[go: up one dir, main page]

WO2006130453A1 - Additions d'aldol asymetrique au moyen de catalyseurs a base d'alcaloide de quinquina bifonctionnels - Google Patents

Additions d'aldol asymetrique au moyen de catalyseurs a base d'alcaloide de quinquina bifonctionnels Download PDF

Info

Publication number
WO2006130453A1
WO2006130453A1 PCT/US2006/020376 US2006020376W WO2006130453A1 WO 2006130453 A1 WO2006130453 A1 WO 2006130453A1 US 2006020376 W US2006020376 W US 2006020376W WO 2006130453 A1 WO2006130453 A1 WO 2006130453A1
Authority
WO
WIPO (PCT)
Prior art keywords
certain embodiments
present
alkenyl
alkyl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2006/020376
Other languages
English (en)
Inventor
Li Deng
Hongming Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Brandeis University
Original Assignee
Brandeis University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/140,574 external-priority patent/US7312335B2/en
Application filed by Brandeis University filed Critical Brandeis University
Priority to JP2008513745A priority Critical patent/JP2008545706A/ja
Publication of WO2006130453A1 publication Critical patent/WO2006130453A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • 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
    • B01J31/0201—Oxygen-containing compounds
    • B01J31/0209—Esters of carboxylic or carbonic acids
    • 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
    • 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
    • B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/12—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • 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
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • 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 1960s 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 commercial price (Aldrich Chemical Company) for a mole of (DHQD) 2 AQN is more than $100,000.00.
  • 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 monomeric 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.
  • Wynberg and coworkers demonstrated that natural cinchona alkaloids, via their CP-OH and amine groups, served as bifunctional chiral organic catalysts for enantioselective reactions by activating the nucleophile and electrophile, respectively.
  • the nitroaldol reaction constitutes an important class of C-C bond forming reactions that provides straightforward access to important synthetic intermediates from readily accessible nitroalkanes and carbonyl compounds.
  • Henry reaction constitutes an important class of C-C bond forming reactions that provides straightforward access to important synthetic intermediates from readily accessible nitroalkanes and carbonyl compounds.
  • the enantioselectivity was high for reactions with aryl ⁇ -keto ethyl esters bearing an electron-withdrawing group on the aromatic ring, it became moderate when the electron- withdrawing group was replaced with an electron-donating substituent.
  • the enantioselectivity could be either high or modest.
  • synthetically useful enantioselectivity was not attainable.
  • One aspect of the present invention relates to asymmetric catalytic nitroaldol (Henry) reactions with ketones as the electrophilic component.
  • the present invention relates to asymmetric nitroaldol reactions with ⁇ -keto esters catalyzed by a new C6'-OH cinchona alkaloid catalyst.
  • this reaction is operationally simple and affords high enantioselectivity as well as good to excellent yield for an exceptionally broad range of ⁇ -keto esters.
  • Another aspect of the invention relates to a method of preparing a derivatized quinine- or quinidine-based catalyst comprising 1) reacting quinine or quinidine with base and a compound that has a suitable leaving group, and 2) converting the ring methoxy group to a hydroxy group.
  • the leaving group is Cl 5 Br, I, OSO 2 CH 3 , or OSO 2 CF 3 .
  • the leaving group is Cl or I.
  • the base is a trialkyl amine.
  • the hydroxyl group of the quinine- or quinidine-based catalyst undergoes reaction with an benzoyl halide.
  • Another aspect of the present invention relates to a method of preparing a chiral, non-racemic alcohol from a prochiral aldehyde or prochiral ketone, comprising the step of: reacting a prochiral aldehyde or prochiral ketone with a nucleophile in the presence of a catalyst; thereby producing a chiral, non-racemic alcohol; wherein said catalyst is a derivatized quinine or quinidine.
  • the nucleophile is a nitroalkane. In certain embodiments the nucleophile is nitromethane.
  • the prochiral aldehyde or prochiral ketone is an electron- deficient prochiral aldehyde or prochiral ketone. In certain embodiments, the prochiral aldehyde or prochiral ketone is an ⁇ -keto ester. In certain embodiments, the prochiral aldehyde or prochiral ketone is an ⁇ -keto ethyl ester. In certain embodiments, the prochiral aldehyde or prochiral ketone is an alkenyl ⁇ -keto ethyl ester.
  • the catalyst is present in less than about 70 mol% relative to said prochiral aldehyde or prochiral ketone, hi certain embodiments, the catalyst is present in less than about 40 mol% relative to said prochiral aldehyde or prochiral ketone, hi certain embodiments, the catalyst is present in less than about 10 mol% relative to said prochiral aldehyde or prochiral ketone. In certain embodiments, the catalyst is present in less than about 5 mol% relative to said prochiral aldehyde or prochiral ketone.
  • the chiral, non-racemic alcohol has an enantiomeric excess or diastereomeric excess greater than about 50%.
  • the chiral, non-racemic alcohol has an enantiomeric excess or diastereomeric excess greater than about 70%.
  • the chiral, non-racemic alcohol has an enantiomeric excess or diastereomeric excess greater than about 90%.
  • the chiral, non-racemic alcohol has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • the chiral, non- racemic alcohol has an enantiomeric excess or diastereomeric excess greater than about 97%.
  • Another aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting racemic chiral ketone or aldehyde with a nucleophile in the presence of a derivatized quinine or quinidine.
  • the nucleophile is a nitroalkane. In certain embodiments, the nucleophile is nitromethane.
  • Figure 2 depicts the bifunctional nature of several cinchona-alkaloid-based catalysts of the present invention
  • R H (a); Bn (b); PHN (c); or Bz (d).
  • Figure 3 depicts enantioselective nitroaldol addition of nitromethane to an ⁇ -keto ester. Unless noted, reactions were carried out with 0.1 mmol of 2a, 1 mmol CH 3 NO 2 in 0.1 mL CH 2 Cl 2 with 10 mol% catalyst at -20 0 C for 12 h. Ratio of 3a/3a' were determined by 1 H NMR analysis. Enantiomeric excess for 3a was determined by HPLC analysis.
  • Figure 4 depicts enantioselective nitroaldol addition of nitromethane to ⁇ -keto ester 2 catalyzed by QD-Id and Q-Id.
  • Figure 5 depicts asymmetric syntheses of ⁇ -lactam, aziridine and ⁇ - methylcysteine derivatives. Key: (a) Raney Ni, H 2 (latm); (b) i-PrMgCl, 38% yield over 2 steps; (c) TfN 3 , CuSO 4 (cat.), for 6c, 84 % yield over 2 steps; for 6j, 63% yield over 2 steps; (d) PPh 3 , CH 3 CN, for 7c, 80% yield; for 7j, 71% yield; (e) BF 3 -Et2O,;?- methoxybenzyl mercaptan, 56% yield.
  • Figure 6 depicts schematics for the preparation of catalyst Q-Id and catalyst QD- Id. For additional details, see the Exemplification, Examples 1 and 2.
  • Figure 7 depicts the results of bifunctional-cinchona-alkaloid-catalyzed enantioselective additions of nitromethane to aldehydes.
  • Figure 8 depicts the results of bifunctional-cinchona-alkaloid-catalyzed enantioselective additions of nitromethane to trifluoromethyl ketones and alpha-diketones.
  • Figure 9 depicts the results of bifunctional-cinchona-alkaloid-catalyzed enantioselective additions of nitromethane, nitroethane, nitropropane and ethyl 3- nitropropanoate to the aldehyde carbonyl moiety of ethyl glyoxalate.
  • Figure 10 depicts the results of the bifunctional-cinchona-alkaloid-catalyzed enantioselective addition of nitromethane to ethyl 2-oxo-2-phenylacetate; and the bifunctional-cinchona-alkaloid-catalyzed dynamic kinetic resolution of diethyl 2-oxo-3- methylsuccinate with nitromethane as the nucleophile.
  • Figure 11 depicts selected C& or C9 thiourea chincona alkaloid derivatives which may be used as catalysts in the inventive methods.
  • 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.
  • Organometallic 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.
