HRP20060010A2 - Catalytic asymmetric desymmetrization of prochiral and meso cyclic anhydrides - Google Patents

Abstract

One aspect of the present invention pertains to catalysts based on the cinchona alkaloid. Another aspect of the invention relates to a method of producing catalyst derivatives based on a cinchona alkaloid. Another aspect of the present invention relates to a method of producing a chiral, non-racemic compound from prochiral cyclic anhydride or meso cyclic anhydride, comprising the step of reacting prochiral cyclic anhydride or meso cyclic anhydride with a nucleophile in the presence of a cinchona alkyl derivative. Another aspect of the present invention relates to a kinetic resolution method, comprising the step of reacting racemic cyclic anhydride with an alcohol in the presence of a cinchona-alkaloid derivative catalyst.

Description

Associated applications

This application claims the benefit of United States Patent Application Serial No. 10/460,051, filed June 12, 2003; United States Provisional Patent Application Serial No. 60/477,531, filed June 11, 2003; and United States Provisional Patent Application Serial No. 60/484,218, filed Jun. 1, 2003.

Government support

The invention was made with support under the terms of the National Institute of Health (permit number GM-61591); because, the government has certain rights to the patent.

Background of the invention

The need for enantiomerically pure compounds has been growing rapidly in recent years. A significant use of such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For example, it is becoming increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages include the numerous side effects and higher potency often associated with enantiomerically pure compounds.

Traditional methods of organic synthesis are often optimized for the production of racemic materials. The production of enantiomerically pure materials has historically been achieved in one of two ways: the use of enantiomerically pure starting materials derived from natural sources (so-called "chiral pools"); and by redissolving racemic mixtures with classical techniques. Each of these methods has a serious drawback, however. Chiral pool is limited to compounds found in nature, so only certain structures and configurations are readily available.Resolution of racemates, which requires the use of a resolution agent, can be inconvenient and time-consuming.

One method for obtaining enantiomerically pure materials is with enantioselective alcoholysis of meso, prochiral, and racemic cyclic anhydrides (EACA). These reactions appear to be widely applicable in both laboratory and industrial scale asymmetric synthesis of a wide variety of significant chiral building blocks, such as hemiester, α-amino acid, and α-hydroxy acid.

Summary of the invention

One of the aspects of the presented invention generally relates to catalysts based on cinchona-alkaloids. In a particular embodiment, the quinidine-based catalyst contains a ketone, ester, amide, cyano, or alkynyl group. In a preferred embodiment, the catalyst is QD-IP, QD-(-)-MN, or QD-AD. In other embodiments, the cinchona-alkaloid son catalyst is Q-AD.

Another aspect of the invention relates to a process for the production of cinchona-alkaloid derivative catalysts by reacting cinchona-alkaloid with a base and the compound thus has a corresponding residual group. In certain embodiments, the remaining group is Cl, Br, I, OSO2CH3, or OSO2CF3. In a preferred embodiment, the remaining group is Cl. In a preferred embodiment, the base is a metal hydride. In a preferred embodiment, the hydroxyl group of the cinchona alkaloid is reacted with an alkyl chloride to form the catalyst.

One aspect of the presented invention relates to the process of producing a chiral, non-racemic compound from a prochiral substituted chiral anhydride or a meso substituted cyclic anhydride, which includes the phase: reaction of a prolyral substituted cyclic anhydride or a meso substituted cyclic anhydride with a nucleophile in the presence of a chiral, non-racemic catalyst tertiary amine; wherein said prochiral substituted cyclic anhydride or said meso substituted cyclic anhydride comprises an internal degree of symmetry or a 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; and in this way a chiral, non-racemic compound is produced.

In certain embodiments of the above-mentioned method, the prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or is substituted glutaric anhydride.

In certain embodiments of the aforementioned method, said nucleophile is an alcohol.

In a certain embodiment of the aforementioned method, said nucleophile is a primary alcohol.

In a certain embodiment of the aforementioned method, said nucleophile is methanol or CF3CH2OH.

In a particular embodiment of the aforementioned method, said chiral catalyst non-racemic tertiary amine is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ)2PHAL, (DHQD)2PHAL, (DHQ)2PYR, (DHQD) 2PYR, (DHQ)2AQN, (DHQD)2AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.

In a particular embodiment of the aforementioned method, said chiral catalyst non-racemic tertiary amine is DHQD-PHN or (DHQD)2AQN.

In a particular embodiment of the aforementioned method, said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB.

In a particular embodiment of the aforementioned method, said chiral, non-racemic tertiary amine catalyst is QD-PP.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is 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)2PHAL, (DHQD)2PHAL, (DHQ)2PYR, (DHQD)2PYR, (DHQ) 2AQN, (DHQD)2AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is 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)2PHAL, (DHQD)2PHAL, (DHQ)2PYR, (DHQD)2PYR, (DHQ) 2AQN, (DHQD)2AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is methanol or CF;3CH2OH; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ)2PHAL, (DHQD)2PHAL, (DHQ)2PYR, (DHQD)2PYR, (DHQ) 2AQN, (DHQD)2AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is 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)2AQN.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is 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)2AQN.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is methanol or CF3CH2OH; and said chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD)2AQN.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is 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.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is 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.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is methanol or CF3CH2OH; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is an alcohol; and said chiral, non-racemic tertiary amine catalyst is QD-PP.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is a primary alcohol; and said chiral, non-racemic tertiary amine catalyst is QD-PP.

In a certain embodiment of the aforementioned method, said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is methanol or CF3CH2OH; and said chiral, non-racemic tertiary amine catalyst is QD-PP.

In a certain embodiment of the aforementioned method, said chiral catalyst non-racemic tertiary amine is present in less than about 30 mol% relative to said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride.

In a particular embodiment of the aforementioned method, said chiral catalyst non-racemic tertiary amine is present in less than about 20 mol% relative to said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride.

In a particular embodiment of the aforementioned method, said chiral catalyst non-racemic tertiary amine is present in less than about 10 mol% relative to said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride.

The next aspect of the presented invention relates to the process of producing a chiral, non-racemic compound from a prochiral cyclic anhydride or a meso cyclic anhydride, which includes the phase: reaction of a prochiral cyclic anhydride or a meso cyclic anhydride with a nucleophile in the presence of a catalyst; wherein the prochiral cyclic anhydride or meso cyclic anhydride comprises an internal degree of symmetry or a point of symmetry or both; wherein said chiral, non-racemic compound; wherein said catalyst is a cinchona-alkaloid derivative. In a preferred embodiment, the catalyst is QD-IP, QD-(-)-MN, or QD-AD. In a certain embodiment, the nucleophile is a primary alcohol.

In a preferred embodiment, the nucleophile is methanol or CF3CH2OH. In a certain embodiment, the prochiral cyclic anhydride or meso cyclic anhydride is a substituted succinic anhydride or a substituted glutaric anhydride. In a particular embodiment, the catalyst is present at less than about 70 mol% relative to the prochiral cyclic anhydride or meso cyclic anhydride. In a preferred embodiment, the catalyst is present at less than about 10% relative to said prochiral cyclic anhydride or meso cyclic anhydride. In a particular embodiment, the chiral, non-racemic compound has an enantiomeric excess greater than about 90%. In a certain embodiment, said catalyst is Q-IP, Q-PC, Q-AD, or Q-(-)-MN.

Another aspect of the presented invention relates to the method of kinetic resolution, which includes the phase: reaction of racemic cyclic anhydride with alcohol in the presence of a catalyst derived from cinchona-alkaloid. In a preferred embodiment, the catalyst is QD-IP, QD-(-)-MN, or QD-AD. In a preferred embodiment, the alcohol is a primary alcohol. In these embodiments, the catalyst is Q-IP, Q-PC, Q-AD, or Q-(-)-MN.

In a particular embodiment of the above method, said chiral, non-racemic compound has an enantiomeric excess greater than about 50%.

In a particular embodiment of the above method, said chiral, non-racemic compound has an enantiomeric excess greater than about 70%.

In a particular embodiment of the above method, said chiral, non-racemic compound has an enantiomeric excess greater than about 90%.

In a particular embodiment of the above method, said chiral, non-racemic compound has an enantiomeric excess greater than about 95%.

Brief description of graphic displays

Figure 1 presents the enantiomeric excess of the product obtained from the asymmetric desymmetrization of cis-2,3-dimethylsuccinic anhydride, as a function of the used solvent and catalyst.

Figure 2 presents the enantiomeric excess of the product obtained from the asymmetric desymmetrization of various meso cyclic anhydrides, as a function of the used reaction conditions. The absolute configuration for each product is determined by comparison with an authentic sample. Enantiomeric excess is determined using chiral GC or literature methods. In Entries 1-3, the enantiomeric excess in parentheses belongs to the products opposite to the absolute configuration obtained using (DHO)2AON as catalyst. In Entry 4, (DHQD)2PHAL is used as a catalyst.

Figure 3 presents the enantiomeric excess of the product obtained from the asymmetric desymmetrization of various meso cyclic anhydrides, as a function of the used reaction conditions. The absolute configuration for each product is determined by comparison with an authentic sample. Enantiomeric excess is determined using chiral GC or literature methods. In Entries 7 and 8, (DHQD)2PHAL is used as a catalyst.

Figure 4 presents the enantiomeric excess of the product obtained from the asymmetric desymmetrization of various meso cyclic anhydrides, as a function of the used reaction conditions. The absolute configuration for each product is determined by comparison with an authentic sample. Enantiomeric excess is determined using chiral GC or literature methods. In Entries 9 and 11, (DHQD)2PHAL is used as a catalyst.

Figure 5 shows the structure of certain catalysts used in the processes of the present invention, and the abbreviations used therein.

Figure 6 shows the structure of certain catalysts used in the processes of the present invention, and the abbreviations used therein.

Figure 7 shows the structure of certain catalysts used in the processes of the present invention, and the abbreviations used therein.

Figure 8 shows the enantiomeric excess of the product obtained from the asymmetric desymmetrization of various meso cyclic anhydrides, as a function of the reaction conditions used.

Figure 9 shows the enantiomeric excess of the product obtained from the asymmetric desymmetrization of various meso cyclic anhydrides, as a function of the reaction conditions used. The absolute configuration of each product is determined by comparison with an authentic sample. Enantiomeric excess is determined using chiral GC or literature methods.

Figure 10 shows the result of the desymmetrization of a number of prochiral cyclic anhydrides. In each example: the amount of substrate is 0.1 mmol; substrate concentration is 0.2 M; 110 mol% catalyst is used in relation to the substrate; the amount of alcohol is 1.5 equiv; the solvent is toluene; and the reaction temperature is –43°C.

Figure 11 shows the result of desymmetrization of a number of meso cyclic anhydrides. In each example: the amount of substrate is 0.1 mmol; substrate concentration is 0.02 M; and the solvent is ether.

Figure 12 shows the result of desymmetrization of a number of meso cyclic anhydrides. In each example: the amount of substrate is 0.1 mmol; substrate concentration is 0.02 M; and the solvent is ether.

Figure 13 shows the result of desymmetrization of cis-2,3-diniethyl succinic anhydride. In each example: the amount of substrate is 0.1 mmol; substrate concentration is 0.02 M; the catalyst is QD-PP; 20 mol% of the catalyst is used in relation to the substrate; the amount of alcohol is 10 equiv; and the reaction is carried out at room temperature.

Figure 14 shows the result of desymmetrization of cis-2,3-dimethyl succinic anhydride. In each example: the amount of substrate is 0.1 mmol; substrate concentration is 0.2 M; the catalyst is QD-PP; alcohol is methanol; the reaction is carried out at room temperature.

Figure 15 shows the result of desymmetrization of cis-2,3-dimethyl succinic anhydride. In each example: the amount of substrate is 0.1 mmol; substrate concentration is 0.2 M; the catalyst is QD-PP; alcohol is methanol; the reaction is performed at -25 °C.

Figure 16 shows the result of desymmetrization of cis-2,3-dimethyl succinic anhydride. In any case: the amount of substrate is 0.2 mmol; substrate concentration is 0.4 M; the catalyst is QD-PP; alcohol is methanol; the reaction is carried out at -25 °C, and the reaction time is 6 hours.

Figure 17 shows the result of desymmetrization of cis-2,3-dimethyl succinic anhydride. In any case: the substrate concentration is 0.02 M; the catalyst is 20 mol% in relation to the substrate; the amount of alcohol is 10 equiv; the reaction is carried out at ambient temperature.

Figure 18 shows the structure of QD-PH, QD-AN, QD-NT, QD-AC and QD-CH.

Figure 19 presents a comparison of the efficiency of the catalyst in the methanolysis of 2,3-dimethylsuccinic anhydride in Et2O at a concentration of 0.02 M.

Figure 20 presents a comparison of the effectiveness of the catalyst in the methanolysis of 2,3-dimethylsuccinic anhydride in Et2O at a concentration of 0.02 M.

Figure 21 presents a comparison of the effectiveness of the catalyst in the trifluoroethanolysis of 2,3-dimethylsuccinic anhydride in Et2O at a concentration of 0.02 M.

Figure 22 represents the optimization of the reaction conditions in the methanolysis of 3-inethylglutaric anhydride in Et2O at a concentration of 0.02 M.

Figure 23 presents the screening of reaction conditions in the alcoholysis of 3-methyl-glutaric anhydride in 0.02 M concentration.

Figure 24 presents a comparison of the efficiency of the catalyst for the methanolysis of 3-methyl-glutaric anhydride in toluene for a 0.02 M concentration.

Figure 25 presents a comparison of the efficiency of the catalyst in trifluoroethanolysis of 3-methyl-glutaric anhydride in toluene at a concentration of 0.02 M.

Figure 26 presents a comparison of the effectiveness of the catalyst in the methanolysis of 3-phenyl-glutaric anhydride in toluene at a concentration of 0.02 M.

Figure 27 presents a comparison of the effectiveness of the catalyst in trifluoroethanolysis of 3-phenyl-glutaric anhydride in toluene at a concentration of 0.02 M.

Figure 28 presents a comparison of the efficiency of the catalyst in the methanolysis of 3-isopropyl glutaric anhydride in toluene at a concentration of 0.02 M.

Figure 29 presents a comparison of the effectiveness of the catalyst in the trifluoroethanolysis of 3-isopropyl glutaric anhydride in toluene at a concentration of 0.02 M.

Figure 30 presents a comparison of the efficiency of the catalyst for the methanolysis of 3-TBSO glutaric anhydride in toluene at a concentration of 0.02 M.

Figure 31 presents a comparison of the efficiency of the catalyst in the trifluoroethanolysis of 3-TBSO glutaric anhydride in toluene for 0.02 M concentration.

Figure 32 represents Q-AD catalyzing the methanolysis of 3-substituted glutaric anhydride in toluene at 0.2 M concentration.

Figure 33 presents Q-AD catalyzing trifluoromethanolysis of 3-substituted glutaric anhydride in toluene at 0.2 M concentration.

Figure 34 presents a comparison of the efficiency for the alcoholysis of cis 1,2,3,6-tetrahydrophthalic anhydride with methanol in Et2O at a concentration of 0.02 M.

Figure 35 presents a comparison of the efficiency in the alcoholysis of cis 1,2,3,6-tetrahydrophthalic anhydride with trifluoroethanol in Et2O at a concentration of 0.02 M.

Figure 36 represents the QD-AD catalyzed alcoholysis of 1,2-cyclohexanedicarboxylic anhydride with methanol in Et2O at 0.02 M concentration.

Figure 37 presents a comparison of the effectiveness of the catalyst in the alcoholysis of 1,2-cyclohexanedicarboxylic anhydride with trifluoroethanol in Et2O at a 0.02 H concentration.

Figure 38 presents a comparison of the efficiency of the catalyst for the alcoholysis of cis-norbornene-endo-2,3-dicarboxylic anhydride in Et2O at a concentration of 0.02 M.

Figure 39 presents a comparison of the effectiveness of the catalyst in the alcoholysis of exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride in Et2O at a concentration of 0.02 M.

Figure 40 represents the optimization of reaction conditions in the ecolysis of cis-1,2,3,6-tetrahydrophthalic anhydride in Et2O in 0.02 M concentration.

Figure 41 represents the optimization of the reaction conditions in the alcoholysis of cis-1,2,3,6-tetrahydrophthalic anhydride in toluene at a concentration of 0.02 M.

Figure 42 represents the optimization of the reaction conditions in the alcoholysis of cis-1,2,3,6-tetrahydrophthalic anhydride in 0.5 M toluene.

Figure 43 represents the alcoholysis of succinic anhydrides with Q-AD.

Figure 44 presents a comparison of the efficiency of the catalyst in the methanolysis of 2,3-dimethylsuccinic anhydride in Et2O at a concentration of 0.02 M.

Figure 45 presents a comparison of the efficiency of the catalyst in the trifluoroethanolysis of 3-isopropyl glutaric anhydride in toluene at a concentration of 0.02 M.

Detailed description of the invention

The invention will now be described in more detail with reference to the accompanying examples, in which certain preferred embodiments of the invention are shown. This invention may, however, be achieved in various forms and shall not be further construed as limiting the choice of embodiments, rather, those embodiments are provided that such disclosures shall be whole and complete, and shall fully convey the object of the invention to those skilled in the art.

