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WO2006130437A2 - Reactions asymetriques formatrices de liaison carbone-carbone catalysees par des alcaloides quinquina bifonctionnels - Google Patents

Reactions asymetriques formatrices de liaison carbone-carbone catalysees par des alcaloides quinquina bifonctionnels Download PDF

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WO2006130437A2
WO2006130437A2 PCT/US2006/020324 US2006020324W WO2006130437A2 WO 2006130437 A2 WO2006130437 A2 WO 2006130437A2 US 2006020324 W US2006020324 W US 2006020324W WO 2006130437 A2 WO2006130437 A2 WO 2006130437A2
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cyano
racemic
chiral
prochiral
ester
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WO2006130437A3 (fr
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Li Deng
Hongming Li
Yi Wang
Fanghui Wu
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Brandeis University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0237—Amines
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
    • B01J2231/341—1,2-additions, e.g. aldol or Knoevenagel condensations
    • C—CHEMISTRY; METALLURGY
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered

Definitions

  • Enantiomerically pure materials may be obtained by asymmetric conjugate addition of a nucleophile to an electron-poor alkene.
  • the asymmetric conjugate addition is one of the most powerful bond-forming reactions to construct enantioenriched, highly functional carbon skeletons for the total synthesis of natural and biologically active compounds.
  • nitroalkenes are very attractive, because the nitro group is the most electron-withdrawing group known.
  • N. Ono The Nitro Group in Organic Synthesis, Wiley-VCH, New York, 2001; D. Seebach, E. W. Colvin, F Lehr, T Weller, Chimia 1979, 33, 1-18. Often described as a "synthetic chameleon," the nitro group can serve as masked functionality to be further transformed after the addition has taken place.
  • G. Calderari D. Seebach, HeIv. CMm. Acta 1995, 68, 1592-1604.
  • the Nef reaction, the nucleophilic displacement, the reduction to amino group, the Myer reaction, and the conversion into a nitrile oxide are only examples of the transformations that nitro groups can undergo.
  • the present invention relates to the catalytic asymmetric synthesis of chiral compounds from prochiral substrates, such as nitroalkenes, alkenyl sulfones and alkenyl ketones.
  • Catalytic asymmetric synthesis is providing chemists with new and powerful tools for the efficient synthesis of complex molecules. While many of the catalytic systems are metal-based and rely on chiral Lewis acid and organometallic redox-based catalysis, increasing numbers of asymmetric reactions are catalyzed by chiral nucleophiles, building on the vast assortment of situations in nature in which nucleophiles play pivotal roles. For leading references, see: (a) In Comprehensive Asymmetric Catalysis; Jacobsen, E.
  • Chiral amines play a central role in this expanding area of asymmetric catalysis. Although chiral amines have been utilized extensively as chiral ligands, they have also shown great promise in catalyzing a broad range of asymmetric transformations, yielding optically enriched products in high selectivity and yield that may not be accessible through alternative asymmetric technology. Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; Wiley & Sons: New York, 1995.
  • Cinchona alkaloids were the first chiral amines to be used in asymmetric catalysis, most notably in the pioneering work of Pracejus from the 1960's on disubstituted ketene alcoholysis. Cinchona alkaloids also possess a rich and colorful history that is rooted in natural products and pharmaceutical chemistry. Turner, R. B.; Woodward, R. B. In In the Alkaloids; Manske, R. H. F.; Holmes, H. L., Eds.; Academic Press: New York, 1953; Vol. 3, p 24; Verpoorte, R.; Schripsema, J.; Van der Leer, T. InIn the Alkaloids.
  • the dimeric catalyst is not available in large quantity (e.g., in kilogram quantity). Therefore, stereoselective reactions using dimeric catalysts are not practical on a relatively large scale (>0.1 mol). Consequently, the development of a new generation of monomelic catalysts that is comparably effective to (DHQD) 2 AQN, but substantially less costly to produce, is of significant practical value.
  • Chiral metal and organic catalysts that possess both an acidic and a basic/nucleophilic structural moiety constitute an increasingly powerful platform for the development of asymmetric catalysis.
  • the design and development of such bifunctional chiral catalysts that are efficient yet easily accessible continues to be a major challenge.
  • Another aspect of the present invention relates to a method of preparing a chiral, non-racemic compound from a prochiral electron-deficient alkene or prochiral imine, comprising the step of: reacting a prochiral alkene or imine with a nucleophile in the presence of a catalyst; thereby producing a chiral, non-racemic compound; wherein said catalyst is a derivatized quinine or quinidine.
  • the nucleophile is a malonate or ⁇ -ketoester.
  • the nucleophile is an alkyl or aryl or aralkyl 2-cyano-2-alkylacetate.
  • the nucleophile is an alkyl or aryl or aralkyl 2-cyano-2-arylacetate.
  • Another aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic aldehyde or racemic ketone with a nucleophile in the presence of a derivatized quinine or quinidine, thereby producing a non-racemic, chiral compound.
  • the kinetic resolution is dynamic.
  • Figure 1 depicts the structure and nomenclature of several cinchona-alkaloid-based catalysts of the present invention.
  • Figure 2 depicts the bifunctional nature of several cinchona-alkaloid-based catalysts of the present invention.
  • Figure 3 depicts a proposed mechanism for the enantioselective C-C bond forming nucleophilic addition of a trisubstituted carbon donor to an alpha-substituted Michael acceptor and the subsequent diasteroselective protonation of the resulting enolate.
  • Figure 4 depicts selected catalysts of the invention.
  • Figure 5 depicts the results of catalytic Michael additons using the catalysts of the invention. All the reactions, unless noted otherwise, were run with 0.05 mmol of 3a, 0.2 mmol of 2 in toluene with 10 mol% of catalysts. Key: b Determined by 1 H NMR analysis. c Determined by Chiral GC [ ⁇ -CD, 100 0 C, 4 min then 100 0 C-150 0 C (0.75 0 C / min.)]). d Reaction was run with 20 mol% of catalyst.
  • Figure 6 depicts asymmeteric 1,4-addition-protonation reactions on cyclic Michael donors. Unless noted, all the reactions were run with 0.1 mmol of 3, 0.4 mmol of 2 in 1 mL of toluene with the catalysis of Qd-I a at room temperature for the period of time listed in the table; The results within parentheses are referring to the reaction catalyzed by Q-Ia. Key: b Isolated yield. c Determined by 1 H NMR analysis of crude reaction mixture. d Determined by Chiral HPLC or GC analysis. e 0.8 mmol of 2 was used instead/ Absolute configuration were determined by X-ray analysis.
  • Figure 7 depicts asymmetric 1,4-addition-protonation reactions of acyclic Michael donors. Unless noted, all the reactions were run with 0.1 mmol of 2, 0.8 mmol of 1 in 1 mL of toluene with the 20 mol% catalysts at room temperature for the period of time listed in the table. Key: h Isolated yield. c Determined by 1 H NMR analysis of crude reaction mixture. d Determined by Chiral HPLC or GC analysis (see Supporting Information). e Conversion instead of yield was listed. ⁇ 0.5 mL of toluene was used. g Pure diastereomer was obtained. h Absolute configuration was confirmed after later synthetic study.
  • Figure 8 depicts the effect of temperature on the 1,4-addition-protonation reactions of the invention, using catalyst Q-bisCF 3 TU.
  • Figure 9 depicts asymmeteric Michael additions of alpha-cyano carbonyl compounds to arcyloiiitrile. Unless noted, reactions were carried out with 0.2 mmol of donor, 0.6 mmol of acceptor in 2.0 mL of toluene with Q-catalyst. The results in parentheses were obtained with QD-catalyst to give opposite enantiomer. Key: b Isolated yield. c Determined by chiral HPLC analysis. d Absolute configuration was determined by comparasion with previous results.
  • Figure 10 depicts asymmeteric conjugate addition-protonation of alpha-cyano carbonyl compounds with 2-chloroacrylonitrile.
