), 1.79 (d, J = 14.39 Hz, 1H), 1.58-1.54 (m, 2H), 1.46-1.21 (m, 7H), 1.04 (d, J = 6.3, 3H), 1.01- 0.91 (m, 2H).

¹³C NMR (151 MHz, C₆D₆) 6 144.94, 141.75, 138.03, 120.10, 81.73, 59.43, 56.54, 55.01, 51.64, 41.36, 41.33, 40.59, 35.15, 33.52, 32.02, 27.82, 26.96, 26.18, 24.67, 23.20, 22.82. R/ 0.57 (7N NH₃ in MeOH/CH₂Cl₂ = 1/9)

HRMS: m/z (ESI): Calcd. for C₂₁H₃₂NO₂ [M+H]: 329.1000; found: 329.1003.

GB13 (2): To 14 (16 mg, 0.05 mmol) was added 2 mL of 2 M HC1 (aq.). The mixture was stirred for 2 hours. LCMS analysis showed no remaining enol ether (m/z = 330). At this point, 4 M NaOH was added until the solution reached pH 12 (~2 mL). After addition of CH₂Cl₂ , the mixture was stirred for an additional 2 hours. The aqueous layer was then extracted 5 times with CH₂Cl₂ (2 mL), dried over Na₂SO₄ and concentrated under vacuum on a rotovap. The crude mixture was purified by preparative TLC. The silica plate was deactivated with 2% Et₃N/ CH₂Cl₂ and allowed to dry completely before loading the sample, which was eluted with 2% Et₃N/ CH₂Cl₂to afford GB13 (11 mg, 0.035 mmol, 71%) as a 7: 1 mixture of diastereomers and a 5:2 mixture with the ring tautomer 16-oxo-himgaline (15), as reported by prior syntheses.¹⁰ 'H NMR (600 MHz, C₆D₆) 6 6.10 (d, J = 2.2 Hz, 1H), 3.30 (dt, 1H, J = 11.43, 2.44 Hz), 2.90 (t, 1H, J = 5.14 Hz), 2.70-2.65 (m, 1H), 2.63-2.58 (m, 1H), 2.20-2.13 (m, 1H), 1.96-1.93 (m, 1H), 1.85-1.82 (m, 1H), 1.78 (dd, J = 11.4, 3.7 Hz, 1H), 1.74-1.69 (m, 1H), 1.66-1.61 (m, 1H), 1.58 (ddd, J = 14, 5.8, 3.08, 1H), 1.55-1.52 (m, 1H), 1.50 (ddd, J = 10.8, 5.6, 2.1 Hz, 1H), 1.30 (dd, J = 10.9, 2.5, J = 1H), 1.20-1.12 (m, 4H), 1.09-0.97 (m, approx. 4H), 0.81-0.79 (m, 1H), 0.76 (d, J = 6.17, 3H).

¹³C NMR (151 MHz, C₆D₆) 6 199.51, 179.14, 118.91, 79.41, 55.13, 52.96, 52.84, 50.92, 47.83, 47.32, 46.40, 40.71, 32.75, 31.57, 30.27, 26.93, 26.34, 25.77, 24.70, 23.29.

R/ 0.51 (7 N NH₃ in MeOH/CH₂Cl₂= 1/9)

HRMS: m/z (ESI): Calcd. for C₂₁H₃₁NO₂ [M+H]: 316.2277; found: 316.2276.

Himgaline (1): GB13 (2) (6 mg, 0.02 mmol) was stirred with a 1 : 1 mixture of AcOH:MeCN (total volume 1 mL) for 30 minutes, at which point NaBH(OAc)₃ (20 mg, 0.09 mmol) was added. The reaction, monitored by LCMS analysis, was observed to complete within an hour. The reaction was quenched with solid Na₂CO₃ but 4 N NaOH (aq.) was added to further basify the mixture. Once gas evolution ceased, the reaction mixture was extracted with CH₂C1₂ (10 mL X 10 times times). Extensive extraction is important to remove most of the material from the aqueous phase. The combined organics were washed with brine, dried over Na₂SO4, and purified by preparative TLC. The silica plate was deactivated with 2% Et₃N/ CH₂C1₂ and allowed to dry completely before loading the sample, which was eluted with 6% 7 N NH₃ in MeOH, 20% z-PrOH, and 74% CH₂Cl₂to afford himgaline (3 mg, 0.01 mmol, 53%). To avoid line broadening in the NMR, K₂CO₃ was added to the flask that contained 1 just prior to data collection. To the mixture of himgaline and K₂CO₃ was added CDC1₃ (which had already been filtered through basic alumina) and the heterogeneous sample was then filtered through cotton and Na₂SO4 into an NMR tube.

'H NMR (600 MHz, C₆D₆) 6 3.31-3.26 (m, 1H), 3.01 (s, 1H), 2.93-2.87 (m, 1H), 2.41 (dd, J = 12.3, 3.6 Hz, 1H), 2.24-2.07 (m, 3H), 2.06-1.98 (m, 2H), 1.89-1.80 (m, 3H), 1.79-1.54 (m, approx 10H), 1.52-1.44 (m, 1H), 1.29 (d, J = 7.25 Hz, 3H), 1.23-1.10 (m, 2H), 1.02 (qd, J = 10.34, 3.34 Hz, 1H), 0.94-0.83 (m, 3H).

¹³C NMR (151 MHz, C₆D₆) 6 86.92, 74.43, 72.34, 68.43, 61.39, 60.08, 55.05, 48.01, 47.62, 42.59, 37.39, 36.77, 35.83, 32.28, 28.72, 27.15, 26.47, 25.82, 25.38, 24.85.

R/ 0.37 (7N NH₃ in MeOH/CH₂CL₂ = 1/9), visualized via I₂

HRMS: m/z (ESI): Calcd. for C21H33NO2 [M+H]: 318.2433; found: 318.2435

Unlike GB13, himgaline could be prepared from the crude enol ether 14 without any intermediate separation due to ease of separation of himgaline and over-reduced byproduct (m/z = 302).

To a stirred solution of 12b (9 mg, 0.03 mmol) in THF (300 μL), ethylenediamine (30 μL) and Z-BuOH (2 drops), was added lithium metal rinsed with hexanes (6 mg, 0.86 mmol, 6 eq.). Once the reaction turned pale blue, the reaction was monitored every 15 minutes by LCMS. Upon completion (90 minutes), the reaction was quenched with water (1 mL) and extracted 5 times with CH₂Cl₂ . Drying over Na2SOi and filtration yielded crude product 14 (49% yield by 1H NMR using 10 μL 1,2-di chlorobenzene as internal standard).

The crude product was subjected to the procedure for preparing GB13 as described above. To the crude GB13 was added 0.5 mL of AcOH and 0.5 mL of MeCN. The mixture was stirred for 30 minutes before adding NaBH(OAc)3 (30 mg, 0.14 mmol). LCMS analysis deemed the reaction complete in 1 hour. The reaction was quenched with solid Na₂CO₃ but 4 N NaOH (aq.) was added to further basify the mixture. Once gas evolution ceased, the reaction mixture was extracted with CH₂Cl₂ (10 mL x 10). The combined organics were washed with brine and dried over Na₂SO₄ to afford himgaline (25% NMR yield over 3 steps using 10 μL 1,2- dichlorobenzene as internal standard). To avoid line broadening in the NMR, K2CO₃ was added to the flask that contained 1 just prior to data collection. To the mixture of himgaline and K2CO₃ was added CDCI₃ (which had already been filtered through basic alumina) and the heterogeneous sample was then filtered through cotton and Na₂SO₄ into an NMR tube. GB13 crude NMR yield from direct hydrolysis'.