The possibility of selective transformation of prochiral and meso compounds on enantiomerically enriched or enantiomerically pure chiral compounds has a wide application, especially in agriculture and the pharmaceutical industry, as well as in the polymer industry. As described herein, the present invention relates to methods and catalysts for catalytic asymmetric desymmetrization of prochiral and meso compounds and the like. The basic component of the methods, which are presented in detail below; are a non-raceraic chiral tertiary-amine-containing catalyst; prochiral or meso substrate, as a rule, a heterocycle contains a pair of electrophilic atoms connected to an internal degree of symmetry or a point of symmetry; and nucleophiles, a common solvent, which under reaction conditions selectively attack one of the two electrophilic atoms listed above, producing an enantiomerically enriched chiral product. In addition, the catalyst and methods of the present invention can be used for efficient kinetic resolution of racemic mixtures and the like.

Definitions

For convenience, the following are collected here: certain terms used in the specification, examples, and added requirements.

The term "nucleophile" is recognized in the art, and as used herein refers to a chemical moiety having a reactive pair of electrons. Examples of nucleophiles include uncharged compounds such as water, amines, mercaptans, and alcohols, and uncharged moieties such as alkoxides, thiolates, carbanions, and various 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 organocopper, organozinc, organolithium compounds, Gringard reagents , enolates, acelides, and the like may, under appropriate reaction conditions, be suitable nucleophiles.Hydrides may also be suitable nucleophiles when substrate reduction is required.

The term "electrophile" is known in the art and refers to chemical moieties that can accept a pair of electrons from a nucleophile as defined above. Commonly used electrophiles in the methods of the present invention include cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones, lactams, etc. Non-cyclic electrophiles include sulfates, sulfonates (eg, tosylates), chlorides, bromides, iodides, and the like.

The terms "electrophilic atom," "electrophilic center," and "reactive center" as used herein refer to the substrate atom that is engaged with, and forms a new bond to, the nucleophile. In most (but not all) cases, this will be the atom from which the rest of the group deviates.

The term "electron withdrawing group" is recognized in the art and as used herein means a functionality that withdraws more electrons to itself than a hydrogen atom at the same position. An example of an electron withdrawing group includes nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, -CN, chloride, and the like. The term "electron-donating group," as used herein, means a functionality that withdraws electrons to itself less than a hydrogen atom at the same position. An example of an electron-donating group includes amino, methoxy, and the like.

The terms "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 various other organic anions.

The terms "Lewis acid" and Lewis acid" are recognized in the art and refer to a chemical part that is capable of accepting a pair of electrons from a Lewis base.

The term "meso compound" is recognized in the art and means a chemical compound that has at least two chiral centers or is achiral due to an internal degree of symmetry or point of symmetry.

The term "chiral" refers to molecules that have the property of non-superimposability on their mirror image partner, while the term "achiral" refers to molecules that are superimposable on their mirror image partner. A "prochiral molecule" is an achiral molecule that has the potential to be converted into a chiral molecule in a particular process.

The term "stereoisomerism" refers to compounds that have an identical chemical constitution, but differ in the arrangement of their atoms or groups in space. More precisely, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. . The term "diastereomers", on the other hand, refers to a bond between a pair of stereoisomers such that they involve two or more asymmetric centers and are not mirror images of each other.

Furthermore, a "stereoselective process" is one that produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of the product. An "enantioselective process" is one that favors the production of one of the two possible enantiomers of the reaction product. The subject method is specified for the production of a "stereoselectively enriched" product (eg enantioselectively-enriched or diastereoselectively-enriched) when the yield of certain stereoisomers of the product is greater than a statistically significant amount in relation to the yield of that stereoisomer resulting from the same reaction carried out in the absence of a chiral catalyst. For example, an enantioselective reaction catalyzed with one of the subject chiral catalysts produces an e.e. for a particular enantiomer that is greater than the e.e. of a reaction lacking the chiral catalyst.

The term "regioisomers" refers to compounds that have the same molecular formula but differ in the connection of atoms. Accordingly, a "regioselective process" is one that favors the production of certain regioisomers over others, e.g. reaction procedures with statistically significant superiority of a certain regioisomer.

The term "reaction product" means a compound resulting from the reaction of a nucleophile and a substrate. In general, the term "reaction product" as used herein refers to a stable, isolated compound and not to unstable intermediates or transition states.

The term "substrate" is intended to mean a chemical compound that can react with a nucleophile, or with a ring-expansion reagent, in accordance with the present invention, to give at least a product having a stereogenic center.

The term "catalytic amount" is known in the art to mean a substoichiorietric amount relative to the reactant. As used herein, catalytic amount means from 0.0001 to 90 mole percent relative to the reactant, more preferably from 0.001 to 50 mole percent, more preferably from 0.01 to 10 mol percent, and even more preferably from 0.1 to 5 mol percent relative to the reactant.

As discussed in more detail below, reactions contemplated by the present invention include reactions that are enantioselective, diastereoselective, and/or regioselective. An enantioselective reaction is a reaction that converts an achiral reactant into a chiral product enriched in one enantiomer. Enantioselectivity is generally quantified as "enantiomeric excess" (ee) defined as follows:

% enantiomeric excess A (ee) = (% enantiomer A) -(% enantiomer B)

where A and B are the enantiomers formed. Additionally, the terms used in conjunction with enantioselectivity are "optical purity" or "optical action". The yield of the enantioselective reaction product with e.e. is greater than zero. The preferred yield of the enantioselective reaction product is 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 can be racemic or enantiomerically pure) into 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 much more slowly than the other. This class of reaction is called resolution kinetics, where the reactant enantiomers are resolved by a differential reaction in relation to the yield of both enantiomerically-enriched products and enantiomerically-enriched unreacted substrate. Kinetic resolution is usually achieved by using excess reagent to react with only one reactant enantiomer (ie, one-half mole of reagent per mole of racemic substrate). Examples of catalytic reactions that will be used for the kinetic resolution of a racemic reactant include Sharpless epoxidation and Noyori hydrogenation.

A regioselective reaction is a reaction that preferentially occurs at one reactive center rather than at another non-identical reactive center. For example, the regioselective reaction of an unsymmetrically substituted epoxy substrate involves a preferential reaction at one of the two carbons of the epoxy ring.

The term "non-racemic" with respect to a chiral catalyst means a preparation having more than 50% of the enantiomer indicated, more preferably at least 75%. "Highly non-racemic" refers to a catalyst preparation having more than 90% ee for the indicated enantiomer of the catalyst, more preferably greater than 95% ee.

The term "alkyl" refers to the radical of saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl(alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In a preferred embodiment, straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (eg C1-C30 for a straight chain, C3-C30 for a branched chain), more preferably 20 or less Similarly, preferred cycloalkyls have from 4-10 carbon atoms in their ring structure , and it is more preferred to have 5, 6 or 7 carbons in the ring structure.

Unless the number of carbons is otherwise specified, "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 basic structure. Similarly , "lower alkenyl" and "lower alkynyl" have the same chain length.

The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length to, and possible substitution on, the alkyl described above, but containing at least one double or triple carbon-carbon bond.

The terms "alkyl" or "alkyl" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representatives of alkyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently bonded to oxygen. Accordingly, an alkyl substituent is one that makes an alkyl ether is or resembles an alkoxyl, so it can be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl , -O-(CH 2 ) m -R 8 , where m and R 8 are as described above.

As used herein, the term "amino" means -NH2; the term "nitro" means -NO2; the term "halogen" means -F, -Cl, -Br or -I; the term "thiol" means -SH; the term "hydroxyl" means -OH; the term "sulfonyl" means -SO2-; and the term "organometallic" refers to an atom of a metal (such as mercury, zinc, lead, magnesium, or lithium) or a metalloid (such as silicon, arsenic, or selenium) that is directly bonded to a carbon atom, such as a diphenylmethylsilyl group.

The terms "amine" and "amino" are known in the art and refer to both unsubstituted and substituted amines, e.g. a moiety that can be represented by the general formula:

[image]

where R9, R10 and R'10 each independently represent a group allowed by the valence rule.

The term "acylamino" is known in the art and refers to a part that can be represented by the general formula:

[image]

where R9 is defined above, and R'11 represents hydrogen, alkyl, alkenyl or -(CH2)m-R8, where m and R8 are defined above.

The term "amido" is known in the art for an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:

[image]

where R9, R11 are as defined above. A preferred embodiment of the amide will not include imides which can be unstable.

The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical added thereto. In a preferred embodiment, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl , and -S-(CH 2 ) m -R 8 , where m and R 8 are as defined above. Representative alkylthio groups include methylthio, ethylthio, and the like.

The term "carbonyl" is known in the art and thus includes parts that can be represented by the general formula:

[image]

where X is a bond or represents oxygen or sulfur, and R11 represents hydrogen, alkyl, alkenyl, -(CH2)m-R8 or a pharmaceutically acceptable salt, R'11 represents hydrogen, alkyl, alkenyl or -(CH2)m-R8, where are m and R8 as defined above. When X is oxygen then R 11 or R' 11 is not hydrogen, the formula represents "ester". When X is oxygen and R 11 is as defined above, the moiety specified herein as a carboxyl group, and especially when R 11 is hydrogen, the formula represents " carboxylic acid". When X is oxygen and R'11 is hydrogen, the formula represents a "formate." In general, when the oxygen atom of the above formula is replaced with sulfur, the formula represents a "thiolcarbonyl" group. When X is sulfur and R 11 or R' 11 is not hydrogen, the formula represents a "thiolester". When X is sulfur and R 11 is hydrogen, the formula represents a "thiolcarboxylic acid". When X is sulfur and R'11 is hydrogen, the formula represents a "thiolformate." On the other hand, when X is a bond and R11 is not hydrogen, the above formula represents a "ketone" group. When X is a bond and R11 is hydrogen, the above formula represents an "aldehyde" group.

The term "sulfonate" is known in the art and includes a part that can be represented by the general formula:

[image]

wherein R41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term "sulfonylamino" is known in the art and includes a moiety that can be represented by the general formula:

[image]

The term "sulfamoyl" is known in the art and includes a part that can be represented by the general formula:

[image]

The term "sulfonyl" as used herein refers to a moiety that can be represented by the general formula:

[image]

wherein R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

The term "sulfoxide" as used herein refers to a moiety that can be represented by the general formula:

[image]

wherein R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, or aryl.

The term "sulfate" as used herein means a sulfonyl group, as defined above, attached to both hydroxy and alkoxy groups. Thus, in a preferred embodiment, the sulfate has the structure:

[image]

wherein R 40 and R 41 are independently absent, hydrogen, alkyl, or aryl. Furthermore, R40 and R41, together with the sulfonyl group and the oxygen atoms to which they are added, can form a ring structure having 5 to 10 members.

Analogous substituents can be formed on alkenyl or alkynyl groups to produce, for example, alkenylamines, alkynylamines, alkenylamides, alkynylamides, alkynylimines, alkynylimines, thioalkenyls, thiolalkynyls, carbonyl-substituted alkenyls or alkynyls, alkenoxyls, alkynyloxyls, metalloalkenyls, or methanolalkynyls.

The term "aryl" is used herein to include 4-, 5-, 6-, and 7-membered simple-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. Those aryl groups that have heteroatoms in the ring structure refer to an "aryl heterocycle". The aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenethers, ketones, aldehydes, esters, or -(CH2)m-R7, -CF3, -CN, or the like.

The term "heterocycle" or "heterocyclic group" refers to a 4- to 10-membered ring structure, more preferably a 5- to 7-membered ring structure, which includes a ring structure of one to four heteroatoms. The heterocyclic group includes pyrrolidine, oxolane, thiolane, imidazole, oxazole, piperidine, piperazine, morpholine. The heterocyclic ring may be substituted at one or more positions with the substituents described above, such as, for example, halogens, alkyls, alkenyls, alkynyls, hydroxyls, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenethers, ketones, aldehydes, esters, or -(CH2)m-R7, -CF3, -CN, or the like.

The terms "polycycle" or "polycyclic group" refer to two or more cyclic rings (eg, cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles) in which two or more carbons are usually on two adjacent rings, eg, rings are adjacent rings, i.e. the rings are "fused rings". Rings so joined via non-adjacent atoms are called "bridged" rings. Each of the polycycle rings may be substituted with such substituents as described above, such as, for example, halogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, nitro , thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenethers, ketones, aldehydes, esters or -(CH2)m-R7, -CF3, -CN, or the like.

The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, phosphorus or selenium.

For the purposes of this invention, chemical elements are equal according to the Periodic Table of Elements, CAS version, Hanbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

The terms ortho, meta, and para as applied to 1,2-, 1,3-, and 1,4-disubstituted benzenes. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonyms.

The terms triflyl, tosyl, mesyl, and nonafyl are known in the art and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups. The terms triflate, tosylate, mesylate, and nonaflate are known in the art and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules containing said groups.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, and methanesulfonyl. A comprehensive list of abbreviations used by organic chemists in the profession can be found in the first volume of the Journal of Organic Chemistry; as a rule, the list is presented in a table entitled Standard list of abbreviations. Abbreviations in the above list, and all abbreviations used by organic chemists in the field, are hereby incorporated by reference.

The phrase "protecting group" as used herein means temporary substituents that protect a potentially reactive group from unwanted chemical transformation. Examples of such protecting groups include carboxylic acid, alcohol silyl ethers, and acetals and ketals of aldehydes and ketones. The field of protecting group chemistry is shown (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).

As used herein, the term "substituted" is intended to include all permitted substituents of organic compounds. The broad spectrum of compounds permitted includes acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Examples of substituents include , for example, those described above. The permissible substituents may be one or more and the same or different for the respective organic compounds. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituent of the organic compounds herein satisfy the valency of heteroatoms.This invention is not intended to limit in any way the permissible substituents of organic compounds.

The term "1-adamantyl" is known in the art and includes the part represented by the formula:

[image]

The term "(-)-menthyl" is known in the art and includes the part represented by the formula:

[image]

The term "(+)-menthyl" is known in the art and includes the part represented by the formula:

[image]

The term "isobornil" is known in the art and includes the part represented by the formula:

[image]

The term "isopinocampile" is known in the art and includes the part represented by the formula:

[image]

The term "(+)-fenkyl" is known in the art and includes the part represented by the formula:

[image]

The term "QD" is represented by the formula:

[image]

The term "Q" is represented by the formula:

[image]

Catalysts of invention

The catalysts used in the subject methods are non-racemic chiral amines representing an asymmetric environment, which cause differentiation between two or more parts symmetrically connected in a prochiral or meso molecule, i.e., the molecule comprises at least two chiral centers, and comprises an internal degree of symmetry or point of symmetry or both. In general, the catalysts intended with the present invention can be characterized in terms of a number of characteristics. For example, a major aspect of any catalyst contemplated with the present invention considers the use of asymmetric bicycles or polycycles a true platform for the incorporation of tertiary amine moieties that provide a rigid or semi-rigid environment near the amine nitrogen. This form, through the fundamental structural rigidity on the amine nitrogen in the vicinity of one or more asymmetric centers present in the created podium, contributes to certain significant differences in the energy of the corresponding diastereomeric transition state for the general transformation. Furthermore, the choice of substituent can also affect the reactivity of the catalyst. For example, bulkier substituents on the catalyst are generally found to provide more catalyst turnover.

A preferred embodiment for each of the embodiments described herein provides a catalyst having a molecular weight of less than 2,000 g/mol, more preferably less than 1,000 g/mol, and even more preferably less than 500 g/mol. In addition, the substituents on the catalyst can be chosen to affect the solubility of the catalyst, more precisely the solvent system.

In certain embodiments, the chiral, non-racemic tertiary amine catalyst comprises a 1-azabicyclo[2.2.2]octane moiety or a 1,4-diazabicyclo[2.2.2]octane moiety. In certain embodiments, the chiral, non-racemic tertiary amine catalyst is cinchona alkaloid, Q-PP, Q-TB, QD-TB, (DHQ)2PHAL, (DHQD)2PHAL, (DHQ)2PYR, (DHQD)2PYR, (DHQ )2AQN, (DHQD)2AQN, DHQ-CLB, DHQD-CLB, DHQ-MEO, DHQD-MEO, DHQ-AQN, DHQD-AQN, DHQ-PHN or DHQD-PHN. In certain embodiments, the chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD}2AQN. In some embodiments, the chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, or QD-TB In some embodiments, the chiral, non-racemic tertiary amine catalyst is QD-PP.

As briefly mentioned above, the choice of catalyst substituents can also affect the electronic properties of the catalyst. Substitution of the catalyst with electron-poor (electron donor) moieties (including, for example, alkoxy or amino groups) can increase the electron density of the catalyst on the tertiary nitrogen of the amine, rendering them a stronger nucleophile and/or Bronstad base and/or Lewis base. Conversely, substitution of the catalyst with electron-poor moieties (for example, chlorine or trifluoromethyl groups) can result in a lower electron density of the catalyst on the tertiary amine nitrogen, rendering them weaker nucleophiles and/or Bronsted bases and/or Lewis bases. To summarize this reasoning, the electron density of the catalyst can be significant due to the electron density of the nitrogen on the tertiary amine which can affect the Lewis basicity of the nitrogen and its nucleophilicity. The choice of appropriate substituents thus makes it possible to "adjust" the degree of reaction and the stereoselectivity of the reaction.