  • Electrophile 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.
  • electron-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 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 or both.
  • the term “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 0.001 to 50 mole percent, still more preferably from 0.01 to 10 mole percent, and even more preferably from 0.1 to 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.
  • An enantioselective reaction yields a product with an ee greater than zero.
  • Preferred enantioselective reactions yield a product with an ee greater than 20%, more preferably greater than 50%, even more preferably greater than 70%, and most preferably greater than 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-raceniic 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 enantiomerically-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.
  • 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 75%. “Substantially non-racemic” refers to preparations of the catalyst which have greater than
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • alkyl is art-recognized, and includes 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 about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chain, C 3 -C 3O for branched chain), and alternatively, about 20 or fewer.
  • cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • alkyl is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or “heteroaromatics.”
  • the aromatic ring may be substituted at one or more ring positions with such substituents as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings maybe cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively.
  • 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
  • heterocyclyl refers to 3- to about 10-membered ring structures, alternatively 3- to about 7- membered rings, whose ring structures include one to four heteroatoms.
  • Heterocycles may also be polycycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • polycyclyl or “polycyclic group” are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • the term "carbocycle” is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • nitro is art-recognized and refers to -NO 2 ;
  • halogen is art- recognized and refers to -F, -Cl, -Br or -I;
  • sulfhydryl is art-recognized and refers to -SH;
  • hydroxyl means -OH;
  • sulfonyl is art-recognized and refers to -SO 2 " .
  • Halide designates the corresponding anion of the halogens, and "pseudohalide” has the definition set forth on page 560 of "Advanced Inorganic Chemistry" by Cotton and Wilkinson.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that maybe represented by the general formulas:
  • R50, R51, R52 and R53 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R61, or R50 and R51 or R52, 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 ) m -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.
  • 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.
  • 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 fo ⁇ nula represents a "thiolcarbonyl” group.
  • the formula represents a "thiolester.”
  • the formula represents a "thiolcarboxylic acid.”
  • 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.
  • Representative 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, -O-alkynyl, -O-(CH 2 ) m -R61, where m and R61 are described above.
  • sulfonate is art recognized and refers to a moiety that may be represented by the general formula: in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • R50 O in which R50 and R56 are as defined above.
  • 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:
  • R58 is defined above.
  • 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.
  • (-)-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:
  • 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.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafiuorobutanesulfonyl, p-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.
  • 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 nonaroniatic 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 catalysts employed in the subject methods are non-racemic chiral amines which present an asymmetric environment, causing stereochemical discrimination between two stereogenic faces of a carbonyl moiety; 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 a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • 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
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R 4 represents -OH.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents aryl or heteroaryl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents aryl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents substituted or unsubstituted phenyl. In certain embodiments, the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents mono-substituted phenyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R represents unsubstituted phenyl.
  • 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.
  • 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 m is 0.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R is aryl and R 1 is alkyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R is unsubstituted phenyl 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 aryl and R 1 is alkenyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkenyl.
  • the compounds of the present invention are represented by formula I and any of the attendant definitions, wherein R is aryl, R 1 is alkyl, 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 is substituted or unsubstituted phenyl, R 1 is alkyl, m is 0, and n 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 unsubstituted phenyl, 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 is aryl, R 1 is alkenyl, m 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 substituted or unsubstituted phenyl, R 1 is alkenyl, m is 0, and n is 0.
  • Another aspect of the present invention relates to a compound represented by formula II:
  • R represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • 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
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R 4 represents -OH.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents aryl or heteroaryl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents aryl. In certain embodiments, the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents substituted or unsubstituted phenyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents mono-substituted phenyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R represents unsubstituted phenyl.
  • 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 n is O. In certain embodiments, 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 aryl and Ri is alkyl. In certain embodiments, the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and Ri is alkyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R is unsubstituted phenyl and Ri is ethyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R is aryl and R 1 is alkenyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkenyl.
  • the compounds of the present invention are represented by formula II and any of the attendant definitions, wherein R is aryl, R 1 is alkyl, 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 substituted or unsubstituted phenyl, R 1 is alkyl, 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 unsubstituted phenyl, 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 aryl, Ri is alkenyl, 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 substituted or unsubstituted phenyl, R 1 is alkenyl, m is 0, and n is 0.
  • One aspect of the invention relates to a method of preparing a bifunctional catalyst as depicted in Scheme 1 :
  • R represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • R 1 represents -Si(R") 3 , aralkyl or tetrahydropyranyl;
  • R" represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • 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 O to 5 inclusive; m is an integer from 0 to 8 inclusive; base is a Bronsted base; and acid is a Bronsted acid.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein X is Cl or I. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said base is a trialkyl amine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said base is triethylamine. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said acid is HF, HCl, HBr, HI, HNO 3 , or H 2 SO 4 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said acid is HF. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl or heteroaryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents substituted or unsubstituted phenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents mono-substituted phenyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents unsubstituted phenyl.
