WO2014022454A1

WO2014022454A1 - Organocatalytic carbonyl-olefin and olefin-olefin metathesis

Info

Publication number: WO2014022454A1
Application number: PCT/US2013/052818
Authority: WO
Inventors: Tristan Hayes LAMBERT; Allison GRIFFITH; Christine VANOS
Original assignee: The Trustees Of Columbia University In The City Of New York
Priority date: 2012-07-31
Filing date: 2013-07-31
Publication date: 2014-02-06

Abstract

The present invention provides, inter alia, organocatalytic carbonyl-olefin metathesis process. This process involves contacting a carbonyl-containing moiety with an olefin-containing moiety in the presence of a catalyst and under conditions sufficient to form a metathesis product with the proviso that the process takes place in the absence of photochemical promotion, stoichiometric amounts of transition metals, and Brnsted and Lewis acid catalysts. The present invention also provides an organocatalytic olefin-olefin metathesis process. This process involves contacting a first olefin-containing moiety with a second olefin-containing moiety in the presence of a catalyst and under conditions sufficient to form a metathesis product with the proviso that the process takes place in the absence of stoichiometric amounts of transition metals. Products made by the processes disclosed herein are also provided.

Description

ORGANOCATALYTIC CARBONYL-OLEFIN AND OLEFIN-OLEFIN METATHESIS

GOVERNMENT FUNDING

[0001] This invention was made with governnnent support under grant no. CHE-0953259 awarded by the National Science Foundation. The governnnent has certain rights in the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The present invention claims benefit to U.S. provisional application serial number 61/677,847 filed on July 31 , 2012 and number 61/712,012 filed on October 10, 2012. The entire contents of the above applications are incorporated by reference.

FIELD OF INVENTION

[0003] The present invention provides, inter alia, organocatalytic carbonyl- olefin metathesis processes and organocatalytic olefin-olefin metathesis processes. Products made by the processes disclosed herein are also provided.

BACKGROUND OF THE INVENTION

[0004] The concept of double bond metathesis is one of enormous practical importance to the field of organic synthesis. Indeed, processes such as Wittig olefination (shown below) (Wittig et al., 1954; Wittig et al., 1955, Maryanoff et al., Schrock et al., 2003; Trnka et al., 2001 ), both of which have been recognized with Nobel Prizes in chemistry, have revolutionized the way in which chemists approach a broad array of synthetic problems.

Wittig Olefination

[0005] Olefin metathesis in particular is being used in an ever-increasing number of transformative biomedical applications (Nicolaou et al., 2005; Hoveyda, 2010; Furstner et al., 201 1 ; Lin et al., 2009; Binder et al., 2008; Farina et al., 2009; Dragutan et al., 2012; Gaul et al., 2003; Nicola et al., 2005). It stands to reason that the development of other double bond metathesis reactions could have a similarly strong impact in the field of chemical synthesis. With little doubt, no such process would have greater impact than catalytic carbonyl-olefin metathesis, a process which nevertheless has eluded realization.

[0006] Chemists have long appreciated the potential utility of carbonyl-olefin metathesis, particularly in light of the transformative effect that the development of other double bond metathesis modalities have had on the field of organic synthesis (Wittig et al., 1954; Wittig et al., 1955, Maryanoff et al., 1989; Vougioukalakis et al., 2010; Hoveyda et al., 2007; Schrock et al., 2003; Trnka et al., 2001 ). Unfortunately, while isolated examples of carbonyl-olefin metathesis have been reported, no general catalytic strategy has yet been achieved (Shaik et al., 1994; Jones et al., 1973; Jones et al., 1975; D'Auria et al., 2010; Prez-Ruiz et al., 2005; Perez-Ruiz et al., 2006, Valiulin et al., 2009; Khripach et ai, 2006; Stille et ai, 1990; Stille et al. 1986; Fu et al., 1993).

[0007] Examples of stoichiometric transition metal mediated carbonyl-olefin metathesis are known (Stille et al., 1990; Stille et al. 1986; Fu et al., 1993), and such reactions provide a potential blueprint for a catalytic process (as shown below). Unfortunately, the difficulties in achieving turnover of what are typically strong metal- oxo bonds has prevented realization of this goal.

known

alkylidene

[0008] Alternative strategies have been envisioned involving the direct metathesis of carbonyl and olefin partners; however, success in this regard has been limited. While [2+2] cycloadditions between carbonyls and olefins are well known (Paterno-Buchi reaction, for example) (Bach, 1998), these reactions are typically only achievable under photochemical conditions:

• lacks generality • low practicality • no catalytic control

[0009] Substrates must thus possess proper chromophores to react, not to mention to undergo the requisite cycloreversion process. Not surprisingly, although there have been a few examples of this type of carbonyl-olefin metathesis reaction (Jones et al., 1973; Jones et al., 1975; D'Auria et ai, 2010; Prez-Ruiz et ai, 2005; Perez-Ruiz et al., 2006, Valiulin et al., 2009), photochemistry has not provided a general solution to this goal. Finally, there have been isolated reports of Br0nsted (Shaik et al., 1994) and Lewis acid (Khripach et al., 2006) promoted carbonyl-olefin metathesis reactions, but only with substrates that are heavily predisposed to undergo stepwise [2+2] cycloadditions/cycloreversions.

[0010] History has shown that the introduction of new double bond metathesis strategies (Wittig, olefin metathesis) can have a tremendous impact on the way in which chemists approach synthetic challenges and can inspire a variety of novel research endeavors. In the same way, the ability to achieve catalytic carbonyl-olefin metathesis is expected to serve as an enabling technology for a wide range of new and exciting directions for the field of chemical synthesis and biomedical research.

[0011] Accordingly, there is a need for a carbonyl-olefin metathesis reaction that is general, operationally simple, and catalytically mediated by a structurally well- defined and tunable catalyst. The present invention is directed to meeting these and other needs. SUMMARY OF THE INVENTION

[0012] The inventors have developed the first organocatalytic carbonyl-olefin metathesis reaction, using a new conceptual paradigm for metathesis chemistry. This paradigm, which utilizes simple hydrazine based organocatalysts, promises to enable a broad menu of previously unknown transformations involving the exchange of carbonyl and olefinic substrates as well as novel strategies for complex molecule synthesis. It also provides the means to realize the first organocatalytic olefin metathesis reactions, a possibility with immense implications for the field of chemical synthesis.

Carbonyl-olefin metathesis

• ring opening carbonyl olefin metathesis

• ring closing carbonyl olefin metathesis

• organocatalytic carbonyl olefination

• enantioselective carbonyl olefin metathesis

• organocatalytic olefin metathesis

[0013] The invention disclosed herein will provide a substantial increase in the ability of chemists to prepare complex, biomedically relevant molecules, and will introduce a fundamental new capability to the organic synthetic toolbox, a capability whose application will offer numerous new avenues of scientific investigation in both academic and industrial settings.

[0014] Accordingly, one embodiment of the present invention is an organocatalytic carbonyl-olefin metathesis process. This process comprises contacting a carbonyl-containing moiety with an olefin-containing moiety in the presence of a catalyst and under conditions sufficient to form a metathesis product with the proviso that the process takes place in the absence of photochemical promotion, stoichiometric amounts of transition metals, and Br0nsted and Lewis acids as the sole catalysts. [0015] Another embodiment of the present invention is a process for carbonyl- olefin metathesis according to the following reaction:

wherein R-i , R₂, and R3 are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis. This process comprises contacting an aldehyde according to formula (2) with a cyclopropene according to formula (64) in the presence of a hydrazine catalyst according to formula (1 1 ) under conditions suitable for carbonyl-olefin metathesis.

[0016] Yet another embodiment of the present invention is a process for carbonyl-olefin metathesis according to the following reaction:

wherein R-i , R₂, R3, and R₄ are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis.

[0017] A further embodiment of the present invention is an organocatalytic olefin-olefin metathesis process. This process comprises contacting a first olefin- containing moiety with a second olefin-containing moiety in the presence of a catalyst and under conditions sufficient to form a metathesis product with the proviso that the process takes place in the absence of stoichiometric amounts of transition metals.

[0018] An additional embodiment of the present invention is a process for organocatalytic olefin-olefin metathesis according to the following reaction:

wherein R-i , R₂, and R₃ are independently selected from the group consisting of H and any organic substituent suitable for participating in the organocatalytic olefin- olefin metathesis. This process comprises contacting an aldehyde according to formula (2) with a cyclopropene according to formula (64) in the presence of a hydrazine catalyst according to formula (1 1 ) under conditions suitable for organocatalytic olefin-olefin metathesis to occur.

[0019] Another embodiment of the present invention is a process for organocatalytic olefin-olefin metathesis according to the following reaction:

wherein R-ι, R₂, and R₃ are independently selected from the group consisting of H and any organic substituent suitable for participating in the organocatalytic olefin- olefin metathesis

[0020] An additional embodiment of the present invention is a product made by any process disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

[0021] One embodiment of the present invention is an organocatalytic carbonyl-olefin metathesis process. This process comprises contacting a carbonyl- containing moiety with an olefin-containing moiety in the presence of a catalyst and under conditions sufficient to form a metathesis product with the proviso that the process takes place in the absence of photochemical promotion, stoichiometric amounts of transition metals, and Br0nsted and Lewis acids as the sole catalysts. [0022] As used herein, "organocatalytic" means that the reaction is catalyzed by organic compounds. The term "organic" compound refers to any carbon-based compound. In addition to carbon, organic compounds may contain bromide, calcium, chlorine, fluorine, hydrogen, iodine, potassium, nitrogen, oxygen, sulfur and other elements.

[0023] As used herein, "carbonyl" means a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. Carbonyls include without limitation, aldehydes, ketones, carboxylic acids, esters, and amides.

[0024] As used herein, an "olefin" refers to an aliphatic group containing at least one double bond.

[0025] As used herein, a "metathesis" process means a reaction that entails the redistribution of fragments of carbonyls and olefins or fragments of olefins by the scission and regeneration of carbon - carbon double bonds.

[0026] As used herein, a "moiety" means a portion of a molecule. The carbonyl-containing moiety and the olefin-containing moiety may be a part of two separate molecules. Alternatively, the carbonyl-containing moiety and the olefin- containing moiety may be a part of the same molecule such that the metathesis may be a ring-closing reaction and one of the products from the metathesis process is cyclized, as disclosed below in the Examples section.

[0027] Non-limiting exemplary "conditions sufficient" to form a metathesis product are disclosed in the Examples herein and may be further apparent to those skilled in the art in view of the disclosures herein.

[0028] As used herein, metathesis mediated by "photochemical promotion" means a [2+2] cycloaddtition/cycloreversion between carbonyls and olefins achieved via absorption of light, such as uv light, by the reactants or catalysts. Examples of metathesis mediated by photochemical promotion include Paterno-Buchi reaction (Bach, 1998) and those reported by Jones et al., 1973; Jones et al., 1975; D'Auria et ai, 2010; Prez-Ruiz et ai, 2005; Perez-Ruiz et ai, 2006; and Valiulin et ai, 2009. A "cycloaddition" is a reaction in which two or more unsaturated molecules (or parts of the same molecule) combine with to form a cyclic adduct, thus resulting in cyclization. The numbers, such as [2+2] or [2+3], refer to the backbone size of the participants. Thus, a [2+2] reaction results in a 4-membered ring, whereas a [2+3] reaction results in a 5-membered ring. A "cycloreversion" is the reverse of cycloaddition.

[0029] As used herein, metathesis mediated by "stoichiometic amounts of transition metals" means a [2+2] cycloaddtition/cycloreversion between carbonyls and olefins or between two olefins in which the same molar ratio of transition metal as the reactants are used, and metal-oxo bonds are formed. As used herein, a "transition metal" means any element in the d-block of the periodic table, which includes groups 3 to 12 elements of the periodic table. Examples of metathesis mediated by stoichiometic amounts of transitional metals include those reported by Stille et al., 1990; Stille et al. 1986; and Fu et al., 1993.

[0030] As used herein, metathesis mediated by "Br0nsted and Lewis acid catalysts" means a [2+2] cycloaddtition/cycloreversion between carbonyls and olefins catalyzed either by a molecule that is able to lose a hydrogen cation (a Br0nsted acid) or an electron-pair acceptor (a Lewis acid) in which the Br0nsted or Lewis acid is present as the sole catalyst. Examples of metathesis mediated by Bransted and Lewis acid catalysts include those reported by Shaik et ai, 1994 and Khripach et ai, 2006. [0031] In one aspect of this embodiment, the metathesis process occurs via a [3+2] cycloaddition/cycloreversion mechanism.

[0032] In another aspect of this embodiment, the catalyst is a hydrazine. As used herein, a "hydrazine" means any compound containing a -NH-NH- functional group.

[0033] Preferably, the catalyst is selected from the group consisting of:

(1

Although the · 2HCI salts are shown, in the present invention any form of the catalyst may be used so long as it does not substantially hinder the reaction.

[0034] In another preferred embodiment, the catalyst is a bicyclic hydrazine. As used herein, a "bicyclic" molecule means a molecule having two cyclic rings in which two carbons or other heteroatoms are common to two adjoining rings. The rings may be substituted or unsubstituted aromatic or non-aromatic rings, preferably 3- to 8-membered rings. As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0035] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with the permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0036] In a further preferred embodiment, the catalyst is a 1 ,2- dialkylhydrazine. As used herein, a "1 ,2-dialkylhydrazine" means a compound of the following formula: R-NH-NH-R', in which R and R' are alkyls. Optionally, R and R' may be joined to form a cyclic compound or a bicyclic compound. The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., C-i-C-io for straight chains, C3-C10 for branched chains). Likewise, certain cycloalkyls have from 3-8 carbon atoms in their ring structure, including 5, 6 or 7 carbons in the ring structure.

[0037] Moreover, unless otherwise indicated, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, an aromatic, or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF₃, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CF₃, -CN, and the like.

[0038] The term "C_x-y" when used in conjunction with a chemical moiety, such as, alkyl or alkenyl, is meant to include groups that contain from x to y carbons in the chain. For example, the term "C_x-yalkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyi groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. Thus, alkyl includes for example C-i-20 alkyl, such as d-10 alkyl, including C1-5 alkyl.