To a stirred solution of 12b (9 mg, 0.03 mmol) in THF (300 μL), ethylenediamine (30 μL) and Z-BuOH (2 drops), was added lithium metal rinsed with hexanes (6 mg, 0.86 mmol, 6 eq.). Once the reaction turned pale blue, the reaction was monitored every 15 minutes by LCMS. Upon completion (90 minutes), the reaction was quenched with 2M HC1 (4 mL) and stirred for 1 hour at pH ~ 1. 4N NaOH was added until the pH reached about 14 (~2 mL) and CH₂Cl₂ was added. The biphasic mixture was stirred for an additional hour and extracted 5 times with CH₂CI₂. Drying over Na₂SO₄ and filtration yielded crude GB13. To the crude GB13 was added potassium carbonate and C₆D₆. The sample was filtered through cotton and Na₂SO₄. [(CH₃)₃Si]₂O (HMDSO) internal standard was added, and the NMR yield determined to be approximately 29% as a mixture of GB13 and 16-oxo-himgaline (based on doublet, 3H at 0.76 and doublet, 1H at 2.99, 10 μL of stock solution prepared with 10 μL of HMDSO in 1 mL of C₆De). Based on the doublet of triplets, 1H at 3.31 and the doublet, 1H at 2.99 the yield was found to be 29%. Based on the doublet, 1H at 6.08 and the doublet, 1H at 2.99, the yield was found to be 25%.

GB16: To a mixture of GB13 (5 mg, 16 pmol), CaCO₃ (3.2 mg, 0.032 mmol), and benzene (0.1 mL) was added I2 (4.0 mg, 1.0 eq) as a solution in 0.16 mL of benzene. The reaction was quenched with Na2S2C>3 (aq.) and extracted with EtOAc (5 mL X 5 times). The combined organics were dried over Na₂SO₄, and purified by preparative TLC eluted with 100% EtOAc to provide GB16 (2.7 mg, 16 pmol, 54%).

1H NMR (600 MHz, CDCl₃) 6 5.38 (s, 1H), 3.81 (s, 1H), 3.40-3.36 (m, 1H), 2.71 (s, 1H), 2.65 - 2.59 (m, 1H), 2.57 - 2.51 (m, 1H), 2.48 - 2.44 (m, 1H), 2.41 - 2.31 (m, 3H), 2.27 (td, J= 9.7, 4.7 Hz, 2H), 2.04 (qd, J= 12.7, 4.6 Hz, 1H), 1.90 - 1.71 (m, 4H), 1.58-1.49 (m, 3H).

1.47 (d, J= 7.2 Hz, 3H), 1.35 - 1.30 (m, 1H), 1.21 - 1.06 (m, 3H), 0.99 (qd, J= 12.4, 3.7 Hz, 1H).

¹³C NMR (151 MHz, CDCl₃) 6 207.86, 198.05, 158.74, 104.83, 63.34, 62.68, 51.23, 48.29, 46.77, 42.25, 39.40, 33.55, 30.28, 30.03, 26.05, 25.71, 25.50, 24.53, 23.96, 20.63.

14.2 nM

Himbadine: To a stirred solution of 14 (55 mg, 166 pmol) in MeOH/AcOH (1.0 / 0.1 mL) were added aq. formaldehyde (ca. 10 wt%, 1.0 mL) and NaBH₃CN (11.5 mg, 182 pmol) at room temperature. The reaction was monitored by LCMS to determine conversion. After stirring for 1 h, NaBH₃CN (11.5 mg, 185 pmol) was added and stirring continued for another hour. Upon completion, the reaction was quenched with solid Na₂CO₃ but 4 N NaOH (aq.) was added to further basify the mixture. Once gas evolution ceased, the reaction mixture was extracted with CH₂Cl₂ (10 mL X 10 times times). Extensive extraction is important to remove most of the material from the aqueous phase. The combined organics were washed with brine, dried over Na₂SO₄, and concentrated under vacuum on a rotovap. To the crude enol ether was added 2 mL of 2 M HCI (aq.). The mixture was stirred for 2 hours. LCMS analysis showed no remaining enol ether (m/z = 345). At this point, 4 M NaOH was added until the solution reached pH 12 (~2 mL). After addition of CH₂Cl₂ , the mixture was stirred for an additional 2 hours. The aqueous layer was then extracted 5 times with CH₂Cl₂ (2 mL), dried over Na₂SO₄, concentrated under vacuum on a rotovap, and purified by column chromatography (0-2% Et₃N/DCM). This afforded himbadine as a mixture of diastereomers (21 mg, 63 pmol, 38%). The desired diastereomer of himbadine can be isolated via preparative chromatography with 100% EtOAc.

'H NMR (600 MHz, C₆D₆) 6 6.18 (s, 1H), 3.28 - 3.12 (m, 1H), 2.69 (s, 1H), 2.58 (dt, J= 13.5, 3.0 Hz, 1H), 2.25 (t, J= 5.0 Hz, 1H), 2.08 (m,lH), 2.04 (s, 3H), 1.81 (td, J= 11.4, 4.1 Hz, 2H), 1.73 (d, J= 12.3 Hz, 1H), 1.67 (ddd, J= 11.0, 5.8, 2.9 Hz, 2H), 1.57 (ddd, J= 10.6, 5.8, 2.2 Hz, 2H), 1.34 (dd, J= 10.5, 2.6 Hz, 1H), 1.23 - 0.97 (m, 11H), 0.88 (d, J= 5.9 Hz, 3H).

¹³C NMR (151 MHz, C₆D₆) 6 199.30, 179.33, 118.96, 79.53, 63.08, 59.50, 52.86, 49.49, 48.39, 48.04, 47.26, 39.79, 34.56, 33.02, 31.89, 30.67, 26.90, 26.33, 25.78, 24.59, 22.59.

PDSP Screen A screen by PDSP of 45 common receptors identified himbadine as a high affinity ligand of sigmal (ol) receptors (K_i = 14 nM). Sigma2 (δ2) receptors did not show significant ligation even at 10 μM himbadine (Fig. 14).

¹³C Comparison Table

In this report In Chackalamannil’s report

(±)-Himgaline (-)-Himgaline

¹³C NMR (151 MHz, ( ¹³C NMR, 125 MHz, CDCl₃) A<5 CDCl₃)

27.4 27.5 -0.1

26.7 26.8 -0.1

26.1 26. 1

25.6 25.7 -0. 1

25.1 25.2 -0.1

*CDCl₃ center peak standardized to 77.4 8. Predicted relative energies of GB13 and 16-oxo-himgaline

Relative energies of GB13 diastereomers with different C9, C10 and C15 configurations compared to the lowest energy diastereomer in which all three carbons are reversed from GB13 (i.e. 9-epi -10-epi-15-epi-GB13). If the natural configuration of C10 is favored by Birch reduction, then the unnatural configuration at C15 should be favored under equilibrating conditions.

Structures minimized using UCSF Chimera,⁸ developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311.

“Natural” C10 configuration (convex-face protonation of Birch/ Benkeser radical anion) with different configurations at epimerizable C9/C15 positions (Figure 9)

“Unnatural” C10 configuration (concave-face protonation of Birch/ Benkeser radical anion) with different configurations at epimerizable C9/C16 positions (Figure 10)

Relative energies of 15-oxo-himgaline diastereomers with different C9 and Cl 5 configurations compared to the lowest energy diastereomer, which happens to be 16-oxo-himgaline itself. If the natural configuration of C10 is favored by Birch reduction and equilibration occurs under acidic conditions (which favor the aza-Michael ring -tautomer, 16-oxo-himgaline), then the natural configuration at Cl 5 should be favored under equilibrating conditions (Figure 11).