  • 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 m is 0. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R' represents -Si(R") 3 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R' represents -Si(R") 3 ; and R" represents alkyl or aryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl and R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is unsubstituted phenyl and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl and R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl, R 1 is alkyl, 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 substituted or unsubstituted phenyl, R 1 is alkyl, m is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is unsubstituted phenyl, 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 aryl, R 1 is alkenyl, m is 0, and n is O. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl, R 1 is alkenyl, m is 0, and n is 0.
  • Another aspect of the invention relates to a method of preparing a bifunctional catalyst as depicted in Scheme 2:
  • X represents Cl, Br, I, OSO 2 CH 3 , or OSO 2 CF 3 ;
  • R represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • R' represents -Si(R") 3 , aralkyl or tetrahydropyranyl;
  • R" represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • 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; base is a Bronsted base; and acid is a Bronsted acid.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein X is Cl or I.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said base is a trialkyl amine. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said base is triethylamine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said acid is HF, HCl, HBr, HI, HNO 3 , or H 2 SO 4 . In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said acid is HF.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl or heteroaryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents substituted or unsubstituted phenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents mono-substituted phenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents unsubstituted phenyl.
  • 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 n is 0. In 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 R' represents -Si(R") 3 . In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R' represents -Si(R") 3 ; and R" represents alkyl or aryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R' represents -Si(R") 3 ; and R" is i-Pr. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl and R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is unsubstituted phenyl and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl and R 1 is alkenyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl, R 1 is alkyl, m is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl, R 1 is alkyl, 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 unsubstituted phenyl, 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 aryl, R 1 is alkenyl, m is 0, and n is O.
  • the invention features a stereoselective nucleophilic addition process which comprises combining a nucleophile, a prochiral or chiral substrate, and at least a catalytic amount of non-racemic chiral catalyst of particular characteristics (as described herein).
  • the substrate of the reaction will include carbonyls susceptible to attack by the nucleophile.
  • the combination is maintained under conditions appropriate for the chiral catalyst to catalyze the nucleophilic addition between the nucleophilic reactant and carbonyl-containing substrate (e.g., an ⁇ -keto ester).
  • This reaction can be applied to enantioselective processes as well as diastereoselective processes. It may also be adapted for regioselective reactions. Examples of enantioselective reactions, kinetic resolutions, and regioselective reactions which may be catalyzed according to the present invention follow.
  • the processes of this invention can provide optically active products with very high stereoselectivity (e.g., enantioselectivity or diastereoselectivity) or regioselectivity.
  • very high stereoselectivity e.g., enantioselectivity or diastereoselectivity
  • regioselectivity e.g., acetylcholine
  • products with enantiomeric excesses of greater than about 50%, greater than about 70%, greater than about 90%, and most preferably greater than about 95% can be obtained.
  • the processes 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.
  • the chiral products produced by the asymmetric synthesis processes of this invention can undergo further reaction(s) to afford desired derivatives thereof (e.g., Scheme 3).
  • Such permissible derivatization reactions can be carried out in accordance with conventional procedures known in the art.
  • potential nitro-derivatization reactions include the Nef reaction, the nucleophilic displacement, the reduction to amino group, the Myer reaction, the conversion into a nitrile oxide, and the like.
  • the invention expressly contemplates the preparation of end- products and synthetic intermediates which are useful for the preparation or development or both of therapeutic compounds.
  • One aspect of the present invention relates to a method of preparing a chiral, non- racemic alcohol from a prochiral aldehyde or prochiral ketone, comprising the step of: reacting a prochiral aldehyde or prochiral ketone with a nitroalkane in the presence of a catalyst; thereby producing a chiral, non-racemic alcohol; 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.
  • n is an integer from 0 to 5 inclusive
  • m is an integer from 0 to 8 inclusive
  • 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.
  • 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. In certain embodiments, 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. In certain embodiments, 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.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said nitroalkane is nitromethane, nitroethane, nitropropane or nitrobutane.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said nitroalkane is nitromethane or nitroethane.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said nitroalkane is nitromethane.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by A:
  • X represents alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and Z represents H, perfluoroalkyl, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by A; and Z represents H or trifluoromethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by B :
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino;
  • J represents H, perfluoroalkyl, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and G and J may be connected by a covalent bond to form a 4, 5, 6, 7, or 8-membered ring.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by B; and J represents H.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by B; and B represents cyclobutane-l,2-dione, cyclopentane-1,2- dione, cyclohexane- 1 ,2-dione, cycloheptane- 1 ,2-dione, or cyclooctane- 1 ,2-dione.
  • 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 aldehyde or prochiral ketone.
  • 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 aldehyde or prochiral ketone.
  • 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 aldehyde or prochiral ketone.
  • 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 aldehyde or prochiral ketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic alcohol 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 alcohol 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 alcohol 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 alcohol has an enantiomeric excess or diastereomeric excess greater than about 95%.
  • One aspect of the present invention relates to a method of preparing a cliiral, non- racemic alcohol from a prochiral aldehyde or prochiral ketone, comprising the step of: reacting a prochiral aldehyde or prochiral ketone with a nitroalkane in the presence of a catalyst; thereby producing a chiral, non-racemic alcohol; 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.
  • 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 is phenanthrene and R 1 is ethyl. In certain embodiments, 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 is phenanthrene; 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 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.