One aspect of the invention relates to compounds represented by the formula. AND:

[image]

where

R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, (C( R3)2)nC(O)R5, -(C(R3)2)nC=CR6, -(C(R3)2)nCOPO(OR5)2, -(C(R3)2)nOR5, -(C( R3)2)nN(R5)2, -(C(R3)2)nSR5, or –(C(R3)2)nNO2;

R 1 represents alkyl or alkenyl;

R 2 represents alkyl, cycloalkyl or alkenyl;

R3 represents independently in each case 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, selenether, ketone, aldehyde or ester;

R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl or aralkyl;

R 5 represents independently in each case H, alkyl, alkenyl, aryl, cycloalkyl or aralkyl;

R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and

N is 1-10.

In some embodiments, the compounds of the present invention are represented by formula I, where R represents -C(O)R2, (C(R')2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, -(C(R3)2)nC(O)R5, or -(C(R3)2)nC≡CR6;

In some embodiments, the compounds of the present invention are represented by formula I, where R 1 is ethyl.

In some embodiments, the compounds of the present invention are represented by formula I, where R1 is -CH=CH2.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -C(O)R 2 .

In some embodiments, the compounds of the present invention are represented by formula I, where R is -C(O)R 2 and R 2 is alkyl.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -(C(R'3)2)nCO2R4.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -(C(R3)2)nCO2R4, R4 is -CH(R3)2, n is 1.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -(C(R3)2)nCO2R4 and R4 is cycloalkyl.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -CH 2 CO 2 R 4 and R 4 is cycloalkyl.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -CH2CO2R4 and R4 is cyclohexyl; and R 1 is -CH=CH 2 .

In some embodiments, the compounds of the present invention are represented by formula I, where R is -CH2CO2R4, and R4 is (-)-mantyl, 1-adamantyl, isobornyl, (-)-isopinocampyl, or (+)phenyl; and R 1 is -CH=CH 2 .

In some embodiments, the compounds of the present invention are represented by formula I, where R is -(C(R3)2)nC(O)N(R5)2.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -CH2C(O)N(R5)2 and R1 is -CH=CH2.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -CH2C(O)NH-1-adamantyl and R1 is -CH=CH2.

In some embodiments, the compounds of the present invention are represented by formula I, where R is –(C(R3)2)nCN.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -CH2CN and R1 is -CH=CH2.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -(C(R3)2)nCOR5.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -CH 2 C(O)R 5 and R 5 is alkyl.

In some embodiments, the compounds of the present invention are represented by formula I, where R is -CH2C(O)C(CH3)3 and R1 is -CH=CH2.

In some embodiments, said compound 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.

In said embodiments, said compound is QD-IP, QD-(-)-MN, or QD-AD.

The following aspect of the present invention relates to the compound represented by formula II:

[image]

R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, -(C (R3)2)nC(O)R5, -C(C(R3)2)nOCR6, (C(R3)2)nOPO(OR5)2, -(C(R3)2)nOR5, -(C(R3 )2)nN(R5)2, -(C(R3)2)nSR5, or -(C(R3)2)nNO2;

R 1 represents alkyl or alkenyl;

R 2 represents alkyl, cycloalkyl or alkenyl;

R3 represents independently in each case 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, selenether, ketone, aldehyde or ester;

R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl or aralkyl;

R 5 represents independently in each case H, alkyl, alkenyl, aryl, cycloalkyl or aralkyl;

R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and

n is 1-10.

In some embodiments, 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 - Production of catalysts containing an asymmetric tertiary amine

A certain aspect of the presented invention relates to methods for the production of tertiary amines, tertiary amines that will be usable in the desymmetrization methods of the presented invention. In certain embodiments, the tertiary amines are synthesized according to the general procedure, where the diamine is reacted with two equivalents of a chiral, non-racemic glycidyl sulfonate or halide. For example, the scheme below shows the achievement of these methods, where ethylene diamine and two equivalents of a chiral, non-racemic glycidyl carrier are reacted to give a chiral, non-racemic bi-tertiary amine. See also Example 2.

[image]

One aspect of the invention relates to a method of producing a cinchona alkaloid derivative catalyst as shown in Scheme 1:

[image]

where,

X represents Cl, Br, I, OSO2CH3, or OSO2CF3;

R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, -(C (R3)2)nC(O)R5, -C(C(R3)2)nC=CR6, (C(R3)2)nOPO(OR5)2, -(C(R3)2)nOR5, -(C (R3)2)nN(R5)2, -(C(R3)2)nSR6, or -(C(R3)2)nNO2;

R 1 represents alkyl or alkenyl;

R 2 represents alkyl, cycloalkyl or alkenyl;

R3 represents independently in each case 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, selenether, ketone, aldehyde or ester;

R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl or aralkyl;

R 5 represents independently in each case H, alkyl, alkenyl, aryl, cycloalkyl or aralkyl;

R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and

N is 1-10; and

the base is a Bronsted base.

In some embodiments, the present invention relates to the aforementioned method, where X is Cl or Br.

In some embodiments, the presented invention relates to the above-mentioned method, where the specified base is a metal hydride, alkoxide, or amide, carbanion.

In some embodiments, the present invention relates to the aforementioned method, where the specified base is NaH, CaH2, KH, or Na.

In some embodiments, the presented invention relates to the above-mentioned method, where R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2 , -(C(R3)2)nCN, -(C(R3)2)nC(O)R5, or C(C(R3)2)nC≡CR6.

In some embodiments, the present invention relates to the aforementioned method, where R 1 is ethyl.

In some embodiments, the present invention relates to the aforementioned method, where R1 is -CH=CH2.

In some embodiments, the present invention relates to the aforementioned method, where R is -C(O)R 2 .

In some embodiments, the present invention relates to the above-mentioned method, where R is -C(O)R2 and R2 is alkyl,

In some embodiments, the present invention relates to the above-mentioned method, where R is -C(O)C(CH3)3 and R1 is -CH=CH2.

In some embodiments, the present invention relates to the above-mentioned method, where R is -(C(R3)2)nCO2R4.

In some embodiments, the present invention relates to the above method, where R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2.

In some embodiments, the presented invention relates to the above-mentioned method, where R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2, n is 1.

In some embodiments, the presented invention relates to the above-mentioned method, where R is -CH2CO2CH(CH3)2 and R4 is -CH=CH2.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2CO2CH2CH(CH3)2 and R1 is -CH=CH2.

In some embodiments, the present invention relates to the above-mentioned method, where R is -(C(R3)2)nCO2R4 and R4 is cycloalkyl.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2CO2R4 and R4 is cyclohexyl.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2CO2R4 and R4 is cyclohexyl; and R 1 is -CH=CH 2 .

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2CO2R4 and R4 is (-)-menthyl, 1-adamantyl, isobornyl, (-)-isopinocamphyl, or (+)-phenyl; and R 1 is -CH=CH 2 .

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2CO2R4 and R4 is (-)-menthyl or 1-adamantyl; and R 1 is -CH=CH 2 .

In some embodiments, the present invention relates to the above-mentioned method, where R is -(C(R3)2)n)C(O)N(R5)2.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2C(O)N(R5)2 and R1 is -CH=CH2.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2CN and R1 is -CH=CH2.

In some embodiments, the present invention relates to the above method, where R is -(C(R3)2)nCN.

In some embodiments, the present invention relates to the above-mentioned method, where R is -(C(R3)2)nCN and R1 is -CH=CH2.

In some embodiments, the present invention relates to the above method, where R is -(C(R3)2)nC(O)R5.

In some embodiments, the present invention relates to the above-mentioned method, where R is CH2C(O)R5 and R5 is alkyl.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2C(O)C(CH3)3 and R1 is -CH=CH2.

In some embodiments, the presented invention relates to the above-mentioned method, where the mentioned catalyst is QD-IP, QD-PC, QD-AD, QD-(-)-MN, QD-(+)-MN, QD-AC, QD - Beer, QD-PH, QD-AN. QD-NT, QD-CN, QD-CH, QD-IB, QD-EF, QD-AA, QD-MP, or QD-IPC.

In some embodiments, the present invention relates to the above-mentioned method, where said catalyst is QD-IP, QD-(-)-MN or QD-AD.

The following aspect of the invention relates to a method of producing a cinchona alkaloid derivative catalyst as shown in Scheme 2:

[image]

where,

X represents Cl, Br, I, OSO2CH3, or OSO2CF3;

R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)riCN, -(C (R3)2)nC(O)R5, -C(C(R3)2)nC≡CR6, -(C(R3)2)nOPO(OR5)2, -(C(R3)2)nOR5, -( C(R3)2)nN(R5)2, -(C(R3)2)nSR5, or –(C(R3)2)nNO2;

R 1 represents alkyl or alkylene;

R 2 represents alkyl, cycloalkyl, or alkenyl;

R3 represents independently in each case 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, selenether, ketone, aldehyde, or ester;

R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl, or aralkyl;

R 5 represents independently in each case H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl;

R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl;

n is 1-10; and

the base is a Bronsted base.

In some embodiments, the present invention relates to the above-mentioned method, where 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.

Methods of the invention - catalyzed reactions

In one of the aspects of the presented invention, a method of stereoselective production of compounds with at least a singular 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 the yield of all losses associated with the production of undesired enantiomers can be greatly reduced or eliminated.

In general, a property of the invention is a stereoselective ring opening comprising the coupling of a nucleophilic reactant, a prochiral or chiral cyclic substrate, and finally a catalytic amount of a non-racemic chiral catalyst of certain characteristics (as described below). A cyclic substrate includes carbocycles or heterocycles that have an electrophilic atom susceptible to nucleophile attack. The combination is carried out under suitable conditions for a chiral catalyst for stereoselective opening of a cyclic substrate on an electrophilic atom by reaction with a nucleophilic reactant. This reaction can be applied to enantioselective processes as well as to diastereoselective processes. The same can be adapted for regioselective reactions. The following are examples of enantioselective reactions, kinetic resolution, and regioselective reactions that can be catalyzed in accordance with the invention.

In the next aspect of the presented invention, the kinetic resolution of the enantiomer occurs with catalysis, using the subject chiral catalyst, by transforming the racemic substrate. In the subject kinetic resolution process for a racemic substrate, one enantiomer can be recovered as unreacted substrate while the others are transformed into the required product. Of course, it is held that kinetic resolution can be performed by removing the undesired enantiomer by reaction with a nucleophile, and recovering the desired unchanged enantiomer from the reaction mixture. A significant advantage of this approach is the possibility of using cheap racemic starting materials better than expensive, enantiomerically pure starting materials. In some embodiments, the subject of catalysis can be used in the kinetic resolution of chemical cyclic substrates where the nucleophile is a co-solvent. Suitable nucleophiles of this type include water, alcohols, and thiols.

The methods of this invention provide optically active products with very high stereoselectivity (eg, enantioselectivity or diastereoselectivity) or regioselectivity. In preferred embodiments of the desymmetrization reaction, products with an enantiomeric excess greater than about SOS, greater than about 70%, greater than about 90%, and more preferably greater than about 95% can be obtained. The methods of the invention can also be carried out under reaction conditions suitable for commercial use, and, typically, proceed at reaction ratios suitable for large-scale production.

In certain embodiments, the chiral, catalyst non-racemic tertiary amine is present in less than about 30 mol% relative to the prochiral starting material, In some embodiments, the chiral, catalyst non-racemic tertiary amine is present in less than about 20 mol% relative to to the prochiral starting material. In certain embodiments, the chiral, non-racemic tertiary amine catalyst is present in less than 10 mol% relative to the prochiral starting material. In a particular embodiment, the chiral, non-racemic tertiary amine catalyst is present in less than 5 mol% relative to the prochiral starting material.

As will be apparent from the discussion, the chiral products produced by the asymmetric synthesis methods of the present invention may be subjected to further reaction(s) to provide the desired derivatives thereof. Such an allowed derivatization reaction can be carried out according to conventional procedures known in the art. For example, potential derivatization reactions include esterification, N-alkylation of amides, and the like. The invention particularly contemplates the production of final product and synthetic intermediates that are useful for the production or development or both of cardiovascular drugs, non-steroidal anti-inflammatory drugs, central nervous system agents, and antihistamines.

One of the aspects of the invention relates to the method of producing a chiral, non-racemic compound from a prochiral cyclic anhydride or a meso chiral anhydride, includes the phase: reaction of a prochiral cyclic anhydride or a meso cyclic anhydride with a nucleophile in the presence of a catalyst, where said prochiral cyclic anhydride or meso cyclic anhydride include an internal degree of symmetry or a point of symmetry or both; due to the production of a chiral, non-racemic compound; wherein said catalyst is represented by formula I:

[image]

where

R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, -(C (R3)2)nC(O)R5, -C(C(R3)2)nC≡CR6, -(C(R3)2)nOPO(OR5)2, -(C(R3)2)nOR5, -( C(R3)2)nN(R5)2, -(C(R3)2)nSR5, or –(C(R3)2)nNO2;

R 1 represents alkyl or alkylene;

R 2 represents alkyl, cycloalkyl, or alkenyl;

R3 represents independently in each case 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, selenether, ketone, aldehyde, or ester;

R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl, or aralkyl;

R 5 represents independently in each case H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl;

R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl;

n is 1-10.

In some embodiments, the present invention relates to the above-mentioned method, where R represents -C(O)R2, -(C(R3)2)NCO2R4, -(C(R3)2)nC(O)N(R5)2 , (C(R3)2)nCN, (C(R3)2)nC(O)R5, or (C(R3)2)nC≡CR6.

In some embodiments, the present invention relates to the above-mentioned method, where R 1 is ethyl.

In some embodiments, the present invention relates to the above-mentioned method, where R 1 is -CH=CH 2 .

In some embodiments, the present invention relates to the above-mentioned method, where R is -C(O)R 2 .

In some embodiments, the present invention relates to the above-mentioned method, where R is -C(O)R 2 and R 2 is alkyl.

In some embodiments, the present invention relates to the above-mentioned method, where R is -(C(R3)2)nCO2R4.

In some embodiments, the present invention relates to the above method, where R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2.

In some embodiments, the presented invention relates to the above-mentioned method, where R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2, n is 1.

In some embodiments, the present invention relates to the above-mentioned method, where R is -(C(R3)2)nCO2R4 and R4 is cycloalkyl.

In some embodiments, the present invention relates to the above method, where R is –CH2CO2R4 and R4 is cycloalkyl.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2CO2R4, R4 is cyclohexyl; and R 1 is -CH=CH 2 .

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2CO2R4 and R4 is (-)-menthyl, 1-adamantyl, isobornyl, (-)-isopinocampyl, or (+)-phenyl; and R 1 is -CH=CH 2 .

In some embodiments, the present invention relates to the above method, where R is -C(R3)2)nC(O)N(R5)2.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2C(O)N(R5)2 and R1 is -CH=CH2.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2C(O)NH-1-adamantyl and R1 is -CH=CH2.

In some embodiments, the present invention relates to the above-mentioned method, where R is -C(R3)2)nCN.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2CN and R1 is -CH=CH2.

In some embodiments, the present invention relates to the above method, where R is -(C(R3)2)nC(O)R5.

In some embodiments, the present invention relates to the above method, where R is -CH2C(O)R5 and R5 is alkyl.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2C(O)C(CH3)3 and R1 -CH=CH2.

In some embodiments, the presented invention relates to the above-mentioned method, where the mentioned 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.

In some embodiments, the present invention relates to the above-mentioned method, where said catalyst is QD-IP, QD-(-)-MN or QD-AD.

In some embodiments, the present invention relates to the above-mentioned method, where said nucleophile is an alcohol.

In some embodiments, the present invention relates to the above-mentioned method, where said nucleophile is a primary alcohol.

In some embodiments, the present invention relates to the above-mentioned method, where said nucleophile is methanol or CF3CH2OH.

In some embodiments, the present invention relates to the above-mentioned method, where said prolyral cyclic anhydride or meso cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride.

In some embodiments, the present invention relates to the above-mentioned method, where said catalyst is present in an amount of less than about 70 mol% in relation to said prochiral cyclic anhydride or meso cyclic anhydride.

In some embodiments, the present invention relates to the above-mentioned method, where said catalyst is present in an amount less than about 40 mol% in relation to said prochiral cyclic anhydride or meso cyclic anhydride.

In some embodiments, the present invention relates to the above-mentioned method, where said catalyst is present in an amount of less than about 10 mol% in relation to said prochiral cyclic anhydride or meso cyclic anhydride.

In some embodiments, the present invention relates to the above method, wherein said chiral, non-racemic compound having an enantiomeric excess greater than about 50%.

In some embodiments, the present invention relates to the above method, wherein said chiral, non-racemic compound having an enantiomeric excess greater than about 70%.

In some embodiments, the present invention relates to the above method, wherein said chiral, non-racemic compound having an enantiomeric excess greater than about 90%.