X-ray Crystal Structure Reports

The single crystal X-ray diffraction studies were carried out on a Bruker SMART Ptl35 CCD diffractometer equipped with Cu K_a radiation (X =1.54178 A).

Crystals of the subject compound were used as received. A 0.2 x 0.18 x 0.08 mm piece of a colorless crystal was mounted on a Cryoloop with Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using Φ) and to scans. Crystal-to-detector distance was 45 mm and exposure time was 2, 5, 7 and 9 seconds depending on the 20 range per frame using a scan width of 1.25°. Data collection was 98.8 % complete to 67.679° in 0. A total of 26256 reflections were collected covering the indices, -14<=h<=14, -18<=k<=l 8, -12<=1<=14. 3803 reflections were found to be symmetry independent, with a R_int of 0.0651. Indexing and unit cell refinement indicated a Primitive, Monoclinic lattice. The space group was found to be P21/n. The data were integrated using the Bruker SAINT Software program and scaled using the SADABS software program. Solution by direct methods (SHELXT) produced a complete phasing model consistent with the proposed structure.

All nonhydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-2014. Crystallographic data are summarized in Table 1.

Notes for Structure 14 X-ray: The solvent in the pores was disordered, a total of 118 electrons per void were squeezed from the unit cell. This is approximately 0.75 CH₂Cl₂ molecules. There is a disorder on the 6 member ring with the methoxy group and it is highly possible that there is some chemical impurity some other fragment than the methoxy group on the less occupied part. We decided to not model this disorder. disorder.

Table 1. Crystal data and structure refinement for Shenvi270B.

Identification code shenvi270b

Empirical formula C21 H31 N O2

Formula weight 329.47

Temperature 100.15 K

Wavelength 1.54178 A

Crystal system Monoclinic

Space group P 1 21/n 1

Unit cell dimensions a = 11.8522(7) A oc= 90°. b = 15.5371(12) A P= 109.006(2)°. c = 11.9823(7) A y = 90°.

Volume 2086.2(2) A³

Z 4

Density (calculated) 1.049 Mg/m³

Absorption coefficient 0.516 mm ¹

F(000) 720

Crystal size 0.2 x 0.18 x 0.08 mm³

Theta range for data collection 4.557 to 69.038°.

Index ranges -14<=h<=14, -18<=k<=18, -12<=1<=14

Reflections collected 26256

Independent reflections 3803 [R(int) = 0.0651]

Completeness to theta = 67.679° 98.8 %

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.7533 and 0.5917 Refinement method Full-matrix least-squares on F²

Data / restraints / parameters 3803 / 6 / 224 Goodness-of-fit on F² 1.077

Final R indices [I>2sigma(I)] R1 = 0.0852, wR2 = 0.2320 R indices (all data) R1 = 0.0959, wR2 = 0.2434 Extinction coefficient n/a Largest diff peak and hole 0.769 and -0.584 e.A"³ Table 2. Atomic coordinates ( x 10⁴) and equivalent isotropic displacement parameters (A²x 10³) for Shenvi270B. U(eq) is defined as one third of the trace of the orthogonalized Ui> tensor. x y z U(eq)

0(1) 3047(2) 2948(2) 4259(2) 39(1)

0(2) 6936(4) 2920(2) 2795(3) 88(1)

N(1) 6664(2) 2904(2) 7134(2) 25(1)

C(1) 6774(2) 3847(2) 7134(2) 30(1)

C(2) 5751(3) 4273(2) 6168(2) 33(1)

C(3) 4535(3) 3975(2) 6193(2) 34(1)

C(4) 4391(2) 2995(2) 6249(2) 30(1)

C(5) 5501(2) 2592(2) 7185(2) 26(1)

C(6) 7981(3) 4080(2) 7016(3) 39(1)

C(7) 4016(2) 2494(2) 5063(2) 31(1)

C(8) 3715(3) 1570(2) 5355(3) 38(1)

C(9) 4985(3) 1208(2) 5928(2) 34(1)

C(10) 5479(2) 1595(2) 7179(2) 31(1)

C(11) 5039(2) 2295(2) 4600(2) 30(1)

C(12) 5586(3) 1566(2) 5094(2) 32(1)

C(13) 6629(3) 1179(2) 4842(3) 46(1)

C(14) 7101(4) 1768(3) 4089(3) 60(1)

C(15) 6523(4) 2479(3) 3585(3) 55(1)

C(16) 5377(3) 2798(2) 3700(3) 38(1)

C(17) 7634(3) 907(2) 5960(3) 48(1)

C(18) 8680(4) 516(3) 5663(5) 74(1)

C(19) 9172(5) 1160(4) 5004(6) 93(2)

C(20) 8234(6) 1449(4) 3887(5) 95(2)

C(21) 6954(6) 3800(4) 2824(7) 101(2)

Table 3. Bond lengths [A] and angles [°] for Shenvi270B. (1)-H(1) 0.8400

O(1)-C(7) 1.423(3)

O(2)-C(15) 1.381(5)

O(2)-C(21) 1.368(7)

N(1)-H(1A) 0.78(4)

N(1)-C(1) 1.470(4)

N(1)-C(5) 1.481(3)

C(1)-H(1B) 1.0000

C(1)-C(2) 1.528(4)

C(1)-C(6) 1.526(4)

C(2)-H(2A) 0.9900

C(2)-H(2B) 0.9900

C(2)-C(3) 1.523(4)

C(3)-H(3A) 0.9900

C(3)-H(3B) 0.9900

C(3)-C(4) 1.536(4)

C(4)-H(4) 1.0000

C(4)-C(5) 1.555(3)

C(4)-C(7) 1.552(4)

C(5)-H(5) 1.0000

C(5)-C(10) 1.550(4)

C(6)-H(6A) 0.9800

C(6)-H(6B) 0.9800

C(6)-H(6C) 0.9800

C(7)-C(8) 1.546(4)

C(7)-C(11) 1.520(4)

C(8)-H(8A) 0.9900

C(8)-H(8B) 0.9900

C(8)-C(9) 1.542(4)

C(9)-H(9) 1.0000

C(9)-C(10) 1.543(4)

C(9)-C(12) 1.510(4)

C(10)-H(10A) 0.9900

C(10)-H(10B) 0.9900

C(11)-C(12) 1.344(4)

C(11)-C(16) 1.489(4)

C(12)-C(13) 1.492(5) C(13)-H(13) 1.0000

C(13)-C(14) 1.514(5)

C(13)-C(17) 1.533(5)

C(14)-C(15) 1.335(5)

C(14)-C(20) 1.522(6)

C(15)-C(16) 1.494(5)

C(16)-H(16A) 0.9900

C(16)-H(16B) 0.9900

C(17)-H(17A) 0.9900

C(17)-H(17B) 0.9900

C(17)-C(18) 1.524(5)

C(18)-H(18A) 0.9900

C(18)-H(18B) 0.9900

C(18)-C(19) 1.505(7)

C(19)-H(19A) 0.9900

C(19)-H(19B) 0.9900

C(19)-C(20) 1.504(8)