[0039] In an additional preferred embodiment, the catalyst is:

[0040] In an additional aspect of this embodiment, the catalyst is a chiral hydrazine. Preferably, the chiral hydrazine is selected from the group consisting of:

and a stereoisomer thereof. As used herein, "chiral" means being asymmetric in such a way that the structure and its mirror image are not superimposable. The term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. Stereoisomers include enantiomers, optical isomers, and diastereomers.

[0041] In a further aspect of this embodiment, the olefin-containing moiety is selected from the group consisting of:

wherein R₂, R3, and R are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis.

[0042] As used herein, the term "substituent" means a functional group. Such functional groups include without limitation, cyano, oxo, nitro, acyl, acylamino, halogen, hydroxy, amino acid, amine, amide, carbamate, ester, ether, carboxylic acid, thio, thioalkyl, thioester, thioether, alkyl, alkoxy, alkynyl, aralkyl, carbocyclic, heterocyclic, aryl, or heteroaryl, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, alkylsulfonyl, and arylsulfonyl.

[0043] As used herein, an organic substituent "suitable for participating" in the carbonyl-olefin metathesis means any organic substituent that does not substantially interfere with the carbonyl-olefin metathesis. Non-limiting examples of such organic substituents include, without limitation,

[0044] In another aspect of this embodiment, the olefin-containing moiety comprises a cyclopropene. As used herein, a "cyclopropene" means a molecule containing the following structure:

Preferably, the olefin-containing moiety is a cyclopropene of formula

(64)

wherein R₂ and R3 are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis. [0046] Preferably, the olefin-containing moiety is a cyclopropene having the structure:

(64a) wherein X is selected from atoms from Group 16 of the periodic table, including O and S; and Y is selected from silyl ethers, such as tert-butyldiphenylsilyl (TBDPS) ethers, benzyl, phenyl, acyl, including acetyl, and C_2-8 alkenyl, including C_2-6 alkenyl and C_2-4 alkenyl. For example, the olefin-containing moiety is a cyclopropene selected from the group consisting of: TBDPS

(10) , (101 ) , (103)

(104) , and (105)

[0047] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0048] In a further aspect of this embodiment, the carbonyl-containing moiety is selected from the group consisting of:

wherein R-i , R₂, and R₃ are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis.

[0049] In another aspect of this embodiment, the carbonyl-containing moiety comprises an aldehyde. As used herein, the term "aldehyde" refers to an organic

compound containing a functional group with the structure:

Preferably, the carbonyl-containing moiety is a aldehyde of formula (2):

(2)

wherein is any organic substituent suitable for participating in the carbonyl-olefin metathesis. [0050] In a further aspect of this embodiment, the organocatalytic carbonyl- olefin metathesis is carried out according to the following reaction:

(6) (65) (66) (67) (4) wherein

R-i , R₂, and R₃ are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis; and

X is selected from the group consisting of any atom or group of atoms that do not substantially hinder the reaction and non-stoichiometric amounts of a transition metal complex that does not substantially hinder the reaction.

[0051] As used herein, "transition metal complex" means a transition metal bound to a surrounding array of molecules or anions. In the present invention, atoms, groups of atoms, or transition metal complexes that do not "substantially hinder" the reaction means those that do not significantly impede the progression of the metathesis reaction, for example, by forming excessive reaction by-products (e.g., greater than 1 %, such as greater than 5% or greater than 10%-50%).

[0052] Preferably, the atom is or the group of atoms includes main group elements. As used herein, "main group elements" are elements (except hydrogen) that are in groups 1 and 2 (s-block) and groups 13 to 18 (p-block) of the periodic table. More preferably, the main group elements are selected from the group consisting of O, N, S, and P. [0053] In another preferred embodiment, the transition metal complex comprises an atom selected from the group consisting of Ru, Mo, Ti, and W.

[0054] In an additional aspect of this embodiment, the organocatalytic carbonyl-olefin metathesis is carried out according to the following reaction:

wherein R-i, R₂, and R3 are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis.

[0055] Preferably, Ri, R2, and R3 are independently selected from the group consisting of substituted or unsubstituted C3-C12 aryl, C3-C12 heteroaryl, C3-C12 cycloalkyl, and Ci-12 alkyl.

[0056] The term "aryl" as used herein includes single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 3- to 12-membered ring, more preferably 5- to 7-membered rings, even more preferably 5- to 6- membered rings. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. [0057] The term "heteroaryl" includes aromatic single ring structures, preferably 3- to 12-membered rings, more preferably 5- to 7-membered rings, even more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[0058] As used herein, cycloalkyl means a non-aromatic saturated ring in which each atom of the ring is carbon. Preferably a cycloalkyl ring contains from 3 to 8 atoms, including 5 to 7 atoms, such as for example, 6 atoms.

[0059] In another preferred embodiment, R-i , R₂, and R3 are independently selected from the group consisting of:

[0060] In another aspect of this embodiment, the olefin-containing moiety is cyclic. Preferably, the olefin-containing moiety is selected from the group consisting of:

wherein R is selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis.

[0061] In a further aspect of this embodiment, the carbonyl-containing moiety is linked to the olefin-containing moiety. Preferably, a compound comprising both the carbonyl-containing moiety and the olefin-containing moiety is selected from the group consisting of:

[0062] In an additional aspect of this embodiment, the olefin-containing moiety is in excess of the carbonyl-containing moiety. Preferably, the olefin-containing moiety is a compound of formula (29):

(29)

[0063] Another embodiment of the present invention is a process for carbonyl- olefin metathesis according to the following reaction:

wherein

R-i , R₂, and R₃ are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl- olefin metathesis. This process comprises contacting an aldehyde according to formula (2) with a cyclopropene according to formula (64) in the presence of a hydrazine catalyst according to formula (1 1 ) under conditions suitable for carbonyl-olefin metathesis.

[0064] In one aspect of this embodiment, the conditions suitable for carbonyl- olefin metathesis comprise reacting the aldehyde (2), cyclopropene (64), and hydrazine (1 1 ) in the presence of 1 ,2-dichloroethane (DCE) at a temperature between 75-90°C for 24 hours.

[0065] In another aspect of this embodiment, R-i , R₂, and R3 are independently selected from the group consisting of substituted or unsubstituted C3-C12 aryl, C3-C12 heteroaryl, C3-C12 cycloalkyl, and Ci-12 alkyl.

[0066] In a further aspect of this embodiment, R-i , R₂, and R3 are independently selected from the group consisting of:

[0067] Yet another embodiment of the present invention is a process for carbonyl-olefin metathesis according to the following reaction:

wherein R-i , R₂, R3, and R are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis.

[0068] A further embodiment of the present invention is an organocatalytic olefin-olefin metathesis process. This process comprises contacting a first olefin- containing moiety with a second olefin-containing moiety in the presence of a catalyst and under conditions sufficient to form a metathesis product with the proviso that the process takes place in the absence of stoichiometric amounts of transition metals.

[0069] The first and the second olefin-containing moieties may be a part of two different molecules. Alternatively, the first and the second olefin-containing moieties may be a part of the same molecule such that the metathesis may be a ring-closing reaction, and one of the products from the metathesis process is cyclized.

[0070] In one aspect of this embodiment, the metathesis process occurs via a [3+2] cycloaddition/cycloreversion mechanism.

[0071] In another aspect of this embodiment, the catalyst is a hydrazine, such as a bicyclic hydrazine. In a further aspect of this embodiment, the catalyst is a 1 ,2- dialkylhydrazine. In yet another aspect of this embodiment, the catalyst is:

[0072] In an additional aspect of this embodiment, at least one of the first and the second olefin-containing moiety comprises a cyclopropene. Suitable first and/or second olefin-containing cyclopropene moieties include those set forth herein, including, e.g., compounds 10, 101 , and 103-105, and compounds within the scope of formulae 64 and 64a, as defined herein. Preferably, at least one of the first and second olefin-containing moieties are a cyclopropene of formula (102):

(102)

wherein X is an agent for delivery to a subject in need thereof, such as a pharmaceutical drug for the treatment of a medical condition.

[0073] In another aspect of this embodiment, the organocatalytic olefin-olefin metathesis process is carried out according to the following reaction:

(71 ) (72) (73) (74) (6) wherein

Ri and R₂ are independently selected from the group consisting of H and any organic substituent suitable for participating in the organocatalytic olefin-olefin metathesis; and

X is any atom or group of atoms that do not substantially hinder the reaction.

[0074] Preferably, the atom is or the group of atoms includes main group elements, such as O, N, S, and P.

[0075] In an additional aspect of this embodiment, the organocatalytic olefin- olefin metathesis process is carried out in the presence of a carbonyl moiety.

[0076] In a further aspect of this embodiment, the organocatalytic olefin-olefin metathesis process is carried out according to the following reaction:

wherein R-ι , R₂, and R₃ are independently selected from the group consisting of H and any organic substituent suitable for participating in the organocatalytic olefin- olefin metathesis.

[0077] Preferably, R-i , R₂, and R₃ are independently selected from the group consisting of substituted or unsubstituted C₃-Ci₂ aryl, C3-C12 heteroaryl, C₃-Ci₂ cycloalkyl, and Ci_i₂ alkyl. More preferably, R-i , R₂, and R₃ are independently selected from the group consisting of

[0078] In a further aspect of this embodiment, at least one of the first or the second olefin-containing moiety is selected from the group consisting of:

[0079] Preferably, the product produced by the metathesis process is selected from the group consisting of a polyoctenamer (such as Vestenamer®), a polydicyclopentadiene (such as Telene®, Metton®, Prometa®, and/or Pentam®), and a polynorbornene (such as Norsorex®). Vestenamer® is a mixture of cyclic and linear polyoctenamers, which may be represented by the following:

Polydicyclopentadienes may be generally represented by the following:

Norsorex® may be generally represented by the following:

[0080] A further embodiment of the present invention is a process for organocatalytic olefin-olefin metathesis according to the following reaction:

wherein

Ri , R2, and R3 are independently selected from the group consisting of H and any organic substituent suitable for participating in the organocatalytic olefin-olefin metathesis.

This process comprises contacting an aldehyde according to formula (2) with a cyclopropene according to formula (64) in the presence of a hydrazine catalyst according to formula (1 1 ) under conditions suitable for organocatalytic olefin-olefin metathesis.

[0081] In one aspect of this embodiment, the conditions suitable for organocatalytic olefin-olefin metathesis comprise reacting the aldehyde (2), cyclopropene (64), and hydrazine (1 1 ) in the presence of acetonitrile at a temperature between 75-90°C for 24 hours.

[0082] In another aspect of this embodiment, R-i , R₂, and R3 are independently selected from the group consisting of substituted or unsubstituted C3-C12 aryl, C3-C12 heteroaryl, C3-C12 cycloalkyl, and Ci-12 alkyl. In a further aspect of this embodiment, Ri , R2, and R3 are independently selected from the group consisting of:

[0083] An additional embodiment of the present invention is a process for organocatalytic olefin-olefin metathesis according to the following reaction:

wherein R-i , R₂, and R3 are independently selected from the group consisting of H and any organic substituent suitable for participating in the organocatalytic olefin- olefin metathesis. [0084] Another embodiment of the present invention is a product made by any process disclosed herein.

[0085] It is understood that the disclosure of a compound herein encompasses all salts of that compound.

[0086] It is appreciated that compounds of the present invention having a chiral center may exist in and be isolated in optically active and racemic forms. The terms "racemate" or "racemic mixture" refer to a mixture of equal parts of enantiomers. The term "enantiomeric enrichment" as used herein refers to the increase in the amount of one enantiomer as compared to the other. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, diastereomeric, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

[0087] Examples of methods to obtain optically active materials are known in the art, and include at least the following: i) physical separation of crystals-a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization-a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions-a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme;

iv) enzymatic asymmetric synthesis-a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

v) chemical asymmetric synthesis-a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts as disclosed in more detail herein or chiral auxiliaries;

vi) diastereomer separations-a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations-a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer;

viii) kinetic resolutions-this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors~a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis;

x) chiral liquid chromatography-a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase. The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions;

xi) chiral gas chromatography~a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase;

xii) extraction with chiral solvents~a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes-a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass through. [0088] The stereoisomers may also be separated by usual techniques known to those skilled in the art including fractional crystallization of the bases or their salts or chromatographic techniques such as LC or flash chromatography. The (+) enantiomer can be separated from the (-) enantiomer using techniques and procedures well known in the art, such as that described by J. Jacques, et ai, antiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981 . For example, chiral chromatography with a suitable organic solvent, such as ethanol/acetonitrile and Chiralpak AD packing, 20 micron can also be utilized to effect separation of the enantiomers.

[0089] The following examples are provided to further illustrate the methods of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

EXAMPLES

Example 1

Conceptual Blueprint For The First Catalytic Carbonyl Olefin Metathesis

Reaction

[0090] A fundamentally different strategy was devised to accomplish carbonyl olefin metathesis that circumvents both the need for metal catalysis as well as the problems associated with [2+2] cycloadditions. Specifically, the inventors recognized that rather than relying on a [2+2] manifold (traditional metathesis paradigm shown below in scheme 1 (a)), a double bond metathesis process could instead be based upon a thermally allowed [3+2] manifold (new metathesis paradigm shown below in scheme 1 (b)), given a few basic requirements. In Scheme 1 below, X indicates a generic atom or group, including main group elements (e.g. O, N, S, P) or transition metal complexes (e.g. Ru, Mo, Ti, W). R _-3 indicates generic organic substituents.