In some embodiments, the present invention relates to the above method, wherein said chiral, non-racemic compound having an enantiomeric excess greater than about 95%.

In some embodiments, the present invention relates to the above-mentioned method, where R is CH2CO2R4; R 4 is (-)-menthyl, 1-adamantyl, isobornyl, (-)-isopinocampyl, or (+)-phenyl; R 1 is -CH=CH 2 ; and the specified nucleophile is an alcohol.

In some embodiments, the present invention relates to the above method, R is CH2CO2R4; R 4 is (-)-menthyl, 1-adamantyl; R 1 is -CH=CH 2 ; and the specified nucleophile is an alcohol.

In some embodiments, the present invention relates to the above method, R is CH2CO2R4; R 4 is (-)-menthyl or 1-adamantyl; R 1 is -CH=CH 2 ; and said nucleophile is methanol or CF3CH2OH.

The next aspect of the presented invention relates to the method of producing a chiral, non-racemic compound from a prochiral cyclic anhydride or a meso cyclic anhydride, which contains the following phase:

reacting a prochiral cyclic anhydride or meso cyclic anhydride with a nucleophile in the presence of a catalyst, wherein said prochiral cyclic anhydride or meso cyclic anhydride comprises an internal degree of symmetry or a point of symmetry or both; due to the production of a chiral, non-racemic compound; wherein said catalyst is represented by formula II:

[image]

where

R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, -(C (R3)2)nC(O)R5, -C(C(R3)2)nC≡CR6, -(C(R3)2)nOPO(OR5)2, -(C(R3)2)nOR5, -( C(R3)2)nN(R5)2, -(C(R3)2)nSR5 or -(C(R3)2)nNO2;

R 1 represents alkyl or alkenyl;

R 2 represents alkyl, cycloalkyl, or alkenyl;

R3 represents independently in each case 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, selenether, ketone, aldehyde, or ester;

R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl, or aralkyl;

R 5 represents independently in each case H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl;

R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl;

n is 1-10.

In some embodiments, the present invention relates to the above-mentioned method, where said catalyst is Q-IP, Q-PC, Q-AD, Q-(-)-MN, Q-(+)-MN, Q-AC, Q - Beer, Q-PH, Q-AN. Q-NT, Q-CN, Q-CH, Q-IB, Q-EF, Q-AA, Q-MP, or Q-IPC.

In some embodiments, the present invention relates to the above-mentioned method, where said nucleophile is an alcohol.

In some embodiments, the present invention relates to the above-mentioned method, where said nucleophile is a primary alcohol.

In some embodiments, the present invention relates to the above-mentioned method, where said nucleophile is methanol or CF3CH2OH.

In some embodiments, the present invention relates to the above-mentioned method, where said prolyral cyclic anhydride or meso cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride.

In some embodiments, the present invention relates to the above-mentioned method, where said catalyst is present in an amount of less than about 70 mol% in relation to said prochiral cyclic anhydride or meso cyclic anhydride.

In some embodiments, the present invention relates to the above-mentioned method, where said catalyst is present in an amount less than about 40 mol% in relation to said prochiral cyclic anhydride or meso cyclic anhydride.

In some embodiments, the present invention relates to the above-mentioned method, where said catalyst is present in an amount of less than about 10 mol% in relation to said prochiral cyclic anhydride or meso cyclic anhydride.

In some embodiments, the present invention relates to the above method, wherein said chiral, non-racemic compound having an enantiomeric excess greater than about 50%.

In some embodiments, the present invention relates to the above method, wherein said chiral, non-racemic compound having an enantiomeric excess greater than about 70%.

In some embodiments, the present invention relates to the above method, wherein said chiral, non-racemic compound having an enantiomeric excess greater than about 90%.

In some embodiments, the present invention relates to the above method, wherein said chiral, non-racemic compound having an enantiomeric excess greater than about 95%.

In some embodiments, the present invention relates to the above-mentioned method, where R is CH2CO2R4; R 4 is (-)-menthyl, 1-adamantyl, isobornyl, (-)-isopinocampyl, or (+)-phenyl; R 1 is -CH=CH 2 ; and the specified nucleophile is an alcohol.

In some embodiments, the present invention relates to the above-mentioned method, where R is CH2CO2R4; R 4 is (-)-menthyl or 1-adamantyl; R 1 is -CH=CH 2 ; and the specified nucleophile is an alcohol.

In some embodiments, the present invention relates to the above-mentioned method, where R is CH2CO2R4; R 4 is (-)-menthyl or 1-adamantyl; R 1 is -CH=CH 2 ; and said nucleophile is methanol or CF3CH2OH.

Methods of the invention - kinetic resolution

In another aspect of the presented invention, the kinetic resolution of enantiomers occurs with catalysis, using the subject chiral catalyst, in the transformation of the racemic substrate. In the present process of kinetic resolution of a racemic substrate, one enantiomer can be recovered as unreacted substrate while the other is transformed into the desired product. Of course, it will be appreciated that kinetic resolution can be performed by removing the undesired enantiomer by reaction with a nucleophile, and recovering the unchanged desired enantiomer from the reaction mixture. A significant advantage of this approach is the property of using inexpensive racemic starting materials rather than expensive, enantiomerically pure starting compounds. In certain embodiments, the subject catalysts can be used in the kinetic resolution of racemic cyclic substrates when the nucleophile is a co-solvent. Suitable nucleophiles of this type include water, alcohols, and thiols.

One of the aspects of the presented invention relates to the kinetic resolution method, and includes the step:

reactions of racemic cyclic anhydride with alcohol in the presence of a catalyst represented by formula I:

[image]

where

R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, -(C (R3)2)nC(O)R5, -(C(R3)2)nOCR6, -(C(R3)2)nOPO(OR5)2, -(C(R3)2)nOR5, -(C(R3 )2)nN(R5)2, -(C(R3)2)nSR5, or -(C(R3)2)nNO2;

R 1 represents alkyl or alkylene;

R 2 represents alkyl, cycloalkyl, or alkenyl;

R3 represents independently in each case 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, selenether, ketone, aldehyde, or ester;

R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl, or aralkyl;

R 5 represents independently in each case H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl;

R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl;

n is 1-10; and

when said kinetic resolution method is completed or terminated by any unreacted cyclic anhydride having an enantiomeric excess greater than zero and the enantiomeric excess of the product greater than zero.

In some embodiments, the presented invention relates to the above-mentioned method, where R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2 , -(C(R3)2)nCN, -(C(R3)2)nC(O)R5 or -(C(R3)2)nOCR6.

In some embodiments, the present invention relates to the above-mentioned method, where R 1 is ethyl.

In some embodiments, the present invention relates to the above-mentioned method, where R 1 is -CH=CH 2 .

In some embodiments, the present invention relates to the above-mentioned method, where R is -C(O)R 2 .

In some embodiments, the present invention relates to the above-mentioned method, where R is -C(O)R 2 and R 2 is alkyl.

In some embodiments, the present invention relates to the above-mentioned method, where R is -(C(R3)2)nCO2R4.

In some embodiments, the present invention relates to the above method, where R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2.

In some embodiments, the presented invention relates to the above-mentioned method, where R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2, n is 1.

In some embodiments, the present invention relates to the above-mentioned method, where R is –(C(R3)2)nCO2R4 and R4 is cycloalkyl.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2CO2R4 and R4 is cyclohexyl; and R 1 is -CH=CH 2 .

In some embodiments, the present invention relates to the above-mentioned method, where R is –CH2CO2R4 and R4 is (-)-menthyl, 1-adamantyl, isobornyl, (-)-isopinocampl11, or (+)-phenyl; and R 1 is -CH=CH 2 .

In some embodiments, the present invention relates to the above method, where R is –(C(R3)2)nC(O)N(R5)2.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2C(O)N(R5)2 and R1 is -CH=CH2.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2C(O)NH-1-adamantyl and R1 is -CH=CH2.

In some embodiments, the present invention relates to the above method, where R is -(C(R3)2)nCN.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2CN and R1 is -CH=CH2.

In some embodiments, the present invention relates to the above method, where R is -(C(R3)2)nCOR5.

In some embodiments, the present invention relates to the above method, where R is -CH2C(O)R5 and R5 is alkyl.

In some embodiments, the present invention relates to the above-mentioned method, where R is -CH2C(O)C(CH3)3 and R1 -CH=CH2.

In some embodiments, the presented invention relates to the above-mentioned method, where the mentioned 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.

In some embodiments, the present invention relates to the above-mentioned method, where said catalyst is QD-IP, QD-(-)-MN or QD-AD.

In some embodiments, the present invention relates to the above-mentioned method, where said alcohol is a primary alcohol.

In some embodiments, the present invention relates to the above-mentioned method, where said nucleophile is methanol or CF3CH2OH.

The next aspect of the presented invention relates to the kinetic resolution method, which includes the step:

reactions of racemic cyclic anhydride with alcohol in the presence of a catalyst represented by formula II:

[image]

where

R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)n-(C(R3)2)nCN, -(C( R3)2)nC(O)R5, -C(C(R3)2)nC≡CR6, -(C(R3)2)nOPO(OR3)2, -(C(R3)2)nOR5, -(C (R3)2)nN(R5)2, -(C(R3)2)nSR5, or -(C(R3)2)nNO2;

R 1 represents alkyl or alkenyl;

R 2 represents alkyl, cycloalkyl, or alkenyl;

R3 represents independently in each case 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, selenether, ketone, aldehyde, or ester;

R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl, or aralkyl;

R 5 represents independently in each case 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 kinetic resolution method is completed or terminated by any unreacted cyclic anhydride having an enantiomeric excess greater than zero and an enantiomeric excess product greater than zero.

In some embodiments, 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.

In some embodiments, the present invention relates to the above-mentioned method, where said alcohol is a primary alcohol.

In some embodiments, the present invention relates to the above-mentioned method, where the specified nucleophile is methanol or CF3CH2OH.

Nucleophiles

Nucleophiles that are usable in the presented invention can be determined by experts according to several criteria. In general, a suitable nucleophile will have one or more of the following properties: 1} that they are capable of reacting with the substrate at the desired electrophilic site; 2) that they are a usable product of the above reaction with the substrate; 3) that they are capable of reacting with the substrate at a different functional site than the required electrophilic site; 4) to react with the substrate at least partially by means of a mechanism catalyzed by a chiral catalyst; 5) that it will not be subjected to a strong unwanted reaction after reaction with the substrate in the desired sense; and 6) that it will not react strongly with or degrade the catalyst. It should be understood that while undesired side reactions (such as catalyst decomposition) may occur, the rate of such reactions can be made slowly - by selection of reactants and conditions - related to the relationship(s) in the desired reaction(s).

Nucleophiles that meet the above criteria can be selected for each individual substrate and vary according to the structure of the substrate and the required product. Routine experimentation may be necessary to determine the preferred nucleophile for a given transformation. If a nitrogen-containing nucleophile is required, for example, it may be selected from ammonia, phthalimide, hydrazine, amine, and the like. Equally, oxygen nucleophiles such as water, hydroxide, alcohols, alkoxides, siloxanes, carboxylates, or peroxides can be used to introduce oxygen; and mercaptans, thiolates, bisulfites, thiocyanates and the like can be used to introduce the sulfur-containing moiety. Additional nucleophiles are clear to those skilled in organic chemistry.

For nucleophiles that exist as anions, the counterion can be any of a variety of common cations, including alkali and alkaline earth metal cations and ammonium cations.

In some embodiments, the nucleophiles can be part of the substrate, which results in an intramolecular reaction.

Substrates

As discussed above, a number of different substrates are useful in the methods of the present invention. The choice of substrate will depend on a number of factors, including the nucleophiles used and the desired product, and the appropriate product, and the appropriate substrate, which will be clear to experts. It will be understood that the substrate preferably does not contain any interfering functionality. In general, a suitable substrate, eg, a prochiral or meso compound, which will contain at least a pair of reactive electrophilic centers or moieties linked to an internal sintery degree which are attacked with the aid of a catalyst. Catalyzed, stereoselective attack of a nucleophile on one of the electrophilic centers will produce a chiral, non-racemic product.

Most of the substrates contemplated for use in the methods of the present invention contain at least one ring having three to seven atoms. Small rings are often unnatural, by changing their reactivity. However, in some embodiments, the cyclic substrate may be unaltered, i.e., may contain a larger ring with electrophilic centers. Examples of suitable substrates that can be opened by the subject method include cyclic anhydrides, cyclic imides, and the like.

In a preferred embodiment, the cyclic substrate is a prochiral or meso compound. In other embodiments, for example, kinetic resolution, the cyclic substrate will be a chiral compound. In some embodiments, the substrate will be a racemic mixture. In some embodiments, the substrate will be a mixture of diastereomers.

In preferred embodiments, the electrophilic atom is carbon, eg, the carbon of the carbonyl moiety covered by an anhydride or an imide. However, in some embodiments, the electrophilic atom may be a heteroatom.

Reaction conditions

The asymmetric reactions of the present invention can be performed under a wide range of conditions, although it is understood that the solvents and temperature limits listed herein are not limiting and merely correspond to the preferred mode of the methods of the invention.

In general, it will be desirable to carry out the reactions using mild conditions that will not have an undesired effect on the substrate, catalyst, or product. For example, temperature affects the reaction rate, as well as the stability of reactants, products, and catalysts. The reactions are usually carried out at a temperature in the range of -78°C to 100°C, more preferably in the range of -30°C to 30°C and even more preferably in the range of -30°C to 0°C.

In general, the asymmetric synthesis reactions of the present invention are carried out in a liquid reaction medium. However, the reactions can be carried out without the addition of a solvent. Alternatively, the reactions may be carried out in an inert solvent, preferably one in which the reactants, including the catalyst, are essentially soluble. Suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran and the like; a halogenated solvent such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, toluene, hexane, pentane and the like; ethers and ketones such as ethyl acetate, acetone, and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or a combination of two or more solvents. Furthermore, in some embodiments, it may be advantageous to use solvents that are not inert to the substrates under the conditions used, eg, the use of ethanol as the solvent when ethanol is the required nucleophile. In embodiments where water and hydroxide are not preferred nucleophiles, the reactions can be carried out under anhydrous conditions. In some embodiments, ethereal or aromatic hydrocarbon solvents are preferred. In some preferred embodiments, the solvent is diethyl ether or toluene. In embodiments where water or hydroxide are the preferred nucleophiles, the reaction can be carried out in a solvent mixture comprising an appropriate amount of water and/or hydroxide.

The invention also contemplates a reaction in a biphasic solvent mixture, in an emulsion or suspension, or a reaction in a lipid bubble or bilayer. In some embodiments, it may be preferred to perform the catalyzed reaction on a solid phase. Further, in some preferred embodiments, the reaction can be carried out in a reactive gas atmosphere. For example, desymmetrization with cyanide as nucleophile can be carried out in an atmosphere of HCN gas. The partial pressure of the reactive gas can be from 0.1 to 1000 atmospheres, more preferably from 0.5 to 100 atm, and more preferably from about i to about 10 atm. On the other hand, in some embodiments it is preferred to carry out the reaction in an inert gas atmosphere such as is nitrogen or argon.

The asymmetric synthesis methods of the presented invention can be performed in a continuous, semi-continuous or batch mode and, if required, can be included in the process of liquid recycling and/or gas recycling. However, the methods of the present invention are preferably carried out in a batch manner. Similarly, the method or sequence of addition of reactants, catalysts and solvents is also not critical and can be accomplished in any conventional manner.

The reaction can be carried out in a separate reaction zone or several reaction zones, in series or in parallel, or can be carried out discontinuously or continuously in an elongated tubular zone or a series of such zones. The materials used for the construction should be inert to the starting materials during the reaction and the production of the accessories should be able to withstand the reaction temperatures and pressures. The method for introducing and/or regulating the amount of starting materials or ingredients introduced discontinuously or continuously in the reaction zone during the reaction can be advantageously used in the presence especially for adjusting the molar ratio of starting materials. Reaction steps can operate by incrementally adding starting materials to another. Also, the reaction step can be combined by the joint addition of starting materials to the optically active catalyst metal-ligand complex. When complete conversion is not desired or not achievable, the starting materials can be separated from the product and can then be recycled again in the reaction zone.

The methods can also be performed in glass, stainless steel, or similar type utensils. The reaction zone can be set up with one or more internal and/or external heat exchangers in such a way as to control excessive temperature fluctuation, or to prevent any possible reaction temperature "transition".

Furthermore, the chiral catalyst can be immobilized or incorporated into a polymer or other insoluble matrix with, for example, covalent bonding to the polymer or solid support by means of one or more substituents. The immobilized catalyst can be easily recovered after the reaction, for example, by filtration or centrifugation. Further, the substrate or nucleophile can be immobilized or incorporated into a polymer or other insoluble matrix with, for example, covalent attachment to the polymer or solid support by means of one or more substituents. Such an approach can from a base to produce a combinatorial collection of compounds that is limited to a solid support.

Enantioselective alcoholysis

Very different catalysts derived from the modified cinchona alkaloid were tested with substituted succinic anhydrides and substituted glutaric anhydrides and the results are summarized in Figures 19-45. The application of the QD-(-)-MM catalyst for the desymmetrization of cis-1, 3-dibenzyl-tetrahydro-2H-furo[3,4-d]imidazole-2,4,6-trione is also shown, which can be significant for the synthesis biotin. The catalyst also shows that it can be easily recycled in more than 95% yield using an extraction process.