  • Figure 12 depicts the catalytic asymmetric formal synthesis of Manzacidin A. Key: a) NaN 3 , DMSO, rt, 56%, 10:1 dr. b) TMSCl 5 MeOH, 0 0 C, 95%, 9:1 d.r. c) NaBH 4 , Hg(OAc) 2 , EtOH, O oC, 83%, 9:1 d.r. d) TBDPSCl, imidazole, DMF, rt, 91%, 10:1, d.r.
  • Figure 13 depicts Cinchona Alkaloid-Catalyzed Addition of Dimethyl Malonate (5a) to N-Boc-imine (4D). Catalysts are those shown in Figure 11. Unless noted, reactions were run with 0.05 mmol of 4D, 0.15 mmol of 5a in 0.10 niL of solvent with 10 mol% catalyst for 16 h. Key: b Cinchona alkaloids bearing no thiourea functionality afforded moderate ee. c Determined by 1 H NMR analysis. d Determined by HPLC analysis. e Reaction was run with Q-Id (20 mol%) at -60 0 C for 24 h.
  • Figure 14 depicts Enantioselective Mannich Reaction of Malonate 5 to N-Boc- imine 4 Catalyzed by QD-Id and Q-Id (in parentheses). Catalysts are those shown in Figure 11. Unless noted, reactions were run with 4 (0.20 mmol) and 5 (0.30 mmol) in acetone (0.4 mL) at -60 °C for 36 h, and the results in parentheses were obtained with Q-Id. Key: b Isolated yield. c Determined by HPLC analysis. d Absolute configuration of (+)-6Ab prepared with a QD-ld-catalyzed reaction with determined to be S, see Supporting
  • Figure 15 depicts [A] Enantioselective Mannich Reactions of ⁇ -Ketoester 8 to N- Boc-imine 4A Catalyzed by QD-Id and Q-Id (in parentheses); catalysts are those shown in Figure 11; unless noted, reactions were run with 4A (0.20 mmol) and 8 (0.30 mmol) in acetone (0.4 mL), and the results in parentheses were obtained with Q-Id; Key: b Isolated yield, c Determined by 1 H NMR analysis, and d Determined by HPLC analysis. It also depicts [B] the synthesis of N-Boc- ⁇ -amino acids. DETAILED DESCRIPTION OF THE INVENTION
  • Enantioselective construction of non-adjacent stereocenters in an acyclic molecule is typically accomplished via a multistep process during which the two stereocenters are generated in different steps.
  • a fundamentally more efficient strategy is to create both stereocenters in one step from readily available achiral starting materials by an asymmetric tandem reaction with an external chiral reagent. While notable examples have been reported in the development of such asymmetric tandem reactions employing a stoichiometric amount of chiral reagents, the implementation of this powerful strategy with efficient catalytic control still represents a daunting challenge.
  • the readily accessible modified cinchona alkaloids, such as 1, are highly efficient catalysts for conjugate additions of various trisubstituted carbon nucleophiles to nitroalkenes, ⁇ , ⁇ -unsaturated sulfones and ketones (see Figure 1 and Figure 9).
  • the transition state model indicated from mechanistic studies of the 1 -catalyzed conjugate addition of trisubstituted carbon nucleophiles it was envisioned that catalysts of type 1 would be able to facilitate both the enantioselective C-C bond forming nucleophilic addition of a trisubstituted carbon donor to an ⁇ -substituted Michael acceptor and the subsequent diastereoselective protonation of the resulting enolate as illustrated in Figure 3. Consequently, the cinchona alkaloids of the invention are herein shown to serve as a dual- function chiral catalyst to control the stereoselective generation of both the tertiary and quaternary stereocenters via a tandem asymmetric reaction.
  • the inventive catalysts can promote asymmetric conjugate additions of trisubstituted carbon donors to ⁇ - substituted Michael acceptors, as described below.
  • a 1 -catalyzed efficient and general tandem asymmetric conjugate addition- protonation with trisubstituted carbon donors and a Michael acceptor bearing a ⁇ -halide has been invented.
  • the synthetic versatility of the halide functionality in combination with a substantial scope of the trisubstituted carbon donors allows this tandem reaction to provide a highly versatile catalytic approach for the asymmetric creation of 1,3-quaternary-tertiary stereocenters.
  • Catalyst screening studies with ⁇ -cyanoketone 3a and ⁇ -chloro acrylnitrile 2 as model substrates were performed in toluene at room temperature (see Figure 5).
  • the reaction catalyzed by Ia afforded the best enantioselectivity as well as diastereoselectivity, and at 10 mol% catalyst loading afforded the corresponding 1,4-adduct 4a in 75% ee and 3:1 dr ratio.
  • the ee and dr was improved to 91% and 7:1, respectively, when the reaction was carried out with 20 mol% of Ia and the reaction concentration was decreased from 1.0 M to 0.1 M.
  • Catalyst Ia was found to be broadly effective for various cyclic trisubstituted carbon donors.
  • the catalyst readily accepted alterations of the cyclic donor in terms of ring size as well as the electronic and the steric property of the substituents attached to the nucleophilic carbon.
  • the tetrahydropyrimidine core bearing the 1,3-tertiary- quaternary stereocenters could be constructed via stereospecific transformations of intermediate 4k, which is accessible directly in excellent yield via the highly diastereoselective and enantioselective tandem conjugate addition-protonation catalyzed by Id ( Figure 12).
  • Substitution of the chloride with azide followed by the selective alcoholysis of the sterically less hindered nitrile group converted 4k to 6 without compromising the stereochemical integrity of the tertiary stereocenter. Both the thioester and ester groups in 6 were then reduced with sodium borohydride.
  • this 9-step synthesis of 12 constitutes a formal asymmetric total synthesis of Manzacidin A (13) in 13 steps. Importantly, this route will allow the preparation of analogues of 13.
  • a catalytic tandem asymmetric conjugate addition-protonation reaction with cinchona alkaloids as dual-function chiral catalysts has been discovered. This reaction establishes a new catalytic approach for the one-step construction of 1,3 -stereocenters. The synthetic value of this approach in the context of total synthesis of natural products is highlighted in the development of a concise and flexible enantioselective route to Manzacidin A.
  • nucleophile is recognized in the art, and as used herein means a chemical moiety having a reactive pair of electrons.
  • nucleophiles include uncharged compounds such as water, amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions.
  • Illustrative anionic nucleophiles include simple anions such as hydroxide, azide, cyanide, thiocyanate, acetate, formate or chloroformate, and bisulfite.
  • Organor ⁇ etallic reagents such as organocuprates, organozincs, organolithiums, Grignard reagents, enolates, acetylides, and the like may, under appropriate reaction conditions, be suitable nucleophiles. Hydride may also be a suitable nucleophile when reduction of the substrate is desired.
  • electrotrophile is art-recognized and refers to chemical moieties which can accept a pair of electrons from a nucleophile as defined above.
  • Electrophiles useful in the method of the present invention include cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones, lactams and the like.
  • Non-cyclic electrophiles include sulfates, sulfonates (e.g. tosylates), chlorides, bromides, iodides, and the like
  • electrophilic atom refers to the atom of the substrate which is attacked by, and forms a new bond to, the nucleophile. In most (but not all) cases, this will also be the atom from which the leaving group departs.
  • electro- withdrawing group is recognized in the art and as used herein means a functionality which draws electrons to itself more than a hydrogen atom would at the same position. Exemplary electron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, -CN, chloride, and the like.
  • electron-donating group as used herein, means a functionality which draws electrons to itself less than a hydrogen atom would at the same position. Exemplary electron-donating groups include amino, methoxy, and the like.
  • Lewis base is art-recognized and refers to an uncharged or charged atom or molecule, e.g., an oxide, amine, alkoxide, or carbonate, that is a proton acceptor.
  • Lewis base and “Lewis basic” are recognized in the art, and refer to a chemical moiety capable of donating a pair of electrons under certain reaction conditions. Examples of Lewis basic moieties include uncharged compounds such as alcohols, thiols, olefins, and amines, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of other organic anions.