  • R represents 4-chlorobenzoyl; 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 nitroalkane is nitromethane, nitroethane, nitropropane or nitrobutane.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said nitroalkane is nitromethane or nitroethane. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said nitroalkane is nitromethane.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by A:
  • X represents alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl
  • Z represents H, perfluoroalkyl, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by A; and Z represents H or trifluoromethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by B :
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino;
  • J represents H, perfluoroalkyl, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
  • G and J may be connected by a covalent bond to form a 4, 5, 6, 7, or 8-membered ring.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by B; and J represents H.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by B; and B represents cyclobutane-l,2-dione, cyclopentane-1,2- dione, cyclohexane-l,2-dione, cycloheptane-l,2-dione, or cyclooctane-l,2-dione.
  • 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 aldehyde or prochiral ketone.
  • 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 aldehyde or prochiral ketone.
  • 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 aldehyde or prochiral ketone.
  • 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 aldehyde or prochiral ketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic alcohol has an enantiomeric excess or diastereomeric excess greater than about 50%. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic alcohol 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 alcohol 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 alcohol 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 alcohol from a prochiral aldehyde or prochiral ketone, comprising the step of: reacting a prochiral aldehyde or prochiral ketone with a nucleophile in the presence of a catalyst; thereby producing a chiral, non-racemic alcohol; wherein said catalyst is represented by formula III:
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • nucleophile is represented by formula IV:
  • Rb represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • Rc represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 represents -OH.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl or heteroaryl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents substituted or unsubstituted phenyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents mono-substituted phenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents unsubstituted phenyl. In certain embodiments, 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.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl and R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is unsubstituted phenyl and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl and R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl, R 1 is alkyl, m is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl, R 1 is alkyl, m is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is unsubstituted phenyl, 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 aryl, R 1 is alkenyl, m is 0, and n is O.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl, R 1 is alkenyl, m is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R], is H. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R a is alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R a is alkyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein E is -NO 2 , R a is alkyl, and R b is H. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein E is -NO 2 , R a is H, and R b is H. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is electron-deficient. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by formula V:
  • W represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl.
  • the present invention relates to the aforementioned method, wherein Y is alkyl, alkenyl, aryl, or aralkyl.
  • 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 aldehyde or prochiral ketone.
  • 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 aldehyde or prochiral ketone. 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 aldehyde or prochiral ketone.
  • 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 aldehyde or prochiral ketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic alcohol 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 alcohol 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 alcohol has an enantiomeric excess or diastereomeric excess greater than about 90%. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic alcohol has an enantiomeric excess or diastereomeric excess greater than about 95%. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic alcohol has an enantiomeric excess or diastereomeric excess greater than about 97%.
  • Another aspect of the present invention relates to a method of preparing a chiral, non-racemic alcohol from a prochiral aldehyde or prochiral ketone, comprising the step of: reacting a prochiral aldehyde or prochiral ketone with a nucleophile in the presence of a catalyst; thereby producing a chiral, non-racemic alcohol; wherein said catalyst is represented by formula VI:
  • 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 b represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • R 0 represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 represents -OH.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl or heteroaryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents substituted or unsubstituted phenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents mono-substituted phenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents unsubstituted phenyl.
  • 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.
  • 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 aryl and R 1 is alkyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and Ri is alkyl. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is unsubstituted phenyl and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl and R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl, R 1 is alkyl, m is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl, Ri is alkyl, m is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein E is -NO 2 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R b is H.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R a is alkyl, aralkyl or heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 3 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein E is -NO 2 , R a is alkyl, and R b is H.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein E is -NO 2 , R a is H, and R b is H.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is electron-deficient.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by formula V:
  • Y represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • Z represents -CF 3 , -C(O)OW, -C(O)N(W) 2 , -C(O)SW, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl; and W represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl.
  • 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 aldehyde or prochiral ketone.
  • 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 aldehyde or prochiral ketone.
  • 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 aldehyde or prochiral ketone.
  • 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 aldehyde or prochiral ketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic alcohol 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 alcohol has an enantiomeric excess or diastereomeric excess greater than about 70%. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic alcohol 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 alcohol 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 said chiral, non-racemic alcohol has an enantiomeric excess or diastereomeric excess greater than about 97%.
  • Another aspect of the present invention relates to any one of the aforementioned methods of preparing a cliiral, non-racemic alcohol from a prochiral aldehyde or prochiral ketone, wherein said catalyst is not represented by formula III or formula VI, but instead is represented by formula VII or formula VIII:
  • 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 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • Another aspect of the present invention relates to any one of the aforementioned methods of preparing a chiral, non-racemic alcohol from a prochiral aldehyde or prochiral ketone, wherein said catalyst is not represented by formula III or formula VI, but instead is represented by formula IX or formula X:
  • 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 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 said catalysts are selected from one of the six catalysts shown in Figure 29.
  • a kinetic resolution of enantiomers or diastereomers of the substrate or the nucleophile occurs by catalysis, using a subject chiral catalyst, of the transformation of a racemic substrate.
  • a subject chiral catalyst In the subject kinetic resolution processes for a racemic substrate, one enantiomer can be recovered as unreacted substrate while the other is transformed to the desired product.
  • the kinetic resolution can be performed by removing the undesired enantiomer by reaction with a nucleophile, and recovering the desired enantiomer unchanged from the reaction mixture.
  • the subject catalysts may be used in kinetic resolutions of racemic substrates comprising a carbonyl moiety.
  • One 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 nitroalkane in the presence of a catalyst; thereby producing a chiral, non-racemic alcohol; 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. In certain embodiments, 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. In certain embodiments, 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.
  • 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.
  • 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 O.
  • 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 nitroalkane is nitromethane, nitroethane, nitropropane or nitrobutane. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said nitroalkane is nitromethane or nitroethane.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said nitroalkane is nitromethane. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic aldehyde or racemic ketone is represented by A:
  • X represents alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl
  • Z represents H, perfluoroalkyl, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic aldehyde or racemic ketone is represented by A; and Z represents H or trifluoromethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic aldehyde or racemic ketone is represented by B:
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino;
  • J represents H, perfluoroalkyl, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and G and J may be connected by a covalent bond to form a 4, 5, 6, 7, or 8-membered ring.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic aldehyde or racemic ketone is represented by B; and J represents H.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic aldehyde or racemic ketone is represented by B; and B represents cyclobutane-l,2-dione, cyclopentane-1,2- dione, cyclohexane- 1 ,2-dione, cycloheptane- 1 ,2-dione, or cyclooctane- 1 ,2-dione.
  • 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 aldehyde or racemic ketone.
  • 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 aldehyde or racemic ketone.
  • 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 aldehyde or racemic ketone. 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 aldehyde or racemic ketone.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic alcohol has an enantiomeric excess or diastereomeric excess greater than about 50%. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic alcohol 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 alcohol 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 alcohol 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 aldehyde or ketone 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 aldehyde or ketone 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 aldehyde or racemic ketone with a nitroalkane in the presence of a catalyst; thereby producing a chiral, non-racemic alcohol; 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.
  • 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. In certain embodiments, 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.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said nitroalkane is nitromethane, nitroethane, nitropropane or nitrobutane. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said nitroalkane is nitromethane or nitroethane.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said nitroalkane is nitromethane. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic aldehyde or racemic ketone is represented by A:
  • X represents alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and Z represents H, perfluoroalkyl, alkyl, aryl, heteroaryl, arallcyl, or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic aldehyde or racemic ketone is represented by A; and Z represents H or trifluoromethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic aldehyde or racemic ketone is represented by B :
  • G represents alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxyl, aryloxyl, heteroaryloxyl, aralkoxyl, heteroaralkoxyl, alkylamino, arylamino, aralkylamino, or heteroaralkylamino ;
  • J represents H, perfluoroalkyl, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and G and J may be connected by a covalent bond to form a 4, 5, 6, 7, or 8-membered ring.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic aldehyde or racemic ketone is represented by B; and J represents H.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said racemic aldehyde or racemic ketone is represented by B; and B represents cyclobutane-l,2-dione, cyclopentane-1,2- dione, cyclohexane- 1 ,2-dione, cycloheptane- 1 ,2-dione, or cyclooctane- 1 ,2-dione.
  • 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 aldehyde or racemic ketone.
  • 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 aldehyde or racemic ketone.
  • 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 aldehyde or racemic ketone. 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 aldehyde or racemic ketone. hi certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said chiral, non-racemic alcohol 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 alcohol 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 alcohol 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 alcohol has an enantiomeric excess or diastereomeric excess greater than about 95%. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein when said method is completed or interrupted the unreacted aldehyde or ketone 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 aldehyde or ketone 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 aldehyde or ketone with a nucleophile in the presence of a catalyst 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; n is an integer from 0 to 5 inclusive; m is an integer from 0 to 8 inclusive; and
  • R b represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, arallcyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • R 0 represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 represents -OH.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl or heteroaryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents substituted or unsubstituted phenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents mono-substituted phenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents unsubstituted phenyl.
  • 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.
  • 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 aryl and R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is unsubstituted phenyl and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl and R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl, R 1 is alkyl, m is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is unsubstituted phenyl, 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 aryl, R 1 is alkenyl, m is 0, and n is O.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl, R 1 is alkenyl, ni is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R b is H. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R a is alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R a is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein E is -NO 2 , R a is alkyl, and R b is H.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein E is -NO 2 , R a is H, and R b is H.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said aldehyde or ketone is electron- deficient.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by formula V:
  • Y represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • W represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl.
  • the present invention relates to the aforementioned method, wherein Y is alkyl, alkenyl, aryl, or aralkyl.
  • 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 aldehyde or ketone.
  • 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 aldehyde or ketone.
  • 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 aldehyde or ketone.
  • Another aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic aldehyde or ketone with a micleophile in the presence of a catalyst represented by formula VI:
  • R 1 represents a substituted or unsubstituted alkyl or alkenyl
  • nucleophile is represented by formula IV:
  • R b represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl; and
  • R 0 represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R 4 represents -OH.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl or heteroaryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents aryl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents substituted or unsubstituted phenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents mono-substituted phenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R represents unsubstituted phenyl.
  • 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 n is 0.
  • 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 aryl and R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is unsubstituted phenyl and R 1 is ethyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl and R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl and R 1 is alkenyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is aryl, R 1 is alkyl, m is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl, R 1 is alkyl, m is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is unsubstituted phenyl, 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 aryl, R 1 is alkenyl, m is 0, and n is O. m certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R is substituted or unsubstituted phenyl, R 1 is alkenyl, m is 0, and n is 0.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein E is -NO 2 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R b is H. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein R a is alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein R a is alkyl.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein E is -NO 2 , R a is alkyl, and R b is H.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein E is -NO 2 , R a is H, and R b is H.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said aldehyde or ketone is electron- deficient.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said prochiral aldehyde or prochiral ketone is represented by formula V:
  • Y represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl;
  • Z represents -CF 3 , -C(K ) )OW, -C(K ) )N(W) 2 , -C(K ) )SW, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl; and
  • W represents H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, or heterocycloalkyl.
  • the present invention relates to the aforementioned method, wherein Y is alkyl, alkenyl, aryl, or aralkyl.
  • the present invention relates to the aforementioned method, wherein Z is -C(K))OW. In certain embodiments, the present invention relates to the aforementioned method, wherein Z is -C(K))OW, and W is alkyl. hi certain embodiments, the present invention relates to the aforementioned method, wherein Z is -C(K))OEt. hi 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 70 mol% relative to said aldehyde or ketone.
  • 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 aldehyde or ketone.
  • 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 aldehyde or ketone.
  • 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 aldehyde or ketone.
  • Another aspect of the present invention relates to any one of the aforementioned methods of kinetic resolution, wherein said catalyst is not represented by formula III or formula VI, but instead is represented by formula VII or formula VIII:
  • 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 6 inclusive; and m is an integer from 0 to 8 inclusive.
  • Another aspect of the present invention relates to any one of the aforementioned methods of kinetic resolution, wherein said catalyst is not represented by formula III or formula VI, but instead is represented by formula IX or formula X:
  • 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 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 said catalysts are selected from one of the six catalysts shown in Figure 29.
  • Nucleophiles 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.
  • the nucleophile may be a primary, secondary, or tertiary nucleophile.
  • 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; or at least two electrophilic moieties related by an internal plane or point of symmetry or both at which a nucleophile may attack with the assistance of the catalyst. The catalyzed, stereoselective attack of the nucleophile at the electrophilic center will produce a chiral, non-racemic product.
  • the substrates contemplated for use in the methods of the present invention contain at least one carbonyl.
  • the carbonyl-containing substrate in some embodiments, will additionally comprise an electron withdrawing group making the carbonyl more susceptible to nucleophilic attack.
  • suitable carbonyl- containing substrates which are susceptible to nucleophilic attack by the subject method include ⁇ -keto esters.
  • 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.
  • 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.
  • ethereal solvents are preferred.
  • 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. In certain embodiments, it may be preferred to perform the catalyzed reactions in the solid phase.
  • the reaction may be carried out under an atmosphere of a reactive gas.
  • a reactive gas For example, 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 atm, 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. When complete conversion is not desired or not obtainable, 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.
  • catalysts 1 could serve as acid-base bifunctional catalysts via hydrogen bonding interactions with the Michael donor and acceptor via the quinuclidine nitrogen and the C6'-OH, respectively ( Figure 2).
  • nitromethane is added to alkenyl ⁇ -keto ester 2a.
  • Infrared spectra were recorded on a Perkin Elmer FT-IR Spectrometer and are reported in frequency of absorption. Low resolution mass spectra for all the new compounds were performed by 70SE CI+, and were recorded and exact mass spectra on a 70- VSE-B high resolution mass spectrometer. Specific rotations were measured on a Jasco Digital Polarimeter. High performance liquid chromatography (HPLC) analysis was performed on a Hewlett-Packard 1100 Series instrument equipped with a quaternary pump, using a Daicel Chiralcel OJ, OD Column (250 x 4.6 mm) or Chiralpak AD, AS Column (250 x 4.6 mm). UV absorption was monitored at 220 nm or at 280 nm.
  • HPLC high performance liquid chromatography
  • ⁇ -keto esters 2a and 2b were prepared according to literature procedures. Jesen, K. B.; Thorhauge, J.; Hazell, R. G.; J ⁇ rgensen, K. A. Angew. Chem. Int. Ed. 2001, 40, 160-163.
  • the other ⁇ -keto esters 2 were commercially available and purified by flash chromatography (silica gel 60, 0.040 mm to 0.063 mm, purchased from EM SCIENCE Inc.) before they were used for the nitroaldol reaction.
  • Catalysts QD, DHQD-PHN, (DHQD) 2 AQN were purchased from Aldrich company and used without any further purification.
  • C6'-OH catalysts Q-la-c and QD-la-c were prepared following procedures previously reported and ⁇ -ICD was prepared according to literature procedures. Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906- 9907; Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C; Foxman, B. M.; Deng L. Angew. ChemJnt. Ed.
  • (-)-3i This product was obtained as a colorless oil in 97% yield and 94% ee from a reaction catalyzed by Q-Id (5.0 mol %) at - 20 0 C for 60 hours.
  • (+)-3j This product was obtained as a colorless oil in 90% yield and 95% ee from a reaction catalyzed by Q-Id (5.0 mol %) at -20 0 C for 12 hours.
  • (+)-3m This product was obtained as a colorless oil in 86% yield and 93% ee from a reaction catalyzed by Q-Id (5 mol %) at -20 0 C for 11 hours.
  • Example 4 Synthesis of 3-phenyl-3-hydroxyazetidin-2-one 5c jPrtt ⁇ Ci " R j ⁇ /