Figures 19 and 20 summarize the results of a study comparing the efficiency of different catalysts for the methanolysis of 2,3-dimethylsuccinic anhydride in Et2O in a 0.02 M concentration at room temperature. Modified monomeric cinchona alkaloid carrier alkylacetate side chain, including QD-AD, QD-(+)-MN, QD-(-)-MN, QD-IP, QD-TB, QD-IB and QD-EF show overall efficacy (activity plus selectivity) comparable or superior to (DHQD)2AQN. However, it is important to remember that OQ-AD, QD-(+)-MN, QD-(-)-MN can be produced in reasonable yield and at a cost significantly less than (<0.5% based on Aldrich starting material cost) than that for (DHQD)2AQN. In addition, as described in more detail later, the QD-(-)-MN catalyst is shown to be stable enough against acid that it can actually be recycled using a simple extraction procedure. On the other hand, initial experiments indicate that QD-TB may be too sensitive to acid to be recycled via a conventional extraction procedure.

The effectiveness of various modified monomeric cinchona alkaloids in trifluoroethanololysis reactions was tested. Figure 21 summarizes the results of a comparison of the effectiveness of different catalysts for the trifluoroethanolysis of 2,3-dimethylsuccinic anhydride in Et2O in a 0.02 M concentration at room temperature. The data indicate that QD-AD, QD-(+)-MN, and QD(-)-MN have higher efficiency than (DHQD)2AQN when trifluoroethanol is used for asymmetric alcoholysis. Interestingly, the enantioselectivity shown with these three catalysts in combination with trifluoroethanol is equal to or better than that shown by the combination of (DHQD)2AQN and methanol.

In order to evaluate the substrate target, a study was performed for the alcoholysis of 3-methyl glutaric anhydride. The results of the alcoholysis of 3-methyl-glutaric anhydride in 0.02 and 0.2 M are summarized in Figures 22 and 23. 3-substituted glutaric anhydrides are among the most frequently readily available cyclic anhydrides. The corresponding ring-opening products, 3-substituted hemiesters, are among the most widely used chiral building blocks in organic synthesis. However, this class of anhydrides is the biggest challenge for alcoholysis due to its weak activity and stronger inhibition of the inhibition product. While (DHQD}2AQN-catalyzed rnetanolysis of prochiral glutaric anhydrides yields a hemiester greater than 90% ee, the reaction will be performed with a higher catalyst loading (30 moles) at a lower concentration (0.02 M); however, the transformation does not go to completion, making the procedure problematic to be applied in a large production ratio. And that is why it is significant that QD-AD can catalyze the opening of the alcoholic ring of glutaric anhydrides in a relatively high concentration (0.2 M) providing a hemiester in a high ee. Although the amount of catalyst is 100-110 mol, the rest of the process is practically shows that QD-AD can be produced from inexpensive starting material and can be efficiently recycled.Notably, unmodified quinidine is ineffective in transforming the 3-substituted glutaric anhydride used.

Therefore, in the evaluation of the effect of the solvent, toluene was used as the solvent in the study. Figure 24 shows the results of methanolysis of 3-methyl glutaric anhydride in 0.02 M toluene with different catalysts. Compared to (DHQD)2AQN under these conditions, QD-AD and QD-MN show comparable enantioselectivity and slightly lower activity. On the other hand, QP-PP shows significantly lower enantioselectivity and activity. QD-AD and QD-MN are clearly superior considering the price and catalytic properties of these catalysts.

Figure 25 shows the results of the trifluoroethanololysis of 3-methyl glutaric anhydride in toluene at 0.2 M with different catalysts. Comparing with (DHQD)2AQN or QD-PP under these conditions, QD-AD and QD-MN show better enantioselectivity and activity. Efficacy shown with the combination of QS-(-)-MN with trifluoroethanol adjusted so with the combination of (DHQD)2AQN with methanol. In addition, considering both cost and catalytic properties, QD-AD and QD-MN are clearly superior to dimeric catalysts.

Figure 26 summarizes the results of the methanolysis of 3-phenyl glutaric anhydride in 0.2 M toluene with different catalysts. The results suggest that QD-AD and QD-(-)-MN are effective for 3-alkyl glutaric anhydride and 3-aryl glutaric anhydride. Comparing with (DHQD)2AQN under the mentioned conditions, QD-AD and QD-MN show slightly lower enantioselectivity and slightly lower activity. On the other hand, QD-PP shows significantly lower enantioselectivity and activity. Considering both cost and catalytic properties, QD-AD and QD-MN are superior dimeric catalysts.

Figure 27 summarizes the results of the trifluoroethanololysis of 3-phenyl glutaric anhydride in 0.2 M toluene with different catalysts. Comparing with (DHQD)2AQN or QD-PP under the mentioned conditions, QD-AD and QD-MN show better enantioselectivity and activity. The efficiency shown by the combination of QD-(-)-MN with trifluoroethanol is thus adapted to the combination of (DHQD)2AQN with methanol. In addition, considering both cost and catalytic properties, QD-AD and QD-MN are superior dimeric catalysts.

Figure 28 summarizes the results of the methanolysis of 3-isopropyl glutaric anhydride in 0.2 M toluene with different catalysts. First of all the results here indicate that QD-AD and QD-(-)-MN are effective for 3-alkyl glutaric anhydride which is a branched substituent carrier. Comparing with (DHQD)2AQN under the mentioned conditions, QD-AD and QD-MN show equal enantioselectivity and activity. On the other hand, QD-PP shows significantly lower enantioselectivity and activity. Considering both cost and catalytic properties, QD-AD and QD-MN are clearly superior dimeric catalysts.

Figure 29 summarizes the results of the trifluoroethanololysis of 3-isopropyl glutaric anhydride in 0.2 M toluene with different catalysts. Comparing with (DHQD)2AQN or QD-PP under the mentioned conditions, QD-AD and QD-MN show better enantioselectivity and activity. The efficiency shown by the combination of QD-(-)MN with trifluoroethanol thus adapted to the combination of (DHQD)2AQN with methanol. In addition, considering both cost and catalytic properties, QD-AD and especially QD-MN are clearly superior dimeric catalysts.

Figure 30 summarizes the results of methanolysis of 3-OTBS glutaric anhydride in 0.2 M toluene with different catalysts. Comparing with (DHQD)2AQN under the mentioned conditions, QD-AD and QD-MN show the same enantioselectivity and slightly lower activity. On the other hand, QD-PP shows much weaker catalytic properties. In addition, considering both cost and catalytic properties, QD-AD and QD-MN are clearly superior dimeric catalysts.

Figure 31 summarizes the results of the trifluoroethanololysis of 3-OTBS glutaric anhydride in 0.2 M toluene with different catalysts. Comparing with (DHQD)2AQN or QD-PP under the mentioned conditions, QD-AD and QD-MN show better enantioselectivity and activity. In addition, considering both cost and catalytic properties, QD-AD and especially QD-MN are clearly superior dimeric catalysts.

Figures 32 and 33 summarize the results of methanolysis and trifluoroethanolysis of 3-substituted glutaric anhydride with mononieric catalysts (Q-AD) derived from quinine. The products are the antipodes of those obtained with monomeric catalysts derived from quinidine.

Therefore, for further evaluation, an assortment of substrates suitable for this procedure, alcoholysis of 1,2,3,6-tetrahydrophthalic anhydrides, was examined. The results of methanolysis and trifluoroethanolysis of cis-1,2,3,6-tetrahydrophthalic anhydrides, succinic anhydrides, are summarized in Figures 34-35. With methanol as a nucleophile, QD-AD is comparable to (DHQA)2AQN in terms of activity and selectivity. With trifluoroethanol as nucleophile, QD-AD and QD-MN show better activity and comparable selectivity to that shown with (DHQD)2AQN. However, the selectivity of QD-PP is somewhat worse.

The results of alcoholysis of different structurally unique anhydrides are shown in Figures 36 and 37 are the results of methanolysis and tricyclic succinic anhydrides, QD-AD and QD-MN show better activity and selectivity than those shown with (DHQD)2AQN and QD-PP. Figures 38 and 39 summarize the results of methanolysis and trifluoroethanolysis of cis-1,2-cyclohexanedicarboxylic anhydrides. With trifluoroethanol as a nucleophile, QD-AD and QD-MN show comparable activity and selectivity to those shown with (DHQD)2AQN and better catalytic properties than that of QD-PP. Figures 40 and 41 summarize the results of the trifluoroethanololysis of cis-1,2-cyclohexanecarboxylic anhydride for 0.2M toluene and ether. In toluene, the influence of the amount of alcohol used in the enantioselectivity reaction. Figure 42 summarizes the results of the trifluoroethanololysis of 0.5 M cis-1,2-cyclohexanedicarboxylic anhydride in toluene. The use of a molecular sieve is beneficial for the reaction. Figure 43 summarizes the results of the alcoholysis of various succinic anhydrides with Q-AD.

Proving with examples

The invention will now be generally described, will be readily understood with reference to the following examples which are included only for the purpose of illustrating certain aspects and embodiments of the present invention and are not intended to limit the invention.

Example 1

Highly enantioselective catalytic desymmetrization of catalytic meso anhydrides

Enantioselective opening of readily yielding meso-cyclic anhydrides generates enantiomerically enriched chiral hemiesters containing one or more stereogenic centers and two commercially differentiated carbonyl functionalities (eq 1). These optically active bifunctional hemiesters are universal chiral building blocks for asymmetric synthesis.1,2,3,4,5,6,7,8,9

Due to their significance in organic synthesis, the development of highly selective desymmetrization of meso-cyclic anhydrides will be the subject of intensive research.10,11,12,13,14,15

The selectivity usable in the synthesis is obtained in the desymmetrization assisted by a stoichiometric amount of chiral auxiliary devices or chiral mediators.10,11 Despite considerable effort,11-15 the development of a general and efficient catalytic desymmetrization of meso-cyclic anhydrides has not yet been achieved and therefore remains desirable and the goal of a great challenge.

[image]

1a: R = H; R' is not H 2a: R= H; R' is not H

1b: R is not H; R' = H 2b: R is not H; R' = H

1c: R is not H; R' is not H 2c: R is not H; R' is not H

Our main goal in the asymmetric catalysis of chiral Lewis bases brings our attention to the amine-catalyzed alcoholysis of cyclic anhydrides. Oda was the first to report that cinchona alkaloids catalyzed the asymmetric methanolysis of various mono- and bicyclic anhydrides.12 Atkin later extended these reactions to the desymmetrization of some tricyclic anhydrides.13 Despite the reaction yield being good, the hemiesters were obtained in low to decent enantiomeric excess. We suspect that the unsatisfactory enantioselectivity may be partly due to the existence of non-selective catalysis with the quinoline nitrogen, since quinine monohydrochloride was reported by Atkin to catalyze the methanolysis of a cyclic anhydride with non-enantioselectivity.l3a In this way, the nitrogen of the catalyzed racemic quinoline becomes increasingly competitive as a high-conversion reaction yield. when the ratio of the quinuclidine nitrogen-catalyzed enantioselective reaction was expectedly reduced significantly as a result of catalyst deactivation caused by protonation of the quinuclidine nitrogen with the acidic hemiester. In principle, the racemic pathway can be suppressed by using cinchona alkaloid analogs as catalysts. Implementation of this approach is, however, experimentally problematic due to the considerable synthetic effort required to produce such analogs.16 Furthermore, a large, if not stoichiometric, amount of quinuclidine catalyst may be required to accelerate reaction completion. We are interested in researching an alternative strategy to reduce basicity with regard to the formation of free catalysts of free amines. Such an approach can lead to significant improvements in both the efficiency and selectivity of asymmetric catalysts by reducing the free base deactivation of amine catalysts with an acid hemiester. Furthermore, this approach can be easily implemented experimentally by changing the environment around the quinuclidine nitrogen through a simple modification of the cinchona alkaloid. We predicted that simple derivatizations of C-9 alcohols with bulky alkyl or aryl groups could generate cinchona alkaloid ethers with reduced basicity of the quinuclidine nitrogen with destabilization of the ammonia ion x via the creation of a steric barrier to the solvation ion. Finally, following the conditions outlined by Oda,12 various commercially available aryl ethers and esters of cinchona alkaloids were screened for their ability to catalyze the enantioselective methanolysis of 2,3-dimethyl succinic anhydride (3). The results of our screening study are described in Figure 1.

We are pleased to find that very good enantioselectivity can be obtained by reactions mediated by aryl esters of both monocinchone (DHQD.PHN) and biscincho alkaloid [(DHQD)2AQN].17 While both alkaloids are effective catalysts, the latter in principle gives higher enantioselectivity. When one equivalent of anhydride 3 is treated with 10 equivalents of methanol in dry toluene in the presence of 5 mol% DHQD.PHN or (DHQD)2AQN as catalyst, the reaction proceeds to completion in 2-4 hours to give the corresponding hemiester in 81% and 85% ee . The structure of the aryl group of the modified cinchona alkaloid has a dramatic effect on the selectivity of the catalyst. While catalysts bearing bulky aromatic groups such as PHN and AQN give high enantioselectivity, a dramatic deterioration in enantioselectivity is observed with catalysts bearing relatively small heterocyclic rings as substituents at the O-9 position (Entry 2, 3, 6, 7 in Figure 1 ). The reaction can be further optimized to give the product with excellent ee (93% ee) at room temperature using ether as solvent.

Encouraged by these promising results, we investigated the catalytic desymmetrization of various cyclic anhydrides. The results are summarized in Figure 2-4. The goal of the reaction is very general in providing excellent enantioselectivities and yields for the desymmetrization of a large number of meso-cyclic anhydrides. Particularly high enantioselectivity was observed for anhydrides 3 as well as for any of the bicyclic anhydrides used in our research (Entries 1, 5, 6 and 7 in Figure 2-4). Excellent enantioselectivity is obtained with monocyclic or tricyclic anhydrides (Entry 2, 3, 8, 9, 10, and 11 in Figures 2-4) to provide acyclic and bicyclic chiral hemiesters in highly enantiomeric enriched form. Substrates containing heterocyclic rings, all other than the cyclic anhydride, were also converted into the desired product in a very high enantioselectivity (Entry 10 and 11 in Figure 2-4). It is significant that even a monocyclic anhydride with a p-methyl substituent was transformed in 89% ee despite the requirement for relatively high catalytic loading. The high enantioselectivity for the ring opening of 1,2-cyclopentyl anhydride (Entry 5 in Figures 2-4) is particularly significant, considering that it is significantly higher than that obtained by the reaction using a stoichiometric amount of chiral promoters.11 Furthermore, the synthesis route based on hydrolytic enzymes can provide only cyclopentyl ester for low ee. It is significant to note that when (DHQ)2AQN is used to catalyze the ring opening of 2,3-dimethylsuccinic anhydride (3) opposite the enantiomer of the corresponding hemiester is obtained in 96% ee, thus ensuring that any enantiomer of the hemiester can be produced in an open and highly enantioselective manner. way via the reaction described here. We were surprised to find that with (DHQ)2AQN-mediated ring opening of 2,4-dimethylglutaric hydride gave the desired hemiester in good yield but with a very low ee (30% ee). Enantioselectivity can, however, be significantly improved when the reaction is promoted with (DHQD)2PHAL (site 4 in Figure 2-4).

We carried out a production ratio reaction to demonstrate the practicality of this catalytic desymmetrization. Anhydride 3 is transformed at a 0.5 mmol ratio with respect to the corresponding hemiester in more than 98% ee with a catalyst input of 5 mol%. When the starting material is consumed (24 hours), a simple extraction of the reaction mixture with aqueous HCl (1N) separates the catalyst from the product. Evaporation of the organic solvent provides the desired product of high purity (purity by NMR) and excellent yield (95%). The catalyst can easily be quantitatively regenerated. Basification of the aqueous phase with KOH followed by extraction of the alkaline aqueous solution with EtOAc and removal of the organic solvent affords a recovered catalyst of high purity (purity by NMR). The recovered catalyst is used without further treatment for other reactions in production ratio to obtain a new batch of product without deterioration in ee and yield.

We have shown that a novel undiscovered desymmetrization of meso-cyclic anhydrides mediated by commercially available aryl ethers of cinchona alkaloids is a general, highly selective, and practically catalytic asymmetric transformation. The reaction described here represents the first catalytic reaction that provides open access to both enantiomers of a wide range of valuable chiral hemiesters of high optical purity. It is important to state that many of these chiral hemiesters will be used in the synthesis of various natural products and biologically significant compounds.1-8 The availability of catalysts, a simple experimental procedure, and ease regardless of the quantitative recovery of the catalyst make this reaction a very attractive method of synthesis. The studies are helping to expand the synthetic means of reaction and gain mechanistic insight into the origin of the highly selective catalysts that are on the rise.