C(20)-H(20A) 0.9900

C(20)-H(20B) 0.9900

C(21)-H(21A) 0.9800

C(21)-H(21B) 0.9800

C(21)-H(21C) 0.9800

C(7)-O(1)-H(1) 109.5

C(21)-O(2)-C(15) 119.0(4)

C(1)-N(1)-H(1A) 106(3)

C(1)-N(1)-C(5) 114.2(2)

C(5)-N(1)-H(1A) 108(3)

N(1)-C(1)-H(1B) 108.0

N(1)-C(1)-C(2) 112.5(2)

N(1)-C(1)-C(6) 108.8(2)

C(2)-C(1)-H(1B) 108.0

C(6)-C(1)-H(1B) 108.0

C(6)-C(1)-C(2) 111.3(2)

C(1)-C(2)-H(2A) 109.2

C(1)-C(2)-H(2B) 109.2

H(2A)-C(2)-H(2B) 107.9

C(3)-C(2)-C(1) 112.1(2)

C(3)-C(2)-H(2A) 109.2 C(3)-C(2)-H(2B) 109.2

C(2)-C(3)-H(3A) 108.5

C(2)-C(3)-H(3B) 108.5

C(2)-C(3)-C(4) 115.0(2)

H(3A)-C(3)-H(3B) 107.5

C(4)-C(3)-H(3A) 108.5

C(4)-C(3)-H(3B) 108.5

C(3)-C(4)-H(4) 105.1

C(3)-C(4)-C(5) 110.5(2)

C(3)-C(4)-C(7) 117.3(2)

C(5)-C(4)-H(4) 105.1

C(7)-C(4)-H(4) 105.1

C(7)-C(4)-C(5) 112.4(2)

N(1)-C(5)-C(4) 114.8(2)

N(1)-C(5)-H(5) 106.2

N(1)-C(5)-C(10) 110.0(2)

C(4)-C(5)-H(5) 106.2

C(10)-C(5)-C(4) 112.9(2)

C(10)-C(5)-H(5) 106.2

C(1)-C(6)-H(6A) 109.5

C(1)-C(6)-H(6B) 109.5

C(1)-C(6)-H(6C) 109.5

H(6A)-C(6)-H(6B) 109.5

H(6A)-C(6)-H(6C) 109.5

H(6B)-C(6)-H(6C) 109.5

O(1)-C(7)-C(4) 107.4(2)

O(1)-C(7)-C(8) 114.7(2)

O(1)-C(7)-C(11) 114.6(2)

C(8)-C(7)-C(4) 106.1(2)

C(11)-C(7)-C(4) 114.3(2)

C(11)-C(7)-C(8) 99.4(2)

C(7)-C(8)-H(8A) 111.7

C(7)-C(8)-H(8B) 111.7

H(8A)-C(8)-H(8B) 109.5

C(9)-C(8)-C(7) 100.2(2)

C(9)-C(8)-H(8A) 111.7

C(9)-C(8)-H(8B) 111.7

C(8)-C(9)-H(9) 112.0 C(8)-C(9)-C(10) 107.3(3)

C(10)-C(9)-H(9) 112.0

C(12)-C(9)-C(8) 99.9(2)

C(12)-C(9)-H(9) 112.0

C(12)-C(9)-C(10) 112.9(2)

C(5)-C(10)-H(10A) 108.9

C(5)-C(10)-H(10B) 108.9

C(9)-C(10)-C(5) 113.2(2)

C(9)-C(10)-H(10A) 108.9

C(9)-C(10)-H(10B) 108.9

H(10A)-C(10)-H(10B) 107.7

C(12)-C(11)-C(7) 109.8(3)

C(12)-C(11)-C(16) 123.8(3)

C(16)-C(11)-C(7) 126.4(2)

C(11)-C(12)-C(9) 109.8(3)

C(11)-C(12)-C(13) 124.3(3)

C(13)-C(12)-C(9) 125.9(3)

C(12)-C(13)-H(13) 107.0

C(12)-C(13)-C(14) 111.6(3)

C(12)-C(13)-C(17) 113.2(3)

C(14)-C(13)-H(13) 107.0

C(14)-C(13)-C(17) 110.8(3)

C(17)-C(13)-H(13) 107.0

C(13)-C(14)-C(20) 114.5(4)

C(15)-C(14)-C(13) 122.3(3)

C(15)-C(14)-C(20) 123.1(4)

O(2)-C(15)-C(16) 115.7(3)

C(14)-C(15)-O(2) 118.5(3)

C(14)-C(15)-C(16) 125.5(3)

C(11)-C(16)-C(15) 111.1(3)

C(11)-C(16)-H(16A) 109.4

C(11)-C(16)-H(16B) 109.4

C(15)-C(16)-H(16A) 109.4

C(15)-C(16)-H(16B) 109.4

H(16A)-C(16)-H(16B) 108.0

C(13)-C(17)-H(17A) 109.3

C(13)-C(17)-H(17B) 109.3

H(17A)-C(17)-H(17B) 108.0 C(18)-C(17)-C(13) 111.5(3)

C(18)-C(17)-H(17A) 109.3

C(18)-C(17)-H(17B) 109.3

C(17)-C(18)-H(18A) 109.7

C(17)-C(18)-H(18B) 109.7

H(18A)-C(18)-H(18B) 108.2

C(19)-C(18)-C(17) 110.0(3)

C(19)-C(18)-H(18A) 109.7

C(19)-C(18)-H(18B) 109.7

C(18)-C(19)-H(19A) 109.3

C(18)-C(19)-H(19B) 109.3

H(19A)-C(19)-H(19B) 108.0

C(20)-C(19)-C(18) 111.4(5)

C(20)-C(19)-H(19A) 109.3

C(20)-C(19)-H(19B) 109.3

C(14)-C(20)-H(20A) 109.0

C(14)-C(20)-H(20B) 109.0

C(19)-C(20)-C(14) 113.0(4)

C(19)-C(20)-H(20A) 109.0

C(19)-C(20)-H(20B) 109.0

H(20A)-C(20)-H(20B) 107.8

O(2)-C(21)-H(21A) 109.5

O(2)-C(21)-H(21B) 109.5

O(2)-C(21)-H(21C) 109.5

H(21A)-C(21)-H(21B) 109.5

H(21A)-C(21)-H(21C) 109.5

H(21B)-C(21)-H(21C) 109.5

Table 4. Anisotropic displacement parameters (A²x 10³) for Shenvi270B. The anisotropic displacement factor exponent takes the form: -27t²[ h² a*²Uⁿ + ... + 2 h k a* b* U¹² ] u¹¹ u²² u³³ u²³ u¹³ u¹²

0(1) 25(1) 51(1) 25(1) -1(1) -11(1) 8(1)

0(2) 121(3) 87(2) 83(2) 40(2) 69(2) 41(2)

N(1) 22(1) 30(1) 20(1) 1(1) 0(1) -2(1)