Scheme 1

(a) traditional metathesis paradigm

pseudosymmetric

(b) new metathesis paradigm

R¹ - Χ„_{χ +} [3+2] X-X [3+2] _÷ X -

pseuc/osymmefr/^'c

Thus, the new metathesis paradigm outlined above would require simply that (1 ) there exist a facile pathway for conversion of the carbonyl component into a reactive partner for the [3+2] cycloaddition and (2) the intermediate cycloadducts of such a process possessed sufficient pseudosymmetry to allow cycloreversion in either of two directions (i.e. the backward process to regenerate starting materials and the forward process to yield the metathesis products). Fortunately, these requirements are readily fulfilled by the well known azomethine imine 1 ,3-dipolar cycloaddition reaction (Grashey et al. , 1984; Padwa et al., 1976; Pellissier et al., 2007), shown below:

imines pyrazolidines

[0091] Developed by Huisgen in the 1960's (Huisgen et al., 1960; Godtfredsen et al., 1955) and further expanded by Oppolzer (Oppolzer et al., 1970; Oppolzer, 1972; Oppolzer, 1970), the azomethine imine 1 ,3-dipolar cycloaddition reaction entails the condensation of a carbonyl substrate with a hydrazine to form an azomethine imine reactive intermediate (Na et al., 201 1 ; Chen et al., 2006; Suga et al., 2007; Chen et al., 2007; Sibi et al., 2008; Hashimoto et al., 2010; Jones et al., 2007; Zlicar et al., 1992; Roussi et al., 2000; Shintani et al., 2003; Suarez et al., 2005; Chan et al., 2007; Shapiro et al., 2009; Perreault et al., 2008). This intermediate then undergoes a [4π+2π] thermally allowed cycloaddition with an olefin partner to produce a pyrazolidine product. Importantly, this pyrazolidine possesses precisely the required pseudosymmetry noted above, provided that the two N-substituents are similar or identical (e.g. both alkyl). Although azomethine imine cycloadditions with 1 ,2-dialkyl hydrazines (Shimizu et al., 1987) are less common than with acylhydrazines (Grashey, 1984; Padwa, 1976; Pellissier, 2007), there is sufficient precedence with this class of hydrazines to suggest that this concept should be viable. Most crucially, though few in number, examples also exist of the retrocycloaddition of pyrazolidines (Bianchi et al., 1979), providing validity to the metathesis concept (Pettett et ai, 1983).

[0092] With reference to the reaction scheme 2 shown below, the organocatalytic carbonyl-olefin metathesis design entails the use of a symmetric 1 ,2- dialkylhydrazine (Shimizu et al., 1987) catalyst 1 , which can readily engage an aldehyde 2 via condensation to form an azomethine imine 3 reactive intermediate. Cycloaddition of 3 with an olefin substrate 4 would produce a pyrazolidine cycloadduct 5 possessing the pseudosymmetry called for by the mechanistic design. Upon orthogonal cycloreversion of cycloadduct 5, product olefin 6 and a new azomethine imine 7 would be produced (Burger, 1977; Gandolfi et al., 1979; Fevre et ai, 1979). Hydrolysis of 7 would then liberate the product aldehyde 8 and regenerate the hydrazine catalyst 1.

Scheme 2

[0093] The concept outlined in Scheme 2 above provides the conceptual blueprint to realize the first catalytic carbonyl olefin metathesis reaction, a process with major implications for the field of chemical synthesis. Significantly, this organocatalytic process offers the possibility of producing metathesis products, including polymers (vide infra), free of toxic transition metal contaminants. More broadly, this novel [3+2] based concept provides a new paradigm for double bond metathesis chemistry that may prove applicable in other contexts. Example 2

Organocatalytic Carbonyl-Olefin Metathesis Using A Cyclopropene Substrate

[0094] The viability of the carbonyl-olefin metathesis design is demonstrated herein.

Equation (1 )

a-quaternary β,γ-unsaturated aldehydes

• Challenging structural motif

• Synthetically useful building block

• Chemo-orthogonal double bonds

[0095] As shown above, a cyclopropene substrate compound 10 was used to ensure facile retrocycloaddition (due to ring strain) (Rubin et al., 2007; Nakamura et al., 2003). The bicyclic hydrazine (Mellor et al., 1984) catalyst compound 11 · 2HCI was a productive catalyst for this transformation. As shown above, compound 11 · 2HCI readily effects carbonyl-olefin metathesis of cyclopropene 10 with benzaldehyde (compound 9), delivering the desired product 12 in 95% yield (¹H NMR analysis, 80% isolated yield of corresponding alcohol after NaBH₄ reduction) over 24 hours at 75°C in dichloroethane (DCE) as a single observable olefin isomer, as shown in equation (1 ). Importantly, benzaldehyde 9 and cyclopropene 10 do not undergo any reaction in the absence of catalyst 11 , nor in the presence of only HCI or trialkylammonium chlorides. This reaction represents the first example of an organocatalytic carbonyl-olefin metathesis reaction and provides experimental validation of the new metathesis design.

[0096] Notably, the a-quaternary β,γ-unsatu rated aldehyde product 12 resulting from the reaction shown in Equation 1 represents a versatile class of synthetic building blocks that can be challenging to prepare directly by traditional means. The ring-opening carbonyl-olefin metathesis (ROCOM) of cyclopropenes reported here offers a unique and advantageous strategy to access these valuable structures. More broadly, in contrast to olefin metathesis, carbonyl-olefin metathesis results in the use and generation of chemo-orthogonal double bonds, and thus products that readily lend themselves to selective functionalization.

[0097] In contrast to the high efficiency of the catalyst 11^»2HCI, the inventors found that the use of 50 mol% of 1 ,2-dimethylhydrazine, 1 ,2-diethylhydrazine, or pyrazolidine dihydrochlorides resulted in the generation of less than 10% of aldehyde 12 under the optimized conditions. Neither 1 ,2-diphenylhydrazine dihydrochloride nor A/'-methyl phenylacetic hydrazide effected this transformation to any observable extent. Clearly the bicyclic structure of 11 plays a key role in the high performance of this hydrazine catalyst.

<10% product no product [0098] Substrate scope studies for this protocol have revealed a tolerance of a variety of aryl aldehydes and other functionality (Table 1 below). In addition to the reaction shown in equation (1 ) above, the inventors found that hydrazine 11 (shown in Scheme 3 below) efficiently catalyzes carbonyl-olefin metathesis of cyclopropene 10 and a range of other carbonyls, including electron-rich (13), electron-deficient (14), heteroaryl (15) and aliphatic (100) aldehydes. Furthermore, other cyclopropenes may also be employed, including those with acetoxy (17) or trialkylsiloxy (18) substituents.

Scheme 3

Ph indicates phenyl; Bn, benzyl.

y e 74% yield ₄₅o/_{0 yie}|_d

[0099] Table 1 below shows an exemplary survey of the substrate scope for hydrazine catalyzed carbonyl-olefin metathesis. Example 7 sets forth the detailed synthetic conditions for the reactions shown in Table 1 . In addition to benzaldehyde (Table 1 , entry 1 ), the inventors have found that 11^»2HCI catalyzed carbonyl-olefin metathesis of cyclopropene 10 with a range of other substrates, including alkyl- (entries 2 and 3) and oxygen-substituted (entry 4) benzaldehydes. In general, there appeared to be an inverse correlation between the electron rich character of the aldehyde and the isolated yield of metathesis product, which, without wishing to be bound by a particular theory, the inventors believe is due to the sensitivity of the electron-rich styrenyl products to decomposition. Substrates bearing electron- withdrawing functionality such as p-nitro (entry 5) and o-bromo (entry 6) substituents were also viable. The rate of conversion with these substrates was noticeably slower than with less electron deficient substrates, which is consistent with the idea that the highest occupied molecular orbital (HOMO) of the azomethine imine fragment is engaged in normal electron demand 1 ,3-dipolar cycloadditions (Grashey, 1984). Products derived from naphthaldehydes (entries 7 and 8) and heteroaryl aldehydes such as furfural (entry 9) were also readily accommodated in this process. Notably, the use of thiophenecarboxyaldehyde resulted in clean production of the corresponding metathesis product (entry 10), although the isolated yield was only modest due to the sensitive nature of the vinylthiophene functionality. In addition to aryl aldehydes, it was found that carbonyl-olefin metathesis with an aliphatic aldehyde such as hydrocinnamaldehyde could be observed as well (entry 1 1 ). However, the desired product was accompanied by significant amounts of unidentified side products. Given the propensity for aliphatic aldehydes to participate in a variety of amine-catalyzed transformations, this finding is not surprising. Finally, the inventors have found that acetoxy groups on the cyclopropene partner are also well tolerated (entry 12).

Table 1. Exemplary survey of the substrate scope for ring-opening carbonyl-olefin metathesis of cyclopropenes with aldehydes catalyzed by hydrazine 11.

entry product % yield entry product % yield entry product % yield

Percent yields for entries 1 and 6 were determined by ¹H NMR versus an internal standard.

Numbers in parentheses are isolated yields of the corresponding alcohol products obtained after

reduction with NaBH₄. Bn = benzyl; Ac = acetyl; TBDPS = ferf-butyldiphenylsilyl; Bu = n-butyl.

[0100] In terms of variation of the cyclopropene reaction partner, it was found that other useful O-linkages including acetoxy and tert-butyldiphenylsiloxy groups are also well tolerated (entries 12 and 13). Interestingly, the reaction of a substrate bearing allyl ether functionality was found to stall after low conversion, suggesting that the catalyst undergoes some form of inactivation (entry 14). A likely possibility is that the hydrazonium intermediate following ring-opening metathesis undergoes intramolecular cycloaddition with one of the allyl groups (Shimizu et al., 1987). On the other hand, soft heteroatom substituents such as thioethers, which can be problematic with certain metal-based metathesis catalysts due to catalyst poisoning (McReynolds et al., 2004), were found to be compatible with this organocatalytic reaction (entry 15).

[0101] A detailed mechanistic rationale for this metathesis process is depicted in Scheme 3 above. Given that catalyst 11 is used as its dihydrochloride salt, it was assumed that the reaction proceeds via hydrazonium ion 12, the protonated form of the putative azomethine imine (Shimizu et al., 1987; Snyder et al., 1978). Although not wishing to be bound by a particular theory, the inventors believe that cycloaddition of 14 with cyclopropene 11 produces pyrazolidinium salt 15 (Hoffman et al., 1995), although such intermediates have not been observed. It is plausible that cycloaddition and not cycloreversion is the rate-determining step in this transformation due to the high strain of the three membered ring. Conversion of 14 to 15 by proton transfer would then facilitate strain-relieving cycloreversion to produce hydrazonium ion 16. Upon hydrolysis of 16, the metathesis aldehyde 12 would be produced with concomitant regeneration of hydrazine catalyst 11 .

[0102] The complete (E)-olefin selectivity observed in these reactions can be rationalized by invoking cycloaddition of hydrazonium (E)-13 via an exo transition state, which is known to be favored for 3,3-disubstituted cyclopropenes due to the minimization of steric congestion (Apeloig et al., 1987). Although hydrazonium (Z)- 14 is the thermodynamically favored isomer (see below), geometric isomerization of this functional group is known to occur readily (Karabatsos et al., 1964). On the other hand, the production of (Z)-olefin products, via exo cycloaddition of (Z)-13, followed by (Z)→(E) isomerization cannot at this time be ruled out. Indeed, isomerization of sterically congested c/s- -substituted styrenyl olefins, if formed, would be expected under these reaction conditions. However, monitoring by ¹ H NMR has not revealed evidence of olefin isomers, and so any such isomerization, if operable, must be relatively rapid.

[0103] In support of the proposed mechanism, the inventors prepared the known hydrazonium perchlorate (Z)-13 (Snyder et al., 1978), a stable and crystalline solid, which corresponds to the putative intermediate of the catalytic reaction with benzaldehyde (Scheme 4 below). Although the ¹H NMR data of hydrazonium X does not match that reported in Snyder et ai, the X-ray structure confirms the identity of this material. Heating equimolar amounts of hydrazonium 13 and cyclopropene 10 in DCE at 70°C for 6 hours resulted in the production, after aqueous workup, of the metathesis product X in 40% yield along with some oligomeric product. This stoichiometric process was also observed by ¹ H NMR (CD₃CN), whereby peaks corresponding to the putative hydrazonium product 16 (see Scheme 3) were identified. Furthermore, ¹H NMR observation of the catalytic reaction shown in equation (1 ) revealed the steady state presence (about 5%) of hydrazonium 13. Thus the fact that hydrazonium 13 effects the metathesis reaction and is demonstrably present during the catalytic reaction provides strong evidence that this process occurs in the manner proposed. Scheme 4

[0104] In summary, the first platform for catalytic carbonyl-olefin metathesis has been achieved. This organocatalytic transformation and the novel double bond metathesis paradigm upon which it is based are expected to enable a range of significant new research endeavors in the field of chemical synthesis.

[0105] As a prelude to the inclusion of other classes of alkenes in the metathesis process, it was found that hydrazine 1 1 will readily produce pyrazolidine cycloadducts in the presence of a variety of aldehydes and olefin substrates, even those that are not electronically activated (e.g. compounds 19 and 20, as shown in Scheme 5 below). Importantly, identification of conditions to achieve facile retrocycloaddition of such cycloadducts will render such reactions viable for the organocatalytic carbonyl-olefin metathesis chemistry. Scheme 5

Example 3

Extension Of Organocatalytic Carbonyl-Olefin Metathesis Reactions

[0106] As set forth above, the inventors have developed the first catalytic approach to achieve the metathesis of carbonyls with olefins using simple hydrazine catalysts. The extension of the concept through catalyst or reaction condition optimization as set forth below will provide a broadly applicable new reaction tool to the synthetic organic toolbox, including carbonyl-olefin metathesis catalysts and conditions. This organocatalytic carbonyl-olefin metathesis chemistry will be demonstrated on a broad range of substrate classes.

[0107] Because azomethine imine 1 ,3-dipolar cycloadditions are inherently exergonic (with unstrained substrates) (Grashey, 1984), the cycloreversion step in the metathesis process is necessarily more energetically challenging than cycloaddition. Indeed, the inventors have observed facile formation of pyrazolidine products even with unactivated olefins (see Scheme 6), but examples of cycloreversions of pyrazolidine products, while known, are relatively rare (Burger et al., 1977; Gandolfi et al., 1979; Fevre et al., 1979). Catalyst design.

[0108] Accelerating cycloreversion can in theory be accomplished in several ways, including destabilization of the pyrazolidine cycloadduct, stabilization of the azomethine imine cycloreversion product, or by lowering of the transition state energy (Scheme 6 below).