Reference is also made to the notes for Example l

1. Toyota, M.; Yokota, M.; Ihara, M. Organic Lett. 1999, 1, 1627-1629.

2. Couche, E.; Deschatrettes, R.; Poumellec, K.; Bortolussi, M. ; Mandvile, G.; Bloch, R. Synlett. 1999, 87-88.

3. Paterson, I,; Cowden, C.J.; Woodrow, M.D. Tetrahedron Lett. 1998, 39, 6037-6040.

4. a) Borzilleri, R.B. ; Weinreb, S.M. J. Am. Chem. Soc. 1994,116, 9789-9790.

b) Borzilleri, R.B.; Meinreb, S.M. ; Parvez, M. J. Am. Chem. Soc. 1995,117, 10905-10913.

5. Marie, F.B.C.; Mackiewicz, P.; Roul, J.M.; Buendia, J. Tetrahedron Lett. 1992,33, 4889-4892.

6. a) Ohtani, M.; Matsuura, T.; Watanabe, F., Narisada, M. J. Org. Chem. 1991, 56, 4120-4123.

b) Ohtani, M. ; Matsuura, T.; Watanabe, F.; Narisada, M. J. Org. Chem. 1991, 56, 2122-2127.

7. Wender, P.A.; Singh, S.K. Tetrahedron Lett. 1990, 31, 2517-1520.

8. Suzuki, T.; Tomino, A,; Matsuda, Y.; Unno, K.; Kametani, T. Heterocycles, 1980, 14, 1735-1738.

9. a) Heathcock, C.H.; Hadley, C.R.; Rosen, T.; Theisen, P.D.; Hecker, S.J. J. Med. Chem. 1987, 30, 1858-1873.

b) Hecker, S.J.; Heathcock, C.H. J.Am.Chem. Soc. 1986, 108, 4586-4594.

c) Rosen, T.; Heathcock, C.H. J.Am.Chem.Soc. 1985, 107, 3731-3733.

10. For representative examples of chiral auxiliary-based methods see:

a) Albers, T.; Biagini, S.C.G.; Hibbs, D. E.; Hursthouse, M.B.; Malik, K.M.A.; North, M.; Uriarte, E.; Zagotto, G. Synthesis 1996, 393-398.

b) Konoike, T.; Araki, Y. J. Org. Chem. 1994, 59, 7849-7854.

c) Shimizu, M. ; Matsukawa, K.; Fujisawa, T. Bull. Chem. Soc, Jpn. 1993, 66, 2128-2130.

d) Theisen, P.D.; Hethcock, C.H. J. Org. Chem. 1993,58,142-146.

11. For many successful examples of chiral auxiliary-based methods see: a) Seebach, D.; Jaeschke, G.; Wang, Y.M.; Angew. Chem.Int.Ed.Engl. 1995, 34, 2395-2396. b) Jaeschke, G.; Seebach, D. J. Org. Chem. 1998, 63, 1190-1197. c) Bolm, C.; Gerlach, A.; Dinter, C.L. Synlett. 1999, 195-196.

12. a) Hiratake, J.; Yamamoto, Y.; Oada, J. J. Chem.Soc.Chem.Commun. 1985, 1717-1719. b) Hiratake, J; Inagaki, M.; Yamamoto, Y.; Oada, J. J. Chem. Soc. Perkin, Trans. I 1987. 1053-1058.

13. a) Aitken, R.A.; Gopal, J.; Hirst, J.A. J. Chem. Soc. Chem. Commun. 1988. 632-634.

b) Aitken, R.A.; Gopal, J. Tetrahedron: Asymnetry 1990, 1, 517-520.

14. Ozegowski, R.; Kunath, A.; Schick, H. Tetrahedron: Asymmetry 1995, 6, 1191-1194.

15. a) Yamamoto, K.; Nishioka, T.; Oada, J. Tetrahedra Lett. 1988, 29, 1717-1720. b) Yamamoto, K.; Yamamoto, K.; Oada, J. J. Agric. Biol. Chem. 1988, 52,307-3092.

16. Pluim, H.Ph.D.Thesis, University of Groningen, Groningen, The Nederlands, 1982.

17. These modified cinchona alkaloids were first mentioned by Sharples and co-authors as highly efficient ligands for the asymmetric dihydroxylation of alkenes. For leading references see: a) Sharpless, K.B.; Amberg, W.; Bennani, Y.L.; Crispino, G.A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768. b) Crispino, G.A.; Jeong, K.-S.; Hatmuth, C.K.; Wang, Z.-M.; Xu, D.; Sharpless, K.B. J. Org. Chem. 1993,58,3785. c) Becker, H.; Sharpless, K.B. Angew. Chem. ,Int. Ed. Engl. 1996, 35, 451-454. d) Sharpless, K.B.; Amberg, W.; Bennani, Y, L.; Crispino, G.A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M; Xu, D,; Zhang, X.-L. J. Org. Chem. 1991, 56, 4585. e) Harmuth, C.K.; VanNieuwenhze, M.S.; Sharpless, K.B. Chem.rev.1994, 94, 2483-2547.

Example 2

General method of synthesizing tertiary amine catalysts

[image]

Sodium hydride (60% suspension in mineral oil, 1.87g, 46.7 mmol) was added to a solution of diamine 1 (1.40 g, 4.67 mmol) in dry tetrahydrofuran (93 mL) under nitrogen at room temperature. The mixture is stirred for 10 min, and then glycidol carrier 2 is added. After stirring for 88 hours, the mixture is filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was purified by chromatography [basic alumina, CH3OH:CH2Cl2 (1:100 to 1:20)] to give the tertiary amine 3 (667 mg, 35%) as a white solid.

Example 3

Catalytic desymmetrization of urea-containing meso-bicyclic succinic anhydride

[image]

91% yield

93% ee

Anhydrous MeOH (0.5 mmol, 20.2 μl) cooled to -20°C. The resulting mixture was stirred until the reaction was complete (~30 hours) as monitored by TLC (20% MeOH in CH2Cl2). The reaction was quenched with aqueous HCl (1N, 3 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (100?; CH2Cl2 on 10% MeOH in CH2Cl2) to give the hemiester (16.7 mg, 91% yield). The ee of the hemiester was determined to be 93% with conversion of the hemiester to the corresponding ester amide (J.Chem.Soc.Perkin. Trans I 1987, 1053) via reaction of the hemiester with (R)-1-(1-naphthyl)ethyl amine. The ester amide is analyzed with chiral HPLC (Chiralpak, OD, 280 nm, 0.6 mL/min; retention times for the relevant diastereomers are 20,030 and 25,312 minutes).

Example 4

Catalytic desymmetrization of ketone-containing meso bicyclic succinic anhydride

[image]

93% conversion

84% ee

Dry methanol (32 mg, 1.0 mmol) was added dropwise to a solution of the anhydride (0.1 mol, 15.4 mg) and (DHQD)2AQN (12% mol, 10.3 mg) in t-butyl methyl ether at -16~- 17°C. The reaction mixture is stirred at this temperature for 80 hours. The reaction was then quenched with HCl (1N, 3 mL). The aqueous phase was extracted with EtOAc (2×15mL). The organic phase was combined, dried over Na2SO4, and the solvent was removed under reduced pressure. The ee of the hemiester was determined to be 84% by converting the hemiester to the corresponding ester amide (J.Chem..Soc.Perkin. Trans I 1987, 1053) by reaction of the hemiester with (R)-1-(1-naphthyl)ethyl amine. It was analyzed by HPLC (Hypersil SI 4.6×200 mm, 280 nm, 0.5 mL/min, Hexanes: i-Propanol=9:1; retention times for the relevant diastereomers are 28,040 and 33,479 minutes).

Example 5

General procedure for the alcoholysis of 2,3-dimethyl succinic anhydride using QD-FP as a catalyst

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Alcohol (0.1-1.0 mmol) is added to a solution of anhydride (0.1-0.2 mmol) and QD-PP (10-100 mol%) in ether (0.5-5.0 mL) at the reaction temperature indicated in the Figures. The reaction mixture is initially stirred and then allowed to stand at this temperature until the starting material is consumed as indicated for TLC analysis (43 h) or Chiral GC (p-CD) analysis (0.5-101 h). The reaction is stopped by adding HC1 (1N, 5 mL) in one portion. The aqueous phase is extracted with ether (2×20 mL). The organic phase was combined, dried over Na 2 SO 4 , and concentrated to provide the desired product without further purification. The enantiomeric excess (ee) of each product is determined by HPLC analysis of the diastereomeric mixture of the corresponding amide-ester from the hemiester according to an adapted literature procedure, listed below, or by chiral GC analysis.

Modified literature procedure for determination of enantiomeric excess product (J.Hiratake, M.Inagaki, Y.Yamamoto, J.Oda, J.Chem.Soc., Perkin Trans, l 1987, 1053.)

[image]

Thionyl chloride (14.3 mg, 0.12 mmol) was added to a solution of the hemiester (0.1 mmol) in dry toluene (3 mL) at °C. The mixture was allowed to stir at 0°C for 10 min followed by the addition of (R)-1-(1-naphthyl)ethylamine (18.8 mg, 0.11 mmol) and triethylamine (33.4 mg, 0.33 mmol). The resulting mixture is left to stir for 30 minutes at 0°C, followed by another 30 minutes at room temperature. The reaction was quenched with HCl (1N, 5 mL), diluted with EtOAc (20 mL), and washed with saturated NaHCO 3 (5 mL) and brine (5 mL). The organic layer is dried with Na2SO4.

Example 6

General procedure for the alcoholysis of meso-substituted succinic anhydrides using QD-PP in ether

[image]

Alcohol (1.0 mmol) was added to a solution of anhydride (0.1 mmol) and QD-PP (20-100% mol%) in ether (5.0 mL) at the reaction temperature indicated in the figures. See, eg, Figures 11 and 12. The reaction mixture is initially stirred and then allowed to stir at that temperature until the starting material is consumed as indicated by TLC analysis (2-72 h). The reaction was quenched by adding HCl (1N, 3 mL) in one portion. The aqueous phase is extracted with ether (2×10 mL). The organic phase was combined, dried over Na2SO4, and concentrated to give the desired product without further purification. The product is determined to be pure as indicated by NMR). The enantiomeric excess (ee) for each product is determined by HPLC analysis of the diastereomeric mixture of the corresponding amide-ester produced from the scald hemiester with a modified literature procedure below.

A modified literature procedure for determining the enantiomeric excess of the product (J.Hiratake, M.Inagaki, Y, Yamamoto, J. Oda, J.Chem.Soc., Perkin Trans, l 1987, 1053.)

[image]

To a solution of the hemiester (0.1 mmol) in dry toluene (3 mL) at 0°C was added thionyl chloride (14.3 mg, 0.12 mmol). The mixture was allowed to stir at 0°C for 10 min followed by the addition of (r)-1-(1-naphthyl)ethylamine (18.8 mg, 0.11 mmol) and triethylamine (33.4 mg, 0.33 mmol). The resulting mixture is left to stir for 30 minutes at 0°C, followed by another 30 minutes at room temperature. The reaction mixture was then diluted with EtOAc (820 mL) and washed gradually with HCl (1N, 10 mL), saturated NaHCO3 (10 mL) and saturated brine (10 mL). The organic layer is dried with Na2SO4.

Example 7

Production of adamantyl chloroacetate (2)

[image]

At 10°C under N 2 , chloroacetyl chloride (9 mL, 113 mmol) was slowly added to a suspension of 1-adamantole (11.4 g, 75 mmol) and MgO (4.5 g, 113 mmol) in CHCl 3 (10 mmol). The mixture is heated to slight reflux for 43 hours and cooled to room temperature. The undissolved material is removed by filtration and the solvent is evaporated. The residue was crystallized to give 2 as a white solid (6.324 g, 37%). US 4,456,611; Helv.Chim.Acta 1988, 71,1553.

Example 8

Production of (-)-menthyl chloroacetate (4a)

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A solution of chloroacetyl chloride (6.4 mL, 80 mmol) in 40 mL of anhydrous diethyl ether was added dropwise over 2 hours to a solution of (-)-menthol (3a) (12.5 g, 80 mmol) and pyridine (6.5 mL, 80 mmol). in anhydrous diethyl ether (160 mL) at 0°C. After warming to room temperature, the white suspension is stirred for 2 hours and the resulting mixture is filtered. The filtrate was washed with HCl (60 mL, 2N), saturated NaHCO3 (60 mL), brine and dried over Na2SO4. The solvent was removed and dried in vacuo to give (-)-menthyl chloroacetate (4a) (17.64 g, 94%), which was used without further purification. US 4,456,611; Helv.Chim.Acta 1988, 71, 1553.

Example 9

Production of (+)-manthyl chloroacetate (4b)

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The procedure described in the previous Example is performed at a 40 mmol ratio for the synthesis of (+)-menthyl chloroester (4b) in a 95% yield of (+)-menthol (3b). US 4,456,611; Helv,.Chim.Acta 1988, 71,1553.

Example 10

Synthesis of chloroacetate ester 5

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To a solution of isoborneol (9.255 g, 0.06 mol), pyridine (4.9 mL, 0.06 mol) in anhydrous diethyl ether (120 mL) at 0°C, chloroacetyl chloride (4.78 mL, 0.06 mol) in anhydrous diethyl ether (30 mL) is added drop by drop over a period of 2 hours. The reaction mixture was then allowed to warm to room temperature and stirred for the next 3 hours. The resulting mixture is filtered using Celite, washed with diethyl ether (30 mL). The combined organic layer was washed with aqueous HCl (2N, 45 mL), followed by saturated aqueous NaHCO3 (45 mL), then saturated brine (45 mL), dried over Na2SO4, concentrated to give a yellow greenish oil (13.10 g , 95% yield) in NMR-pure form and used without further purification.

Example 11

Synthesis of (1R,2R,3R,53)-(-)-isopinocamphyl chloroacetate (6)

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Chloroacetyl chloride was added to a solution of (1R,2R,3R,53)-(-)-isopinocampheol (9.255 g, 0.06 mol), pyridine (4.9 mL, 0.06 mol) in anhydrous diethyl ether (120 mL) at 0°C. (4.78 mL, 0.06 mol) in anhydrous diethyl ether (30 mL) dropwise over 2h. The reaction mixture was then allowed to warm to room temperature and stirred for the next 3 hours. The resulting mixture is filtered using Celite, washed with diethyl ether (30 mL). The combined organic layer was washed with aqueous HCl (2N, 45 mL), then with saturated aqueous NaHCO3 (45 mL), then brine (45 mL), dried over Na2SO4, concentrated to give a yellow greenish oil (13.13 g, 95 % yield) in NMR-pure form and used without further purification.

Example 12

Synthesis of (1R)-endo-(+)-phenyl chloroacetate (QD-EF,7)

[image]

To a solution of chloroacetyl chloride (6.4 mL, 80 mmol) in 40 mL of anhydrous diethyl ether was added dropwise over 2 hours to a solution of (1R)-endo-(+)-phenyl alcohol (12.25 g, 79.5 mmol) and pyridine (6.5 mL, 80 mmol) in 160 mL of anhydrous diethyl ether at 0°C. After warming to room temperature, the white suspension is stirred for 2.5 hours. The precipitate was removed by filtration and washed with diethyl ether (30 mL). The combined organic solution was washed with HCl (2N, 60 mL), followed by sat. NaHCO3 (60 mL), satd. NaCl (60 mL) solution and drying with Na2SO4. Removal of the solvent and drying under vacuum gave (1R)-endo-(+)-phenyl chloroacetate (17.33 g, 94.5%) which was used without further purification.

Example 13

Synthesis of O-[(-)-menthylacetate]quinidine and O-[(+)-menthylacetate]quinidine (QD-(-)-MN)

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Procedure A (using chromatographic purification)

Under nitrogen, NaH (60 mg, 1.5 mmol, 60% in mineral oil) was washed with hexane (2×3 mL) and suspended in DMF (5 mL). Quinidine (0.324 g, 1.0 mmol) was added to the mixture in small portions. The reaction solution is stirred until the solution turns yellow (about 3 hours). It is then cooled to 0°C. (-)-Menthyl chloroacetate (4a) (0.349 g, 1.5 mmol) was added dropwise over one minute to the cooled reaction mixture. The reaction mixture is stirred for 0.5 hours at 0°C, then warmed to room temperature and kept at that temperature for 1.5 hours. It is then carefully quenched with H2O (10 mL) and the mixture is mixed with ethyl acetate (15 mL). The organic and inorganic layers are separated. The aqueous phase was extracted with ethyl acetate (15 mL). The organic phases are combined, washed with sat. NaHCO3 (10 mL), water (3×10 mL), brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The brown residue was purified by flash chromatography (ethyl acetate : methanol = 10:1) to give O-((-)-menthylacetate)quinidine (0.2752 g, 53%) as a white foam. 1H NMR (CDCl3): δ 0.73 (d,J=6.8 Hz,3H), 0.76-1.10 (m,9H), 1.22-1.40 (m,2H), 1.40-1.60 (m,3H), 1.60-1.72 ( m,2H), 1.72-1.84 (m,2H), 1.93-2.20 (m,1H), 2.14-3.32 (m,2H), 2.70-2.90 (m,3H), 3.04-3.16 (m,1H), 3.28-3.44 (br, 1H), 3.89 (d, J=16.4 Hz, 1H), 3.93(s, 3H), 4.06 (d, J=16.0 Hz, 1H), 4.77 (td, J=11.2, 4.4, 1H}, 5.08-5.15 (m,2H), 5.20-5.45 (br, 1H), 6.12-6.21 (m, 1H), 7.20-7.50 (m, 3H), 8.04 (d, J=8.8 Hz, 1H) , 8.76 (d, J=4.4 Hz, 1H)

Synthesis of O-((+)-methylacetate) quinidine (QD-(+)-MN)

The procedure described above is used to produce O-[(+)-methylacetate]quinidine as a white foam in 43% yield. 1H NMR (CDCl3): 0.75 (d, J=7.2 Hz, 3H), 0.85 (d, J= 7.6 Hz, 3H) 0.90 (d, J=6.8 Hz, 3H), 0.78-1.12 (m, 3H ), 1.20-1.40 (m, 2H), 1.42-1.94 (m, 7H), 1.97-2.06 (m, 1H), 2.26-2.48 (m, 2H), 2.80-3.30 (m, 4H), 3.46-3.90 (br, 1H), 3.99 (d, J=16 Hz, 1H), 4.00 (s, 3H), 4.08 (d, J=16.0 Hz, 1H), 4.79 (td, J=10.8, 4.8, 1H), 5.10-5.30 (m, 2H), 5.46-6.10 (br, 1H), 6.10-6.24 (m, 1H), 7.36-7.56 (m, 3H), 8.04 (d, J=9.2 Hz, 1H), 8.76 ( d,J=4.4 Hz, 1H).