C(1) 29(1) 31(1) 23(1) 2(1) -1(1) -1(1) C(2) 36(2) 30(1) 26(1) 2(1) 0(1) 4(1) C(3) 30(1) 41(2) 25(1) -1(1) -1(1) 10(1) C(4) 19(1) 45(2) 20(1) -1(1) -1(1) 1(1) C(5) 20(1) 38(2) 16(1) 2(1) 0(1) -1(1) C(6) 34(2) 39(2) 38(2) 4(1) 4(1) -7(1) C(7) 22(1) 43(2) 21(1) 1(1) -4(1) 1(1) C(8) 27(1) 48(2) 29(1) 0(1) -5(1) -9(1) C(9) 29(1) 35(2) 28(1) 2(1) -2(1) -5(1) C(10) 24(1) 40(2) 22(1) 6(1) -1(1) -6(1) C(11) 29(1) 35(2) 17(1) -2(1) -2(1) 3(1) C(12) 36(2) 34(2) 21(1) -1(1) 1(1) 2(1) C(13) 57(2) 43(2) 37(2) 4(1) 15(2) 15(2) C(14) 74(3) 71(3) 48(2) 16(2) 37(2) 31(2) C(15) 67(2) 68(2) 42(2) 21(2) 34(2) 24(2) C(16) 45(2) 44(2) 23(1) 7(1) 8(1) 12(1) C(17) 48(2) 47(2) 50(2) 10(2) 14(2) 15(2) C(18) 71(3) 64(3) 95(3) 26(2) 38(3) 38(2) C(19) 74(3) 103(4) 122(4) 43(3) 61(3) 49(3) C(20) 103(4) 118(5) 90(4) 41(3) 68(3) 60(4) C(21) 120(5) 79(4) 139(6) 14(4) 90(5) 2(3)

Table 5. Hydrogen coordinates ( x 10⁴) and isotropic displacement parameters (A²x 10 ³) for Shenvi270B. x y z U(eq)

H(1) 2736 2643 3658 58

H(1A) 6730(30) 2750(20) 6540(30) 36(10)

H(1B) 6758 4065 7914 36

H(2A) 5810 4905 6270 40

H(2B) 5826 4135 5388 40

H(3A) 3916 4194 5478 41

H(3B) 4388 4236 6886 41

H(4) 3720 2910 6572 36

H(5) 5461 2773 7972 31

H(6A) 8621 3850 7692 59

H(6B) 8055 4708 6995 59

H(6C) 8041 3834 6285 59

H(8A) 3256 1570 5912 46

H(8B) 3269 1247 4634 46

H(9) 4993 565 5942 40

H(10A) 6300 1379 7564 37

H(10B) 4982 1395 7651 37

H(13) 6338 645 4371 55

H(16A) 5462 3413 3929 46

H(16B) 4737 2750 2928 46

H(17A) 7913 1415 6474 58

H(17B) 7322 481 6400 58

H(18A) 9312 344 6399 89

H(18B) 8413 -5 5173 89

H(19A) 9482 1665 5515 111

H(19B) 9845 898 4807 111

H(20A) 8029 963 3322 114

H(20B) 8564 1917 3526 114

H(21A) 7457 4014 2377 152

H(21B) 7279 3995 3644 152

H(21C) 6141 4020 2472 152 Structure 12a X-ray. (Crystal data and structure refinement). See Figure 13. Identification code TO- 156 Empirical formula C21 H33 N O4 Formula weight 363.48

Temperature 100.0 K Wavelength 1.54178 A Crystal system Monoclinic Space group C 2/c Unit cell dimensions a = 22.6778(3) A

b = 13.2319(2) A

c = 15.3819(4) A

Volume 3963.84(13) A³

Z 8

Density (calculated) 1.218 Mg/m³

Absorption coefficient 0.666 mm ¹

F(000) 1584

Crystal size 0.29 x 0.28 x 0.14 mm³

Theta range for data collection 4.442 to 68.277°.

Index ranges -27<=h<=23, 0<=k<=15, 0<=l<=18

Reflections collected 6355 Independent reflections 6355 [R(int) = 0.0343] Completeness to theta = 67.679' 98.9 % Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.585 and 0.501 Refinement method Full-matrix least-squares on F²

Data / restraints / parameters 6355 / 0 / 271 Goodness-of-fit on F² 1.064

Final R indices [I>2sigma(I)] R1 = 0.0408, wR2 = 0.1083 R indices (all data) R1 = 0.0437, wR2 = 0.1106 Extinction coefficient n/a Largest diff. peak and hole 0.235 and -0.189 e.A"³

Table 2. Atomic coordinates ( x 10⁴) and equivalent isotropic displacement parameters (A²x 10³) for Shenvil62_a. U(eq) is defined as one third of the trace of the orthogonalized Ui> tensor. x y z U(eq)

0(1) 8276(1) 2776(1) 9596(1) 27(1)

0(2) 5704(1) 1405(1) 7085(1) 31(1)

N(1) 6800(1) 4944(1) 7229(1) 26(1)

C(3) 6585(1) 2666(1) 4972(1) 29(1)

C(4) 6652(1) 2517(1) 5998(1) 24(1)

C(5) 6136(1) 2030(1) 6088(1) 24(1)

C(6) 5494(1) 1614(1) 5174(1) 31(1)

C(7) 6220(1) 1912(1) 7054(1) 24(1)

C(8) 6798(1) 2263(1) 7929(1) 23(1)

C(9) 7305(1) 2741(1) 7825(1) 22(1)

C(10) 7238(1) 2852(1) 6877(1) 23(1)

C(l l) 7868(1) 3405(1) 7011(1) 26(1)

C(12) 7779(1) 4561(1) 6983(1) 28(1)

C(13) 7561(1) 4942(1) 7725(1) 26(1)

C(14) 7930(1) 4379(1) 8753(1) 25(1)

C(15) 7638(1) 4695(1) 9421(1) 28(1)

C(16) 6857(1) 4715(1) 8868(1) 28(1)

C(17) 6566(1) 5333(1) 7899(1) 31(1)

C(18) 5788(1) 5358(2) 7326(1) 41(1)

C(19) 8402(1) 3098(1) 8101(1) 27(1)

C(20) 7979(1) 3228(1) 8623(1) 24(1)

C(1) 5574(2) 1508(3) 4251(3) 27(1)

C(2) 5854(2) 2533(3) 4100(3) 28(1)

C(l') 5394(4) 1977(9) 4152(5) 67(2)

C(2') 5979(5) 2088(8) 4115(6) 55(2)

0(3) 8671(1) 927(1) 9518(1) 39(1)

C(21) 9348(1) 699(2) 10249(1) 42(1)

0(4) 5735(1) 1175(1) 8800(1) 35(1) Table 3. Bond lengths [A] and angles [°] for Shenvil62_a.

O(1)-H(1) 0.89(3)

O(1)-C(20) 1.4215(18)

O(2)-H(2) 0.8400

O(2)-C(7) 1.3706(18)

N(1)-H(1A) 0.89(2)

N(1)-C(13) 1.486(2)

N(1)-C(17) 1.474(2)

C(3)-H(3AA) 0.9900

C(3)-H(3AB) 0.9900

C(3)-H(3BC) 0.9900

C(3)-H(3BD) 0.9900

C(3)-C(4) 1.519(2)

C(3)-C(2) 1.517(5)

C(3)-C(2') 1.535(9)

C(4)-C(5) 1.403(2)

C(4)-C(10) 1.396(2)

C(5)-C(6) 1.518(2)

C(5)-C(7) 1.407(2)

C(6)-H(6AA) 0.9900

C(6)-H(6AB) 0.9900

C(6)-H(6BC) 0.9900

C(6)-H(6BD) 0.9900

C(6)-C(1) 1.527(4)

C(6)-C(l') 1.546(7)

C(7)-C(8) 1.392(2)

C(8)-H(8) 0.9500

C(8)-C(9) 1.392(2)

C(9)-C(10) 1.395(2)

C(9)-C(20) 1.529(2)

C(10)-C(11) 1.523(2)

C(H)-H(11) 1.0000

C(11)-C(12) 1.541(2)

C(11)-C(19) 1.537(2)