  • Lewis acid and “Lewis acidic” are art-recognized and refer to chemical moieties which can accept a pair of electrons from a Lewis base.
  • the term “meso compound” is recognized in the art and means a chemical compound which has at least two chiral centers but is achiral due to an internal plane, or point, of symmetry.
  • chiral refers to molecules which have the property of non- superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • a "prochiral molecule” is an achiral molecule which has the potential to be converted to a chiral molecule in a particular process.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
  • enantiomers refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • diastereomers refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.
  • a “stereoselective process” is one which produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of that product.
  • An “enantioselective process” is one which favors production of one of the two possible enantiomers of a reaction product.
  • the subject method is said to produce a "stereoselectively-enriched" product (e.g., enantioselectively-enriched or diastereoselectively-enriched) when the yield of a particular stereoisomer of the product is greater by a statistically significant amount relative to the yield of that stereoisomer resulting from the same reaction run in the absence of a chiral catalyst.
  • an enantioselective reaction catalyzed by one of the subject chiral catalysts will yield an ee for a particular enantiomer that is larger than the ee of the reaction lacking the chiral catalyst.
  • regioisomers refers to compounds which have the same molecular formula but differ in the connectivity of the atoms. Accordingly, a "regioselective process" is one which favors the production of a particular regioisomer over others, e.g., the reaction produces a statistically significant preponderence of a certain regioisomer.
  • reaction product means a compound which results from the reaction of a nucleophile and a substrate.
  • reaction product will be used herein to refer to a stable, isolable compound, and not to unstable intermediates or transition states.
  • substrate is intended to mean a chemical compound which can react with a nucleophile, or with a ring-expansion reagent, according to the present invention, to yield at least one product having a stereogenic center.
  • catalytic amount is recognized in the art and means a substoichiometric amount relative to a reactant. As used herein, a catalytic amount means from 0.0001 to 90 mole percent relative to a reactant, more preferably from about 0.001 to about 50 mole percent, still more preferably from about 0.01 to about 10 mole percent, and even more preferably from about 0.1 to about 5 mole percent relative to a reactant.
  • the reactions contemplated in the present invention include reactions which are enantioselective, diastereoselective, and/or regioselective.
  • An enantioselective reaction is a reaction which converts an achiral reactant to a chiral product enriched in one enantiomer. Enantioselectivity is generally quantified as "enantiomeric excess" (ee) defined as follows:
  • % Enantiomeric Excess A (ee) (% Enantiomer A) - (% Enantiomer B) where A and B are the enantiomers formed. Additional terms that are used in conjunction with enatioselectivity include "optical purity" or "optical activity".
  • An enantioselective reaction yields a product with an ee greater than zero.
  • Preferred enantioselective reactions yield a product with an ee greater than about 20%, more preferably greater than about 50%, even more preferably greater than about 70%, and most preferably greater than about 80%.
  • a diastereoselective reaction converts a chiral reactant (which may be racemic or enantiomerically pure) to a product enriched in one diastereomer. If the chiral reactant is racemic, in the presence of a chiral non-racemic reagent or catalyst, one reactant enantiomer may react more slowly than the other. This class of reaction is termed a kinetic resolution, wherein the reactant enantiomers are resolved by differential reaction rate to yield both enantiornerically-enriched product and enantiomerically-enriched unreacted substrate.
  • Kinetic resolution is usually achieved by the use of sufficient reagent to react with only one reactant enantiomer (i.e., one-half mole of reagent per mole of racemic substrate).
  • Examples of catalytic reactions which have been used for kinetic resolution of racemic reactants include the Sharpless epoxidation and the Noyori hydrogenation.
  • a regioselective reaction is a reaction which occurs preferentially at one reactive center rather than another non-identical reactive center. For example, a regioselective reaction of an unsymmetrically substituted epoxide substrate would involve preferential reaction at one of the two epoxide ring carbons.
  • non-racemic with respect to the chiral catalyst, means a preparation of catalyst having greater than 50% of a given enantiomer, more preferably at least about 75%.
  • substantially non-racemic refers to preparations of the catalyst which have greater than about 90% ee for a given enantiomer of the catalyst, more preferably greater than about 95% ee.
  • 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.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 of fewer.
  • preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple carbon-carbon bond, respectively.
  • amino means -NH2; the term “nitro” means -NO2; the term “halogen” designates -F, -Cl, -Br or -I; the term “thiol” means -SH; the term “hydroxyl” means -OH; the term “sulfonyl” means -SO2-; and the term “organometallic” refers to a metallic atom (such as mercury, zinc, lead, magnesium or lithium) or a metalloid (such as silicon, arsenic or selenium) which is bonded directly to a carbon atom, such as a diphenylmethylsilyl group.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: R50
  • R51 R52 wherein R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, - (CH 2 ) m -R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
  • R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH 2 ) ra -R61.
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
  • acylamino is art-recognized and refers to a moiety that may be represented by the general formula:
  • R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or - (CH 2 ) m -R61, where m and R61 are as defined above.
  • R54 represents a hydrogen, an alkyl, an alkenyl or - (CH 2 ) m -R61, where m and R61 are as defined above.
  • the term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto, hi certain embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH 2 ) m -R61, wherein m and R61 are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • carboxyl is art recognized and includes such moieties as may be represented by the general formulas:
  • X50 is a bond or represents an oxygen or a sulfur
  • R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R61or a pharmaceutically acceptable salt
  • R56 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R61, where m and R61 are defined above.
  • X50 is an oxygen and R55 or R56 is not hydrogen
  • the formula represents an "ester”.
  • X50 is an oxygen
  • R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid".
  • X50 is an oxygen, and R56 is hydrogen
  • the formula represents a "formate".
  • the oxygen atom of the above formula is replaced by sulfur
  • the formula represents a "thiolcarbonyl” group.
  • X50 is a sulfur and R55 or R56 is not hydrogen
  • the formula represents a "thiolester.”
  • X50 is a sulfur and R55 is hydrogen
  • the formula represents a "thiolcarboxylic acid.”
  • X50 is a sulfur and R56 is hydrogen
  • the formula represents a "thiolformate.”
  • X50 is a bond, and R55 is not hydrogen
  • the above formula represents a "ketone” group.
  • X50 is a bond, and R55 is hydrogen
  • the above formula represents an "aldehyde” group.
  • oxime and "oxime ether” are art-recognized and refer to moieties that may be represented by the general formula:
  • R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH 2 ) m -R61.
  • the moiety is an "oxime” when R is H; and it is an "oxime ether” when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH 2 ) m -R61.
  • alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -0-alkynyl, -O--(CH 2 ) m -R61, where m and R61 are described above.
  • R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • sulfamoyl is art-recognized and refers to a moiety that may be represented by the general formula:
  • sulfonyl is art-recognized and refers to a moiety that may be represented by the general formula:
  • R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  • sulfoxido is art-recognized and refers to a moiety that may be represented by the general formula:
  • phosphoryl is art-recognized and may in general be represented by the formula:
  • Q50 and R59 each independently, are defined above, and Q51 represents O 5 S or N.
  • Q50 is S
  • the phosphoryl moiety is a "phosphorothioate”.
  • phosphoramidite is art-recognized and may be represented in the general formulas: wherein Q51, R50, R51 and R59 are as defined above.
  • R60 represents a lower alkyl or an aryl.
  • Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • each expression e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • selenoalkyl is art-recognized and refers to an alkyl group having a substituted seleno group attached thereto.
  • exemplary "selenoethers" which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and - Se-(CH 2 )m-R61, m and R61 being defined above.
  • trifiyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, />-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, />-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, j>-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.
  • Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with 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, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • 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. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • the phrase "protecting group” as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups examples include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.
  • perfluoroalkyl is art-recognized and refers to an alkyl group in which all hydrogens have been replaced with fluorines.
  • fluorines for example, trifluoromethyl and pentafluoroethyl are perfluoroalkyl groups.