Scheme 6

A

One well understood strategy for cycloadduct destabilization is to incorporate elements of strain, a principle employed through the use of cyclopropene substrates (Ferguson, 1970). To generalize the metathesis process, however, the strain must instead arise from the catalyst structure instead of the substrate. Thus, catalyst variants that introduce additional elements of ring strain or steric strain to the pyrazolidine cycloadducts are preferred and will be investigated further. For example, cyclopropanated bicycle 21 (Alfred et al. 1969) should be readily available in three steps from commercially available materials, via a route analogous to the one set forth above to prepare catalyst 11 (with cyclopropanation instead of hydrogenation) (Mellor et al., 1984). Alternatively, a diazabicyclohexane 22 or diazetidine 23 based catalyst should provide significantly enhanced levels of ring strain (Brown et al., 201 1 ).

[0109] Another means to destabilize the pyrazolidine intermediates is to incorporate elements into the catalyst structure that will produce steric strain in and thus destabilize the pyrazolidine cycloadducts. For example, a bicyclic hydrazine bearing methyl substituents at one or both of the bridgehead positions (e.g., compound 24 as shown above) may serve to raise the total strain energy of the cycloadducts (more than that of the azomethine imines).

[0110] For accelerating cycloreversion, an alternative to destabilizing the cycloadducts is to instead stabilize the precursor dipoles, namely the azomethine imines, or the transition state structures themselves. Such stabilization may be accomplished by increasing the electron density of the hydrazine catalyst, for example by the presence of methoxy group(s) at the 7-position of the catalyst (cf. compound 25). The incorporation of electron-withdrawing groups, should that instead prove more beneficial, will also be investigated (cf. compound 26).

[0111] Another variable which is expected to be of high value in expanding the scope of this process is the nature of the acid cocatalyst. It is expected that the protonation state of various intermediates along the reaction coordinate is of crucial importance to a successful metathesis reaction. It stands to reason then that the nature of the coacid counterions should play an integral role in the reaction rate and efficiency of the overall process. Acid cocatalysts of a wide range of acidities and structures, including diacids (e.g. oxalic acid), may be developed for this process and are within the scope of the present invention.

Reaction conditions:

[0112] In addition to catalyst optimization, it is expected that reaction conditions may play an important role in broadening the range and increasing the efficiency of the carbonyl olefin metathesis reaction of the present invention. Besides variables such as solvent, temperature, and concentration, techniques such as microwave irradiation (Azizian et al, 2002; Diaz-Ortiz et al., 2000; Bougrin et al., 2005) should substantially accelerate the rate of cycloreversion, and thereby enable the use of a much broader range of substrates. All such techniques are within the scope of the present invention.

Cocatalysts:

[0113] To assist with cycloreversion in the most challenging cases, it may prove possible to assist this process through the use of cocatalysts. For example, it is well known that transition metals can catalyze cycloaddition reactions including 1 ,3-dipolar cycloadditions (Lautens et al., 1996; Fruhauf, 1997), and the same may be true of azomethine imine cycloadditions. Cocatalysts that may prove useful in this regard include copper, silver, gold, or iron salts. Alternatively, Lewis acids have been found to accelerate azomethine imine reactions (Frank et al, 2009; Frank et al., 2007), and Lewis acid co-catalyzed metathesis may be a possibility as well. All such co-catalysts are within the scope of the present invention. Substrate classes that will be targeted:

[0114] The development of increasingly reactive and general catalysts will be coincident with efforts to demonstrate these catalysts with an ever-widening selection of challenging substrates shown below.

ing st Orain

acyclic olefins

electronically modulated olefins

F

Me0₂C ^_C02Me Ph^ _ph ^ ^ _F

F

carbonyls

aldehydes ketones electron- highly

deficient functionalized

All of these exemplary substrates are within the scope of the present invention. [0115] In terms of the olefin component, the chemistry of the present invention will include cyclic olefins of increasingly lower ring strain, as well as acyclic olefins. In terms of acyclic olefins, mono-, di-, tri-, and tetra-substituted olefins as well as a variety of electronically modulated olefins will be targeted and are part of the present invention. In the present invention, carbonyl-olefin metathesis may be achieved with both aldehydes and ketones, including those that are sterically hindered, electronically modulated, or highly functionalized. The result will be a robust and broadly applicable metathesis process capable of implementation in a wide variety of important contexts. Example 4

Applying Carbonyl-Olefin Metathesis to Unprecedented Reaction Processes

[0116] The prospect of achieving the facile metathesis of carbonyl compounds and olefins raises the possibility of providing a wide range of powerful yet unprecedented reaction processes. The application of this new technology may be demonstrated for (1 ) ring-opening carbonyl-olefin metathesis (ROCOM), (2) ring- closing carbonyl-olefin metathesis (RCCOM), and (3) carbonyl olefination via carbonyl-olefin metathesis (COCOM).

Development of ring opening carbonyl-olefin metathesis reactions:

[0117] The utility of ring-opening olefin metathesis for complex molecule synthesis has been powerfully demonstrated in a variety of contexts (Zuercher et al. 199; Nickel et al., 2004; La et al., 1999; Randall et al., 1995; Snapper et al., 1997; Limanto et al., 2000; Strgies et al., 1998; La et al., 2001 ; Ibrahem et al., 2009; Pfeiffer et al., 2005; Minger et al. 2002; Hart et al., 2006). The true power of such strategies is that they allow for the conversion of relatively simple, readily accessed cyclic olefins to metathesis products possessing dramatically greater levels of structural and stereochemical complexity. This same exceptional utility is offered by the prospect of ring-opening carbonyl-olefin metathesis (ROCOM), with the substantial added benefit that both the reactants and the product termini of ROCOM are chemoorthogonal. This orthogonal reactivity is expected to enable highly advantageous strategies for functionalization of ROCOM products as well as the rapid buildup of complexity prior to the metathesis event. As one of the most versatile functionalities, the aldehyde (or ketone) group that results from ROCOM can be readily engaged in a wide array of useful derivatizations. A ring-opening carbonyl olefin metathesis reaction is expected to provide a powerful new strategic tool for complex molecule construction.

[0118] Two major strategies are envisioned for ring-opening carbonyl olefin metathesis. The first entails an intermolecular metathesis of the carbonyl and cyclic olefin (Scheme 7 below). The principal utility of this strategy will be in the ring opening of strained cycloalkenes to produce alkenal products. For example, ring opening carbonyl-olefin metathesis of cyclopropenes and cyclobutenes will allow for the production of β,γ-unsatu rated and γ,δ-unsaturated aldehydes respectively, two broadly useful building blocks with orthogonally functionalized termini. In addition, ROCOM of strained bicyclic compounds, which are readily available through cycloaddition chemistry, will furnish complex cyclic architectures which again are amenable to bidirectional derivatization.

Scheme 7

differentiated

termini

substrate product substrate product

[0119] The second major ROCOM strategy is the intramolecular process in which both the carbonyl and the alkene are tethered to one another (Table 2 below). Table 2 substrate product substrate product

[0120] In this process, one ring is converted to another, resulting in a major increase in molecular complexity. This type of strategy has been utilized to great effect in the context of olefin metathesis (Zuercher et al. 199; Nickel et ai, 2004; La et al., 1999; Randall et al., 1995; Snapper et al., 1997; Limanto et al., 2000; Strgies et al., 1998; La et al., 2001 ; Ibrahem et al., 2009). Because of the chemoorthogonality discussed above, intramolecular ROCOM should facilitate an even wider range of rapid and efficient synthetic strategies involving post-metathesis functionalization of both the carbonyl and olefin functionalities.

Development of ring closing carbonyl olefin metathesis (RCCOM) reactions:

[0121] For complex molecule synthesis, perhaps the greatest impact of olefin metathesis has been in its application to the synthesis of cyclic compounds, via ring- closing metathesis (RCM) (Nicolaou et al., 2005; Hoveyda, 2010; Furstner et al., 201 1 ). Indeed, RCM has become a transformative technology for the field of natural product synthesis and pharmaceutical development (Farina et al., 2009; Dragutan et al., 2012; Gaul et al., 2003). The ability to achieve ring closing metathesis with carbonyl and alkene functionalities stands to have a similar impact on how chemists approach the synthesis of complex rings (Scheme 8).

Scheme 8

metathesis

[0122] One of the major benefits of ring-closing carbonyl-olefin metathesis (RCCOM) is that a very broad range of complexity building transformations may be achieved using the carbonyl functionality, which may then be directly employed in the ring-closing metathesis event. The novel ring forming synthetic strategies that RCCOM will enable are expected to find widespread application in the field of synthesis. In this example, the first ring-closing carbonyl-olefin metathesis reactions will be developed and the utility of the reactions in the context of several unprecedented synthetic sequences will be demonstrated.

[0123] In terms of stereochemistry, it is predicted that successful ring closing carbonyl-olefin metathesis to form small rings will require the intermediacy of cis- bicyclic pyrazolidines 27, the product of endo 1 ,3-dipolar cycloaddition, because cycloreversion to produce the trans cyclic alkenes would not be thermally allowed (Scheme 9). Fortunately, whether the reactions do proceed with endo selectivity or not, the inherent reversibility of the process should allow access to the required endo intermediate, and thus to the metathesis products. Scheme 9

·— (unproductive)—I

[0124] The carbonyl olefin metathesis strategy set forth above will be applied to the development of a RCCOM reaction to form ring sizes ranging from 5-7 (small rings), 8-13 (medium rings), and 14 and up (macrocycles). Of particular interest will be developing metathesis reactions that work in the presence of a broad range of functionality. Because of the nature of the azomethine imine cycloaddition, it is expected that there will be significant functional group compatibility, including with alcohols, amines, esters, amides, ethers, silyl ethers, carbamates, sulfides, and thiols. Functionality that may require optimization for full compatibility include acetals, alkynes, and alkyl halides.

[0125] Among the numerous potential applications of RCCOM, one target is to achieve geometry selective macrocyclic ring-closing carbonyl-olefin metathesis. The formation of macrocyclic olefins with defined geometry is an important goal for synthesis, and has been a key step in the total synthesis of a number of important drug candidates, yet achieving this goal with precise control over olefin geometry remains a major challenge. Because the geometry of the olefin metathesis product in this process is dictated by the stereochemistry in the intermediate cycloadduct, which is in turn dictated by the geometry of the starting olefin and the cycloaddition transition state (endo vs. exo), it may be possible to select product olefin geometry simply by choosing the opposite starting olefin geometry (see below for details). This is predicated on the assumption that there will not be thermodynamic scrambling of the olefin stereochemistry, in which case catalyst controlled geometric selectivity would be required.

Carbonyl olefination via carbonyl-olefin metathesis (COCOM):

[0126] The conversion of aldehydes and ketones to olefins is a critical process for modern organic synthesis, and a remarkable variety of methods have been developed to accomplish this fundamental transformation (Korotchenko et ai, 2004). Nevertheless, carbonyl olefination remains a significant synthetic challenge, particularly in complex molecular settings or when olefin geometry selectivity is required (as it usually is). A great many olefination reagents are highly basic and/or strongly nucleophilic and thus suffer from significant limitations of substrate scope (Korotchenko et ai, 2004; Wittig, 1954; Wittig et ai, 1955; Maryanoff et ai, 1989; Ager et ai, 1990; Kocienski et ai, 1985). Several metal alkylidene species, most famously the Tebbe reagent, are capable of olefinating carbonyls; however, the sensitivity of these species and difficulties in their preparation are crucial liabilities (Harley et ai, 2007). In addition, many such metal alkylidenes are found to be more reactive with esters and amides than with aldehydes, which raises chemoselectivity problems in complex molecules. Catalytic olefination reactions have been developed that utilize diazoalkanes (for example, Lebel et ai, 2008), but the problems associated with these reagents limit the generality and applicability of the method.

[0127] Without question, a general, mild, and selective catalytic olefination technology utilizing alkenes as the olefinating reagents would be of tremendous value to the field of organic synthesis. This goal may be achieved by a carbonyl- olefin metathesis reaction for the development of the first catalytic olefination procedure (equation (2) below).

Equation (2) catalytic

R ,R

JM-N · 2HX

R^O — eXCeSS ^~ zz \^ R^^^R'

R' R"

[0128] In its basic conception, the olefination procedure is identical to the carbonyl-olefin metathesis methods already described, with the major difference being that in most cases excess olefin would be employed to ensure full and selective conversion of the carbonyl substrate. For example, treatment of an aldehyde with an excess of 1 ,4-benzyloxy-2-butene (29) in the presence of a hydrazine metathesis catalyst would result in conversion to an allylic ether 30 (along with a-benzyloxyacetaldehyde) (equation (3) below). Importantly, attempting to do the same olefination using a Wittig reagent would be unsuccessful because the highly basic ylide 31 would readily undergo β-elimination of the benzyloxy group. In addition to the fundamental method development efforts, challenging olefination procedures such as this that are difficult or impossible to achieve by other means will be pursued. Equation (3) catalytic

,R

Wittig not viable

+

► Ph₃P^

[0129] In addition, geometry selective olefination catalysts for the synthesis of both cis and trans olefins may be developed (Scheme 10 below). It is expected that this may be accomplished in a straightforward fashion by the use of simple catalyst structures and the judicious selection of starting material olefin geometry. Specifically, an azomethine imine intermediate derived from bicyclic catalyst 32 is expected to undergo 1 ,3-dipolar cycloaddition with alkenes via exo transition states (exo-33 or exo-34) that minimize steric interaction with the one carbon bridge of the catalyst and the olefin substituents. Importantly, this selectivity would produce trans products from cis starting materials and cis products from trans starting materials, assuming the mixture is not allowed to come to thermodynamic equilibrium (e.g. by adding excess of the olefinating reagent). Notably, the inventors have observed complete trans product selectivity from the carbonyl olefin metathesis of cyclopropenes, which are necessarily cis, lending support to this selectivity. Scheme 10

favored disfavored favored disfavored

R R R R

N-N R N -N

R""^\/^R R' R

R' trans CIS

R' R'

Example 5

Chiral Catalysts for Enantioselective Carbonyl Olefin Metathesis

[0130] The new metathesis paradigm raises the possibility of developing a number of unprecedented asymmetric processes to prepare enantioenriched products. Chiral hydrazine catalysts that can effect enantioselective ring opening carbonyl olefin metathesis of achiral or meso cyclic olefins may be developed. In addition, application of carbonyl olefin metathesis for dynamic kinetic resolution of chiral aldehydes via enantioselective olefination are also targeted. This new catalytic technology will provide ready access to valuable, enantioenriched building blocks by means that have previously been unavailable. Development of an enantioselective catalytic ring-opening carbonyl olefin metathesis reaction:

[0131] As noted above, carbonyl-olefin metathesis offers tremendous synthetic value because the metathesis products are chemo-orthogonal. One particularly interesting consequence of this fact is that asymmetric ring opening processes of symmetric olefins have the potential to produce highly valuable bifunctional products in enantioenriched form. Effective chiral hydrazine catalysts that can effect enantioselective ring opening carbonyl olefin metathesis of achiral cyclic olefins may be designed.