C(12)-H(12A) 0.9900

C(12)-H(12B) 0.9900

C(12)-C(13) 1.542(2) C(13)-H(13) 1.0000 C(13)-C(14) 1.549(2) C(14)-H(14) 1.0000 C(14)-C(15) 1.538(2) C(14)-C(20) 1.548(2) C(15)-H(15A) 0.9900

C(15)-H(15B) 0.9900 C(15)-C(16) 1.522(2) C(16)-H(16A) 0.9900 C(16)-H(16B) 0.9900 C(16)-C(17) 1.523(2) C(17)-H(17) 1.0000

C(17)-C(18) 1.515(2) C(18)-H(18A) 0.9800 C(18)-H(18B) 0.9800 C(18)-H(18C) 0.9800 C(19)-H(19A) 0.9900 C(19)-H(19B) 0.9900

C(19)-C(20) 1.543(2) C(1)-H(1B) 0.9900 C(1)-H(1C) 0.9900 C(1)-C(2) 1.565(6) C(2)-H(2A) 0.9900 C(2)-H(2B) 0.9900

C(1')-H(1'A) 0.9900 C(1')-H(1B) 0.9900 C(l')-C(2') 1.363(12) C(2')-H(2'A) 0.9900 C(2')-H(2'B) 0.9900 O(3)-H(3) 1.04(3)

O(3)-C(21) 1.394(2) C(21)-H(21A) 0.9800 C(21)-H(21B) 0.9800 C(21)-H(21C) 0.9800 O(4)-H(4A) 0.8699 O(4)-H(4B) 0.8699

C(20)-O(1)-H(1) 107.3(16) C(7)-O(2)-H(2) 109.5

C(13)-N(1)-H(1A) 109.9(12)

C(17)-N(1)-H(1A) 106.6(12)

C(17)-N(1)-C(13) 112.44(13)

H(3AA)-C(3)-H(3AB) 107.8

H(3BC)-C(3)-H(3BD) 107.7

C(4)-C(3)-H(3AA) 109.0

C(4)-C(3)-H(3AB) 109.0

C(4)-C(3)-H(3BC) 108.9

C(4)-C(3)-H(3BD) 108.9

C(4)-C(3)-C(2') 113.4(3)

C(2)-C(3)-H(3AA) 109.0

C(2)-C(3)-H(3AB) 109.0

C(2)-C(3)-C(4) 112.7(2)

C(2')-C(3)-H(3BC) 108.9

C(2')-C(3)-H(3BD) 108.9

C(5)-C(4)-C(3) 121.15(14)

C(10)-C(4)-C(3) 120.26(14)

C(10)-C(4)-C(5) 118.58(13)

C(4)-C(5)-C(6) 121.86(14)

C(4)-C(5)-C(7) 119.15(14)

C(7)-C(5)-C(6) 118.99(14)

C(5)-C(6)-H(6AA) 109.1

C(5)-C(6)-H(6AB) 109.1

C(5)-C(6)-H(6BC) 108.8

C(5)-C(6)-H(6BD) 108.8

C(5)-C(6)-C(1) 112.34(19)

C(5)-C(6)-C(l') 113.6(3)

H(6AA)-C(6)-H(6AB) 107.9

H(6BC)-C(6)-H(6BD) 107.7

C(1)-C(6)-H(6AA) 109.1

C(1)-C(6)-H(6AB) 109.1

C(1')-C(6)-H(6BC) 108.8

C(1')-C(6)-H(6BD) 108.8

O(2)-C(7)-C(5) 115.82(13)

O(2)-C(7)-C(8) 121.78(13)

C(8)-C(7)-C(5) 122.37(14)

C(7)-C(8)-H(8) 121.2 C(7)-C(8)-C(9) 117.65(14)

C(9)-C(8)-H(8) 121.2

C(8)-C(9)-C(10) 121.00(14)

C(8)-C(9)-C(20) 130.19(13)

C(10)-C(9)-C(20) 108.80(13)

C(4)-C(10)-C(11) 130.18(13)

C(9)-C(10)-C(4) 121.21(14)

C(9)-C(10)-C(11) 108.56(13)

C(10)-C(11)-H(11) 112.0

C(10)-C(11)-C(12) 111.84(12)

C(10)-C(11)-C(19) 100.35(12)

C(12)-C(11)-H(11) 112.0

C(19)-C(11)-H(11) 112.0

C(19)-C(11)-C(12) 108.19(13)

C(11)-C(12)-H(12A) 109.0

C(11)-C(12)-H(12B) 109.0

C(11)-C(12)-C(13) 113.05(12)

H(12A)-C(12)-H(12B) 107.8

C(13)-C(12)-H(12A) 109.0

C(13)-C(12)-H(12B) 109.0

N(1)-C(13)-C(12) 110.37(13)

N(1)-C(13)-H(13) 106.4

N(1)-C(13)-C(14) 113.74(13)

C(12)-C(13)-H(13) 106.4

C(12)-C(13)-C(14) 112.85(13)

C(14)-C(13)-H(13) 106.4

C(13)-C(14)-H(14) 105.5

C(15)-C(14)-C(13) 111.00(13)

C(15)-C(14)-H(14) 105.5

C(15)-C(14)-C(20) 116.06(13)

C(20)-C(14)-C(13) 112.21(12)

C(20)-C(14)-H(14) 105.5

C(14)-C(15)-H(15A) 108.7

C(14)-C(15)-H(15B) 108.7

H(15A)-C(15)-H(15B) 107.6

C(16)-C(15)-C(14) 114.04(13)

C(16)-C(15)-H(15A) 108.7

C(16)-C(15)-H(15B) 108.7 C(15)-C(16)-H(16A) 109.5

C(15)-C(16)-H(16B) 109.5

C(15)-C(16)-C(17) 110.67(13)

H(16A)-C(16)-H(16B) 108.1

C(17)-C(16)-H(16A) 109.5

C(17)-C(16)-H(16B) 109.5

N(1)-C(17)-C(16) 111.42(13)

N(1)-C(17)-H(17) 108.0

N(1)-C(17)-C(18) 109.28(14)

C(16)-C(17)-H(17) 108.0

C(18)-C(17)-C(16) 111.89(14)

C(18)-C(17)-H(17) 108.0

C(17)-C(18)-H(18A) 109.5

C(17)-C(18)-H(18B) 109.5

C(17)-C(18)-H(18C) 109.5

H(18A)-C(18)-H(18B) 109.5

H(18A)-C(18)-H(18C) 109.5

H(18B)-C(18)-H(18C) 109.5

C(11)-C(19)-H(19A) 111.6

C(11)-C(19)-H(19B) 111.6

C(11)-C(19)-C(20) 100.74(12)

H(19A)-C(19)-H(19B) 109.4

C(20)-C(19)-H(19A) 111.6

C(20)-C(19)-H(19B) 111.6

O(1)-C(20)-C(9) 114.02(12)

O(1)-C(20)-C(14) 107.67(12)

O(1)-C(20)-C(19) 114.63(12)

C(9)-C(20)-C(14) 114.17(12)

C(9)-C(20)-C(19) 99.71(11)

C(19)-C(20)-C(14) 106.42(12)

C(6)-C(1)-H(1B) 110.1

C(6)-C(1)-H(1C) 110.1

C(6)-C(1)-C(2) 108.0(3)

H(1B)-C(1)-H(1C) 108.4

C(2)-C(1)-H(1B) 110.1

C(2)-C(1)-H(1C) 110.1

C(3)-C(2)-C(1) 108.1(3)