  • (-)-menthyl is art-recognized and includes a moiety represented by the formula:
  • isopinocamphyl is art-recognized and includes a moiety represented by the formula:
  • (+)-fenchyl is art-recognized and includes a moiety represented by the formula:
  • QD represents a moiety according to the following formula:
  • ⁇ -amino ⁇ -cyano ketone " ⁇ -amino ⁇ -keto ester”, " ⁇ -amino ⁇ -cyano ester” and " ⁇ -amino 1,3-diketone” represent a moitey according to one of the following formulas:
  • catalysts employed in the subject methods are non-racemic chiral amines which present an asymmetric environment, causing stereochemical discrimination between two stereogenic faces of an alkene; or two or more prochiral moieties (e.g., related by symmetry in a prochiral or meso molecule, (i.e., a molecule comprising at least two chiral centers), both of which comprise an internal plane or point of symmetry or both.
  • prochiral moieties e.g., related by symmetry in a prochiral or meso molecule, (i.e., a molecule comprising at least two chiral centers), both of which comprise an internal plane or point of symmetry or both.
  • catalysts intended by the present invention can be characterized in terms of a number of features.
  • a salient aspect of each of the catalysts contemplated by the instant invention concerns the use of asymmetric bicyclic or polycyclic scaffolds incorporating the tertiary amine moiety which provide a rigid or semi-rigid environment near the amine nitrogen.
  • This feature through imposition of structural rigidity on the amine nitrogen in proximity to one or more asymmetric centers present in the scaffold, contributes to the creation of a meaningful difference in the energies of the corresponding diastereomeric transitions states for the overall transformation.
  • the choice of substituents may also effect catalyst reactivity.
  • the choice of catalyst substituents can also effect the electronic properties of the catalyst.
  • Substitution of the catalyst with electron-rich (electron-donating) moieties may increase the electron density of the catalyst at the tertiary amine nitrogen, rendering it a stronger nucleophile and/or Bronsted base and/or Lewis base.
  • substitution of the catalyst with electron-poor moieties can result in lower electron density of the catalyst at the tertiary amine nitrogen, rendering it a weaker nucleophile and/or Bronsted base and/or Lewis base.
  • the electron density of the catalyst can be important because the electron density at the tertiary amine nitrogen will influence the Lewis basicity of the nitrogen and its nucleophilicity. Choice of appropriate substituents thus makes possible the "tuning" of the reaction rate and the stereoselectivity of the reaction.
  • One aspect of the present invention relates to a compound represented by formula I:
  • R represents substituted or unsubstituted nitrogen-containing heteroaryl, or benzoyl
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester; n is an integer from 0 to 5 inclusive; m is an integer from 0 to 8 inclusive; and R 4 represents -OH.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents substituted or unsubstituted diazene.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents 5-chloro-3,6-di ⁇ henyl- 2,4-diazene.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents halobenzoyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents 4-chlorobenzoyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R 1 is alkyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R 1 is ethyl. In certain embodiments, the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R 1 is alkenyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein n is 0.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein m is 0. In certain embodiments, the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R is diazene and R 1 is ethyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R is halobenzoyl and R 1 is ethyl.
  • R represents 5-chloro-3,6-diphenyl- 2,4-diazene; and R 1 is ethyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents 4-chlorobenzoyl; and R 1 is ethyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R is diazene; R 1 is ethyl; ni is 0; and n is O.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R is halobenzoyl; R 1 is ethyl; m is 0; and n is 0.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl- 2,4-diazene; R 1 is ethyl; m is 0; and n is 0.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents 4-chlorobenzoyl; R 1 is ethyl; m is 0; and n is 0.
  • Another aspect of the present invention relates to a compound represented by formula II:
  • R represents substituted or unsubstituted nitrogen-containing heteroaryl, or benzoyl
  • R 1 represents alkyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester; n is an integer from 0 to 5 inclusive; m is an integer from 0 to 8 inclusive; and
  • R 4 represents -OH.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents substituted or unsubstituted diazene.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl- 2,4-diazene.
  • the compounds of the present invention are represented by formula ⁇ and any of the attendant definitions, wherein R represents halobenzoyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents 4-chlorobenzoyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R 1 is alkyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R 1 is ethyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R 1 is alkenyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein n is 0.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein m is 0.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R is diazene and R 1 is ethyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R is halobenzoyl and R 1 is ethyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl- 2,4-diazene; and R 1 is ethyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents 4-chlorobenzoyl; and R 1 is ethyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R is diazene; R 1 is ethyl; m is 0; and n is 0.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R is halobenzoyl; R 1 is ethyl; m is 0; and n is 0.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl- 2,4-diazene; R 1 is ethyl; m is 0; and n is 0.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents 4-chlorobenzoyl; R 1 is ethyl; m is 0; and n is 0.
  • R represents 4-chlorobenzoyl
  • R 1 is ethyl
  • m is 0
  • n is 0.
  • Another aspect of the present invention relates to a compound represented by formula III:
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thi
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the compounds of the present invention are represented by formula HI and any of the attendant definitions, wherein R 1 is alkyl.
  • the compounds of the present invention are represented by formula KI and any of the attendant definitions, wherein R 1 is ethyl.
  • the compounds of the present invention are represented by formula IH and any of the attendant definitions, wherein R 1 is alkenyl.
  • the compounds of the present invention are represented by formula m and any of the attendant definitions, wherein R 4 is hydrogen or ether.
  • the compounds of the present invention are represented by formula IH and any of the attendant definitions, wherein R 4 is hydrogen or -OCH 3 .
  • the compounds of the present invention are represented by formula IH and any of the attendant definitions, wherein R 5 is hydrogen.
  • the compounds of the present invention are represented by formula DI and any of the attendant definitions, wherein m is 0. In certain embodiments, the compounds of the present invention are represented by formula HI and any of the attendant definitions, wherein n is 0.
  • Another aspect of the present invention relates to a compound represented by formula IV:
  • R 1 represents a substituted or unsubstituted allcyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the compounds of the present invention are represented by formula IV and any of the attendant definitions, wherein R 1 is alkyl. In certain embodiments, the compounds of the present invention are represented by formula IV and any of the attendant definitions, wherein R 1 is ethyl.
  • the compounds of the present invention are represented by formula IV and any of the attendant definitions, wherein R 1 is alkenyl.
  • the compounds of the present invention are represented by formula IV and any of the attendant definitions, wherein R 4 is hydrogen or ether.
  • the compounds of the present invention are represented by formula IV and any of the attendant definitions, wherein R 4 is hydrogen or -OCH 3 .
  • the compounds of the present invention are represented by formula IV and any of the attendant definitions, wherein R 5 is hydrogen.
  • the compounds of the present invention are represented by formula IV and any of the attendant definitions, wherein m is 0.
  • the compounds of the present invention are represented by formula IV and any of the attendant definitions, wherein n is 0.
  • Another aspect of the present invention relates to a compound represented by formula V:
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the compounds of the present invention are represented by formula V and any of the attendant definitions, wherein R 1 is alkyl.
  • the compounds of the present invention are represented by formula V and any of the attendant definitions, wherein R 1 is ethyl.
  • the compounds of the present invention are represented by formula V and any of the attendant definitions, wherein R 1 is alkenyl.
  • the compounds of the present invention are represented by formula V and any of the attendant definitions, wherein R 5 is hydrogen.
  • the compounds of the present invention are represented by formula V and any of the attendant definitions, wherein m is 0.
  • the compounds of the present invention are represented by formula V and any of the attendant definitions, wherein n is 0.
  • a process for stereoselectively producing compounds with at least one stereogenic center from prochiral, or racemic starting materials is provided.
  • An advantage of this invention is that enantiomerically enriched products can be synthesized from prochiral or racemic reactants.
  • Another advantage is that yield losses associated with the production of an undesired enantiomer can be substantially reduced or eliminated altogether.
