EP1638677A4 - CATALYTIC ASYMMETRIC DESYMMETRIZATION OF PROCHIRAL AND MESO-FORM CYCLIC ANHYDRIDES - Google Patents

CATALYTIC ASYMMETRIC DESYMMETRIZATION OF PROCHIRAL AND MESO-FORM CYCLIC ANHYDRIDES

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Publication number
EP1638677A4
EP1638677A4 EP04755066A EP04755066A EP1638677A4 EP 1638677 A4 EP1638677 A4 EP 1638677A4 EP 04755066 A EP04755066 A EP 04755066A EP 04755066 A EP04755066 A EP 04755066A EP 1638677 A4 EP1638677 A4 EP 1638677A4
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EP
European Patent Office
Prior art keywords
cyclic anhydride
substituted
anhydride
chiral
dhqd
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.)
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Application number
EP04755066A
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German (de)
English (en)
French (fr)
Other versions
EP1638677A2 (en
Inventor
Li Deng
Xiaofeng Liu
Yonggang Chen
Shikai Tian
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Brandeis University
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Brandeis University
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Priority claimed from US10/460,051 external-priority patent/US7053236B2/en
Application filed by Brandeis University filed Critical Brandeis University
Publication of EP1638677A2 publication Critical patent/EP1638677A2/en
Publication of EP1638677A4 publication Critical patent/EP1638677A4/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • EACA enantioselective alcoholysis of meso, prochiral, and racemic cyclic anhydrides
  • the quinidine-based catalyst contains a ketone, ester, amide, cyano, or alkynyl group.
  • the catalyst is QD-IP, QD-(-)-MN, or QD- AD.
  • the cinchona-alkaloid-based catalyst is Q-AD.
  • Another aspect of the invention relates to a method of preparing a derivatized cinchona alkaloid catalyst by reacting a cinchona-alkaloid with base and a compound that has a suitable leaving group.
  • the leaving group is Cl, Br, I, OSO 2 CH 3 , or OSO 2 CF 3 .
  • the leaving group is Cl.
  • the base is a metal hydride.
  • the hydroxyl group of the cinchona alkaloid undergoes reaction with an alkyl chloride to form the catalyst.
  • One aspect of the present invention relates to a method of preparing a chiral, non- racemic compound from a prochiral substituted cyclic anhydride or a meso substituted cyclic anhydride, comprising the step of: reacting a prochiral substituted cyclic anhydride or a meso substituted cyclic anhydride with a nucleophile in the presence of a chiral, non-racemic tertiary amine catalyst; wherein said prochiral substituted cyclic anhydride or said meso substituted cyclic anhydride comprises an internal plane of symmetry or point of symmetry or both; wherein said meso substituted cyclic anhydride comprises at least two chiral centers; and wherein said nucleophile is an alcohol, thiol or amine; thereby producing a chiral, non-racemic compound.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or a substituted glutaric anhydride.
  • said nucleophile is an alcohol, hi certain embodiments of the aforementioned method said nucleophile is a primary alcohol.
  • said nucleophile is methanol or CF 3 CH 2 OH.
  • said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ) 2 PHAL, (DHQD) 2 PHAL, (DHQ) 2 PYR, (DHQD) 2 PYR, (DHQ) 2 AQN, (DHQD) 2 AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD- MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.
  • said chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD) 2 AQN.
  • said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB.
  • said chiral, non-racemic tertiary amine catalyst is QD-PP.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is an alcohol; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ) 2 PHAL, (DHQD) 2 PHAL, (DHQ) 2 PYR, (DHQD) 2 PYR, (DHQ) 2 AQN, (DHQD) 2 AQN, DHQ-CLB, DHQD-CLB, DHQ- MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is a primary alcohol; and said chiral, non- racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ) 2 PHAL, (DHQD) 2 PHAL, (DHQ) 2 PYR, (DHQD) 2 PYR, (DHQ) 2 AQN, (DHQD) 2 AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD- PHN.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is methanol or CF 3 CH 2 OH; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ) 2 PHAL,
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is an alcohol; and said chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD) 2 AQN.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is a primary alcohol; and said chiral, non- racemic tertiary amine catalyst is DHQD-PHN or (DHQD) 2 AQN.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is methanol or CF 3 CH 2 OH; and said chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD) 2 AQN.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is an alcohol; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is a primary alcohol; and said chiral, non- racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is methanol or CF 3 CH 2 OH; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is an alcohol; and said chiral, non-racemic tertiary amine catalyst is QD-PP.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is a primary alcohol; and said chiral, non- racemic tertiary amine catalyst is QD-PP.
  • said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is methanol or CF 3 CH 2 OH; and said chiral, non-racemic tertiary amine catalyst is QD-PP.
  • said chiral, non-racemic tertiary amine catalyst is present in less than about 30 mol% relative to said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride.
  • said chiral, non-racemic tertiary amine catalyst is present in less than about 20 mol% relative to said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride.
  • said chiral, non-racemic tertiary amine catalyst is present in less than about 10 mol% relative to said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride.
  • Another aspect of the present invention relates to a method of preparing a chiral, non- racemic compound from a prochiral cyclic anhydride or a meso cyclic anhydride, comprising the step of: reacting a prochiral cyclic anhydride or a meso cyclic anhydride with a nucleophile in the presence of a catalyst; wherein said prochiral cyclic anhydride or meso cyclic anhydride comprises an internal plane of symmetry or point of symmetry or both; thereby producing a chiral, non-racemic compound; wherein said catalyst is a derivatized cinchona-alkaloid.
  • the catalyst is QD-IP, QD-(-)-MN, or QD-AD.
  • the nucleophile is a primary alcohol. hi a preferred embodiment, the nucleophile is methanol or CF 3 CH 2 OH.
  • the prochiral cyclic anhydride or meso cyclic anhydride is a substituted succinic anhydride or a substituted glutaric anhydride
  • the catalyst is present in less than about 70 mol% relative to said prochiral cyclic anhydride or meso cyclic anhydride, hi a preferred embodiment, the catalyst is present in less than about 10 mol% relative to said prochiral cyclic anhydride or meso cyclic anhydride.
  • the chiral, non- racemic compound has an enantiomeric excess greater than about 90%.
  • said catalyst is Q-IP, Q-PC, Q-AD, or Q-(-)-MN.
  • Another aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic cyclic anhydride with an alcohol in the presence of a derivatized cinchona-alkaloid catalyst, hi preferred embodiments, the catalyst is QD-IP, QD-(-
  • the alcohol is a primary alcohol.
  • the catalyst is Q-IP, Q-PC, Q-AD, or Q-(-)-MN.
  • said chiral, non-racemic compound has an enantiomeric excess greater than about 90%.
  • said chiral, non-racemic compound has an enantiomeric excess greater than about 95%.
  • Figure 1 presents the enantiomeric excess of the product obtained from the asymmetric desymmetrization of czs-2,3-dimethylsuccinic anhydride, as a function of the solvent and the catalyst used.
  • Figure 2 presents the enantiomeric excesses of the products obtained from the asymmetric desymmetrization of various meso cyclic anhydrides, as a function of the reaction conditions used.