Procedure B (purification without chromatographic separation) for the production of QD-(-)-MN

Under nitrogen, NaH (0.52 g, 12.9 mmol, 60% in mineral oil) was washed with hexane (2×9 mL) and suspended in DMF (453 mL). Quinidine (2.786 g, 8.6 mmol) was added to the mixture in small portions. The reaction mixture is stirred until the solution turns yellow (about 2.5 hours). It is then cooled to 0°C. (-)-Menthyl chloroacetate (3.0 g, 12.9 mmol) was added dropwise over a period of 1 min to cool the reaction mixture. The reaction mixture is stirred for 1 hour at 0°C, 1.5 hours at room temperature. The mixture was cooled again to 0°C, carefully quenched with H2O (60 mL) and then ethyl acetate (60 mL) was added. The organic and inorganic layers are separated. The aqueous phase is extracted with ethyl acetate (30 mL). The organic phases are combined, washed with sat. NaHCO3 (30 mL), water (3×30 mL), sat. NaCl (30 mL), and then extracted with 3×40 mL of 5%w/w HCl. The combined acidic aqueous phases are extracted with 2×50 mL of CH2Cl2. The combined organic phases are washed with 25 mL of 5%w/w HCl and concentrated under reduced pressure. The brown residue is dissolved in 100 mL of 0.1 N HCl. The aqueous phase is extracted with 50 mL Et2O to remove trace impurities, basified to pH=11 with KOH and extracted with 2×50 mL ether. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give crude O-{(-)-methylacetate)quinidine as a yellowish foam. This crude product is dissolved in 40 mL of anhydrous diethyl ether and treated drop by drop with 0.95 equiv. of a 1.0 M solution of hydrogen chloride in diethyl ether (Aldrich) to precipitate O-((-)-methylacetate)quinidine hydrochloride. The separated precipitate is washed with 2×10 mL of diethyl ether, dried in air and suspended in 50 mL of H2O. KOH is used to adjust the pH of the solution to PH=11 and the resulting mixture is extracted with 3x50 mL of diethyl ether. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give O-((-)-menthylacetate)quinidine (1.1783 g, 40%) as an off-white crystalline foam.

Example 14

Synthesis of O-(1-adamantylacetate)quinidine (QD-AD)

[image]

Under nitrogen, NaH (80 mg, 2 mmol, 60% in mineral oil) was washed with hexane (2×3 mL) and suspended in DMF (3 mL). Quinidine (0.1944 g, 0.6 mmol) is added to the mixture in small portions. The reaction mixture is stirred until the solution turns yellow (about 2 hours). It is then cooled to 0°C. Add 1-adamantyl chloroacetate (0.2285 g, 1 mmol) in small portions to the cooled reaction mixture. The reaction mixture was stirred for 3 hours at room temperature, cooled to 0°C, carefully quenched with H2O (5 mL) and then extracted with toluene (4×10 mL). The organic phases are combined, washed with brine (5×5 mL), dried over Na2SO4, and concentrated under reduced pressure. The brown residue was purified by flash chromatography (ethyl acetate : methanol = 9:1) to give O-(1-adamantyl acetate)quinidine (0.1640 g, 53%} as a white foam. 1H NMR (CDCl3): δ 1.22-1.38 (m , 1H), 1.44-1.59 (m,2H), 1.59-1.69 (m,6H), 1.74-1.80 (m,1H), 2.04-2.12 (m,6H), 2.12-2.18 (m,3H), 2.18 -2.31 (m,2H), 2.70-3.15 (m,4H), 2.30-3.48 (m,1H), 3.78 (d,J=16 Hz, 1H), 3.94 (s,3H), 3.95 {d ,J=16.0 Hz, IH), 5.08-5.15 (m,2H), 5.20-5.50 (br,1H), 6.11-6.22 (m,IH), 7.27-7.50 (m,3H), 8.04 (d,J =9.2 Hz, 1H), 8.76 (d, J=4 Hz, IH}).

Example 15

Synthesis of O-(isopropylacetate)quinidine (QD-IP)

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Under nitrogen, NaH (160 mg, 4 min L, 60% in mineral oil) was washed with hexane (2x5 mL) and suspended in DMF (15 mL). Quinidine (0.972 g, 3 mmol) was added to the mixture in small portions. The reaction mixture is stirred until the solution turns yellow (about 2 hours). Isopropyl chloroacetate (0.683 g, 5 mmol) was added all at once to the cooled reaction mixture. The reaction mixture was stirred for 3 hours at 0°C, 25 hours at room temperature. Then the second portion of isopropyl chloroacetate (0.342 g, 2.5 mmol) is added all at once. The mixture was stirred at room temperature for 13 hours and carefully quenched with H2O (20 mL) and then toluene (20 mL) was added. The organic and aqueous layers are separated. The aqueous phase is extracted with toluene (3×10 mL). The organic phases are combined, washed with water (5×10 mL), dried over Na2SO4 and concentrated under reduced pressure. The brown residue was purified by flash chromatography (ethyl acetate : methanol =10:1) to give O-(isopropylacetate)quinidine (0.1884 g, 15%) as a light yellow oil. 1H NMR (CDCl3) : δ 1.23 (d, J=6.0 Hz, 6H), 1.20-1.38 (m, 1H), 1.42-1.60 (m, 2H), 1.75-1.84 (m, 1H), 2.16-2.32 ( m,2H), 2.71-3.02 (m,3H), 3.05-3.18 (m,1H), 3.30-3.50 (m,1H), 3.86 (d,J=16.8 Hz, 1H), 3.94 (s,3H) . (d,J=9.2 Hz, 1H), 8.76 (d,J=4.4 Hz, 1H).

Example 16

Synthesis of isobornyl quinidine and (1R,2R,3R,5S)-(-)-isopinocampyl quinidine (QD-IB)

[image]

Under nitrogen, NaH (300 mg, 7.5 mmol), 60% in mineral oil was washed with hexane (2×5 mL) and suspended in DMF (25 mL). Quinidine (1.62 g, 5.0 mmol) is added to the mixture in small portions. The reaction mixture is stirred until the solution turns yellow (about 2 hours). It is then cooled to 0°C. Isobornyl chloroacetate (1.728 g, 7.5 mmol) was added dropwise over a period of over 2 minutes to the cooled reaction mixture. The reaction mixture was stirred for 1 hour at 0°C, 1 hour at room temperature, and carefully quenched by addition of H 2 O (35 mL) followed by ethyl acetate (35 mL). The organic and inorganic layers are separated. The aqueous phase was extracted with ethyl acetate (35 mL). Combine the organic phases, wash with NaHCO3 (17 mL), water (3×17 mL), sat. NaCl (17mL), dried over Na2SO4 and concentrated under reduced pressure. The brown residue was purified by flash chromatography (ethyl acetate : methanol - 20:1) to give quinidine isobornyl acetate (1.218 g, 47%} as a white foam.

Example 17

Synthesis of (1R, 2R, 3R,5S)-(-)-isopinocamphil quinidine [QD-(-)-IPC]

CH2COO-(1R,2R,3R,5S)-(-)-from pinocamfil

[image]

The procedure described in the above-described example gives (1R,2R,3R,5S)-(-)-isopinocamphyl chloroacetate)quinidine (QD-(-)-IPC) as a white foam in 45% yield.

Example 18

Synthesis of O-((1R)-endo-(+)-phenylacetate)quinidine

[image]

Under nitrogen, NaH (0.3 g, 7.5 mmol, 60% in mineral oil) was washed with hexane (2×5 mL) and suspended in DMF (25 mL). Quinidine (1,620 g, 5 mmol) is added to the mixture in small portions. The reaction mixture is stirred until the solution turns yellow (about 2.5 hours). It is then cooled to 0°C. (1R)-endo-(+)-phenyl chloroacetate (1.728 g, 7.5 mmol) was added dropwise over a period of over 1 minute to the cooled reaction mixture. The reaction mixture was stirred for 1 hour at 0°C, 1.5 hour at room temperature, and carefully quenched by addition of H2O (35 mL) and then ethyl acetate (35 mL) was added. The organic and inorganic layers are separated. The aqueous phase was extracted with ethyl acetate (35 mL). Combine the organic phases, wash with NaHCO3 (17 mL), water (3×17 mL), sat. NaCl (17 mL), dried over Na2SO4 and concentrated under reduced pressure. The brown residue was purified by flash chromatography (ethyl acetate : methanol = 9:1) to give O-((1R)-endo-(+)-phenylacetate)quinidine (1.0119 g, 39%) as a light yellowish foam.

Example 19

Synthesis of O-cyanomethylquinidine (QD-CN)

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Under nitrogen, NaH (0.266 mg, 6.66 mmol, 60% in mineral oil) was washed with hexane (2×10 mL) and suspended in DMF (10 mL). Quinidine (0.648 g, 2.0 mmol) was added to the mixture in small portions. The reaction mixture is stirred until the solution turns yellow (about 2 hours). It is then cooled to 0°C. Chloroacetonitrile (0.227 g, 3 mmol) was added dropwise over 5 minutes to the cooled reaction mixture. The reaction mixture is stirred for 1.5 hours at 0°C, 1.5 hours at room temperature (control with TLC, conversion 40%, ethyl acetate:methanol=5:2). The mixture was cooled again to 0°C, chloroacetonitrile (0.227 g, 3 mmol) was added dropwise over a period of over 5 minutes and the reaction mixture was left to stir overnight at room temperature (TLC control, conversion improvement, ethyl acetate: methanol= 5:2), The mixture was cooled to 0°C, and carefully quenched by addition of H2O (13 mL) and then toluene (13 mL) was added. The organic and inorganic layers are separated. The aqueous phase is extracted with toluene (3×7 mL). The organic phases were combined, washed with NaHCO 3 (7 mL), satd. NaCl (7 mL), water (5x7 mL), dried over Na2SO4 and concentrated under reduced pressure. The black residue was purified by flash chromatography (ethyl acetate : methanol = 5:2) to give O-cyanomethylquinidine (85.4 mg, 12%) as a light brown viscous oil. 1H NMR (CDCl3) : δ 1.32-1.88 (m, 4H), 1.95-2.10 (m, 1H), 2.25-2.36 (m, 1H), 2.70-2.89 (m, 2H), 2.91-3.03 (m, 1H) ), 3.05-3.22 (m,2H), 3.97 (s,3H), 4.03 (d,J=16.0 Hz, 1H), 4.31 (d,J=16.0 Hz, 1H), 5.09-5.18 (m, 2H), 5.33-5.56 (br, 1H), 5.99-6.11 (m, 1H), 7.30-7.46 (m, 3H), 8.05 (d,J=9.2 Hz, 1H), 8.77 (d,J=4.8 Hz , 1H).

Example 20

Synthesis of O-(1-pinacolone)quinidine (QD-PC)

[image]

Under nitrogen, NaH (160 mg, 4 mmol, 60% in mineral oil) was washed with hexane (2×5 mL) and suspended in DMF (15 mL). Quinidine (0.972 g, 3 mmol) was added to the mixture in small portions. The reaction mixture is stirred until the solution turns yellow (about 2 hours). It is then cooled to 0°C. 1-Chloropinacolone (0.670 g, 5 mmol) was added all at once to the cooled reaction mixture. The reaction mixture is stirred for 0.5 hours at 0°C, 3.5 hours at room temperature. Then the second part of the mixture of 1-chlorpinaclone (0.670 g, 5 mmol) was added in one portion. The mixture was stirred at room temperature for 36 hours and carefully quenched by addition of H 2 O (20 mL) and then toluene (20 mL) was added. The organic and inorganic layers are separated. The aqueous phase is extracted with toluene (2×20 mL). The organic phases are combined, washed with water (5×10 mL), dried over Na2SO4 and concentrated under reduced pressure. The brown residue was purified by flash chromatography (ethyl acetate : methanol = 5:1) to give O-(1-pinacolone)quinidine (0.3296 g, 26%) as a colorless oil. 1H MMR (CDCl3) : δ 1.06 (s,9H), 1.23-1.38 (m,1H), 1.45-1.63 (m,2H), 1.76-1.84 (m,1H), 2.22-2.38 (m,2H), 2.72-3.20 (m,4H), 3.32-3.54 (m,1H), 3.95 (s,3H), 4.20 (d,J=18.0 Hz, 1H), 4.29 (d,J=17.2 Hz, 1H), 5.10 -5.20 (m,2H), 5.26-5.48 (m,1H), 6.16-6.26 (m,1H), 7.30-7.48 (m,3H), 8.04 (d,J=9.2 Hz, 1H), 8.75 (d ,J=4.4 Hz, 1H).

Example 21

Synthesis of O-pivaloylquinidine (QD-Piv)

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Pivaloyl chloride (0.362 g, mmol) was added dropwise to a suspension of quinidine (0.972 g, 3 mmol) in toluene, which was stirred at 0 °C, followed by the addition of triethyl amine (1 mL). The reaction mixture is stirred at room temperature for 9.5 hours. Then the second part of pivaloyl chloride (0.362 g, 3 mmol) is added all at once. The mixture was stirred at room temperature for 13 hours and carefully quenched by addition of H2O (20 mL) and then toluene (20 mL) was added. The organic and inorganic layers are separated. The aqueous phase is extracted with toluene (20 mL). The organic phases are combined, washed with saturated NaHCO3 (10 mL), saturated NaCl (2×10 mL), dried over Na2SO4 and concentrated under reduced pressure. The brown residue was purified by flash chromatography (ethyl acetate : methanol = 10:1) to give O-pivaloylquinidine (0.5582 g, 46%) as a colorless oil. 1H NMR (CDCl3): δ 1.22 (s,9H), 1.48-1.66 (m,3H), 1.74-1.86 (m,2H), 2.30-2.52 (m,1H), 2.65-2.82 (m,2H), 2.92 (d, J=8.8 Hz, 2H), 3.26-3.38 (m, 1H), 3.96 (s, 3H), 5.06-5.15 (m, 2H), 5.97-6.08 (m, 1H), 6.44 (d, J=8.0 Hz, 1H), 7.31-7.45 (m,3H), 8.00 (d,J=9.2 Hz, 1H), 8.73 (d,J=4.4 Hz, 1H).

Example 22

Synthesis of O-(1-adamantylacetate)quinidine (Q-AD)

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Under nitrogen, NaH (180 mg, 4.5 mmol, 60% in mineral oil) was washed with hexane (2×5 mL) and suspended in DMF (15 mL). Quinidine (0.972 g, 3 mmol) was added to the mixture in small portions. The reaction mixture is stirred until the solution turns yellow (about 4.5 hours). It is then cooled to 0°C. 1-adamantyl chloroacetate (1.028 g, 4.5 mmol) was added in small portions to the cooled reaction mixture. The reaction mixture was stirred for 1 hour at 0°C, 1 hour at room temperature, cooled to 0°C, carefully quenched by addition of H2O (20 mL) and then extracted with ethyl acetate (20 mL, 10 mL). The organic phases are combined, washed with sat. NaHCO3 (10 mL), water (3×10 mL), sat. NaCl (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The brown residue was purified by flash chromatography (ethyl acetate : methanol = 10:1) to give O-(1-adamantylacetate)quinidine (0.4222 g, 27%) as a white foam, 1H NMR (CDCl3): 1H NMR (CDCl3) : δ 1.48-1.76 (m,8H), 1.78-2.01 (m,3H), 2.04-2.12 (m,6H), 2.12-2.20 (m,3H), 2.24-2.39 (m,1H), 2.56-2.80 ( m,2H), 3.03-3.27(m,2H), 3.44-3.72 (m,1H), 3.76 (d,J=16 Hz, 1H), 3.96(s,3H), 3.97 (d,J=16 Hz , 1H), 4.90-5.01(m,2H), 5.20-5.56 (br, 1H9, 5.70-5.80 (m, 1H), 7.30-7.50 (m, 3H), 8.04 (d,J=9.2 Hz, 1H) , 8.76 (d,J=4.4 Hz, 1H).