  • the invention features a stereoselective addition process which comprises combining a iiucleophilic reactant, a prochiral or chiral substrate, and at least a catalytic amount of non-racemic chiral catalyst of particular characteristics (as described below).
  • Suitable substrates for the reaction include prochiral electron-deficient alkenes, prochiral aldehydes and prochiral ketones susceptible to attack by the nucleophile.
  • the combination of substrate, nucleophile, and catalyst is maintained under conditions appropriate for the chiral catalyst to catalyze the addition of the nucleophilic reactant to the prochiral electron- deficient alkene or prochiral aldehyde or prochiral ketone.
  • This reaction can be applied to enantioselective processes as well as diastereoselective processes. It may also be adapted for regioselective reactions. Below are examples of enantioselective and diastereoselective reactions, kinetic resolutions, dynamic kinetic resolutions, and regioselective reactions which may be catalyzed according to the present invention.
  • the methods of the invention can provide optically active products with very high stereoselectivity (e.g., enantioselectivity or diastereoselectivity) or regioselectivity.
  • products with enantiomeric excess or diastereomeric excess of greater than about 50%, greater than about 70%, greater than about 90%, and greater than about 95% can be obtained.
  • the methods of this invention can also be carried out under reaction conditions suitable for commercial use, and typically proceed at reaction rates suitable for large scale operations.
  • One aspect of the present invention relates to a method of preparing a chiral, non- racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone, comprising the step of: reacting a prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone with an electron-deficient alkene in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone; wherein said catalyst is represented by formula I:
  • R represents substituted or unsubstituted aryl, heteroaryl, aralkyl, heteroaralkyl, arylcarbonyl, or heteroarylcarbonyl;
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl;
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester; n is an integer from 0 to 5 inclusive; m is an integer from 0 to 8 inclusive; and
  • R 4 represents -OH.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents phenanthrene.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents substituted or unsubstituted diazene.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl-2,4- diazene.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents halobenzoyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 4-chlorobenzoyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is phenanthrene and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is diazene and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is halobenzoyl and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl-2,4- diazene; and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 4-chlorobenzoyl; and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is phenanthrene; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is diazene; R 1 is ethyl; m is 0; and n is 0. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is halobenzoyl; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl-2,4- diazene; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 4-chlorobenzoyl; R 1 is ethyl; m is 0; and n is 0.
  • R represents 4-chlorobenzoyl
  • R 1 is ethyl
  • m is 0
  • n is 0.
  • X represents fluorine, chlorine, bromine, or iodine
  • Y represents cyano, nitro, alkyl ester, aryl ester, heteroaryl ester, aralkyl ester, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and X represents chlorine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; X represents chlorine; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D:
  • Q represents cyano, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl;
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and Q represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • Another aspect of the present invention relates to a method of preparing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone, comprising the step of: reacting a prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1 ,3-diketone with an electron-deficient alkene in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone; wherein said catalyst is represented by formula II:
  • R represents substituted or unsubstituted aryl, heteroaryl, aralkyl, heteroaralkyl, arylcarbonyl, or heteroarylcarbonyl;
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester; n is an integer from 0 to 5 inclusive; m is an integer from O to 8 inclusive; and
  • R 4 represents -OH.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents phenanthrene.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents substituted or unsubstituted diazene.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl-2,4- diazene.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents halobenzoyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 4-chlorobenzoyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein n is 0. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is phenanthrene and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is diazene and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is halobenzoyl and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl-2,4- diazene; and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 4-chlorobenzoyl; and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is phenanthrene; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is diazene; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is halobenzoyl; R 1 is ethyl; m is 0; and n is 0.
  • R represents 5-chloro-3,6-diphenyl-2,4- diazene; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by
  • X represents fluorine, chlorine, bromine, or iodine
  • Y represents cyano, nitro, alkyl ester, aryl ester, heteroaryl ester, aralkyl ester, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and X represents chlorine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; X represents chlorine; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D:
  • Q represents cyano, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl;
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and Q represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • Another aspect of the present invention relates to a method of preparing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone, comprising the step of: reacting a prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone with an electron-deficient alkene in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone; wherein said catalyst is represented by formula III:
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thi
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein Ri is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or ether. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or -OCH 3 . In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C:
  • X represents fluorine, chlorine, bromine, or iodine
  • Y represents cyano, nitro, alkyl ester, aryl ester, heteroaryl ester, aralkyl ester, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and X represents chlorine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; X represents chlorine; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D:
  • Q represents cyano, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and Q represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • Another aspect of the present invention relates to a method of preparing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone, comprising the step of: reacting a prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1 ,3-diketone with an electron-deficient alkene in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone; wherein said catalyst is represented by formula IV:
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or ether.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or -OCH 3 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by
  • X represents fluorine, chlorine, bromine, or iodine
  • Y represents cyano, nitro, alkyl ester, aryl ester, heteroaryl ester, aralkyl ester, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and X represents chlorine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; X represents chlorine; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D:
  • Q represents cyano, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl;
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and Q represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • Another aspect of the present invention relates to a method of preparing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone, comprising the step of: reacting a prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone with an electron-deficient alkene in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone; wherein said catalyst is represented by formula V:
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C:
  • X represents fluorine, chlorine, bromine, or iodine
  • Y represents cyano, nitro, alkyl ester, aryl ester, heteroaryl ester, aralkyl ester, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and X represents chlorine. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; X represents chlorine; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D:
  • Q represents cyano, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and Q represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • One aspect of the present invention relates to a method of preparing a chiral, non- racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non- racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone, comprising the step of: reacting a prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1 ,3-diketone with an imine in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or ether.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or -OCH 3 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E:
  • R represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl;
  • X represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
  • Y represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents alyl or alkyloxycarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents t-butyloxycarbonyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and X represents alkyl, aryl, or heteroaryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 -Ph-, 2-furyl-, 2-thienyl-, 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph-, CH 3 CH 2 -, CH 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E ; and Y represents hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; R represents t-butyloxycarbonyl; X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 - Ph-, 2-furyl-, 2-thienyl-, 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph-, CH 3 CH 2 -, CH- 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-; and Y represents hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F:
  • Q represents cyano, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl; and G represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, or, aralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents -C(O)CH 3 , -C(O)CH 2 CH 2 OH 2 , or, -CH 2 Ph.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents alkyloxy, aralkyloxy or alkenyloxy.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents methyl, benzyl or allyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents -C(O)CH 2 Ph; and G represents -CH 2 Ph.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • One aspect of the present invention relates to a method of preparing a chiral, non- racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non- racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone, comprising the step of: reacting a prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone with an inline in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thi
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen. m certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E:
  • R represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl;
  • X represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
  • Y represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents alyl or alkyloxycarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents t-butyloxycarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and X represents alkyl, aryl, or heteroaryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 -Ph-, 2-furyl-, 2-thienyl-, 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph-, CH 3 CH 2 -, CH 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and Y represents hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; R represents /-butyloxycarbonyl;
  • X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 - Ph-, 2-furyl-, 2-thienyl-, 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph-, CH 3 CH 2 -, CH- 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-; and Y represents hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F:
  • Q represents cyano, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl;
  • G represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylaniino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, or, aralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents alkyloxy, aralkyloxy or alkenyloxy.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents methyl, benzyl or allyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents -C(K))CH 2 Ph; and G represents -CH 2 Ph.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • One aspect of the present invention relates to a method of preparing a chiral, non- racemic ⁇ -amino ⁇ -cyano ketone, cliiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non- racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone, comprising the step of: reacting a prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1 ,3-diketone with an imine in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E:
  • R represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl;
  • X represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
  • Y represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents alyl or alkyloxycarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents t-butyloxycarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and X represents alkyl, aryl, or heteroaryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 -Ph-, 2-furyl-, 2-thienyl-, 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph-, CH 3 CH 2 -, CH 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and Y represents hydrogen.