  • the absolute configuration of each product was determined by comparison to an authentic sample. Enantiomeric excesses were determined using chiral GC or literature methods, hi Entries 1-3, the enantiomeric excesses in parentheses pertain to products of the opposite absolute configuration obtained using (DHQ) 2 AQN as the catalyst. In Entry 4, (DHQD) 2 PHAL was used as the catalyst.
  • Figure 3 presents the enantiomeric excesses of the products obtained from the asymmetric desymmetrization of various meso cyclic anhydrides, as a function of the reaction conditions used. The absolute configuration of each product was determined by comparison to an authentic sample. Enantiomeric excesses were determined using chiral GC or literature methods. In Entries 7 and 8, (DHQD) 2 PHAL was used as the catalyst.
  • Figure 4 presents the enantiomeric excesses of the products obtained from the asymmetric desymmetrization of various meso cyclic anhydrides, as a function of the reaction conditions used. The absolute configuration of each product was determined by comparison to an authentic sample. Enantiomeric excesses were determined using chiral GC or literature methods. In Entries 9 and 11, (DHQD) 2 PHAL was used as the catalyst.
  • Figure 5 depicts the structures of certain catalysts used in the methods of the present invention, and the abbreviations used herein for them.
  • Figure 6 depicts the structures of certain catalysts used in the methods of the present invention, and the abbreviations used herein for them.
  • FIG. 7 depicts the structures of certain catalysts used in the methods of the present invention, and the abbreviations used herein for them.
  • Figure 8 depicts the enantiomeric excesses of the products obtained from the asymmetric desymmetrization of various meso cyclic anhydrides, as a function of the reaction conditions used.
  • Figure 9 depicts the enantiomeric excesses of the products obtained from the asymmetric desymmetrization of various meso cyclic anhydrides, as a function of the reaction conditions used. The absolute configuration of each product was determined by comparison to an authentic sample. Enantiomeric excesses were determined using chiral GC or literature methods.
  • Figure 10 depicts the results from desymmetrization of a number of prochiral cyclic anhydrides.
  • the amount of substrate was 0.1 mmol; the concentration of the substrate was 0.2 M; 110 mol% catalyst was used relative to the substrate; the amount of alcohol was 1.5 equiv; the solvent was toluene; and the reaction temperature was -43 C.
  • Figure 11 depicts the results from desymmetrization of a number of meso cyclic anhydrides. In each case: the amount of substrate was 0.1 mmol; the concentration of the substrate was 0.02 M; and the solvent was ether.
  • Figure 12 depicts the results from desymmetrization of a number of meso cyclic anhydrides. In each case: the amount of substrate was 0.1 rnmol; the concentration of the substrate was 0.02 M; and the solvent was ether.
  • Figure 13 depicts the results from desymmetrization of cw-2,3-dimethyl succinic anhydride, hi each case: the amount of substrate was 0.1 mmol; the concentration of the substrate was 0.02 M; the catalyst was QD-PP; 20 mol% catalyst was used relative to the substrate; the amount of alcohol was 10 equiv; and the reaction was run at ambient temperature.
  • Figure 14 depicts the results from desymmetrization of cw-2,3-dimethyl succinic anhydride.
  • the amount of substrate was 0.1 mmol; the concentration of the substrate was 0.2 M; the catalyst was QD-PP; the alcohol was methanol; and the reaction was run at ambient temperature.
  • Figure 15 depicts the results from desymmetrization of cz5-2,3-dimethyl succinic anhydride, hi each case: the amount of substrate was 0.1 mmol; the concentration of the substrate was 0.2 M; the catalyst was QD-PP; the alcohol was methanol; and the reaction was run at -25 C.
  • Figure 16 depicts the results from desymmetrization of cis-2,3 -dimethyl succinic anhydride.
  • the amount of substrate was 0.2 mmol; the concentration of the substrate was 0.4 M; the catalyst was QD-PP; the alcohol was methanol; the reaction was run at -25 C; and the reaction time was 6 hours.
  • Figure 17 depicts the results from desymmetrization of cw-2,3-dimethyl succinic anhydride. In each case: the concentration of the substrate was 0.02 M; 20 mol% catalyst was used relative to the substrate; the amount of alcohol was 10 equiv; and the reaction was run at ambient temperature.
  • Figure 18 depicts the structures of QD-PH, QD-AN, QD-NT, QD-AC and QD-CH.
  • Figure 19 presents a comparison of catalysts' efficiency for methanolysis of 2,3- dimethylsuccinic anhydride in Et 2 O at 0.02 M concentration.
  • Figure 20 presents a comparison of catalysts' efficiency for methanolysis of 2,3- dimethylsuccinic anhydride in Et 2 O at 0.02 M concentration.
  • Figure 21 presents a comparison of catalysts' efficiency for trifluoroethanolysis of 2,3- dimethylsuccinic anhydride in Et 2 O at 0.02 M concentration.
  • Figure 22 presents reaction conditions optimization for methanolysis of 3- methylglutaric anhydride in Et 2 O and 0.02 M concentration.
  • Figure 23 presents screening of reaction conditions for alcoholysis of 3-methyl-glutaric anhydride at 0.2 M concentration.
  • Figure 24 presents a comparison of catalysts' efficiency for methanolysis of 3 -methyl glutaric anhydride in toluene at 0.2 M concentration.
  • Figure 25 presents a comparison of catalysts' efficiency for trifluoroethanolysis of 3- methyl glutaric anhydride in toluene at 0.2 M concentration.
  • Figure 26 presents a comparison of catalysts' efficiency for methanolysis of 3-phenyl glutaric anhydride in toluene at 0.2 M concentration.
  • Figure 27 presents a comparison of catalysts' efficiency for trifluoroethanolysis of 3- phenyl glutaric anhydride in toluene at 0.2 M concentration.
  • Figure 28 presents a comparison of catalysts' efficiency for methanolysis of 3-isopropyl glutaric anhydride in toluene at 0.2 M concentration.
  • Figure 29 presents a comparison of catalysts' efficiency for trifluoroethanolysis of 3- isopropyl glutaric anhydride in toluene at 0.2 M concentration.
  • Figure 30 presents a comparison of catalysts' efficiency for methanolysis of 3-TBSO glutaric anhydride in toluene at 0.2 M concentration.
  • Figure 31 presents a comparison of catalysts' efficiency for trifluoroethanolysis of 3- TBSO glutaric anhydride in toluene at 0.2 M concentration.
  • Figure 32 presents Q-AD catalyzed methanolysis of 3-substituted glutaric anhydride in toluene at 0.2 M concentration.
  • Figure 33 presents Q-AD catalyzed trifluoromethanolysis of 3-substituted glutaric anhydride in toluene at 0.2 M concentration.
  • Figure 34 presents a comparison of catalysts' efficiency for the alcoholysis of cis- 1,2,3,6-tetrahydrophthalic anhydride with methanol in Et 2 O at 0.02 M concentration.