[0132] The initial focus will be the ring opening desymmetrization of 3,3- disubstituted cyclopropenes to produce β-enal products bearing a-quaternary carbon stereocenters (equation (4) below). Such products are potentially of high utility for complex molecule synthesis, but the synthesis of such materials is quite challenging using established approaches. To achieve this goal, chiral hydrazine catalysts will be prepared, with an initial focus on the bicyclic catalyst structure 11.

Equation (4)

chiral catalyst

achiral enantioenriched

[0133] The synthesis of chiral versions of hydrazine catalyst 11 is expected to be relatively straightforward, and to generally follow the strategy used for preparation of the achiral structure (Mellor et ai, 1985). Thus, [4+2] cycloaddition of dibenzyl azodicarboxylate with substituted cyclopentadienes 35 should produce the asymmetric adducts 36 (Scheme 1 1 below). Hydrogenolytic deprotection followed by classic resolution (e.g. via tartrate salts) should then furnish chiral catalysts 37 optically pure form. A representative set of proposed structures is shown below.

Scheme 1 1

proposed catalysts

[0134] With strained cycloalkenes, it is assumed that cycloreversion of the intermediate cycloadducts to regenerate starting materials will be prohibitively disfavored relative to the strain release ring opening process. This scenario would render the cycloaddition as the enantiodetermining step, which lends itself to a relatively straightforward stereochemical model (Scheme 12 below). Thus, a chiral hydrazine of the same type as compound 38 would preferentially form the regioisomeric azomethine intermediate 39. Assuming a selective exo approach of the cyclopropene 40 from the less hindered Re-face of the dipole, two diastereomeric transition states 41a and 41 b are possible. It is expected that the exo-exo transition state 41 b, which places the small substituent on the side of the approaching dipole will be most favored, leading ultimately to the formation of the (S)-enantiomeric metathesis product 43. Scheme 12

[0135] In addition to enantioselective ring opening of cyclopropenes, the desymmetrization of other strained cycloalkenes, including meso cyclobutenes (equation (5) below), norbornenes (equation (6) below), and oxabicyclooctenes (equation (7) below) will be pursued. Notably, the desymmetrization of meso cyclobutenes would furnish enantioenriched a, -disubstituted-y,5-unsaturated aldehydes, which are formal allyl vinyl Claisen rearrangement products difficult to access enantioselectively (Geherty et al., 2010; Nelson et ai, 2006; Abraham et ai, 2001 , Korner et al., 2004; Akiyama et al., 2004; Uyeda et al., 2008), while the ring opening of norbornenes by carbonyl olefin metathesis will produce stereochemically complex cyclopentenes, a valuable core building block. Ring opening carbonyl-olefin metathesis of oxabicyclooctenes will furnish optically enriched pyranyl aldehydes, which should be of high utility for the synthesis of numerous complex molecules (Wright et al., 2001 ). Equation (5) chiral catalyst

enantioennched

(formal Claisen

rearrangement products)

Equation (6) chiral catalyst

enantioennched

Equation (7) chiral catalyst

R^' enantioennched

Kinetic resolution of chiral aldehydes via enantioselective olefination: [0136] As basic building blocks, a-chiral olefins are of extremely high value, yet the production of these motifs remains a significant challenge for synthetic chemists. Thus, carbonyl olefin metathesis may be used for the synthesis of enantioennched a-chiral olefins via the enantioselective catalytic olefination of readily available racemic α-chiral aldehydes (Tanaka et ai, 2004). The basic premise is to use chiral hydrazine catalysts to selectively engage one enantiomer of an equilibrating racemic mixture of aldehydes, and thereby to achieve dynamic kinetic resolution (DKR) by enantioselective olefination (equation (8)). Equation (8)

chiral catalyst

enantioenriched

[0137] Chiral hydrazine catalysts such as compound 44 may be used to selectively engage α-chiral aldehyde substrates for carbonyl-olefin metathesis (Scheme 13 below). Racemization of the aldehyde substrate can be envisioned to occur in either the bound or unbound state, both of which have ample precedent. Alternatively, it could well be that the process shown in scheme 13 represents a classic Curtin-Hammett situation, in which the less favored azomethine imine stereoisomer would undergo cycloaddition at a much faster rate than the diastereomeric alternative. The final possibility is that the enantiodetermining step could be cycloreversion to form the metathesis product, a likely scenario given the exergonic nature of azomethine imine 1 ,3-dipolar cycloadditions. In sum, differences in conformational energies between the diastereomeric cycloadducts would lead to a large difference in the rate of cycloreversions, thus leading to high enantioselection. Which of these scenarios is operative will likely depend on the exact nature of the catalyst structure.

Scheme 13

racemize

here , selective

selective selective

azomethine imine

cycloaddition cycloreversion

formation

[0138] The ability to achieve the enantioselective olefination of racemic aldehydes will offer a powerful and unprecedented new tool for the production of optically enriched building blocks. Among the numerous potential applications that can be envisioned, one intriguing possibility is for ring opening carbonyl-olefin metathesis, such as the example shown in equation (9) below. This type of process would generate structurally and stereochemically complex products with three stereocenters from racemic and meso fragments. Applications of this type are expected to be highly relevant for complex molecule synthesis. Equation (9)

chiral catalyst

Example 6

Organocatalytic Olefin-Olefin Metathesis Reactions And Polymerizations

[0139] The ability to achieve organocatalytic olefin-olefin metathesis will enable the synthesis of metal free metathesis products and polymers, which is particularly desirable for biomedical applications. Thus, this new reaction paradigm is leveraged for the development of (1 ) a general organocatalytic olefin-olefin metathesis process using catalytic amounts of hydrazines and aldehydes, and (2) organocatalytic ring opening metathesis polymerization for the synthesis of metal free metathesis polymers.

Develop a general organocatalytic olefin-olefin metathesis process:

[0140] One of the most compelling implications of the carbonyl-olefin metathesis platform is that it also provides the means to target development of the first organocatalytic olefin-olefin metathesis platform, a process that would offer a powerful orthogonal approach to established procedures. This process is expected to be analogous to traditional metal catalyzed olefin metathesis, in which a metal alkylidene engages an olefin substrate via [2+2] cycloaddition to form a metallocyclobutane and then undergoes cycloreversion to produce the metathesis product and regenerate a metal alkylidene (Vougioukalakis et al., 2010; Hoveyda et al., 2007; Schrock et al., 2003; Trnka et al., 2001 ), except for the modifications set forth in more detail below.

This organocatalytic process follows the same general strategy, with the key difference that azomethine imines serve the role of active catalyst, and the metathesis is achieved via a thermally allowed [3+2] cycloaddition/cycloreversion paradigm (Scheme 14).

Scheme 14

[0141] As a proof of principle that this organocatalytic olefin-olefin metathesis is viable, cyclopropene 10 was added to hydrazine catalyst 11 and catalytic benzaldehyde (equation (10) below).

Equation (10) fin

hesis

30% yield ^{n n}

[0142] Notably, in addition to the carbonyl olefin metathesis product observed previously (cf. compound 12, equation 1 ), dienyl aldehyde 45 was also observed, arising from a reaction of the initially formed azomethine imine metathesis product with another molecule of cyclopropene 10. Importantly, the central olefin of product 45 represents realization of the idea espoused in scheme 14 and is the first example of an organocatalytic olefin-olefin metathesis reaction. Furthermore, it is straightforward to envision the extension of this oligomerization process to a full- fledged ring opening metathesis polymerization (ROMP), which would generate olefin metathesis polymers in an organocatalytic fashion, free of metal contaminants.

[0143] The optimization and extension of this organocatalytic metathesis reaction will require identifying conditions that retain the integrity of the azomethine intermediates rather than allowing for their hydrolysis. This requirement may be accomplished by pre-formation of an azomethine imine active catalyst from substoichiometric amounts of a hydrazine and aldehyde precatalyst under dehydrative conditions, or by use of a pyrazolidine 46 or oxadiazolidinone 47 precatalyst (El-Din et ai, 1984; El-Din et ai, 1983), which would generate azomethine imine in situ via cycloreversion (Scheme 15).

Scheme 15

precatalyst R precatalyst

/ >U2

[0144] Ultimately, it will be ideal to develop catalysts and conditions that are impervious to the presence of water, or ideally that could even be run in water. To accomplish this, metathesis organocatalysts in which the hydrazine and aldehyde components are linked may be developed (Scheme 16). In such a scenario, the azomethine imine-hydrolysis equilibrium would be expected to be much more favorable than untethered catalysts for entropic reasons. Thus, a bicyclic catalyst such as 48 (or variations on this theme) engaging an olefin substrate via [3+2] cycloaddition is envisioned. The strained tricyclic intermediate 49 should then undergo facile cycloreversion and hydrolysis to produce the alkenyl hydrazine 51 . Engagement of a different aldehyde followed by intramolecular cycloaddition would produce tricycle 53, which, following cycloreversion, would regenerate the catalyst 48 and liberate the olefin metathesis product.

Scheme 16

[0145] It is expected that this novel approach to olefin metathesis will enable numerous new avenues of research in chemical synthesis.

Development of an orqanocatalytic ring openinp metathesis polymerization for the production of metal-free metathesis polymers:

[0146] The polymers produced by ring opening metathesis polymerization (ROMP) are highly valued because of their unique physical properties (Harned et ai, 2005; Dragutan et ai, 2000; Mol et ai, 2004). Indeed, metal catalyzed ROMP is now being employed for the commercial production of a number of valuable polymeric materials, including polynorbornenes (such as Norsorex^®), which are obtained from ROMP of norbornene; polydicyclopentadienes (such as Telene^® Metton^®, Pentam^®, and Prometa^®), which are obtained from ROMP of dicyclopentadiene; and polyoctenamers (such as Vestenamer^®), which are obtained from ROMP of cyclooctene (Scheme 17). The monomeric starting materials, norbornene, dicyclopentadiene, and cyclooctene, are available from commercial vendors such as ABI Chemicals GmbH (Munich, Germany) and Sigma (St. Louis, MO).

Scheme 17

established catalysts

R R

R - N-N +

[Ru] =/ \^_R1

not compatible with expected to have

in vivo applications high biocompatibility

[0147] Among the numerous applications that can be envisioned with these polymers, the construction of medical implants (Pruitt et al., 2009) or drug delivery vehicles (Pillai et al., 2001 ) is of high potential value for the issue of human health. Unfortunately, the ROMP polymers generated by traditional olefin metathesis techniques are necessarily contaminated with toxic transition metals that can be challenging to remove (Buchmeiser, 2009). The presence of such metals is obviously unacceptable for use in vivo.

[0148] Although there have been approaches developed to remove these metal contaminants, (Maynard et al., 1999; Ahn et al., 2001 ; Galan et al., 2007; Hong et al., 2007; Cho et al., 2003; Haack et al., 2005; Sinner et al., 1998; Buchmeiser et al., 1997), the organocatalytic process offers a completely different approach. Thus, ROMP materials generated by an organocatalytic process would be free of metal contaminants and should be much more suitable for a variety of biomedical applications while retaining the desirable properties of these polymeric materials.

[0149] The results from proof of principle are shown in equation 10. As noted above, conducting these reactions under anhydrous conditions so that the intermediate azomethine imines are not subject to hydrolysis is expected to be key to achieving successful polymerization. The means to accomplish these anhydrous conditions include the use of molecular sieves, pregeneration of the azomethine imine under Dean-Stark conditions, or the use of alternative precatalysts like those shown in Scheme 15 (which would exclude water entirely).

[0150] A metal-free means to achieve ring-opening metathesis polymerization will find broad application. Two such applications, in particular, include the ROMP of cyclopropenes and other rings bearing payload molecules as a vehicle for drug delivery (Scheme 18 (a)). In addition, telechelic polymerizations of highly functionalized substrates, with the intention of generating unique polyolefins with chemoorthogonal termini, may be developed. These polymers should enable the facile synthesis of unique novel triblock copolymers (Scheme 18 (b)).

Scheme 18

a dru deliver vehicles

(b) Telechelic polymerization for triblock copolymer synthesis

metathesis

organocatalyst

(example)

. functionalize

metal free

triblock copolymer

Example 7

Detailed Synthetic Conditions

General Information.

[0151] All reactions were performed using oven-dried glassware under an atmosphere of dry argon. Reagents were transferred by syringe under argon. Organic solutions were concentrated using a Buchi rotary evaporator. Dichloroethane (DCE) was freshly distilled over CaH₂ under argon. All liquid aldehydes were purified by distillation prior to use, and all solid aldehydes were purified by recrystallization. All other commercial reagents were used as provided. Flash column chromatography was performed employing 32-63 μιτι silica (Dynamic Adsorbents Inc., Norcross, GA). Thin-layer chromatography (TLC) performed on silica gel 60 F254 plates (EMD Institute Inc., Watsonville, CA).

[0152] TMS acetylene and boc anhydride were purchased from Oakwood

Products Inc. (West Columbia, SC). p-acetamidobenzenesulfonyl azide was purchased from Alfa Aesar (Ward Hill, MA). Unless otherwise indicated below, all other starting materials were purchased from Sigma (St. Louis, MO).