  • said imine is represented by E; R represents t-butyloxycarbonyl;
  • X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 - Ph-, 2-furyl-, 2-thienyl-, 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph-, CH 3 CH 2 -, CH- 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-; and Y represents hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F:
  • Q represents cyano, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl; and G represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, or, aralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents alkyloxy, aralkyloxy or alkenyloxy.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents methyl, benzyl or allyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents -C(K))CH 3 ; and G represents -CH 3 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • a kinetic resolution of enantiomers or diastereomers of the substrate or the nucleophile is catalyzed by a subject non-racemic, chiral catalyst.
  • a subject non-racemic, chiral catalyst for example, in the subject kinetic resolution processes for a racemic substrate, when the transformation is complete or interrupted one enantiomer can be preferentially recovered as unreacted substrate while the other has been preferentially transformed to the desired product.
  • the kinetic resolution of the substrate can be performed to provide the desired enantiomer or diastereomer of the product.
  • the kinetic resolution of the substrate can also be performed by removing the undesired enantiomer by reaction with a nucleophile, and recovering the desired enantiomer of the substrate unchanged from the reaction mixture.
  • the kinetic resolution of the nucleophile can be performed by removing the undesired enantiomer by reaction with a substrate, and recovering the desired enantiomer of the nucleophile unchanged from the reaction mixture.
  • One significant advantage of kinetic resolutions is the ability to use inexpensive racemic starting materials rather than expensive, enantiomerically pure starting compounds. hi the non-dynamic kinetic resolution methods, as applied to a racemic substrate, one enantiomer can be recovered as unreacted substrate while the other is transformed to the desired product.
  • the desired product of a kinetic resolution can be the enantiomer or diastereomer that reacts, the enantiomer or diastereomer that does not react, or both.
  • One significant advantage of the methods of the present invention is the ability to use inexpensive racemic or diastereomeric mixtures of the starting materials, rather than expensive, enantiomerically or diastereomerically pure starting compounds.
  • the methods can also be applied to dynamic kinetic resolutions, e.g., wherein the yield of the enantiomerically or diastereomerically pure product from a kinetic resolution of a racemic substrate exceeds 50% due to in situ equilibration of the enantiomers or diastereomers of the substrate prior to the catalyzed attack of the nucleophile. Dynamic kinetic resolution methods are preferred for this reason.
  • the present invention relates to a method of performing a kinetic resolution of a racemic mixture or a diastereomeric mixture of a chiral substrate, comprising the step of combining a racemic mixture or a diastereomeric mixture of a chiral substrate with a nucleophile, in the presence of a chiral, non-racemic catalyst, wherein said chiral non-racemic catalyst catalyzes the addition of said nucleophile to said chiral substrate to give a chiral product or unreacted chiral substrate or both enriched in one enantiomer or diastereomer.
  • the present invention relates to the aforementioned method of performing a kinetic resolution, wherein said kinetic resolution is dynamic.
  • Kinetic Resolution of Enolates via Asymmetric Addition to Electron-Deficient Alkenes One aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone with an electron-deficient alkene in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone; wherein said catalyst is represented by formula I:
  • R represents substituted or unsubstituted aryl, heteroaryl, aralkyl, heteroaralkyl, arylcarbonyl, or heteroarylcarbonyl;
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester; n is an integer from 0 to 5 inclusive; m is an integer from 0 to 8 inclusive; and
  • R 4 represents -OH.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents phenanthrene.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents substituted or unsubstituted diazene.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl-2,4- diazene.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents halobenzoyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 4-chlorobenzoyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is phenanthrene and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is diazene and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is halobenzoyl and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl-2,4- diazene; and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 4-chlorobenzoyl; and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is phenanthrene; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is diazene; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is halobenzoyl; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl-2,4- diazene; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by
  • X represents fluorine, chlorine, bromine, or iodine
  • Y represents cyano, nitro, alkyl ester, aryl ester, heteroaryl ester, aralkyl ester, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and X represents chlorine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; X represents chlorine; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E:
  • M represents alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl
  • Q represents cyano, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E; and M represents alkyl or aralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E; and Q represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E; M represents alkyl or aralkyl; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein when said method is completed or interrupted the unreacted ⁇ -cyano ketone, ⁇ -keto ester, ⁇ -cyano ester or 1,3-diketone is not racemic, and the enantiomeric excess or diastereomeric excess of the product is greater than zero.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein when said method is completed or interrupted, the unreacted ⁇ -cyano ketone, ⁇ -keto ester, ⁇ -cyano ester or 1,3-diketone is racemic, and the enantiomeric excess or diastereomeric excess of the product is greater than zero.
  • One aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone with an electron-deficient alkene in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone; wherein said catalyst is represented by formula II:
  • R represents substituted or unsubstituted aryl, heteroaryl, aralkyl, heteroaralkyl, arylcarbonyl, or heteroarylcarbonyl;
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester; n is an integer from 0 to 5 inclusive; m is an integer from 0 to 8 inclusive; and
  • R 4 represents -OH.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents phenanthrene.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents substituted or unsubstituted diazene.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl-2,4- diazene. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents halobenzoyl. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 4-chlorobenzoyl. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is phenanthrene and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is diazene and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is halobenzoyl and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl-2,4- diazene; and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 4-chlorobenzoyl; and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is phenanthrene; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is diazene; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is halobenzoyl; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 5-chloro-3,6-diphenyl-2,4- diazene; R 1 is ethyl; m is 0; and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents 4-chlorobenzoyl; R 1 is ethyl; m is 0; and n is 0.
  • R represents 4-chlorobenzoyl
  • R 1 is ethyl
  • m is 0
  • n is 0.
  • X represents fluorine, chlorine, bromine, or iodine
  • Y represents cyano, nitro, alkyl ester, aryl ester, heteroaryl ester, aralkyl ester, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and X represents chlorine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; X represents chlorine; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E:
  • M represents alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl
  • Q represents cyano, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E; and M represents alkyl or aralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E; and Q represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone is represented by E; M represents alkyl or aralkyl; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein when said method is completed or interrupted the unreacted ⁇ -cyano ketone, ⁇ -keto ester, ⁇ -cyano ester or 1,3-diketone is not racemic, and the enantiomeric excess or diastereomeric excess of the product is greater than zero.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein when said method is completed or interrupted, the unreacted ⁇ -cyano ketone, ⁇ -keto ester, ⁇ -cyano ester or 1,3-diketone is racemic, and the enantiomeric excess or diastereomeric excess of the product is greater than zero.
  • One aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone with an electron-deficient alkene in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone; wherein said catalyst is represented by formula III:
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or -OCH 3 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C:
  • X represents fluorine, chlorine, bromine, or iodine
  • Y represents cyano, nitro, alkyl ester, aryl ester, heteroaryl ester, aralkyl ester, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; X represents chlorine; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D:
  • Q represents cyano, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl;
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and Q represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said cliiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein when said method is completed or interrupted the unreacted ⁇ -cyano ketone, ⁇ -keto ester, ⁇ -cyano ester or 1,3-diketone is not racemic, and the enantiomeric excess or diastereomeric excess of the product is greater than zero.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein when said method is completed or interrupted, the unreacted ⁇ -cyano ketone, ⁇ -keto ester, ⁇ -cyano ester or 1,3-diketone is racemic, and the enantiomeric excess or diastereomeric excess of the product is greater than zero.
  • One aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone with an electron-deficient alkene in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone; wherein said catalyst is represented by formula IV:
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or ether.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or -OCH 3 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by
  • X represents fluorine, chlorine, bromine, or iodine
  • Y represents cyano, nitro, alkyl ester, aryl ester, heteroaryl ester, aralkyl ester, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and X represents chlorine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; X represents chlorine; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D:
  • Q represents cyano, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and Q represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein when said method is completed or interrupted the unreacted ⁇ -cyano ketone, ⁇ -keto ester, ⁇ -cyano ester or 1,3-diketone is not racemic, and the enantiomeric excess or diastereomeric excess of the product is greater than zero.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein when said method is completed or interrupted, the unreacted ⁇ -cyano ketone, ⁇ -keto ester, ⁇ -cyano ester or 1,3-diketone is racemic, and the enantiomeric excess or diastereomeric excess of the product is greater than zero.