  • Figure 35 presents a comparison of catalysts' efficiency for the alcoholysis of cis- 1,2,3,6-tetrahydrophthalic anhydride with trifluoroethanol in Et 2 O at 0.02 M concentration.
  • Figure 36 presents QD-AD catalyzed alcoholysis of 1,2-cyclohexanedicarboxylic anhydride with methanol in Et 2 O at 0.02 M concentration.
  • Figure 37 presents a comparison of catalysts' efficiency for the alcoholysis of 1,2- cyclohexanedicarboxylic anhydride with trifluoroethanol in Et 2 O at 0.02 M concentration.
  • Figure 38 presents a comparison of catalysts' efficiency for the alcoholysis of cis- norbornene-endo-2,3-dicarboxylic anhydride in Et 2 O at 0.02 M concentration.
  • Figure 39 presents a comparison of catalysts' efficiency for the alcoholysis of exo-3,6- epoxy-l,2,3,6-tetrahydrophthalic anhydride in Et 2 O at 0.02 M concentration.
  • Figure 40 presents reaction conditions optimization for the alcoholysis of cis- 1,2,3, 6- tetrahydrophthalic anhydride in Et 2 O at 0.02 M.
  • Figure 41 presents reaction conditions optimization for the alcoholysis of cis-1,2,3,6- tetrahydrophthalic anhydride in toluene at 0.2 M.
  • Figure 42 presents reaction conditions optimization for the alcoholysis of cis- 1,2,3 ,6- tetrahydrophthalic anhydride in toluene at 0.5 M.
  • Figure 43 presents alcoholysis of succinic anhydrides with Q-AD.
  • Figure 44 presents a comparison of catalysts' efficiency for methanolysis of 2,3- dimethylsuccinic anhydride in in Et 2 O at 0.02 M concentration.
  • Figure 45 presents a comparison of catalysts' efficiency for trifluoroethanolysis of 3- isopropyl glutaric anhydride in toluene at 0.2 M concentration.
  • the ability to transform selectively a prochiral or meso compound to a enantiomerically enriched or enantiomerically pure chiral compound has broad application, especially in the agricultural and pharmaceutical industries, as well as in the polymer industry.
  • the present invention relates to methods and catalysts for the catalytic asymmetric desymmetrization of prochiral and meso compounds and the like.
  • the primary constituents of the methods are: a non-racemic chiral tertiary-amme- containing catalyst; a prochiral or meso substrate, typically a heterocycle comprising a pair of electrophilic atoms related by an internal plane or point of symmetry; and a nucleophile, typically the solvent, which under the reaction conditions selectively attacks one of the two aforementioned electrophilic atoms, generating an enantiomerically enriched chiral product.
  • the catalysts and methods of the present invention can be exploited to effect kinetic resolutions of racemic mixtures and the like. Definitions For convenience, certain terms employed in the specification, examples, and appended claims are collected here.
  • 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.
  • 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. hi most (but not all) cases, this will also be the atom from which the leaving group departs.
  • electro- withdrawing group is recognized in the art and as used herein means a functionality which draws electrons to itself more than a hydrogen atom would at the same position. Exemplary electron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, -CN, chloride, and the like.
  • electron-donating group as used herein, means a functionality which draws electrons to itself less than a hydrogen atom would at the same position. Exemplary electron-donating groups include amino, methoxy, and the like.
  • Lewis base 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.
  • Lewis basic moieties include uncharged compounds such as alcohols, thiols, olefins, and amines, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of other organic anions.
  • Lewis acid and Lewis acidic are art-recognized and refer to chemical moieties which can accept a pair of electrons from a Lewis base.
  • the term “meso compound” is recognized in the art and means a chemical compound which has at least two chiral centers but is achiral due to an internal plane or point of symmetry.
  • chiral refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • a "prochiral molecule” is an achiral molecule which has the potential to be converted to a chiral molecule in a particular process.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
  • enantiomers refers to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • diastereomers refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.
  • a “stereoselective process” is one which produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of that product.
  • An “enantioselective process” is one which favors production of one of the two possible enantiomers of a reaction product.
  • the subject method is said to produce a "stereoselectively- enriched" product (e.g., enantioselectively-enriched or diastereoselectively-enriched) when the yield of a particular stereoisomer of the product is greater by a statistically significant amount relative to the yield of that stereoisomer resulting from the same reaction run in the absence of a chiral catalyst.
  • an enantioselective reaction catalyzed by one of the subject chiral catalysts will yield an e.e. for a particular enantiomer that is larger than the e.e. 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, hi general, the term “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. Enantioselectivity is generally quantified as "enantiomeric excess"
  • % Enantiomeric Excess A (ee) (% Enantiomer A) - (% Enantiomer B) where A and B are the enantiomers formed. Additional terms that are used in conjunction with enatioselectivity include "optical purity" or "optical activity".
  • An enantioselective reaction yields a product with an e.e. greater than zero.
  • Preferred enantioselective reactions yield a product with an e.e. 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-racemic reagent or catalyst, one reactant enantiomer may react more slowly than the other.
  • This class of reaction is termed a kinetic resolution, wherein the reactant enantiomers are resolved by differential reaction rate to yield both enantiomerically-enriched product and enantimerically-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 90% ee for a given enantiomer of the catalyst, more preferably greater than 95% ee.
  • alkyl refers to the radical of saturated aliphatic groups, including straight- chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C j - C 30 for straight chain, C 3 -C 30 for branched chain), and more preferably 20 of fewer.
  • preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple carbon-carbon bond, respectively.
  • alkoxyl or "alkoxy” as used herein refers 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 can be represented by one of -O-alkyl, -O-alkenyl, - 0-alkynyl, -O-(CH2) m -Rg, where m and Rg are described above.
  • amino means -NH2; the term “nitro” means -NO2; the term
  • halogen designates -F, -Cl, -Br or -I; the term “thiol” means -SH; the term “hydroxyl” means -
  • sulfonyl means -SO2S and the term “organometallic” refers to a metallic atom (such as mercury, zinc, lead, magnesium or lithium) or a metalloid (such as silicon, arsenic or selenium) which is bonded directly to a carbon atom, such as a diphenylmethylsilyl group.
  • organometallic refers to a metallic atom (such as mercury, zinc, lead, magnesium or lithium) or a metalloid (such as silicon, arsenic or selenium) which is bonded directly to a carbon atom, such as a diphenylmethylsilyl group.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
  • R9, Ri 0 and R' 10 each independently represent a group permitted by the rules of valence.
  • acylamino is art-recognized and refers to a moiety that can be represented by the general formula:
  • R 9 is as defined above, and R' ⁇ represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -R.8 > where m and Rg are as defined above.
  • atnido is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:
  • R io wherein R9, Rj Q are as defined above.
  • Preferred embodiments of the amide will not include imides which may be unstable.
  • 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-(CH2)m ⁇ R-8 > wherein m and Rg are defined above.
  • alkylthio groups include methylthio, ethyl thio, and the like.
  • carbonyl is art recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an oxygen or a sulfur
  • Rj ⁇ represents a hydrogen, an alkyl, an alkenyl, -(CH2) m -Rg or a pharmaceutically acceptable salt
  • R'n represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -Rg, where m and Rg are as defined above.