[0153] H and ¹³C NMR were recorded in CDCI₃ on Bruker DRX-300, DRX-

400, and DRX-500 spectrometers as noted. Data for ¹H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, brs = broad singlet, d = doublet, dd= doublet of doublets, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), integration, and assignment. Data for ¹³C NMR are reported in terms of chemical shift. Low- resolution mass spectra (LRMS) were acquired on a JEOL JMS-LCmate liquid chromatography mass spectrometer system using CI+ ionization technique.

Synthesis of Cyclopropenes:

68% yield 52% yield

Ac₂Q, pyridine

AcO OAc

DCM

87% yield 1, 1'-i2-cvclopropen-1-ylidenebis(methyleneoxymethylene)lbenzene:

[0154] 1 ,1 '-[2-cyclopropen-1 -ylidenebis(methyleneoxynnethylene)]benzene (10) was prepared according to Kramer (201 1 ). The final product was a clear oil. ¹H NMR (300 MHz, CDCI₃) δ 7.24-7.34 (m, 12 H), 4.49 (s, 4H), 3.54 (s, 4H). ¹³C NMR (100 MHz, CDCIs): 138.89, 128.46, 127.78, 127.59, 1 16.18, 76.40, 72.88, 43.60.

7 , 7 -bis( (acetoxy)meth yl)cvcloprop-2-ene:

[0155] To a solution of 1 ,1 -dimethanol-cyclopropene (0.5 g, 5 mmol, 1 equivalent) and pyridine (2.02 ml, 25 mmol, 5 equivalents) at room temperature in dichloromethane (DCM) under argon, acetic anhydride (1 .04 ml, 1 1 mmol, 2.2. equivalents) was slowly added. The reaction was stirred for approximately 18 hours, then washed with saturated NH₄CI, brine and water. After drying with sodium sulfate, the reaction was concentrated. The product (compound 101 ) was purified by column chromatography on Si (10% EtOAc/hex) to yield the product as a clear oil (800 mg, 4.34 mmol, 87% yield.) ¹H NMR (300 MHz, CDCI₃) δ 7.23 (s, 2H), 4.07 (s, 4H), 2.05 (s, 6H); ¹³C NMR (CDCI₃, 75 MHz): 171 .1 1 , 1 14.69, 69.99, 22.74, 21 .01 . LRMS (APCI+) exact mass calculated for CgHi₃0₄ ⁺ (MH+) requires m/z 185.07, found m/z 184.97. (Cvcloprop-2-ene-1 -diyldimethanol)bis(tert-butyldiphenylsilylether):

TBDPS TBDPS

(103)

[0156] Cycloprop-2-ene-1 ,1 -diyldimethanol)bis(tert-butyldiphenylsilylether) was prepared according to Kramer (201 1 ). Clear oil. ¹H NMR (300 MHz, CDCI₃) δ 7.63-7.60 (m, 8 H), 7.39-7.30 (m, 12 H), 7.04 (s, 2 H), 3.74 (s, 4H), 1 .02 (s, 18 H). ¹³C NMR (CDCI₃, 75MHz): 135.8, 134.4, 129.6, 127.7, 1 16.0, 68.7, 28.4, 27.1 , 19.5.

3, 3-bis( (allyloxy)meth vQcycloprop- 1 -ene:

(104)

[0157] To a solution of NaH (0.16 g, 6.6 mmol, 2.2 equivalents) in THF (3 mL) under argon, 1 ,1 -dimethanol-cyclopropene (0.3 g, 3 mmol, 1 equivalent) was added as a solution in THF (1 .5 mL). The solution was stirred for 2 hours at room temperature followed by addition of allyl bromide (0.57 mL, 6.6 mmol, 2.2 equivalents). The reaction was stirred 12 hours and subsequently quenched with aqueous ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic portions were combined, dried with sodium sulfate and concentrated. The residue was purified by column chromatography on Si (5 % EtOAc/hex) to yield the product as a clear oil (0.2 g, 1 .1 1 mmol, 37 % yield). ¹ H NMR (300 MHz, CDCI₃) δ 7.33 (s, 2 H), 5.99-5.83 (m, 2 H), 5.28-5.14 (m, 4 H), 3.96 (d, 4 H, J=5.7 Hz), 3.475 (s, 4 H); ¹³C NMR (CDCI₃, 75MHz): 135.21 , 1 16.81 , 1 16.1 1 , 76.22, 71 .81 . LRMS (APCI+) exact mass calculated for Cn H ₆O₂ + (MH+) requires m/z 180.12, found m/z 181 .35.

(cvcloprop-2-ene-1, 1-diylbis(methylene))bis((4-bromophenyl)sulfane):

(105)

[0158] To a solution of 1 ,1 -dimethanol-cyclopropene (0.5 g, 5 mmol, 1 equivalent) in DCM (25 mL) at 0°C, was added methane sulfonylchloride (0.93 mL, 12 mmol, 2.4 equivalents) and triethylamine (1 .67 mL, 12 mmol, 2.4 equivalents). The reaction was stirred for 0.5 hours and subsequently quenched with water. The organic layer was washed with aqueous sodium bicarbonate and brine, dried and concentrated. The residue was purified by column chromatography on Si (40 % EtOAc/hex) to yield the dimesylate as a white solid (0.63 g, 50 % yield). The solid was then dissolved in DMF (4 mL) with 4-bromothiophenol (0.17 g, 0.92 mmol, 4 equivalents) and potassium carbonate (0.19 g, 1 .38 mmol, 6 equivalents). The reaction was heated to 60 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (50 mL), extracted with EtOAc and washed with aqueous sodium bicarbonate and brine. The solution was dried with sodium sulfate and concentrated. The residue was purified by column chromatography on Si (hexanes) to yield the product (8 mgs, 8 % yield). ¹H NMR (300MHz, CDCI₃) δ 7.24 (d, 4 H, J=8.4Hz), 7.14 (d, 4 H, J=8.5 H), 7.04 (s, 2H), 3.20 (s, 4H). ¹³C NMR (CDCI3, 75MHz): 135.94, 131 .95, 130.86, 128.95, 1 19.80, 42.83, 29.85. Method for Other Hydrazine Catalysts:

[0159] All other catalysts were tested at 50 mol%. Dimethyl hydrazine dihydrochloride and diethyl hydrazine dihydrochloride are commercially available. Diphenyl hydrazine, pyrazolidine dihydrochloride and N-(phenylacetyl)-N'-methyl hydrazine were synthesized according to procedures in the literature (Zhang et al., 2003; Ahn et al., 2003; Theuer et al., 1964). To hydrazine (0.075 mmol), benzaldehyde (55.5 mg, 0.3 mmol, 2 equivalents) was added as a solution in 0.5 ml MeCN, followed by a solution of cyclopropene 11 (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml MeCN. The reaction was heated to 90°C for 6 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. NMR yields were obtained by the use of an internal standard.

Synthesis of the catalyst 11-2HCI

^BOC _'° ^JS^S^ _*AH>* ^BR2' ^PYRIDIN> _R .N^Boc O, J IBOC ^H-^. /- NBOC

81% yield H CH₂CI, CH₂CI₂- eOH

81% yield 89% yield Boc Boc

oc 66-82% yield H

[0160] The catalyst 11^»2HCI was synthesized according to the scheme above (Luna et ai, 2002; Ling et ai, 201 1 ).

Synthesis of the catalyst 2,3-Diazobicvclof2.2.1lheptane bis-hydrochloride:

[0161] 2,3-Diazobicyclo[2.2.1 ]heptane bis-hydrochloride was prepared according to the procedure set forth in the literature (Luna et al., 2002; Ling et al., 201 1 ) up to the Boc-protected hydrazine (2,3-diaza-bicyclo[2.2.1 ]heptane-2,3- dicarboxylic acid di-tert butyl ester). This precursor could then be deprotected by adding 5 equivalents of 4M HCI (in dioxane) at room temperature, and stirring under air for 3 hours. The compound was isolated by vacuum filtration, rinsed with hexanes, and dried under vacuum to yield a white powder. While generally pure (by ¹ H NMR), the hydrazine could be recrystallized (EtOH/hexanes) to produce white needles. ¹ H NMR (300 MHz, d₆-DMSO) δ 6.7 (brs), 3.94 (s, 2H), 1 .78-1 .67 (m, 6H). ¹³C NMR (100 MHz, d₆-DMSO): 56.88, 37.14, 26.54. LRMS (APCI+) exact mass calculated for CsHn ^* (MH+) requires m/z 99.08, found m/z 99.08.

Procedure for Hydrazine-catalyzed Carbonyl-Olefin Metathesis:

[0162] Hydrazine 11^»2HCI was accurately measured by making a solution in anhydrous MeOH. Transfer of the solution to the reaction vessel was followed by concentration. The vessel was left under vacuum for 0.5 hours to assure removal of

MeOH.

(3E)-2,2-di(methyleneoxybenzyl)-4-phenyl-3-butenal (Table 1, Entry 1):

[0163] To hydrazine 11^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of benzaldehyde (55.5 mg, 0.3 mmol, 2 equivalents) in 0.5 ml dichloroethene (DCE) was added, followed by a solution of cyclopropene 10 (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 24 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. After excess benzaldehyde was removed by leaving under vacuum for a few hours, this crude mixture was then dissolved in MeOH, and 0.3 mmol NaBH₄ was added. The reaction was stirred at room temperature for 30 minutes, then diluted with water, extracted into EtOAc, dried with sodium sulfate and concentrated. The product was purified by column chromatography on Si (5% EtOAc/hex) to yield the reduced compound as a clear oil (46.6 mg, 0.12 mmol, 80% yield). ¹ H NMR (300 MHz, CDCIs) δ 7.20-7.35 (m, 15H), 6.47 (d, 2H, J=16.5Hz), 6.18 (d, 2H, J=16.5Hz), 4.53 (s, 4H), 3.80 (s, 2H), 3.69 (s, 2H), 2.77 (brs, 1 H); ¹³C NMR (CDCI₃, 75 MHz): 138.29, 137.42, 130.63, 130.01 , 128.60, 128.53, 127.78, 127.70, 127.52, 126.34, 73.74, 72.99, 67.29, 46.61 ; LRMS (APCI+) exact mass calculated for C₂6H₂8O₃ ⁺ (MH+) requires m/z 389.20, found m/z 389.57.

(3E)-2,2-di(methyleneoxybenzyl)-4-(2'-methylDhenyl)-3-butenal (Table 7, Entry 2):

[0164] To hydrazine 11*2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of o-tolualdehyde (36.1 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of cyclopropene 10 (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 24 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. The product was purified by column chromatography on Silica (5% EtOAc/hex) to yield the compound as a clear oil (50.8 mg, 0.13 mmol, 84% yield). ¹H NMR (300 MHz, CDCI₃) δ 9.64 (s, 1 H), 7.24-7.40 (m, 1 1 H), 7.13-7.16 (m, 3H), 6.69 (d, 1 H, J=16.6Hz), 6.02 (d, 1 H, J=16.5Hz), 4.55 (s, 4H), 3.88 (dd, 4H, J=9.2Hz), 2.26 (s, 3H); ¹³C NMR (CDCI₃): 200.81 , 138.1 1 , 136.02, 135.61 , 131 .48, 130.36, 128.49, 127.95, 127.78, 127.68, 127.56, 126.22, 125.70, 73.72, 70.20, 57.96, 19.83; LRMS (APCI+) exact mass calculated for C₂7H₂9O₃ ⁺ (MH+) requires m/z 401 .20, found m/z 401 .12. (3E)-2,2-di(methyleneoxybenzyl)-4-(2,4'-dimethylphenyl)-3-butenal (Table 1, Entry 3}:

[0165] To hydrazine 11^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of 2,4-dimethylbenzaldehyde (40.2 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of cyclopropene 10 (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 48 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. The product was purified by column chromatography on Si (5% EtOAc/hex) to yield the compound as a clear oil (40.6mg, 0.1 mmol, 66% yield). ¹ H NMR (300 MHz, CDCI₃) δ 9.63 (s, 1 H), 7.29-7.34 (m, 1 1 H), 6.96 (m, 2H), 6.66 (d, 1 H, J=16.5Hz), 6.96 (d, 1 H, J=16.5Hz), 4.55 (s, 4H), 3.87 (dd, 4H, J=9.1 Hz), 2.29 (s, 3H), 2.24 (s, 3H); ¹³C NMR (CDCI₃, 75 MHz): 200.79, 138.17, 137.73, 135.19, 133.19, 131 .33, 131 .14, 128.48, 127.75, 126.96, 125.62, 125.18, 73.73, 70.25, 57.95, 21 .18, 19.74; (APCI+) exact mass calculated for C₂8H₃iO₃ ⁺ (MH+) requires m/z 415.22, found m/z 415.13.

(3E)-2,2-di(methyleneoxybenzyl)-4-(4'-methoxyphenyl)-3-butenal (Table 7, Entry 4):

[0166] To hydrazine 11^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of 4-anisaldehyde (40.8 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of cyclopropene 10 (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 24 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. The product was purified by column chromatography on Si (5% EtOAc/hex) to yield the compound as a yellow oil (31 .2 mg, 0.075 mmol, 50% yield). ¹H NMR (300 MHz, CDCI₃) δ 9.59 (s, 1 H), 7.29 (m, 12 H), 6.83 (d, 1 H, J=8.7 Hz), 6.39 (d, 1 H, J=16.5 Hz), 5.99 (d, 2 H, J=16.8 Hz), 4.54 (s, 4 H), 3.86 (dd, 4 H, J=9.0 Hz), 3.79 (s, 3 H); ¹³C NMR (CDCI₃, 75 MHz): 200.75, 159.65, 138.18, 132.82, 129.57, 128.50, 127.72, 122.34, 1 14.12, 73.71 , 70.10, 57.66, 55.42; LRMS (APCI+) exact mass calculated for C₂7H₂9O₅ ⁺ (MH+) requires m/z 417.20, found m/z 416.07.