C(3)-C(2)-H(2A) 110.1 C(3)-C(2)-H(2B) 110.1

C(1)-C(2)-H(2A) 110.1

C(1)-C(2)-H(2B) 110.1

H(2A)-C(2)-H(2B) 108.4

C(6)-C(1')-H(TA) 108.3

C(6)-C(1')-H(TB) 108.3

H(TA)-C(T)-H(TB) 107.4

C(2')-C(l')-C(6) 115.9(7)

C(2')-C(T)-H(TA) 108.3

C(2')-C(1')-H(TB) 108.3

C(3)-C(2')-H(2'A) 107.6

C(3)-C(2')-H(2B) 107.6

C(l')-C(2')-C(3) 118.7(7)

C(1')-C(2')-H(2'A) 107.6

C(1')-C(2')-H(2B) 107.6

H(2'A)-C(2')-H(2B) 107.1

C(21)-O(3)-H(3) 110.3(14)

O(3)-C(21)-H(21A) 109.5

O(3)-C(21)-H(21B) 109.5

O(3)-C(21)-H(21C) 109.5

H(21A)-C(21)-H(21B) 109.5

H(21A)-C(21)-H(21C) 109.5

H(21B)-C(21)-H(21C) 109.5

H(4A)-O(4)-H(4B) 104.5

Symmetry transformations used to generate equivalent atoms:

Table 4. Anisotropic displacement parame

he anisotropic displacement factor exponent takes the form:

u¹¹ u²² u³³ u²³ u¹³ u¹²

0(1) 25(1) 32(1) 21(1) 0(1) 10(1) 2(1)

0(2) 24(1) 46(1) 24(1) -1(1) 13(1) -8(1)

N(1) 28(1) 25(1) 25(1) -1(1) 15(1) -1(1)

C(3) 32(1) 33(1) 23(1) 1(1) 17(1) 1(1)

C(4) 26(1) 24(1) 23(1) 2(1) 14(1) 4(1)

C(5) 23(1) 26(1) 24(1) -1(1) 12(1) 2(1) C(6) 25(1) 43(1) 24(1) -2(1) H(1) -3(1) C(7) 22(1) 25(1) 26(1) 1(1) 13(1) 1(1) C(8) 24(1) 25(1) 21(1) 1(1) 13(1) 2(1) C(9) 24(1) 21(1) 23(1) 0(1) 13(1) 2(1) C(10) 25(1) 22(1) 25(1) 0(1) 15(1) 1(1)

C(H) 26(1) 31(1) 26(1) -2(1) 18(1) -2(1) C(12) 30(1) 31(1) 28(1) -1(1) 18(1) -5(1) C(13) 28(1) 24(1) 28(1) -1(1) 16(1) -3(1) C(14) 23(1) 28(1) 24(1) -4(1) 12(1) -4(1) C(15) 31(1) 29(1) 23(1) -3(1) 14(1) 0(1) C(16) 32(1) 30(1) 26(1) -2(1) 19(1) 0(1) C(17) 31(1) 37(1) 28(1) 0(1) 17(1) 3(1) C(18) 31(1) 61(1) 33(1) 2(1) 18(1) 7(1) C(19) 23(1) 34(1) 28(1) -3(1) 16(1) -2(1) C(20) 22(1) 30(1) 21(1) 0(1) 12(1) 0(1) C(1) 22(2) 32(2) 19(2) -1(1) 4(1) 3(1)

C(2) 34(2) 31(2) 17(1) 2(1) 13(1) 6(2) C(l') 48(5) 123(9) 23(3) 3(5) 13(3) -27(5) C(2') 50(5) 86(7) 30(3) -5(5) 21(3) -18(5) 0(3) 43(1) 42(1) 25(1) -1(1) 12(1) 12(1) C(21) 38(1) 53(1) 33(1) 1(1) 17(1) 5(1) 0(4) 24(1) 55(1) 25(1) -5(1) 12(1) -4(1)

Table 5. Hydrogen coordinates ( x 10⁴) and isotropic displacement parameters (A²x 10 ³) for Shenvil62_a. y U(eq)

H(1) 8374(12) 2140(20) 9537(19) 61(7) H(2) 5790 1384 7685 46 H(1A) 6640(10) 4313(16) 7063(14) 31 H(3AA) 6746 3353 4941 34 H(3AB) 6885 2174 4898 34 H(3BC) 7015 2440 5013 34 H(3BD) 6528 3395 4807 34

H(6AA) 5103 2068 5004 38 H(6AB) 5388 943 5346 38 H(6BC) 5089 1817 5215 38 H(6BD) 5517 866 5196 38 H(8) 6844 2179 8575 27 H(H) 8000 3171 6515 31 H(12A) 7428 4767 6287 34

H(12B) 8217 4888 7150 34 H(13) 7710 5664 7874 31 H(14) 8414 4631 9111 30

H(15A) 7809 4221 9998 33 H(15B) 7813 5377 9699 33

H(16A) 6707 5012 9314 33 H(16B) 6678 4015 8701 33 H(17) 6736 6043 8089 37

H(18A) 5621 5769 6713 62

H(18B) 5631 5652 7756 62 H(18C) 5610 4668 7136 62 H(19A) 8807 3551 8398 32 H(19B) 8554 2390 8137 32 H(1B) 5126 1348 3643 33 H(1C) 5899 954 4359 33 H(2A) 5845 2527 3449 33

H(2B) 5564 3099 4087 33 H(l'A) 5092 1489 3621 80 H(l'B) 5152 2634 3982 80

H(2'A) 5853 2432 3471 66

H(2'B) 6144 1404 4083 66

H(3) 8527(13) 540(20) 8860(20) 65(7)

H(21A) 9660 1033 10076 63

H(21B) 9417 -34 10274 63

H(21C) 9442 938 10912 63

H(4A) 5986 1526 9347 52

H(4B) 5315 1279 8656 52

References Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R. A.; Malliaras, G. G.; Bernhard, S. Single-Layer Electroluminescent Devices and Photoinduced Hydrogen Production from an Ionic Iridium(III) Complex. Chem. Mater. 2005, 77, 5712-5719. Speckmeier, E.; Fischer, T. G.; Zeitler, K., A Toolbox Approach To Construct Broadly Applicable Metal -Free Catalysts for Photoredox Chemistry: Deliberate Tuning of Redox Potentials and Importance of Halogens in Donor-Acceptor Cyanoarenes. J. Am. Chem. Soc. 2018, 140, 15353-15365. Walker, J. A.; Vickerman, K. L.; Humke, J. N.; Stanley, L. M., Ni -Catalyzed Alkene Carboacylation via Amide C-N Bond Activation. J. Am. Chem. Soc. 2017, 139 (30), 10228-10231. Allais, C.; Lieby-Muller, F.; Rodriguez. J.; Constantieux, T. Metal-Free Michael- Additi on-initiated Three-Component Reaction for the Regioselective Synthesis of Highly Functionalized Pyridines: Scope, Mechanistic Investigations and Applications. Eur. J. Org. Chem. 2013, 4131-4145. Uyanik, M.; Yasui, T.; Ishihara, K. Hydrogen Bonding and Alcohol Effects in Asymmetric Hypervalent Iodine Catalysis: Enantioselective Oxidative Dearomatization of Phenols. Angew. Chem. Int. Ed. 2013, 52, 9215-9218. Burrows, J., Kamo, S., Koide, K. Scalable Birch reduction with lithium and ethylenediamine in tetrahydrofuran. Science 2021, 374, 741-746. Lowe, J. A., Ill; Qian, W .; Drozda, S. E.; Volkmann, R. A.; Nason, D.; Nelson, R. B.; Nolan, C.; Liston, D.; Ward, K.; Faraci, S.; Verdries, K.; Seymour, P.; Majchrzak, M.; Villalobos, A.; White, W. F. Structure-activity relationships of potent, selective inhibitors of neuronal nitric oxide synthase based on the 6-phenyl-2-aminopyridine structure. J. Med. Chem. 2004, 47, 1575-1586. Lan, P.; Herlt, A. J.; Willis, A. C.; Taylor, W. C.; Mander, L. N. Structures of New Alkaloids from Rain Forest Trees Galbulimima belgraveana and Galbulimima baccata in Papua New Guinea, Indonesia, and Northern Australia. ACS Omega 2018, 32, 1912-1921. Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF Chimera— a visualization system for exploratory research and analysis J. Comput. Chem. 2004 25, 1605-1612. 10. Larson, K. K., Sarpong, R. Total Synthesis of Alkaloid (±)-G.B. 13 Using a Rh(I)- Catalyzed Ketone Hydroarylation and Late-Stage Pyridine Reduction J. Am. Chem. Soc. 131, 13244-13245 (2009).