  • X is an oxygen and R ⁇ ⁇ or R'i ⁇ is not hydrogen, the formula represents an "ester".
  • R41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • sulfonylamino is art recognized and includes a moiety that can be represented by the general formula:
  • sulfonyl refers to a moiety that can be represented by the general formula:
  • R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • sulfoxido refers to a moiety that can be represented by the general formula:
  • sulfate means a sulfonyl group, as defined above, attached to two hydroxy or alkoxy groups.
  • a sulfate has the structure:
  • R40 and R44 are independently absent, a hydrogen, an alkyl, or an aryl. Furthermore, R40 and R44, taken together with the sulfonyl group and the oxygen atoms to which they are attached, may form a ring structure having from 5 to 10 members.
  • Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, alkenylamines, alkynylamines, alkenylamides, alkynylamides, alkenylimines, alkynylimines, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls, alkenoxyls, alkynoxyls, metalloalkenyls and metalloalkynyls.
  • aryl as used herein includes 4-, 5-, 6- and 7-membered single-ring aromatic groups which 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 heterocycle 4-, 5-, 6- and 7-membered single-ring aromatic groups which 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.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or -(CB ⁇ ) 1n -Rv, -CFs 5 "CN, or the like.
  • substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls,
  • heterocycle or “heterocyclic group” refer to 4 to 10-membered ring structures, more preferably 5 to 7 membered rings, which ring structures include one to four heteroatoms.
  • Heterocyclic groups include pyrrolidine, oxolane, thiolane, imidazole, oxazole, piperidine, piperazine, morpholine.
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or -(CH 2 ) m -R 7 , -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls,
  • polycycle or “polycyclic group” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles) 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 can be substituted with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, ' phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or -(CH2) m -R.7, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, ' phosphonates, phosphines, carbonyls, carboxyls, si
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, phosphorus and selenium.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, />-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, ⁇ -toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf 5 Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, /?-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. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991).
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described hereinabove.
  • the permissible substituents can 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 valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • (-)-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:
  • Catalysts of the Invention are non-racemic chiral amines which present an asymmetric environment, causing differentiation between two or more moieties related by symmetry in a prochiral or meso molecule, i.e., a molecule comprising at least two chiral centers, and 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. For instance, 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. For example, bulkier substituents on the catalyst are generally found to provide higher catalyst turnover numbers.
  • a preferred embodiment for each of the embodiments described above provides a catalyst having a molecular weight less than 2,000 g/mol, more preferably less than 1,000 g/mol, and even more preferably less than 500 g/mol. Additionally, the substituents on the catalyst can be selected to influence the solubility of the catalyst in a particular solvent system.
  • the chiral, non-racemic tertiary amine catalyst comprises a 1- azabicyclo[2.2.2]octane moiety or a l,4-diazabicyclo[2.2.2]octane moiety.
  • the chiral, non-racemic tertiary amine catalyst is a cinchona alkaloid, Q-PP, Q- TB, QD-PP, QD-TB, (DHQ) 2 PHAL, (DHQD) 2 PHAL, (DHQ) 2 PYR, (DHQD) 2 PYR, (DHQ) 2 AQN, (DHQD) 2 AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ- AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.
  • the chiral, non- racemic tertiary amine catalyst is DHQD-PHN or (DHQD) 2 AQN.
  • the chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB.
  • the chiral, non-racemic tertiary amine catalyst is QD-PP.
  • 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 -C(O)R 2 , -(C(R 3 ) 2 ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , -(C(R 3 ) 2 ) n CN, - (C(R 3 ) 2 ) n C(O)R 5 , -C(C(R 3 ) 2 ) n C ⁇ CR 6 , -(C(R 3 ) 2 ) n OPO(OR 5 ) 2 , -(C(R 3 ) 2 ) n OR 5 , -(C(R 3 ) 2 ) n N(R 5 ) 2 , -(C(R 3 ) 2 ) n SR 5 , or -(C(R 3 ) 2 ) n NO 2 ;
  • R 1 represents alkyl or alkenyl;
  • R 2 represents alkyl, cycloalkyl, or alkenyl
  • R 3 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl, or aralkyl;
  • R 5 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl;
  • R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and n is 1-10.
  • the compounds of the present invention are represented by formula I, wherein R represents -C(O)R 2 , -(C(R 3 ) 2 ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , - (C(R 3 ) 2 ) n CN, -(C(R 3 ) 2 ) n C(O)R 5 , or -C(C(R 3 ) 2 ) n C ⁇ €R 6 .
  • the compounds of the present invention are represented by formula I, wherein R 1 is ethyl.
  • the compounds of the present invention are represented by formula I, wherein R is -C(O)R 2 and R 2 is alkyl. In certain embodiments, the compounds of the present invention are represented by formula I, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 .
  • the compounds of the present invention are represented by formula I, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 and R 4 is -CH(R 3 ) 2 .
  • the compounds of the present invention are represented by formula I, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 , R 4 is -CH(R 3 ) 2 , n is 1.
  • the compounds of the present invention are represented by formula I, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 and R 4 is cycloalkyl.
  • the compounds of the present invention are represented by formula I, wherein R is -CH 2 CO 2 R 4 and R 4 is cycloalkyl.
  • the compounds of the present invention are represented by formula I, wherein R is -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 .
  • the compounds of the present invention are represented by formula I, wherein R is -(C(R 3 ) 2 ) n CN.
  • the compounds of the present invention are represented by formula I, wherein R is -(C(R 3 ) 2 ) n COR 5 .
  • the compounds of the present invention are represented by formula I, wherein R is -CH 2 C(O)R 5 and R 5 is alkyl.
  • said compound is QD-EP, QD-PC, QD-AD, QD-(-)-MN, QD- (+)-MN, QD-AC, QD-Piv, QD-PH, QD-AN, QD-NT, QD-CN, QD-CH, QD-IB, QD-EF, QD- AA, QD-MP, or QD-IPC.
  • said compound is QD-IP, QD-(-)-MN, or QD-AD.
  • Another aspect of the present invention relates to a compound represented by formula II:
  • R represents -C(O)R 2 , -(C(R 3 ) 2 ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , -(C(R 3 ) 2 ) n CN, - (C(R 3 ) 2 ) n C(O)R 5 , -C(C(R 3 ) 2 ) n C s €R 6 , -(C(R 3 ) 2 ) n OPO(OR 5 ) 2 , -(C(R 3 ) 2 ) n OR 5 , -(C(R 3 ) 2 ) n N(R 5 ) 2 , -(C(R 3 ) 2 ) n SR 5 , or -(C(R 3 ) 2 ) n NO 2 ;
  • R 1 represents alkyl or alkenyl
  • R 2 represents alkyl, cycloalkyl, or alkenyl
  • R 3 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl, or aralkyl
  • R 5 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl
  • R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and n is 1-10.
  • said compound is Q-IP, Q-PC, Q-AD, Q-(-)-MN, Q-(+)-MN, Q-AC, Q-Piv, Q-PH, Q-AN, Q-NT, Q-CN, Q-CH, Q-IB, Q-EF, Q-AA, Q-MP, or Q-IPC.