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'un des aspects de cette invention concerne des réactions (Henry) de nitroaldol catalytique asymétrique avec des cétones en tant que composant électrophile. Dans l'un des modes de réalisation, cette invention concerne des réactions de nitroaldol asymétrique avec des α-céto esters catalysés par un nouveau catalyseur alcaloïde de quinquina C6'-0H. dans certains modes de réalisation, cette réaction est fonctionnellement simple et atteint une énantiosélectivité élevée ainsi qu'un rendement bon à excellent pour d'exceptionnellement larges gammes d'α-céto esters.
PCT/US2006/020376 2005-05-27 2006-05-26 Additions d'aldol asymetrique au moyen de catalyseurs a base d'alcaloide de quinquina bifonctionnels Ceased WO2006130453A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2008513745A JP2008545706A (ja) 2005-05-27 2006-05-26 二官能性シンコナアルカロイド系触媒を用いた不斉アルドール付加

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US11/140,574 2005-05-27
US11/140,574 US7312335B2 (en) 2004-06-03 2005-05-27 Asymmetric Michael and Aldol additions using bifunctional cinchona-alkaloid-based catalysts
US74163905P 2005-12-01 2005-12-01
US60/741,639 2005-12-01
US74210205P 2005-12-02 2005-12-02
US60/742,102 2005-12-02