(3E)-2,2-di(methyleneoxybenzyl)-4-(4'-nitrophenyl)-3-butenal (Table 1, Entry 5):

[0167] To hydrazine 11^»2HCI (5.3 mg, 0.03 mmol, 0.2 equivalent), a solution of p-nitrobenzaldehyde (45.3 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of cyclopropene 10 (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 48 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. The product was purified by column chromatography on Si (5% EtOAc/hex) to yield the compound as a bright yellow solid (39 mg, 0.09 mmol, 60% yield). ¹H NMR (300 MHz, CDCI₃) δ 9.66 (s, 1 H), 8.15 (d, 2H, J=8.7Hz), 7.45 (d, 2H, J= 8.7 Hz) 7.23-7.36 (m, 10H), 6.55 (d, 1 H, J= 16.7 Hz), 6.39 (d, 1 H, J= 16.7Hz), 4.51 (s, 4H), 3.87 (s, 4H); ¹³C NMR (CDCI3): 200.49, 146.87, 143.15, 137.73, 131 .16, 130.10, 128.53, 127.93, 127.75, 127.04, 124.04, 73.74, 69.96, 57.85; LRMS (APCI+) exact mass calculated for C₂6H₂6NO₅ ⁺ (MH+) requires m/z 431 .17, found m/z 431 .27.

(3E)-2,2-di(methyleneoxybenzyl)-4-(3'-bromophenyl)-3-butenal (Table 1, Entry 6):

[0168] To hydrazine 11^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of bromobenzaldehyde (55.5 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of cyclopropene 10 (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 48 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. This crude mixture was then dissolved in MeOH, and 0.3 mmol NaBH was added. The reaction was stirred at room temperature for 30 minutes, then diluted with water, extracted into EtOAc, dried with sodium sulfate and concentrated. The product was purified by column chromatography on Si (10% EtOAc/hex) to yield the reduced compound as a yellow oil (42 mg, 0.09 mmol, 60% yield). ¹ H NMR (300 MHz, CDCI₃) δ 7.34 (s, 1 H), 7.25-7.33 (m, 13H), 6.38 (d, 1 H, J=16.5Hz), 6.16 (d, 1 H, J = 16.5Hz), 4.53 (s, 4H), 3.79 (d, 2H, J = 6 Hz), 3.64 (s, 4H), 2.63 (s, 1 H); ¹³C NMR (CDCI₃, 75 MHz): 139.63, 138.16, 131 .78, 130.33, 130.09, 129.36, 129.18, 128.57, 127.87, 127.76, 125.08, 122.83, 73.76, 72.83, 67.16, 46.73; LRMS (APCI+) exact mass calculated for C₂6H₂₈BrO₃ ⁺ (MH+) requires m/z 467.1 1 , found m/z 467.05. (3E)-2,2-di(methyleneoxybenzyl)-4-(1-naDthyl)-3-butenal (Table 7, Entry 7):

[0169] To hydrazine 11^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of 1 -napthaldehyde (46.9 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of cyclopropene 10 (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 24 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. The product was purified by column chromatography on Si (5% EtOAc/hex) to yield the compound as a yellow oil (43.9 mg, 0.101 mmol, 67% yield). ¹H NMR (300 MHz, CDCI₃) δ 9.74 (s, 1 H), 7.80-7.75 (m, 3 H), 7.55-7.39 (m, 4 H), 7.34-7.20 (m, 1 1 H), 6.17 (d, 1 H, J=16.5 Hz), 4.89 (s, 4 H), 3.96 (dd, 4 H, J=4.5, 9.3 Hz); ¹³C NMR (CDCI₃, 75 MHz): 200.97, 138.07, 134.70, 133.64, 131 .17, 131 .07, 128.54, 128.40, 128.00, 127.83, 127.74, 126.25, 125.96, 125.67, 124.04, 123.89, 76.73, 73.76, 70.20, 58.18. LRMS (APCI+) exact mass calculated for C₂oH₂8O₃ ⁺ (MH+) requires m/z 437.2, found m/z 436.9.

(3E)-2,2-di(methyleneoxybenzyl)-4-(2'-methoxy, 1-napthyl)-3-butenal (Table 7, Entry 8}:

[0170] To hydrazine 11^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of 2-methoxy-1 -napthaldehyde (55.9 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of cyclopropene 10 (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 6 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. The product was purified by column chromatography on Si (5% EtOAc/hex) to yield the compound as a yellow oil (47.6 mg, 0.102 mmol, 68% yield). ¹H NMR (300 MHz, CDCI₃) δ 9.75 (s, 1 H), 8.08 (m, 1 H), 7.53 (m, 2 H), 7.20-7.38 (m, 13 H), 6.87 (d, 1 H, J=16.8 Hz), 6.15 (d, 1 H, J=16.8 Hz), 4.59 (s, 4 H), 3.99 (dd, 4 H, J=7.8 Hz), 3.87 (s, 3 H); ¹³C NMR (CDCIs, 75 MHz): 99.86, 91 .34, 88.37, 87.31 , 87.04, 86.73, 86.70, 86.57, 86.55, 86.43, 86.41 , 86.27, 86.24, 85.81 , 85.68, 85.07, 83.79, 76.53, 75.91 , 73.76, 73.37; LRMS (APCI+) exact mass calculated for C₃i H₃iO₄ ⁺ (MH+) requires m/z 467.21 , found m/z 465.9.

(3E)-2,2-di(methyleneoxybenzyl)-4-(2-furfuryl)-3-butenal (Table 1, Entry 9):

[0171] To hydrazine 11^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of furfural (28.9 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of cyclopropene 10 (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 24 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. After excess furfural was removed by leaving under vacuum for a few hours, this crude mixture was then dissolved in MeOH, and 0.3 mmol NaBH was added. The reaction was stirred at room temperature for 30 minutes, then diluted with water, extracted into EtOAc, dried with sodium sulfate and concentrated. The product was purified by column chromatography on Si (5% EtOAc/hex) to yield the reduced compound as a clear oil (45.5 mg, 0.12 mmol, 80% yield). ¹ H NMR (300 MHz, CDCI₃) δ 7.23-7.35 (m, 1 1 H), 6.34 (m, 1 H), 6.29 (s, 1 H), 6.18 (m, 1 H), 6.08 (s, 1 H), 4.53 (s, 4H), 3.77 (d, 2H, J= 3.5Hz), 3.66 (s, 4H), 2.67 (brs, 1 H); ¹³C NMR (CDCI₃, 75 MHz): 152.96, 141 .81 , 138.24, 128.58, 128.54, 127.80, 127.73, 1 19.54, 1 1 1 .35, 107.61 , 73.77, 72.86, 67.26, 46.54; LRMS (APCI+) exact mass calculated for C₂₄H₂₇O₄ ⁺ (MH+) requires m/z 379.19, found m/z 379.2.

(3E)-2,2-di(methyleneoxybenzyl)-4-(2-thioDhene)-3-butenal (Table 7, Entry 10):

[0172] To hydrazine 11 ^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of 2-thiophenecarboxaldehyde (33.6 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of cyclopropene 10 (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 24 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. This crude mixture was then dissolved in MeOH, and 0.3 mmol NaBH₄ was added. The reaction was stirred at room temperature for 30 minutes, then diluted with water, extracted into EtOAc, dried with sodium sulfate and concentrated. The product was purified by column chromatography on Si (5% EtOAc/hex) to yield the reduced compound as a yellow oil (20.5 mg, 0.052 mmol, 35% yield). ¹H NMR (300 MHz, CDCI₃) δ 7.26-7.37 (m, 10H), 7.12 (d, 1 H, J=5Hz), 6.94 (m, 2H), 6.62 (d, 1 H, J=16.5Hz), 6.00 (d, 1 H, J=16.5Hz), 4.54 (s, 4H), 3.79 (d, 2H, J=6Hz), 3.67 (s, 4H), 2.66 (t, 1 H, J=6Hz); ¹³C NMR (CDCI₃, 75 MHz): 142.84, 138.23, 129.58, 128.54, 127.80, 127.71 , 127.36, 125.42, 124.22, 123.96, 73.71 , 72.81 , 67.21 , 46.67; LRMS (APCI+) exact mass calculated for C₂ H27O₃S⁺ (MH+) requires m/z 394.16, found m/z 394.15.

(3E)-2,2-di(methyleneoxybenzyl)-6-phenyl-3-hexenal (Table 1, Entry 11):

[0173] To hydrazine 11^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), and cyclopropene 10 (42 mg, 0.15 mmol, 1 equivalent) in 0.5 ml DCE at 75°C, hydrocinnamaldehyde (30.2 mg, 0.225 mmol, 1 .5 equivalents) was added via syringe pump over 48 hours as a solution in 0.5 ml DCE. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. The product was obtained with a 35% NMR yield (compared to internal mesitylene standard). ¹H NMR (300 MHz, CDCIs) δ 9.47 (s,1 H), 7.29-7.22 (1 1 H), 7.18-7.1 1 (m, 4H), 5.57 (m, 1 H), 5.38 (d, 1 H, J=16 Hz), 4.5 (m, 4H), 3.73 (q, 4H, J= 9.12), 2.66 (m, 2H), 2.35 (m, 2H); ¹³C NMR (CDCI3, 75 MHz): 201 .06, 138.21 , 134.24, 128.61 , 128.50, 128.45, 127.84, 127.77, 127.68, 127.57, 126.05, 73.63, 69.96, 57.45, 35.68, 35.18; LRMS (APCI+) exact mass calculated for C₂₈H₃iO₃ ⁺ (MH+) requires m/z 415.22, found m/z 414.22.

(3E)-2,2-di(methylenemethylcarboxylate)-4-(2'-methoxy-1-napthyl)-3-butenal (Table 1, Entry 12):

[0174] To hydrazine 11^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of 2-methoxynapthaldehyde (55.9 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of dimethyl cyclopropene-1 ,1 -dicarboxylate (42 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 24 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. The product was purified by column chromatography on Silica (5% EtOAc/hex) to yield the compound as a yellow oil (38 mg, 0.1 mmol, 68% yield). ¹ H NMR (300 MHz, CDCI₃) δ 9.71 (s, 1 H), 7.99 (d, 1 H, J=8.6), 7.79 (m, 2H), 7.45 (m, 1 H), 7.34 (m, 1 H), 7.25 (m, 1 H), 6.93 (d, 1 H, J=17 Hz), 6.05 (d, 1 H, J=17 Hz), 4.59 (dd, 4H, J=1 1 .4 Hz), 3.92 (s, 3H), 2.09 (s, 6H); ¹³C NMR (CDCI₃): 197.76, 170.73, 154.65, 132.29, 129.80, 129.22, 128.74, 128.59, 127.97, 126.98, 123.75, 123.62, 1 19.07, 1 13.09, 63.16, 56.64, 56.41 , 20.86; LRMS (APCI+) exact mass calculated for C₂i H₂2O₆ ⁺ (MH+) requires m/z 371 .14, found m/z 371 .17.

(E)-2,2-bis(((tert-butyldiphenylsilyl)oxy)methyl)-4-(2-methoxyn

enal (Table 1, Entry 13)

[0175] To hydrazine 11 ^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of 2-methoxynapthaldehyde (55.9 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of ((cycloprop-2-ene-1 ,1 - diylbis(methylene))bis(oxy))bis(fe/t-butyldiphenylsilane) (87 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 24 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. The product was purified by column chromatography on Silica (2% EtOAc/hex) to yield the compound as an oil (90 mg, 0.12 mmol, 79% yield). ¹ H NMR (300 MHz, CDCIs) δ 9.78 (s, 1H), 8.07 (m, 1 H), 7.71 -7.65 (m, 10H), 7.50-7.25 (m, 15H), 6.85 (d, 1 H, J=17Hz), 6.22 (d, 1 H, J=17Hz), 4.28 (s, 4H), 3.84 (s, 3H), 1 .08 (s, 18H). ¹³C NMR (CDCIs): 201 .85, 154.52, 135.87, 135.83, 133.23, 133.20, 132.44, 131 .17, 129.89, 129.83, 129.30, 129.15, 128.36, 127.88, 127.85, 127.00, 126.69, 124.31 , 123.59, 120.03, 1 13.14, 64.10, 60.75, 56.32, 27.03, 19.48. LRMS (APCI+) exact mass calculated for C₄₉H₅₄O₄Si₂ ⁺ (MH+) requires m/z 762.36, found m/z 763.76.

(E)-2,2-bis((allyloxy)methyl)-4-(2-methoxynaphthalen-1-yl)but-3-enal (Table 1, Entry 14):

[0176] To hydrazine 11^»2HCI (2.6 mg, 0.015 mmol, 0.1 equivalent), a solution of 2- methoxynapthaldehyde (55.9 mg, 0.3 mmol, 2 equivalents) was added in 0.5 ml DCE, followed by a solution of 3,3-bis((allyloxy)methyl)cycloprop-1 -ene (27 mg, 0.15 mmol, 1 equivalent) in 0.25 ml DCE. The reaction was heated to 90°C for 6 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. The yield was determined with an NMR standard. ¹ H NMR (300 MHz, CDCIs) 5 9.78 (s, 1 H), 6.89 (d, 1 H, J=17.1 Hz), 6.16 (d, 1 H, J=16.8Hz). (E)-2,2-bis(((4-bromophenyl)thio)methyl)-4-(2-methoxynaphthalen-1-v0 (Table 1, Entry 15)

[0177] To hydrazine 11^»2HCI (0.5 mg, 0.003 mmol, 0.1 equivalent) and (cycloprop-2-ene-1 ,1 -diylbis(methylene))bis((4-bromophenyl)sulfane) (1 1 mg, 0.025 mmol, 1 equivalent), a solution of 2-methoxynapthaldehyde (9.3 mg, 0.05 mmol, 2 equivalents) was added in 0.13 ml DCE. The reaction was heated to 90°C for 24 hours. Upon cooling to room temperature, the reaction mixture was diluted with DCM, washed with 1 M NaOH, extracted into DCM, dried with sodium sulfate, and concentrated. The residue was purified by column chromatography on Si (1 % EtOAc/hex) to yield the product (8 mg, 0.012 mmol, 50 % yield). ¹ H NMR (300 MHz, CDCIs) δ 9.58 (s, 1H), 8.07 (d, 1 H, J=9Hz), 7.80 (m, 2H), 7.48-7.25 (m, 1 1 H), 6.96 (d, 1 H, J=17), 6.16 (d, 1 H, J=17Hz), 3.94 (s, 3H), 3.62 (dd, 4H, J=13Hz). ¹³C NMR (CDCI3): 198.22, 154.75, 135.31 , 132.35, 132.20, 132.02, 131 .92, 129.85, 129.28, 128.57, 128.23, 127.04, 123.89, 123.80, 120.93, 1 19.03, 1 13.20, 58.34, 56.56, 38.31 . LRMS (APCI+) exact mass calculated for C₂₉H₂₄Br₂O₂S₂ ⁺ (MH+) requires m/z 628.44, found m/z 629.66.