  • Methods of the Invention Preparation of Asymmetric Tertiary-Amine-Containins Catalysts
  • Certain aspects of the present invention relate to methods for preparing tertiary amines, which tertiary amine will be useful in the desymmetrization methods of the present invention.
  • the tertiary amines are synthesized according to a general procedure, wherein a diamine is reacted with two equivalents of a chiral, non-racemic glycidyl sulfonate or halide.
  • One aspect of the invention relates to a method of preparing a derivatized cinchona alkaloid catalyst as depicted in Scheme 1:
  • X represents Cl, Br, I, OSO 2 CH 3 , or OSO 2 CF 3 ;
  • R represents -C(O)R 2 , -(C(R 3 ) 2 ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , -(C(R 3 ) 2 ) n CN, - (C(R 3 ) 2 ) n C(O)R 5 , -C(C(R 3 ) 2 ) n C ⁇ €R 6 , -(C(R 3 ) 2 ) n OPO(OR 5 ) 2 , -(C(R 3 ) 2 ) n OR 5 , -(C(R 3 ) 2 ) n N(R 5 ) 2 , -(C(R 3 ) 2 ) n SR 5 , or -(C(R 3 ) 2 ) n NO 2 ;
  • R 1 represents alkyl or alkenyl
  • R 2 represents alkyl, cycloalkyl, or alkenyl
  • R 3 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl, or aralkyl;
  • R 5 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl;
  • R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; n is 1-10; and base is a Bronsted base.
  • the present invention relates to the aforementioned method, wherein X is Cl or Br.
  • the present invention relates to the aforementioned method, wherein said base is a metal hydride, alkoxide, or amide, or carbanion.
  • said base is NaH, CaH 2 , KH, or Na.
  • the present invention relates to the aforementioned method, wherein R represents -C(O)R 2 , -(C(R 3 ) 2 ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , -(C(R 3 ) 2 ) n CN, - (C(R 3 ) 2 ) n C(O)R 5 , or -C(C(R 3 ) 2 ) n C ⁇ R 6 .
  • the present invention relates to the aforementioned method, wherein R is -C(O)R 2 . In certain embodiments, the present invention relates to the aforementioned method, wherein R is -C(O)R 2 and R 2 is alkyl.
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 .
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 and R 4 is -CH(R 3 ) 2 .
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 and R 4 is cycloalkyl.
  • the present invention relates to the aforementioned method, wherein R is -CH 2 CO 2 R 4 and R 4 is cycloalkyl.
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CN.
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n C(O)R 5 .
  • the present invention relates to the aforementioned method, wherein said catalyst is QD-IP, QD-PC, QD-AD, QD-(-)-MN, QD-(+)-MN, QD-AC, QD-Piv, QD-PH 5 QD-AN, QD-NT, QD-CN, QD-CH, QD-IB, QD-EF, QD-AA, QD-MP, or QD-IPC.
  • the present invention relates to the aforementioned method, wherein said catalyst is QD-IP, QD-(-)-MN, or QD-AD.
  • Another aspect of the invention relates to a method of preparing a derivatized cinchona alkaloid catalyst as depicted in Scheme 2:
  • R represents -C(O)R 2 , -(C(R 3 ) 2 ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , -(C(R 3 ) 2 ) n CN, - (C(R 3 ) 2 ) n C(O)R 5 , -C(C(R 3 ) 2 ) n C ⁇ €R 6 , -(C(R 3 ) 2 ) n OPO(OR 5 ) 2 , -(C(R 3 ) 2 ) n OR 5 , -(C(R 3 ) 2 ) n N(R 5 ) 2 , -(C(R 3 ) 2 ) n SR 5 , or -(C(R 3 ) 2 ) n NO 2 ;
  • R 1 represents alkyl or alkenyl;
  • R 2 represents alkyl, cycloalkyl, or alkenyl
  • R 3 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl, or aralkyl;
  • R 5 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl;
  • R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; n is 1-10; and base is a Bronsted base.
  • the present invention relates to the aforementioned method, wherein said catalyst is Q-IP, Q-PC, Q-AD, Q-(-)-MN, Q-(+)-MN, Q-AC, Q-Piv, Q-PH, Q- AN, Q-NT, Q-CN, Q-CH, Q-IB, Q-EF, Q-AA, Q-MP, or Q-IPC.
  • a method for stereoselectively producing compounds with at least one stereogenic center from prochiral or meso starting materials is provided.
  • An advantage of this invention is that enantiomerically enriched products can be synthesized from prochiral or racemic reactants.
  • Another advantage is that yield losses associated with the production of an undesired enantiomer can be substantially reduced or eliminated altogether.
  • the invention features a stereoselective ring opening process which comprises combining a nucleophilic reactant, a prochiral or chiral cyclic substrate, and at least a catalytic amount of non-racemic chiral catalyst of particular characteristics (as described below).
  • the cyclic substrate of the reaction will include a carbocycle or heterocycle which has an electrophilic atom susceptible to attack by the nucleophile.
  • the combination is maintained under conditions appropriate for the chiral catalyst to catalyze stereoselective opening of the cyclic substrate at the electrophilic atom by reaction with the nucleophilic reactant.
  • 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.
  • kinetic resolution of enantiomers occurs by catalysis, using a subject chiral catalyst, of the tranformation of 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.
  • One significant advantage of this approach is the ability to use inexpensive racemic starting materials rather than the expensive, enantiomerically pure starting materials.
  • the subject catalysts may be used in kinetic resolutions of racemic cyclic substrates wherein the nucleophile is a co-solvent. Suitable nucleophiles of this type include water, alcohols, and thiols.
  • the methods of this invention can provide optically active products with very high stereoselectivity (e.g., enantioselectivity or diastereoselectivity) or regioselectivity.
  • 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 methods of the invention may also be carried out under reaction conditions suitable for commercial use, and, typically, proceed at reaction rates suitable for large scale operations.
  • the chiral, non-racemic tertiary amine catalyst is present in less than about 30 mol% relative to the prochiral starting material. In certain embodiments, the chiral, non-racemic tertiary amine catalyst is present in less than about 20 mol% relative to the prochiral starting material. In certain embodiments, the chiral, non-racemic tertiary amine catalyst is present in less than about 10 mol% relative to the prochiral starting material. In certain embodiments, the chiral, non-racemic tertiary amine catalyst is present in less than about 5 mol% relative to the prochiral starting material.
  • the chiral products produced by the asymmetric synthesis methods of this invention can undergo further reaction(s) to afford desired derivatives thereof.
  • Such permissible derivatization reactions can be carried out in accordance with conventional procedures known in the art.
  • potential derivatization reactions include esterification, N-alkylation of amides, 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 cardiovascular drugs, non-steroidal antiinflammatory drugs, central nervous system agents, and antihistaminics.