  • One aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic ⁇ -cyano ketone, racemic ⁇ -keto ester, racemic ⁇ -cyano ester, or racemic 1,3-diketone with an electron-deficient alkene in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone; wherein said catalyst is represented by formula V:
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, sibyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl. Li certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by
  • X represents fluorine, chlorine, bromine, or iodine
  • Y represents cyano, nitro, alkyl ester, aryl ester, heteroaryl ester, aralkyl ester, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and X represents chlorine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said electron-deficient alkene is represented by C; X represents chlorine; and Y represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D:
  • Q represents cyano, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and Q represents cyano.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by D; Q represents cyano; and G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, or aralkoxyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -cyano ketone, chiral, non-racemic ⁇ -keto ester, chiral, non-racemic ⁇ -cyano ester or chiral, non-racemic 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein when said method is completed or interrupted the unreacted ⁇ -cyano ketone, ⁇ -keto ester, ⁇ -cyano ester or 1,3-diketone is not racemic, and the enantiomeric excess or diastereomeric excess of the product is greater than zero.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein when said method is completed or interrupted, the unreacted ⁇ -cyano ketone, ⁇ -keto ester, ⁇ -cyano ester or 1,3-diketone is racemic, and the enantiomeric excess or diastereomeric excess of the product is greater than zero.
  • One aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone with an inline in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone; wherein said catalyst is represented by formula III:
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thi
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or ether.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or -OCH 3 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E:
  • R represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl;
  • X represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
  • Y represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents alyl or alkyloxycarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents t-butyloxycarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and X represents alkyl, aryl, or heteroaryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 -Ph-, 2-furyl-, 2-thienyl-, 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph-, CH 3 CH 2 -, CH 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and Y represents hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; R represents t-butyloxycarbonyl; X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 - Ph-, 2-furyl-, 2-thienyl-, 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph-, CH 3 CH 2 -, CH- 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-; and Y represents hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F:
  • Q represents cyano, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl;
  • G represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, or, aralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents alkyloxy, aralkyloxy or alkenyloxy.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents methyl, benzyl or allyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned, method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • One aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone with an imine in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone; wherein said catalyst is represented by formula IV:
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thi
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or ether.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 is hydrogen or -OCH 3 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen.
  • said imine is represented by E:
  • R represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl;
  • X represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
  • Y represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents alyl or alkyloxycarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents t-butyloxycarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and X represents alkyl, aryl, or heteroaryl.
  • said imine is represented by E; and X represents alkyl, aryl, or heteroaryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said irnine is represented by E; and X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 -Ph-, 2-furyl-, 2-thienyl- 5 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph-, CH 3 CH 2 -, CH 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and Y represents hydrogen.
  • said imine is represented by E; R represents t-butyloxycarbonyl;
  • X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 - Ph-, 2-furyl-, 2-thienyl-, 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph- 5 CH 3 CH 2 -, CH- 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-; and Y represents hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F:
  • Q represents cyano, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl;
  • G represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, or, aralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents alkyloxy, aralkyloxy or alkenyloxy.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents methyl, benzyl or allyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • One aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone with an imine in the presence of a catalyst; thereby producing a chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone; wherein said catalyst is represented by formula IV:
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • R 2 and R 3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 5 represents H or lower alkyl; n is an integer from 0 to 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is ethyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E:
  • R represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl;
  • X represents hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
  • Y represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents alyl or alkyloxycarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and R represents t-butyloxycarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and X represents alkyl, aryl, or heteroaryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 -Ph-, 2-furyl-, 2-thienyl-, 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph-, CH 3 CH 2 -, CH 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; and Y represents hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said imine is represented by E; R represents t-butyloxycarbonyl; X represents 2-Me-Ph-, 3-Me-Ph, 4-Me-Ph, 4-F-Ph-, 4-Cl-Ph-, 4-CF 3 - Ph-, 2-furyl-, 2-thienyl-, 4-OCH 3 -Ph-, 3,4-OCH 3 O-Ph-, 3-vinyl-Ph-, CH 3 CH 2 -, CH- 3 CH 2 CH 2 CH 2 -, cyclohexyl-, or Ph-; and Y represents hydrogen.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F:
  • Q represents cyano, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl; and G represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents alkylcarbonyl, alkenylcarbonyl, or, aralkylcarbonyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents alkyloxy, aralkyloxy or alkenyloxy.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and G represents methyl, benzyl or allyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone is represented by F; and Q represents -C(O)CH 3 ; and G represents -CH 3 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 70 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 40 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 10 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said catalyst is present in less than about 5 mol% relative to said prochiral ⁇ -cyano ketone, prochiral ⁇ -keto ester, prochiral ⁇ -cyano ester, or prochiral 1,3-diketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic ⁇ -amino ⁇ -cyano ketone, chiral, non-racemic ⁇ -amino ⁇ -keto ester, chiral, non-racemic ⁇ -amino ⁇ -cyano ester or chiral, non-racemic ⁇ -amino 1,3-diketone has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • Nucleophiles which are useful in the present invention may be determined by the skilled artisan according to several criteria. Suitable nucleophiles can be chosen for each substrate and will vary according to the substrate structure and the desired product. Routine experimentation may be necessary to determine the preferred nucleophile for a given transformation. For example, if a nitrogen-containing nucleophile is desired, it may be selected from ammonia, phthalimide, hydrazine, an amine or the like.
  • oxygen nucleophiles such as water, hydroxide, alcohols, alkoxides, siloxanes, carboxylates, or peroxides may be used to introduce oxygen; and mercaptans, thiolates, bisulfite, thiocyanate and the like may be used to introduce a sulfur-containing moiety. Additional nucleophiles will be apparent to those of ordinary skill in the art.
  • the counterion can be any of a variety of conventional cations, including alkali and alkaline earth metal cations and ammonium cations, hi certain embodiments, the nucleophile may be part of the substrate, thus resulting in an intramolecular reaction.
  • substrates are useful in the methods of the present invention.
  • the choice of substrate will depend on factors such as the nucleophile to be employed and the desired product, and an appropriate substrate will be apparent to the skilled artisan. It will be understood that the substrate preferably will not contain any interfering functionalities.
  • an appropriate substrate will contain at least one reactive electrophilic center or moiety with distinct stereogenic faces. The catalyzed, stereoselective attack of the nucleophile at the electrophilic center will produce a chiral non- racemic product.
  • Most of the substrates contemplated for use in the methods of the present invention contain at least one carbonyl moiety.
  • suitable carbonyl-containing substrates which are susceptible to nucleophilic attack by the subject method include ketones, aldehydes, aldehyde-ketones, diketones, keto-esters, aldehyde-esters, and the like.
  • the electrophilic substrate will be a chiral compound. In certain embodiments, the substrate will be a racemic mixture. In certain embodiments, the substrate will be a mixture of diastereotners. In certain embodiments, the methods of the present invention effect a kinetic resolution, hi certain embodiments, the methods of the present invention effect a dynamic kinetic resolution. Reaction Conditions
  • the asymmetric reactions of the present invention may be performed under a wide range of conditions, though it will be understood that the solvents and temperature ranges recited herein are not limitative and only correspond to a preferred mode of the process of the invention. hi general, it will be desirable that reactions are run using mild conditions which will not adversely effect the substrate, the catalyst, or the product. For example, the reaction temperature influences the speed of the reaction, as well as the stability of the reactants, products, and catalyst. The reactions will usually be run at temperatures in the range of -78 0 C to 100 0 C, more preferably in the range -20 0 C to 50 0 C and still more preferably in the range -20 0 C to 25 0 C.