Publications (1)

Publication Number Publication Date
WO2006130453A1 true WO2006130453A1 (fr) 2006-12-07

Family

ID=36954575

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/020376 Ceased WO2006130453A1 (fr) 2005-05-27 2006-05-26 Additions d'aldol asymetrique au moyen de catalyseurs a base d'alcaloide de quinquina bifonctionnels

Country Status (1)

Country Link
WO (1) WO2006130453A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005121137A1 (fr) * 2004-06-03 2005-12-22 Brandeis University Additions asymetriques de michael et d'aldol utilisant des catalyseurs bifonctionnels a base de cinchonine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005121137A1 (fr) * 2004-06-03 2005-12-22 Brandeis University Additions asymetriques de michael et d'aldol utilisant des catalyseurs bifonctionnels a base de cinchonine

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
LI H ET AL: "Highly Enantioselective Conjugate Addition of Malonate and .beta.-Ketoester to Nitroalkenes: Asymmetric C-C Bond Formation with New Bifunctional Organic Catalysts Based on Cinchona Alkaloids", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, vol. 126, no. 32, 18 August 2004 (2004-08-18), pages 9906 - 9907, XP002344996, ISSN: 0002-7863 *
LI H ET AL: "Stereocontrolled creation of adjacent quaternary and tertiary stereocenters by a catalytic conjugate addition", ANGEWANDTE CHEMIE, WILEY-VCH, WEINHEIM, DE, vol. 44, no. 1, 26 November 2004 (2004-11-26), pages 105 - 108, XP002344994, ISSN: 1433-7851 *
LI, HONGMING ET AL: "Enantioselective Nitroaldol Reaction of .alpha.-Ketoesters Catalyzed by Cinchona Alkaloids", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY , 128(3), 732-733 CODEN: JACSAT; ISSN: 0002-7863, 22 December 2005 (2005-12-22), XP002399210 *
LIU X ET AL: "Highly enantioselective amination of .alpha.-substituted .alpha.-cyanoacetates with chiral catalysts accessible from both quinine and quinidine", ORGANIC LETTERS, ACS, WASHINGTON, DC, US, vol. 7, no. 2, 22 December 2004 (2004-12-22), pages 167 - 169, XP002344995, ISSN: 1523-7060 *
MARCELLI, TOMMASO ET AL: "Cinchona derivatives as bifunctional organocatalysts for the direct asymmetric nitroaldol (Henry) reaction", SYNLETT ( 2005 ), (18), 2817-2819 CODEN: SYNLES; ISSN: 0936-5214, 12 October 2005 (2005-10-12), XP002399211 *
MISUMI, Y. ET AL.: "High pressure mediated asymmetric Henry reaction of nitromethane with carbonyl compounds catalyzed by cinchona alkaloids", HETEROCYCLES, vol. 56, no. 1-2, 2002, pages 599 - 605, XP001247515 *
WANG, YI ET AL: "Dual-Function Cinchona Alkaloid Catalysis: Catalytic Asymmetric Tandem Conjugate Addition-Protonation for the Direct Creation of Nonadjacent Stereocenters", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY , 128(12), 3928-3930 CODEN: JACSAT; ISSN: 0002-7863, 3 March 2006 (2006-03-03), XP002399209 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK

Similar Documents

Publication Publication Date Title
KR100769381B1 (ko) 메소 화합물을 촉매 비대칭 탈대칭화시키는 방법
US7312335B2 (en) Asymmetric Michael and Aldol additions using bifunctional cinchona-alkaloid-based catalysts
Russo et al. Enantioselective organocatalytic α-heterofunctionalization of active methines
KR100799789B1 (ko) 키랄 2- 및 3-치환된 카르복실산의 속도론적 분할
Yu et al. Organocatalyzed asymmetric tandem conjugate addition–protonation of isocyanoacetates to 2-chloroacrylonitrile
Ballini et al. Nitroalkanes as key compounds for the synthesis of amino derivatives
US8765955B2 (en) Asymmetric aldol additions using bifunctional cinchona-alkaloid-based catalysts
WO2006130453A1 (fr) Additions d'aldol asymetrique au moyen de catalyseurs a base d'alcaloide de quinquina bifonctionnels
JP5266128B2 (ja) 二官能性シンコナアルカロイドにより触媒作用が及ぼされる非対称炭素−炭素結合形成反応
US7582764B2 (en) Asymmetric carbon-carbon-bond-forming reactions catalyzed by bifunctional cinchona alkaloids
WO2006130437A2 (fr) Reactions asymetriques formatrices de liaison carbone-carbone catalysees par des alcaloides quinquina bifonctionnels
JP2008163022A (ja) シンコナアルカロイド触媒不斉マンニッヒ反応
JP2017160158A (ja) 光学活性の４−ニトロブタン酸エステル及びプレガバリンの製造方法
US8791262B2 (en) Asymmetric friedel-crafts alkylations catalyzed by bifunctional cinchona alkaloids
JP2008545706A (ja) 二官能性シンコナアルカロイド系触媒を用いた不斉アルドール付加
US9006441B2 (en) Conjugate addition reactions using bifunctional cinchona-alkaloid-based catalysts
US6562967B2 (en) Kinetic resolutions of chiral 2-and-3-substituted carboxylic acids
US7078547B2 (en) Catalytic asymmetric cyanosilylation of ketones, aldehydes, thioketones, thioaldehydes, imines and hydrazones
Olaizola et al. Recent Developments in Catalytic Asymmetric Aziridination
김병수 Enantioselective synthesis of α-alkylthio-α-alkylmalonate via phase-transfer catalytic sulfenylation
CA2456166A1 (fr) Resolutions par voie cinetique composes chiraux d'acides carboxyliques substitues en position 2 et en position 3

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2008513745

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06771258

Country of ref document: EP

Kind code of ref document: A1