  • One aspect of the present invention relates to a method of preparing a chiral, non- racemic compound from a prochiral cyclic anhydride or a meso cyclic anhydride, comprising the step of: reacting a prochiral cyclic anhydride or a meso cyclic anhydride with a nucleophile in the presence of a catalyst; wherein said prochiral cyclic anhydride or meso cyclic anhydride comprises an internal plane of symmetry or point of symmetry or both; thereby producing a chiral, non-racemic compound; wherein said catalyst is represented by formula I:
  • R represents -C(O)R 2 , -(C(R 3 ) 2 ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , -(C(R 3 ) 2 ) n CN, - (C(R 3 ) 2 ) n C(O)R 5 , -C(C(R 3 ) 2 ) n C sCR 6 , -(C(R 3 ) 2 ) n OPO(OR 5 ) 2 , -(C(R 3 ) 2 ) n OR 5 , -(C(R 3 ) 2 ) n N(R 5 ) 2 , -(C(R 3 ) 2 ) n SR 5 , or -(C(R 3 ) 2 ) n NO 2 ;
  • R 1 represents alkyl or alkenyl
  • R 2 represents alkyl, cycloalkyl, or alkenyl
  • R 3 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • X R represents cycloalkyl, -CH(R ) 2 , alkenyl, alkynyl, aryl, or aralkyl;
  • R 5 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl;
  • R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and n is 1-10.
  • the present invention relates to the aforementioned method, wherein R represents -C(O)R 2 , -(C(R 3 ⁇ ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , -(C(R 3 ) 2 ) n CN, - (C(R 3 ) 2 ) n C(O)R 5 , or -C(C(R 3 ) 2 ) n C ⁇ eR 6 .
  • the present invention relates to the aforementioned method, wherein R is -C(O)R 2 .
  • the present invention relates to the aforementioned method, wherein R is -C(O)R 2 and R 2 is alkyl.
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 .
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 and R 4 is -CH(R 3 ) 2 .
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 , R 4 is -CH(R 3 ) 2 , n is 1.
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 and R 4 is cycloalkyl.
  • the present invention relates to the aforementioned method, wherein R is -CH 2 CO 2 R 4 and R 4 is cycloalkyl.
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 .
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CN.
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n C(O)R 5 .
  • the present invention relates to the aforementioned method, wherein R is -CH 2 C(O)R 5 and R 5 is alkyl.
  • the present invention relates to the aforementioned method, wherein said catalyst is QD-IP, QD-PC, QD-AD, QD-(-)-MN, QD-(+)-MN, QD-AC, QD-Piv, QD-PH, QD-AN, QD-NT, QD-CN, QD-CH, QD-IB, QD-EF, QD-AA, QD-MP, or QD-IPC.
  • the present invention relates to the aforementioned method, wherein said catalyst is QD-IP, QD-(-)-MN, or QD-AD.
  • said nucleophile is an alcohol.
  • the present invention relates to the aforementioned method, wherein said nucleophile is a primary alcohol. In certain embodiments, the present invention relates to the aforementioned method, wherein said nucleophile is a methanol or CF 3 CH 2 OH.
  • the present invention relates to the aforementioned method, wherein said prochiral cyclic anhydride or meso cyclic anhydride is a substituted succinic anhydride or a substituted glutaric anhydride.
  • the present invention relates to the aforementioned method, wherein said catalyst is present in less than about 70 mol% relative to said prochiral cyclic anhydride or meso cyclic anhydride.
  • the present invention relates to the aforementioned method, wherein said catalyst is present in less than about 40 mol% relative to said prochiral cyclic anhydride or meso cyclic anhydride.
  • the present invention relates to the aforementioned method, wherein said catalyst is present in less than about 10 mol% relative to said prochiral cyclic anhydride or meso cyclic anhydride. In certain embodiments, the present invention relates to the aforementioned method, wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 50%. hi certain embodiments, the present invention relates to the aforementioned method, wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 70%. hi certain embodiments, the present invention relates to the aforementioned method, wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method, wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 95%.
  • Another aspect of the present invention relates to a method of preparing a chiral, non- racemic compound from a prochiral cyclic anhydride or a meso cyclic anhydride, comprising the step of: reacting a prochiral cyclic anhydride or a meso cyclic anhydride with a nucleophile in the presence of a catalyst; wherein said prochiral cyclic anhydride or meso cyclic anhydride comprises an internal plane of symmetry or point of symmetry or both; thereby producing a chiral, non-racemic compound; wherein said catalyst is represented by formula II:
  • R represents -C(O)R 2 , -(C(R 3 ) 2 ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , -(C(R 3 ) 2 ) n CN, - (C(R 3 ) 2 ) n C(O)R 5 , -C(C(R 3 ) 2 ) n C ⁇ CR 6 , -(C(R 3 ) 2 ) n OPO(OR 5 ) 2 , -(C(R 3 ) 2 ) n OR 5 , -(C(R 3 ) 2 ) n N(R 5 ) 2 , -(C(R 3 ) 2 ) n SR 5 , or -(C(R 3 ) 2 ) n NO 2 ;
  • R 1 represents alkyl or alkenyl
  • R 2 represents alkyl, cycloalkyl, or alkenyl
  • R 3 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl, or aralkyl
  • R 5 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl
  • R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and n is 1-10.
  • said catalyst is Q-IP, Q-PC, Q-AD, Q-(-)-MN, Q-(+)-MN, Q-
  • the present invention relates to the aforementioned method, wherein said nucleophile is an alcohol.
  • the present invention relates to the aforementioned method, wherein said nucleophile is a primary alcohol.
  • the present invention relates to the aforementioned method, wherein said nucleophile is methanol or CF 3 CHiOH.
  • the present invention relates to the aforementioned method, wherein said prochiral cyclic anhydride or meso cyclic anhydride is a substituted succinic anhydride or a substituted glutaric anhydride.
  • the present invention relates to the aforementioned method, wherein said catalyst is present in less than about 70 mol% relative to said prochiral cyclic anhydride or meso cyclic anhydride.
  • the present invention relates to the aforementioned method, wherein said catalyst is present in less than about 40 mol% relative to said prochiral cyclic anhydride or meso cyclic anhydride.
  • the present invention relates to the aforementioned method, wherein said catalyst is present in less than about 10 mol% relative to said prochiral cyclic anhydride or meso cyclic anhydride.
  • the present invention relates to the aforementioned method, wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 50%.
  • the present invention relates to the aforementioned method, wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 70%.
  • the present invention relates to the aforementioned method, wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 90%.
  • the present invention relates to the aforementioned method, wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 95%.
  • kinetic resolution of enantiomers occurs by catalysis, using a subject chiral catalyst, of the tranformation of a racemic substrate.
  • a subject chiral catalyst Li 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 cyclic substrates wherein the nucleophile is a co-solvent. Suitable nucleophiles of this type include water, alcohols, and thiols.