  • the asymmetric synthesis reactions of the present invention are carried out in a liquid reaction medium.
  • the reactions may be run without addition of solvent.
  • the reactions may be run in an inert solvent, preferably one in which the reaction ingredients, including the catalyst, are substantially soluble.
  • Suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or combinations of two or more solvents.
  • ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran and the like
  • halogenated solvents such as chlor
  • a solvent which is not inert to the substrate under the conditions employed, e.g., use of ethanol as a solvent when ethanol is the desired nucleophile.
  • the reactions can be conducted under anhydrous conditions. hi certain embodiments, ethereal solvents are preferred, hi embodiments where water or hydroxide are preferred nucleophiles, the reactions are run in solvent mixtures comprising an appropriate amount of water and/or hydroxide.
  • the invention also contemplates reaction in a biphasic mixture of solvents, in an emulsion or suspension, or reaction in a lipid vesicle or bilayer.
  • the reaction may be carried out under an atmosphere of a reactive gas.
  • desymmetrization with cyanide as nucleophile may be performed under an atmosphere of HCN gas.
  • the partial pressure of the reactive gas may be from 0.1 to 1000 atmospheres, more preferably from 0.5 to 100 ami, and most preferably from about 1 to about 10 atm.
  • the asymmetric synthesis processes of the present invention can be conducted in continuous, semi-continuous or batch fashion and may involve a liquid recycle and/or gas recycle operation as desired.
  • the processes of this invention are preferably conducted in batch fashion.
  • the manner or order of addition of the reaction ingredients, catalyst and solvent are also not critical and may be accomplished in any conventional fashion.
  • the reaction can be conducted in a single reaction zone or in a plurality of reaction zones, in series or in parallel or it may be conducted batchwise or continuously in an elongated tubular zone or series of such zones.
  • the materials of construction employed should be inert to the starting materials during the reaction and the fabrication of the equipment should be able to withstand the reaction temperatures and pressures.
  • Means to introduce and/or adjust the quantity of starting materials or ingredients introduced batchwise or continuously into the reaction zone during the course of the reaction can be conveniently utilized in the processes especially to maintain the desired molar ratio of the starting materials.
  • the reaction steps may be effected by the incremental addition of one of the starting materials to the other. Also, the reaction steps can be combined by the joint addition of the starting materials to the optically active metal-ligand complex catalyst.
  • the starting materials can be separated from the product and then recycled back into the reaction zone.
  • the processes may be conducted in either glass lined, stainless steel or similar type reaction equipment.
  • the reaction zone may be fitted with one or more internal and/or external heat exchanger(s) in order to control undue temperature fluctuations, or to prevent any possible "runaway" reaction temperatures.
  • the chiral catalyst can be immobilized or incorporated into a polymer or other insoluble matrix by, for example, covalently linking it to the polymer or solid support through one or more of its substituents.
  • An immobilized catalyst may be easily recovered after the reaction, for instance, by filtration or centrifugation.
  • 1 H and 13 C NMR spectra were recorded on a Varian instrument (400 MHz and 100 MHz, respectively) and internally referenced to tetramethylsilane signal or residual protic solvent signals.
  • Data for 1 H NMR are recorded as follows: chemical shift ( ⁇ , ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), integration, coupling constant (Hz).
  • Data for 13 C NMR are reported in terms of chemical shift ( ⁇ , ppm).
  • Infrared spectra were recorded on a Perkin Elmer FT-IR Spectrometer and are reported in frequency of absorption.
  • the reaction mixture was transferred to a separatory funnel and the turquoise blue aqueous phase separated from the dark brown organic phase.
  • the aqueous layer was washed twice with methylene chloride (100 mL), and the combined organic phases were extracted three times with aqueous ammonia solution (200 mL, 5%, w/w) until the aqueous phase remained colorless.
  • the organic layer was washed with HCl aq (1 N 2 x 50 mL) twice and washed with H 2 O three times (3 x 50 mL) to remove the left QD.
  • the organic layer was washed with NH 4 OH to neutralize the salt and dried over Na 2 SO 4 and the solvent was removed in vacuo to yield the crude product.
  • Zinc (150 mg, 2.3 mmol, powder) was added to a solution of 3 (80.0 mg, 0.3 mmol) in diethyl ether (1.5 mL). To the resulting suspension, AcOH (1.5 mL) was added in one portion. The resulting mixture was stirred at room temperature for 24h. Zinc powder was removed by silica gel-cotton plug and 4 was washed out from the plug by diethyl ether. The combined ether was washed with water, saturated NaHCO 3 and brine, dried over Na 2 SO 4 , concentrated to give colorless oil 4. Dinitrile 4 was diluted with diethyl ether and subjected to HPLC analysis directly.

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Abstract

Un aspect de cette invention concerne des catalyseurs à base de quinine et de quinidine. Dans certains modes de réalisation, les catalyseurs à base de quinine et de quinidine contiennent un groupe hydroxy en position 6'. Dans d'autres modes de réalisation, les catalyseurs à base de quinine et de quinidine contiennent un groupe O-aryle ou un groupe O-aroyle en position C9. Dans d'autres modes de réalisation, les catalyseurs à base de quinine et de quinidine contiennent un groupe O-diazène éventuellement substitué ou un groupe O-benzoyle éventuellement substitué en position C9. Dans d'autres modes de réalisation encore, les catalyseurs à base de quinine et de quinidine contiennent une thiourée en position C9. Dans d'autres modes de réalisation enfin, les catalyseurs à base de quinine et de quinidine contiennent un groupe NH(=S)NH-aryle en position C9. Un autre aspect de cette invention concerne un procédé de préparation d'un composé non racémique chiral, à partir d'un alcène déficient en électron prochiral ou d'une imine prochirale, ce procédé comprenant les étapes consistant à faire réagir un alcène prochiral ou une imine prochirale avec un nucléophile en présence d'un catalyseur, produisant ainsi un composé non racémique chiral, ce catalyseur étant une quinine ou quinidine dérivée. Dans certains modes de réalisation, le nucléophile est un malonate ou un ß-cétoester. Dans d'autres modes de réalisation, le nucléophile est un alkyle ou aryle ou aralkyle 2-cyano-2-alkylacétate. Dans d'autres modes de réalisation encore, le nucléophile est un alkyle ou aryle ou aralkyle 2-cyano-2-aryleacétate. Un autre aspect de cette invention concerne un procédé de résolution cinétique comprenant l'étape consistant à faire réagir un aldéhyde racémique ou une cétone racémique avec un nucléophile en présence d'une quinine ou quinidine dérivée, ce qui permet de produire un composé chiral non racémique. Dans certains modes de réalisation, la résolution cinétique est dynamique.
PCT/US2006/020324 2005-05-27 2006-05-26 Reactions asymetriques formatrices de liaison carbone-carbone catalysees par des alcaloides quinquina bifonctionnels Ceased WO2006130437A2 (fr)

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JP2008163022A (ja) * 2006-12-20 2008-07-17 Brandeis Univ シンコナアルカロイド触媒不斉マンニッヒ反応
JP2011523654A (ja) * 2008-06-05 2011-08-18 ディーエスエム アイピー アセッツ ビー．ブイ． （４ｓ，５ｒ）−ハーフエステルの調製方法
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains

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US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
CA2905242C (fr) 2013-03-15 2016-11-29 Pfizer Inc. Composes indoliques activant l'ampk

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EP1429771B1 (fr) * 2001-08-30 2009-08-12 ChemoCentryx Inc Composes bicycliques servant d'inhibiteurs de chimiokine se fixant a l'us28

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008163022A (ja) * 2006-12-20 2008-07-17 Brandeis Univ シンコナアルカロイド触媒不斉マンニッヒ反応
JP2011523654A (ja) * 2008-06-05 2011-08-18 ディーエスエム アイピー アセッツ ビー．ブイ． （４ｓ，５ｒ）−ハーフエステルの調製方法
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains

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