The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

This application refers to various issued patents, published patent applications, journal articles, and other publications, each of which are incorporated herein by reference.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a compound of Formula (12):

wherein R in Formula (12) is hydrogen or methyl; comprising the steps of:

Either

(Al) Silylating a compound of Formula (7)

followed by Simmons-Smith cyclopropropanation using Shi modification to form a compound of Formula (8)

or

(A2) Converting methyl 2-chloro-6-methyl-nicotinate having the formula

to the compound of Formula (8);

(B) Cross-coupling the compound of Formula (8) with a compound of Formula (9)

wherein R in Formula (9) is methyl, to form a compound of Formula (10)

wherein R in Formula (10) is methyl;

(C) cyclizing of the compound of Formula (10) in the presence of an acid to a compound of

Formula (11)

wherein R is Formula (11) is hydrogen or methyl; and

(D) Hydrogenating the compound of Formula (11) to form the compound of Formula (12).

2. The process of claim 1, wherein in step (Al), the silylation is carried out in the presence of trimethyl silyl tritiate.

3. The process of claim 1, wherein in step (Al), the cyclopropanation is carried out in the presence of CH2I2.

4. The process of claim 1, wherein in step (A2), the conversion of methyl 2-chloro-6- methyl-nicotinate to the compound of Formula (8) comprises the steps of:

(A2-(i)) Converting methyl 2-chloro-6-methyl-ni cotinate to the compound of formula (SI- 37):

(A2-(ii)) Converting the compound of Formula (SI-37) to the compound of Formula (SI-38):

(A-2-(iii)) Silylating the compound of Formula (SI-38) to the compound of Formula (8).

5. The process of any one of claims 1-4, wherein in step (B), the cross-coupling is a nickel-catalyzed coupling.

6. The process of claim 5, wherein in step (B), the nickel-catalyzed coupling is carried out in the presence of Nickel dihalide, 2,4,6-tri(9H-carbazol-9-yl)-5-chloroisophthalonitrile (3CzClIPN) or 4CzlPN, 2,2’ -bipyridine (Bipy), and 2,6-lutidine.

7. The process of any one of claims 1-6, wherein in step (C), the acid is a Lewis acid.

8. The process of any one of claim 1-7, wherein in step (C), the acid comprises at least one selected from the group consisting of HC1, H₂SO₄, Bis(trifluoromethanesulfonyl)amine, triflic acid, AlCh, AlC1₃/l,l,l,3,3,3-hexafhioro-2-propanol (HFIP), EtAlCl₂/HFIP, and Et₂AlCl/HFIP.

9. The process of any one of claims 1-8, wherein in step (C), the acid is a Lewis acid, and is Et₂AlCl/HFIP.

10. The process of any one of claims 1-9, wherein in step (D), the hydrogenation is a rhodium-catalyzed hydrogenation.

11. The process of claim 10, wherein in step (D), the rhodium-catalyzed hydrogenation is carried out in the presence of Rh/ALCL and hydrogen gas under high pressure.

12. A process for preparing a compound of Formula (2)

comprising the steps of:

(a) conducting a Benkeser reduction of the compound of Formula (12) prepared according to any one of claims 1-11 to form a compound of Formula (14)

and

(b) hydrolyzing the compound of Formula (14) followed by basification to form the compound of Formula (2); wherein step (b) is performed either using the compound of Formula (14) formed in-situ or after isolation.

13. The process of claim 12, wherein in step (a), the Benkeser reduction is conducted in the presence of Li metal and an amine base.

14. A process for preparing a compound of Formula (1)

comprising converting the compound of Formula (2) prepared according to claim 8 or 9 to the compound of Formula (1).

15. The process of claim 14, comprising the steps of:

(i) converting the compound of Formula (2) under acidic conditions to a compound of Formula

(15)

and

(ii) converting the compound of Formula (15) to the compound of Formula (1); wherein step

(ii) is performed either using the compound of Formula (15) formed in-situ or after isolation.

16. The process of claim 15, wherein step (ii) is performed after isolating the compound of Formula (15).

17. The process of claim 15 or 16, wherein in step (ii), the compound of Formula (15) is treated with a hydride reductant to form the compound of Formula (1).

18. The process of claim 17, wherein the hydride reductant is NaBH(OAc)3.

19. A process for preparing a compound of Formula (3)

comprising converting the compound of Formula (12) prepared according to any one of claims 1-7 to the compound of Formula (3).

20. The process of claim 19, comprising the steps of:

(I) converting the compound of Formula (12) wherein R is methyl to the compound of Formula (12) wherein R is H; and

(II) converting the compound of Formula (12) wherein R is H to the compound of Formula (3).

21. The process of claim 20, wherein in step (I), the compound of Formula (12) wherein R is methyl is demethylated in the presence of BBr, to form the compound of Formula (12) wherein R is H; and wherein in step (II) the compound of Formula (12) wherein R is H is treated with formaldehyde (CH₂O) to form the compound of Formula (3).

22. The process of claim 21, wherein the compound of Formula (12) wherein R is H is treated with formaldehyde (CH₂O) to form the compound of Formula (3).

23. A process for preparing a compound of Formula (2)

comprising using the compound of formula (12)

wherein R in Formula (12) is H or methyl; or the compound of Formula (14)

(14); as an intermediate in preparing the compound of Formula (2).

24. A process for preparing a compound of Formula (1)

comprising using the compound of Formula (12)

wherein R in Formula (12) is H or methyl; or the compound of Formula (14)

as an intermediate in preparing the compound of Formula (1).

25. A compound of Formula (14A)

(14A), wherein R is C_1-6alkyl, which is optionally substituted with 1-3 substituents selected from the group consisting of halo, C_1-6alkyl, -OC_1-6alkyl, -OC_1-6alkyl-OC_1-6alkyl, and cyano.

26. A compound of Formula (12)

wherein R is alkyl, which is optionally substituted with 1-3 substituents selected from the group consisting of halo, C_1-6alkyl, -OC_1-6alkyl, -OC_1-6alkyl-OC_1-6alkyl, and cyano.

27. A compound of Formula (GB16)

28. A process for preparing a compound of Formula (GB16) from the compound of Formula (14) according to the following scheme:

eparing himbadine from the compound of Formula (14) according

himbadine

1422 nM