  • One aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic cyclic anhydride with an alcohol in the presence of a catalyst represented by formula I:
  • R represents -C(O)R 2 , -(C(R 3 ) 2 ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , -(C(R 3 ) 2 ) n CN, - (C(R 3 ) 2 ) n C(O)R 5 , -C(C(R 3 ) 2 ) n C ⁇ eR 6 , -(C(R 3 ) 2 ) n OPO(OR 5 ) 2 , -(C(R 3 ) 2 ) n OR 5 , -(C(R 3 ) 2 ) n N(R 5 ) 2 , -(C(R 3 ) 2 ) n SR 5 , or -(C(R 3 ) 2 ) n NO 2 ;
  • R 1 represents alkyl or alkenyl
  • R 2 represents alkyl, cycloalkyl, or alkenyl
  • R 3 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkehyl, alkynyl, aryl, or aralkyl;
  • R 5 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl;
  • R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; n is 1-10; and when said method of kinetic resolution is completed or interrupted any unreacted cyclic anhydride has an enantiomeric excess greater than zero and the enantiomeric excess of the product is greater than zero.
  • the present invention relates to the aforementioned method, wherein R represents -C(O)R 2 , -(C(R 3 ) 2 ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , -(C(R 3 ) 2 ) n CN, - (C(R 3 ) 2 ) n C(O)R 5 , or -C(C(R 3 ) 2 ) n C ⁇ €R 6 .
  • the present invention relates to the aforementioned method, wherein R is -C(O)R 2 .
  • the present invention relates to the aforementioned method, wherein R is -C(O)R 2 and R 2 is alkyl.
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 .
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 and R 4 is -CH(R 3 ) 2 .
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 , R 4 is -CH(R 3 ) 2 , n is 1.
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CO 2 R 4 and R 4 is cycloalkyl.
  • the present invention relates to the aforementioned method, wherein R is -CH 2 CO 2 R 4 and R 4 is cycloalkyl.
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 .
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n CN.
  • the present invention relates to the aforementioned method, wherein R is -(C(R 3 ) 2 ) n COR 5 .
  • the present invention relates to the aforementioned method, wherein R is -CH 2 C(O)R 5 and R 5 is alkyl.
  • the present invention relates to the aforementioned method, wherein said catalyst is QD-IP, QD-PC, QD-AD, QD-(-)-MN, QD-(+)-MN, QD-AC, QD-Piv, QD-PH, QD-AN, QD-NT, QD-CN, QD-CH, QD-IB, QD-EF, QD-AA, QD-MP, or QD-IPC.
  • the present invention relates to the aforementioned method, wherein said catalyst is QD-IP, QD-(-)-MN, or QD-AD.
  • the present invention relates to the aforementioned method, wherein said alcohol is a primary alcohol.
  • the present invention relates to the aforementioned method, wherein said nucleophile is methanol or CF 3 CH 2 OH.
  • Another aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic cyclic anhydride with an alcohol in the presence of a catalyst represented by formula II:
  • R represents -C(O)R 2 , -(C(R 3 ) 2 ) n CO 2 R 4 , -(C(R 3 ) 2 ) n C(O)N(R 5 ) 2 , -(C(R 3 ) 2 ) n CN, - (C(R 3 ) 2 ) n C(O)R 5 , -C(C(R 3 ) 2 ) n C .
  • R 6 represents -(C(R 3 ) 2 ) n OPO(OR 5 ) 2 , -(C(R 3 ) 2 ) n OR 5 , -(C(R 3 ) 2 ) n N(R 5 ) 2 , -(C(R 3 ) 2 ) n SR 5 , or -(C(R 3 ) 2 ) n NO 2 ;
  • R 1 represents alkyl or alkenyl;
  • R 2 represents alkyl, cycloalkyl, or alkenyl
  • R 3 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
  • R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl, or aralkyl;
  • R 5 represents independently for each occurrence H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl; R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and n is 1-10; and when said method of kinetic resolution is completed or interrupted any unreacted cyclic anhydride has an enantiomeric excess greater than zero and the enantiomeric excess of the product is greater than zero.
  • said catalyst is Q-IP, Q-PC, Q-AD, Q-(-)-MN, Q-(+)-MN, Q-
  • the present invention relates to the aforementioned method, wherein said alcohol is a primary alcohol.
  • said nucleophile is methanol or CF 3 CH 2 OH. Nucleophiles
  • nucleophiles which are useful in the present invention may be determined by the skilled artisan according to several criteria.
  • a suitable nucleophile will have one or more of the following properties: 1) It will be capable of reaction with the substrate at the desired electrophilic site; 2) It will yield a useful product upon reaction with the substrate; 3) It will not react with the substrate at functionalities other than the desired electrophilic site; 4) It will react with the substrate at least partly through a mechanism catalyzed by the chiral catalyst; 5) It will not undergo substantial undesired reaction after reacting with the substrate in the desired sense; and 6) It will not substantially react with or degrade the catalyst. It will be understood that while undesirable side reactions (such as catalyst degradation) may occur, the rates of such reactions can be rendered slow ⁇ through the selection of reactants and conditions - relative to the rate(s) of the desired reaction(s).
  • Nucleophiles which satisfy the above criteria 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. If a nitrogen- containing nucleophile is desired, for example, it may be selected from ammonia, phthalimide, hydrazine, an amine or the like. Similarly, 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 of organic chemistry.
  • the counterion can be any of a variety of conventional cations, including alkali and alkaline earth metal cations and ammonium cations.
  • the nucleophile may be part of the substrate, resulting in an intramolecular reaction.
  • an appropriate substrate e.g., a prochiral or meso compound
  • an appropriate substrate e.g., a prochiral or meso compound
  • an appropriate substrate e.g., a prochiral or meso compound
  • an appropriate substrate e.g., a prochiral or meso compound
  • a cyclic substrate may not be strained, i.e., it may comprise a larger ring with electrophilic centers.
  • suitable cyclic substrates which can be opened in the subject method include cyclic anhydrides, cyclic imides, and the like.
  • the cyclic substrate is a prochiral or meso compound. In other embodiments, for example, kinetic resolutions, the cyclic substrate will be a chiral compound. In certain embodiments, the substrate will be a racemic mixture. In certain embodiments, the substrate will be a mixture of diastereomers.
  • the electrophilic atom is carbon, e.g., the carbon of a carbonyl moiety comprised by an anhydride or imide.
  • the electrophilic atom may be a heteroatom.
  • the asymmetric reactions of the present invention may be performed under a wide range of conditions, although it will be understood that the solvents and temperature ranges recited herein are not limitative and only correspond to a preferred mode of the methods of the invention. hi general, it will be desirable that reactions are run using mild conditions which will not adversely effect the substrate, the catalyst, or the product. For example, the reaction temperature influences the speed of the reaction, as well as the stability of the reactants, products, and catalyst. The reactions will usually be run at temperatures in the range of -78 0 C to 100 0 C, more preferably in the range -30 0 C to 30 0 C and still more preferably in the range - 30 0 C to 0 0 C.
  • the asymmetric synthesis reactions of the present invention are carried out in a liquid reaction medium.
  • the reactions may be run without addition of solvent.
  • the reactions may be run in an inert solvent, preferably one in which the reaction ingredients, including the catalyst, are substantially soluble.
  • Suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2- butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or combinations of two or more solvents.
  • ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran and the like
  • halogenated solvents such as chlor
  • a solvent which is not inert to the substrate under the conditions employed, e.g., use of ethanol as a solvent when ethanol is the desired nucleophile.