(Z)-2-benzylidene-2,3-diazabicvcloi2.2. nheptan-2-ium perchlorate (Scheme 4, Structure (Z)-13):

[0178] (Z)-2-benzylidene-2,3-diazabicyclo[2.2.1 ]heptan-2-iunn perchlorate was prepared in accordance with procedures set forth in the literature (Snyder et al., 1978; Sabate et al., 2012). In particular, the perchlorate salt of catalyst 2,3- Diazobicyclo[2.2.1 ]heptane bis-hydrochloride was prepared via silver salt exchange. 2,3-Diazobicyclo[2.2.1 ]heptane bis-hydrochloride (0.2 g, 1 .17 mmol, 1 eq) was dissolved in water (2 mL). Anhydrous silver perchlorate (0.49 g, 2.34 mmol, 2 eq) was dissolved in water (2 mL) and added to the hydrazine bis-hydrochloride solution under the exclusion of light. Silver chloride precipitated immediately. The solution was stirred 30 minutes and then filtered through celite. Water was removed with gentle heating under vacuum and the crude bis-perchlorate salt was isolated. 2,3- Diazobicyclo[2.2.1 ]heptane bis-perchlorate (0.28 g, 0.94 mmol) was then dissolved in 30 mL benzaldehyde and 30 mL dry iPrOH. The solution was refluxed for 1 hour and allowed to return to room temperature. Ether was added and a white solid precipitated and was isolated (0.12 g, 0.41 mmol, 35 % overall yield). X-ray quality crystals were grown in MeOH/Et₂O. ¹ H NMR (300 MHz, d₆-DMSO): 8.77 (s, 1 H), 8.55 (s, 1 H), 8.06-7.68 (m, 5H), 5.15 (s, 1 H), 4.26 (s, 1 H), 2.1 1 -1 .87 (m, 6 H); ¹³C NMR (d₆-DMSO, 75 MHz): 144.95, 134.59, 132.07, 129.48, 127.01 , 72.81 , 59.29, 37.76, 28.31 , 27.93; LRMS (APCI+) exact mass calculated for Ci₂H₁₅N₂ ⁺ (MH+) requires m/z 187.1 , found m/z 186.7.

Reaction with (Z)-hydrazonium (Scheme 4):

[0179] To the hydrazonium perchlorate salt (0.22 g, 0.075 mmol) a solution of cyclopropene (0.021 g, 0.075 mmol) in 0.6 mL CD₃CN was added. The sample was heated to 65°C in the NMR and spectra were obtained every half hour for 2 hours and the formation of the hydrazonium 16 was observed.

Reaction with 2,3-Diazobicvcloi2.2.1lheptane bis-hydrochloride (equation 1):

[0180] To 2,3-Diazobicyclo[2.2.1 ]heptane bis-hydrochloride (2.6 mg, 0.015 mmol), a solution of benzaldehyde (31 .8 mg, 0.3 mmol) in 0.3 mL CD₃CN and a solution of cyclopropene (42.0 mg, 0.15 mmol) in 0.3 mL CD₃CN were added. An NMR spectra was obtained at room temperature. The sealed NMR tube was then heated to 65°C in an oil bath for 24 hours. Another NMR spectra was obtained. Peaks corresponding to the hydrazonium salt as well as the product were both observed in situ.

[0181] Although illustrative embodiments of the present invention have been described herein, it should be understood that the invention is not limited to those described, and that various other changes or modifications may be made by one skilled in the art without departing from the scope or spirit of the invention.

Documents

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Zlicar, M.; Stanovnik, B.; Tisler, M. "A new synthesis of C-nucleosides by 1 ,3-dipolar cycloaddition of chiral azomethine imines to methyl acrylate. The stereoselective synthesis of fused pyrazoles." Tetrahedron 1992, 48, 7965- 7972. Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. "Tandem ring opening-ring closing metathesis of cyclic olefins." J. Am. Chem. Soc. 1996, 118, 6634-6640.

[0182] All documents cited in this application are hereby incorporated by reference as if recited in full herein.

Claims

WHAT IS CLAIMED IS:

1 . An organocatalytic carbonyl-olefin metathesis process comprising contacting a carbonyl-containing moiety with an olefin-containing moiety in the presence of a catalyst and under conditions sufficient to form a metathesis product with the proviso that the process takes place in the absence of photochemical promotion, stoichiometric amounts of transition metals, and Br0nsted and Lewis acids as the sole catalysts.

2. The method according to claim 1 , wherein the metathesis process occurs via a [3+2] cycloaddition/cycloreversion mechanism.

3. The method according to claim 1 , wherein the catalyst is a hydrazine.

4. The method according to claim 1 , wherein the catalyst is selected from the group consisting of:

(61 ) (62) and (63)

5. The method according to claim 3, wherein the catalyst is a bicyclic hydrazine.

6. The method according to claim 3, wherein the catalyst is a 1 ,2- dialkylhydrazine.

7. The method according to claim 3, wherein the catalyst is:

8. The method according to claim 1 , wherein the catalyst is chiral.

9. The method according to claim 8, wherein the chiral catalyst is selected from the group consisting of

and a stereoisomer thereof.

10. The method according to claim 1 , wherein the olefin-containing moiety is selected from the group consisting of:

1 1 . The method according to claim 1 , wherein the olefin-containing moiety comprises a cyclopropene.

12. The method according to claim 1 1 , wherein the olefin-containing moiety is a cyclopropene of formula (64):

(64)

wherein R₂ and R₃ are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis.

13. The method according to claim 1 1 , wherein the olefin-containing moiety is a cyclopropene having the structure:

(64a)

wherein:

X is selected from the group consisting of atoms from Group 16 of the periodic table; and

Y is selected from silyl ethers, benzyl, phenyl, acyl, and C_2-8 alkenyl.

14. The method according to claim 13, wherein X is O or S, and Y is selected from the group consisting of benzyl, phenyl, acetyl, ter-butyldiphenylsilyl (TBDPS) ethers, and C_2-4 alkenyl.

15. The method according to claim 12, wherein the olefin-containing moiety is a cyclopropene selected from the group consisting of TBDPS

(10) (101 ) (103)

(104) and (105)

16. The method according to claim 1 , wherein the carbonyl-containing moiety is selected from the group consisting of:

wherein Ri, R₂, and R3 are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis.

17. The method according to claim 1 , wherein the carbonyl-containing moiety comprises an aldehyde.

18. The method according to claim 17, wherein the carbonyl-containing moiety is a aldehyde of formula (2):

(2)

wherein Ri is any organic substituent suitable for participating in the carbonyl-olefin metathesis.

19. The method according to claim 1 , which is carried out according to the following reaction:

(6) (65) (66) (67) (4) wherein

20. The method according to claim 19, wherein the atom is or the group of atoms includes main group elements.

21 . The method according to claim 20, wherein the main group elements are selected from the group consisting of O, N, S, and P.

22. The method according to claim 19, wherein the transition metal complex comprises an atom selected from the group consisting of Ru, Mo, Ti, and W.

23. The method according to claim 1 , which is carried out according to the following reaction:

wherein R-i , R₂, and R3 are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis.

24. The method according to claim 23, wherein R-i , R₂, and R3 are independently selected from the group consisting of substituted or unsubstituted C3-C12 aryl, C3-C12 heteroaryl, C3-C12 cycloalkyl, and Ci-12 alkyl.

25. The method according to claim 23, wherein R-i , R₂, and R3 are independently selected from the group consisting of:

A process for carbonyl-olefin nnetathesis according to the following reaction

wherein

R-i , R₂, and R₃ are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl- olefin nnetathesis;

the process comprising contacting an aldehyde according to formula (2) with a cyclopropene according to formula (64) in the presence of a hydrazine catalyst according to formula (1 1 ) under conditions suitable for carbonyl-olefin metathesis.

27. The method according to claim 26, wherein the conditions suitable for carbonyl-olefin metathesis comprise reacting the aldehyde (2), cyclopropene (64), and hydrazine (1 1 ) in the presence of 1 ,2-dichloroethane (DCE) at a temperature between 75-90°C for 24 hours.

28. The method according to claim 26, wherein R-i , R₂, and R3 are independently selected from the group consisting of substituted or unsubstituted C3-C12 aryl, C3-C12 heteroaryl, C3-C12 cycloalkyl, and Ci-12 alkyl.

29. The method according to claim 26, wherein R-i , R₂, and R3 are independently selected from the group consisting of:

A process for carbonyl-olefin metathesis according to the following reaction

R₂

(5a) wherein R-i , R₂, R3, and R₄ are independently selected from the group consisting of H and any organic substituent suitable for participating in the carbonyl-olefin metathesis.

31 . An organocatalytic olefin-olefin metathesis process comprising contacting a first olefin-containing moiety with a second olefin-containing moiety in the presence of a catalyst and under conditions sufficient to form a metathesis product with the proviso that the process takes place in the absence of stoichiometric amounts of transition metals.

32. The method according to claim 31 , wherein the metathesis process occurs via a [3+2] cycloaddition/cycloreversion mechanism.

33. The method according to claim 31 , wherein the catalyst is a hydrazine.

34. The method according to claim 33, wherein the catalyst is a bicyclic hydrazine.

35. The method according to claim 33, wherein the catalyst is a 1 ,2- dialkylhydrazine.

37. The method according to claim 31 , wherein at least one of the first and the second olefin-containing moiety comprises a cyclopropene.

38. The method according to claim 37, wherein at least one of the first and the second olefin-containing moiety is a cyclopropene of formula (64):

(64) wherein R₂ and R3 are independently selected from the group consisting of H and any organic substituent suitable for participating in the organocatalytic olefin-olefin metathesis.

39. The method according to claim 31 , wherein at least one of the first and the second olefin-containing moiety is a cyclopropene having the structure:

(64a)

wherein:

Y is selected from silyl ethers, benzyl, phenyl, acyl, and C2-8 alkenyl.

40. The method according to claim 39, wherein X is O or S, and Y is selected from the group consisting of benzyl, phenyl, acetyl, ter-butyldiphenylsilyl (TBDPS) ethers, and C2_-4 alkenyl.

41 . The method according to claim 40, wherein at least one of the first and second olefin-containing moieties is a cyclopropene selected from the group consisting of: TBDPS

(10) (101 ) (103)

(104) , and (105)

(104) and (105)

42. The method according to claim 38, wherein at least one of the first and second olefin-containing moieties are a cyclopropene of formula (102): '

(102)

wherein X is an agent for delivery to a subject in need thereof.

43. The method according to claim 31 , which is carried out according to the following reaction:

(71 ) (72) (73) (74) (6) wherein

Ri and F¾ are independently selected from the group consisting of H and any organic substituent suitable for participating in the organocatalytic olefin-olefin metathesis; and

X is any atom or group of atoms that do not substantially hinder the reaction.

44. The method according to claim 43, wherein the atom is or the group of atoms includes main group elements.

45. The method according to claim 44, wherein the main group elements are selected from the group consisting of O, N, S, and P.

46. The method according to claim 31 , which is carried out in the presence of a carbonyl moiety.

47. The method according to claim 31 , which is carried out according to the following reaction:

wherein R-i, R₂, and R₃ are independently selected from the group consisting of H and any organic substituent suitable for participating in the organocatalytic olefin- olefin metathesis.

48. The method according to claim 47, wherein R-i , R₂, and R₃ are independently selected from the group consisting of substituted or unsubstituted C₃-Ci₂ aryl, C3-C12 heteroaryl, C₃-Ci₂ cycloalkyl, and Ci_i₂ alkyl.

49. The method according to claim 47, wherein R-i , R₂, and R₃ are independently selected from the group consisting of

50. A process for organocatalytic olefin-olefin metathesis according to the following reaction:

wherein

R-i , R₂, and R₃ are independently selected from the group consisting of H and any organic substituent suitable for participating in the organocatalytic olefin-olefin metathesis;

the process comprising contacting an aldehyde according to formula (2) with a cyclopropene according to formula (64) in the presence of a hydrazine catalyst according to formula (1 1 ) under conditions suitable for organocatalytic olefin-olefin metathesis.

51 . The method according to claim 50, wherein the conditions suitable for organocatalytic olefin-olefin metathesis comprise reacting the aldehyde (2), cyclopropene (64), and hydrazine (1 1 ) in the presence of acetonitrile at a temperature between 75-90°C for 24 hours.

52. A process for organocatalytic olefin-olefin metathesis according to the following reaction:

wherein R-i , R₂, and R3 are independently selected from the group consisting of H and any organic substituent suitable for participating in the organocatalytic olefin- olefin metathesis

53. A product made by the process according to any one of claims 1 , 26, 30, 31 , 50, and 52.

54. The method according to claim 31 , wherein at least one of the first or the second olefin-containing moiety is selected from the group consisting of:

55. The method according to claim 54, wherein the product produced by the metathesis process is selected from the group consisting of a polyoctenamer, a polynorbornene, and a polydicyclopentadiene.

56. The method according to claim 1 , wherein the olefin-containing moiety is cyclic.

58. The method according to claim 1 , wherein the carbonyl-containing moiety is linked to the olefin-containing moiety.

59. The method according to claim 58, wherein a compound comprising both the carbonyl-containing moiety and the olefin-containing moiety is selected from the group consisting of:

60. The method according to claim 1 , wherein the olefin-containing moiety is in excess of the carbonyl-containing moiety.

61 . The method according to claim 60, wherein the olefin-containing moiety is a compound of formula (29):

(29)