  • the reactions can be conducted under anhydrous conditions, hi certain embodiments, ethereal or aromatic hydrocarbon solvents are preferred.
  • the solvent is diethyl ether or toluene.
  • the reactions may be run in solvent mixtures comprising an appropriate amount of water and/or hydroxide.
  • the invention also contemplates reaction in a biphasic mixture of solvents, in an emulsion or suspension, or reaction in a lipid vesicle or bilayer.
  • the reaction may be carried out under an atmosphere of a reactive gas.
  • desymmetrization with cyanide as nucleophile may be performed under an atmosphere of HCN gas.
  • the partial pressure of the reactive gas may be from 0.1 to 1000 atmospheres, more preferably from 0.5 to 100 atm, and most preferably from about 1 to about 10 atm.
  • it is preferable to perform the reactions under an inert atmosphere of a gas such as nitrogen or argon.
  • the asymmetric synthesis methods 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. However, the methods of this invention are preferably conducted in batch fashion. Likewise, 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 methods 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 may 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.
  • the substrate or nucleophile may 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.
  • Such an approach may form the basis for the preparation of a combinatorial library of compounds tethered to a solid support.
  • QD-AD QD-(+)-MN
  • QD-(-)-MN can be prepared in reasonable yield and at a cost significantly less than ( ⁇ 0.5% based on Aldrich price for starting material) that of (DHQD) 2 AQN.
  • the QD-(-)-MN catalyst has been shown to be sufficiently stable toward acid to be readily recyclable in high yield using a simple extraction procedure.
  • initial experiments indicate that QD-TB may be too acid-sensitive to be recycled via a similar extraction procedure.
  • Shown in Figure 25 are the results of the trifluoroethanolysis of 3-methyl gluratic anhydride in toluene at 0.2 M with various catalysts. Compared with either (DHQD) 2 AQN or QD-PP under these conditions, QD-AD and QD-MN showed better enantioselectivity and activity. The efficiency demonstrated by the combination of QD-(-)-MN with trifluoroethanol matched that by the combination of (DHQD) 2 AQN with methanol. Again, considering both the cost and catalytic properties, QD-AD and QD-MN are clearly superior to the dimeric catalysts.
  • Example 1 Highly Enantioselective Catalytic Desymmetrization of Cyclic meso Anhydrides
  • Enantioselective opening of the readily accessible meso-cy ⁇ ic anhydrides generates enantiomerically enriched chiral hemiesters containing one or multiple stereogenic centers and two chemically differentiated carbonyl functionalities (eq. 1).
  • These optically active bifunctional hemiesters are versatile chiral buiding blocks in asymmetric synthesis.
  • R is not H; R 1 is not H 2c: R is not H; R 1 is not H
  • the structure of the aryl group of the modified cinchona alkaloids has a dramatic impact on the selectivity of the catalyst. While catalysts bearing bulky aromatic groups such as PHN and AQN afford high enantioselectivities, a dramatic deterioration in enantioselectivity was observed with catalysts bearing relatively small heterocyclic rings as substituents at O-9 position (entries 2, 3, 6, 7 in Figure 1).
  • the reaction can be further optimized to give the product in excellent ee (93% ee) at room temperature by using ether as the solvent.
  • the ee of the hemiester was determined to be 93% by converting the hemiester into the corresponding ester amide (J. Chem.. Soc. Perkin. Trans 11987, 1053) via a reaction of the hemiester with (i?)-l-(l-napthyl) ethyl amine.
  • the ester amide was analyzed by chiral
  • Alcohol (0.1-1.0 mmol) was added to a solution of anhydride (0.1-0.2 mmol) and QD- PP (20-100 mol%) in ether (0.5-5.0 niL) at the reaction temperatures indicated in the Figures.
  • the reaction mixture was initially stirred and then allowed to sit at that temperature until the starting material was consumed as indicated by TLC analysis (43 h) or Chiral GC (/5-CD) analysis (0.5-101 h).
  • the reaction was quenched by adding HCl (1 N, 5 mL) in one portion.
  • the aqueous phase was extracted with ether (2 x 20 mL).
  • the organic phase was combined, dried over Na 2 SO 4 , and concentrated to provide the desired product without further purification.
  • the reaction was then quenched with HCl (1 N, 5 mL), diluted with EtOAc (20 mL), and washed with saturated NaHCO 3 (5 mL) and saturated brine (5 mL), respectively.
  • the organic layer was dried with Na 2 SO 4 .
  • the reaction was then diluted with EtOAc (20 mL) and washed successively with HCl (1 N, 10 mL), saturated NaHCO 3 (10 mL) and saturated brine (10 mL). The organic layer was dried with Na 2 SO 4 .
  • reaction mixture was allowed to warm to room temperature and stirred for another 3 h.
  • the resulting mixture was filtrated with the aid of Celite, washed with diethyl ether (30 mL).
  • the mixture was cooled to 0 0 C again, carefully quenched with H 2 O (60 mL) and then ethyl acetate (60 mL) was added.
  • the organic and aqueous layers were separated.
  • the aqueous phase was extracted with ethyl acetate (30 mL).
  • the organic phases were combined, washed with sat. NaHC ⁇ 3 (30 mL), water (3x30 mL), sat. NaCl (30 mL), and then extracted by 3x40 mL 5%w/w HCl.
  • the combined acidic aqueous phase was extracted by 2x50 mL CH 2 Cl 2 .
  • the combined organic phase was washed by 25 mL 5%w/w HCl and concentrated under reduced pressure.
  • the mixture was cooled to 0 0 C and carefully quenched with H 2 O (13 mL) and then toluene (13 mL) was added. The organic and aqueous layers were separated.
  • the enantiomeric excess (ee) of the product was determined by HPLC analysis of a diastereoisomeric mixture of the corresponding amide-ester prepared from the product according to a modified literature procedure (for trifluoroethyl ester) or chiral GC analysis ( ⁇ - CD, 130 °C/20 min) (for methyl ester).
  • the combined organic layer was dried over Na 2 SO 4 and concentrated to afford the catalyst (Quantity, recovery >95%).
  • the recovered catalyst was used for a new batch of alcoholysis of cis- 1,2,3, 6-tetrahydrophthalic anhyride (1.0 mmol) to give the hemiester in 99% ee and 95% yield.
  • reaction mixture was stirred for 2 h at 0 0 C and carefully quenched with H 2 O (14 niL) and then ethyl acetate (14 mL) was added. The organic and aqueous layers were separated. The aqueous phase was extracted with ethyl acetate (2x14 mL). The organic phases were combined, washed with sat. NaHCO 3 (14 mL), water (3x14 mL), sat. NaCl (14 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure.
  • the reaction mixture was stirred for 4 h at 0 0 C and carefully quenched with H 2 O (14 mL) and then ethyl acetate (14 mL) was added. The organic and aqueous layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 14 mL). The organic phases were combined, washed with sat. NaHCO 3 (14 mL), water (3 x 14 mL), sat. NaCl (14 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure.

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EP1638677A2 (en) 2006-03-29
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