Example 23

General procedure for the alcoholysis of 2,3-dimethyl succinic anhydride

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Alcohol (0.1-1.0 mmol) and catalyst (5-110 mol) in solvent (0.5-5.0 mL) are added to the anhydride solution (0.05-0.2 mmol) at the reaction temperature specified in the table. The reaction mixture is initially stirred and then allowed to settle to the temperature at which the starting material is consumed as indicated by TLC analysis* or chiral GC ((3-CG, 130°C/20 min) ** analysis (0.5 hours -37 days). The reaction was quenched by adding HCl (1N, 5 mL) in one portion. The aqueous phase was extracted with ether (2×20 mL). The organic phase was combined, dried over Na2SO4 and concentrated to give the desired product. Enantiomeric the excess (ee) of the product is determined by HPLC analysis of the diastereoisomeric mixture of the corresponding amide-ester produced from the product according to a modified literature procedure (for the trifluoroethyl ester) or chiral GC analysis (p-CD, 130°C/20 min) (for the methyl ester ).

Example 24

General process of alcoholysis of prochiral cyclic anhydrides

[image]

Alcohol (0.15-1.0 mmol) is added to a solution of anhydride (0.1 mmol) and catalyst (20-110 mol%) in solvent (0.5-5.0 mL) at the reaction temperature indicated in the table. The reaction mixture was stirred at this temperature until the starting material was consumed as indicated by GC (β-CD) analysis (19-141 hours). The reaction is quenched by addition of HCl (1N, 4 mL) in one portion (when the substrate is acid-sensitive, such as 3-tert-butyldimethylsilyl glutaric anhydride used, H 3 PO 4 (1.0 M) is used to quench the reaction). The aqueous phase is extracted with ether (40 mL). The organic phase was washed with another portion of HCl (1N, 4 mL)*, dried over Na 2 SO 4 , and concentrated to give the desired product with or without further purification by flash chromatography. The enantiomeric excess (ee) of each product is determined by HPLC analysis of the diastereoisomeric mixture of the corresponding amide-ester produced from the hemiester according to a modified literature procedure or by chiral GC analysis.

Example 25

Production of amide esters for ee analysis

(See J.Hiratake, M.Inagaki, Y.Yamamoto, J.Oda, J.Chem.Soc., Perkin Trans, l, 1987, 1053)

[image]

A mixture of hemiester (0.1 mmol) and SOCl2 (14.3 mg, 0.12 mmol) in toluene (3 mmol) was allowed to cool to 0°C and kept at that temperature for 10 minutes. (R)-1-(1-naphthyl)ethylamine (18.8 mg, 0.11 mmol) and triethyl amine (33.4 mg, 0.33 mmol) were then added to the resulting solution. The resulting mixture is left to stir for 30 minutes at 0°C, followed by another 30 minutes at room temperature. The reaction was then quenched with HCl (1N, 5 mL), diluted with EtOAc (20 mL), washed with saturated NaHCO3 (5 mL) and brine (5 mL). The organic layer is dried with Na2SO4.

Example 26

General process of alcoholysis of prochiral cyclic anhydrides

[image]

Alcohol (0.15-1.0 mmol) is added to a solution of anhydride (0.1 mmol) and catalyst (20-110 mol%) in a suitable solvent (0.5-5.0 mL) at the reaction temperature specified in the table. The reaction mixture is initially stirred at that temperature and then left at that temperature until the starting material is consumed as indicated by TLC analysis (2-186 hours). The reaction was quenched by adding HCl (1N, 3 mL) in one portion. The aqueous phase is extracted with ether (2×10 mL). The organic phase was combined, washed with HCl (1N, 2×3 mL), dried over Na2SO4, and concentrated to give the desired product without further purification. Product purity is determined by NMR. The enantiomeric excess (ee) of each product is determined by HPLC analysis of the diastereoisomeric mixture of the corresponding amide-ester produced from the hemiester according to a modified literature procedure.

Example 27

Process of trifluoroethanolysis of cis-1,3-dibenzyl-tetrahydro-2H-furo[3,4-d]imidazole-2,4,6-trione

[image]

A mixture of QD-(-)-MN (57.2 mg, 0.11 mmol) and 4A molecular sieve (22 mg) in anhydrous toluene was stirred at room temperature for 5 min, then cis-1,3-dibenzyl-tetrahydro-2H was added -furo-[3,4-d]imidazole-2,4,6-trione (33.6 mg, 0.10 mmol), after which the mixture was cooled to -43°C and stirred for the next 10 min. CF3CH2OH is added in one portion. The mixture was stirred at this temperature until the starting material was consumed as indicated by TLC (20% methanol in methylene chloride) analysis (9 hours). Aq. HCl (1.0 N, 4.0 mL) was added to quench the reaction. The aqueous phase is extracted with 40 mL of diethyl ether. The combined organic phase is washed with a second portion of aq. HCl (1N, 4 mL), dried over NaSO4 and concentrated to give the hemiester as a white solid (38.8 mg, 89%, 94%ee) which was purified by NMR. The enantiomeric excess (ee) of the product is determined by HPLC analysis of the diastereoisomeric mixture of the corresponding amide-ester produced from the hemiester according to a modified procedure from the literature.

Example 28

Analysis procedure ee

(See J. Hiratake, M. Inagaki, Y. Yamamoto, J. Oda, J. Chem. Soc., Perkin Trans, 1, 1987, 1053)

[image]

Thionyl chloride (14.3 mg, 0.12 mmol) was added to a solution of the hemiester (0.1 mmol) in dry toluene (6 mmol) and methylene chloride (6 mL) at 0°C. The mixture was allowed to stir at 0°C for 15 min followed by the addition of (R)-1-(1-naphthyl)ethylamine (18.8 mg, 0.11 mmol) and triethylamine (33.4 mg, 0.33 mmol). The resulting mixture is left to stir for 1 hour at 0°C, followed by 1 hour at room temperature. The reaction was then quenched with HCl (1N, 5 mL), diluted with EtOAc (40 mL), washed with saturated NaHCO3 (5 mL) and brine (5 mL). The organic layer is dried with Na2SO4, and concentrated to half the initial volume.

Example 29

Process of alcoholysis of cis-1,2,3,6-tetrahydrophthalic anhydride in 1.0 mmol ratio and recovery of the catalyst

[image]

A mixture of QD-(-)-MN (purified with hydrochloride salt) (572 mg, 1.1 mmol) and 4A molecular sieves (220 mg) in anhydrous toluene was stirred at room temperature for 10 min, then cis-1,2 was added ,3,6-tetrahydrophthalic anhydride (152 mg, 1.0 mmol), after which the mixture was cooled to -27°C and stirred for the next 15 min. Trifluoroethanol is added dropwise within 1 minute. The mixture was stirred at this temperature until all the starting material was consumed as indicated by TLC (ethyl acetate : hexane = 1:1) analysis (4 hours). Aq.HCl (1N, 10 mL) was added to quench the reaction. The aqueous phase is extracted with 50 mL of diethyl ether. The organic phase is washed with aq. HCl (1N, 2×10 mL), dried with NaSO4 and concentrated to give the hemiester as a colorless oil (239.7 mg, 95%, 98%ee) without further purification.

Catalyst recovery

To recover the QD-(-)-MN catalyst, KOH was added to the aqueous layer to adjust the pH value of the solution to 11. The resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layer is dried over Na2SO4 and concentrated to give the catalyst (amount, recovery >95%). The recovered catalyst is used for a new series of alcoholyses of cis-1,2,3,6-tetrahydrophthalic anhydride (1.0 mmol) to give the hemiester in 99%ee and 95% yield,

Example 30

Synthesis of M-(1-adamantyl)chloroacetamide using a procedure equivalent to that described in Helv.Chim.Acta 1988, 71, 1553

[image]

A solution of chloroacetyl chloride (1.6 mL, 20 mmol) in anhydrous diethyl ether (10 mL) was added dropwise over 5 min to a solution of 1-adamantanamine (3.0 g, 20 mmol) and pyridine (1.63 mL, 20 mmol) in anhydrous diethyl ether (40 mL) at 0°C. The yellow suspension is stirred for 1 hour at this temperature. The precipitate was removed by filtration and washed with diethyl ether (10 mL). The combined organic solution was washed with HCl (2N, 2×15 mL), followed by sat. NaHCO3 (15 mL), sat. NaCl (15 mL) solution and dried with Na2SO4. The solvent was removed under reduced pressure and the residue was recrystallized from diethyl ether-hexanes to give N-(1-adamantyl)chloroacetamide (1.551 g, 34%) as a yellow solid.

Example 31

Synthesis of O-(1-adamantylacetamide) quinidine (chromatographically purified)

[image]

Under nitrogen, NaH (0.12 g, 3.0 mmol, 60% in mineral oil) was washed with hexane (2×3 mL) and suspended in DMF (10 mL). Quinidine (0.652 g, 2.0 mmol) was added in small portions to the mixture. The reaction mixture is stirred until the solution turns yellow (about 2 hours). It is then cooled to 0°C. N-(1-adamantyl)chloroacetamide (0.683 g, 3.0 mmol) was added to the cooled reaction mixture in small portions. The reaction mixture was stirred for 2 hours at 0°C and carefully quenched with H2O (14 mL) and then ethyl acetate (14 mL) was added. The organic and aqueous layers are separated. The aqueous phase is extracted with ethyl acetate (2×14 mL). The organic phase was combined, washed with sat. NaHCO3 (14 mL), water (3×14 mL), sat. NaCl (14 mL), dried over Na2SO4, and concentrated under reduced pressure. The brown residue was purified by flash chromatography (ethyl acetate:methanol=9:1) to give O-(1-adamantylacetamide)quinidine (0.8383 g, 81%) as a white crystalline foam. 1H NMR(CDCl3) : δ 1.27-1.39 (m, 1H), 1.48-1.64 (m, 2H), 1.65-1.76 (br, 6H), 1.85 (s, 1H), 1.91-2.07 (m, 1H), 2.02 (s,6H), 2.07-2.14 (br,3H), 2.26-2.38 (m,1H)), 2.71-3.27 (m,5H), 3.81 (s,2H), 3.96 (s,3H), 5.05 -5.20 (m,2H), 5.20-5.50 (br, 1H), 5.96-6.07 (m, 1H), 6.30-6.50 (br, 1H), 7.20-7.43 (m,3H), 8..05 (s ,J=9.2 Hz, 1H), 8.77 (d,J=4.8 Hz, 1H).

Example 32

Synthesis of 2-methylpropyl chloroacetate (See Hev.Chim.Acta 1988, 71,1553)

[image]

A solution of chloroacetyl chloride (3.2 mL, 40 mmol) in anhydrous diethyl ether (20 mL) was added dropwise over 1 h to a solution of 2-methylpropanol (2.96 g, 40 mmol), pyridine (3.25 mL, 40 mmol) and anhydrous diethyl ether ( 80 mL) at 0°C. After warming to room temperature, the white suspension is stirred for 3 hours. The precipitate was removed by filtration and washed with diethyl ether (15 mL). The combined organic solution was washed with HCl (2N, 30 mL), followed by sat. NaHCO3 (30 mL), sat. NaCl (30 mL) solution and dried with Na2SO4. The solvent is removed at about 60 mmHg/30°C to give 2-methylpropyl chloroacetate (5.65 g, 94%) which is used without further purification.

Example 33

Synthesis of O-(2-methylpropylacetate)quinidine (chromatographic purification)

[image]

quinidine O-(2-methylpropylacetate)quinidine QD-MP

Under nitrogen, NaH (0.12 g, 3 mmol, 60% in mineral oil) was washed with hexane (2×3 mL) and suspended in DMF (10 mL). Quinidine (0.648 g, 2 mmol) was added to the mixture in small portions. The reaction mixture is stirred until the solution turns yellow (about 2 hours). It is then cooled to 0°C. 2-Methylpropyl chloroacetate (0.452 g, 3 mmol) was added dropwise over 1 min to the cooled reaction mixture. The reaction mixture was stirred for 4 h at 0°C and carefully quenched with H2O (14 mL) and then ethyl acetate (14 mL) was added. The organic and aqueous layers are separated. The aqueous phase is extracted with ethyl acetate (2×14 mL). The organic phases are combined, washed with sat. NaHCO3 (14 mL), water (3×14 mL), sat. NaCl (14 mL), dried over Na2SO4, and concentrated under reduced pressure. The brown residue was purified by flash chromatography (ethyl acetate:methanol=9:1) to give O-(2-methylpropylacetate)quinidine (0.278 g, 32%) as a light brown oil. 1H NMR(CDCl3): δ 0.90 (d,J=6.8 Hz, 6H), 1.22-1.39 (m, 1H), 1.48-1.69 (m,2H), 1.79-1.86 (br, 1H), 1.86-1.98 ( m, 1H), 2.21-2.39 (m,2H), 2.75-3.22 (m,4H), 3.44-3.67 (br, 1H), 3.88-4.04 (m, 6H), 4.12 (d,J=16.4 Hz, 1H), 5.08-5.23 (m, 2H), 5.44-5.60(br, 1H), 6.10-6.24(m, 1H), 7.32-7.54(m, 3H), 8.04 (d,J=9.2 Hz, 1H), 8.76 (d, J=4.4Hz, 1H).

Incorporation of references

All U.S. patents and U.S. published patent applications cited herein are hereby incorporated by reference.

Equivalents

Those skilled in the art will recognize, or be able to determine using no more than routine experimentation, the many equivalences for specific embodiments of the invention described herein. Such equivalents are intended to be covered by the claims that follow.

Claims (135)

1. A compound represented by formula I [image] indicated by that R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, -(C (R3)2)nC(O)R5, -(C(R3)2)nOCR6, (C(R3)2)nOPO(OR5)2, -(C(R3)2)nOR5, -(C(R3) 2) nN(R5)2, -(C(R3)2)nSR5 or -(C(R3)2)nNO2; R 1 represents alkyl or alkenyl; R 2 represents alkyl, cycloalkyl or alkenyl; R3 independently represents 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; R5 represents, independently of each case, H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl; R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and n is 1-10. 2. The compound of claim 1 characterized in that R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C (R3)2)nCN, (C(R3)2)nC(O)R5, or -(C(R3)2)nC≡CR6. 3. The compound of claim 1 characterized in that R1 is ethyl. 4. The compound of claim 1 characterized in that R1 is -CH=CH2. 5. The compound of claim 1 characterized in that R is -C(O)R2. 6. The compound of claim 1 characterized in that R is -C(O)R 2 and R 2 is alkyl. 7. The compound of claim 1 characterized in that R is -(C(R3)2)nCO2R4. 8. The compound of claim 1 characterized in that R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2. 9. The compound of claim 1 characterized in that R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2, n is 1. 10. The compound of claim 1 characterized in that R is –(C(R3)2)nCO2R4 and R4 is cycloalkyl. 11. The compound from claim 1 characterized in that R is -CH2CO2R4 and R4 is cycloalkyl, 12. The compound of claim 1 characterized in that R is -CE2CO2R4, R4 is cyclohexyl; and R 1 is -CH=CH 2 . 13. The compound of claim 1 characterized in that R is -CH2CO2R4, R4 is (-)-menthyl, 1-adamantyl, isobornyl, (-)-isopinocamphyl, or (+)-phenyl; and R 1 is -CH-CH 2 . 14. The compound of claim 1 characterized in that R is (C(R3)2)nC(O)N(R5)2. 15. The compound of claim 1 characterized in that R is -CH2C(O)N(R5)2 and R1 is -CH=CH2. 16. The compound of claim 1 characterized in that R is -CH2C(O)NH-1-adamantyl and R1 is -CH=CH2. 17. The compound of claim 1 characterized in that R is -(C(R3)2)nCN. 18. The compound of claim 1 characterized in that R is -CH2CN and R1 is -CH=CH2. 19. The compound of claim 1 characterized in that R is -(C(R3)2)nCOR5. 20. The compound of claim 1 characterized in that R is -CH2C(O)R5 and R5 is alkyl. 21. The compound of claim 1 characterized in that R is -CH2C(O)C(CH3)3 and R1 is -CH-CH2. 22. The compound of claim 1 characterized in that the compound is QD-IP, QD-PC, QD-AD, QS-(-)-MN, QD-(+)-MN, QD-AC, QD-Piv, QD- PH, QD-AN, QD-NT, QDS-NT, QD-CN, QD-CH, QD-IB, QD-EF, QD-AA, QD-MP or QD-IPC. 23. The compound of claim 1 characterized in that the compound is QD-IP, QD-(-)-MN or QD-AD. 24. The compound represented by formula II: [image] indicated by that R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, -(C (R3)2)nC(O)R5, -C(C(R3)2)nOCR6, (C(R3)2)nOPO(OR5)2, -(C(R3)2)nOR5, -(C(R3 )2)nN(R5)2, -(C(R3)2)nSR5 or -(C(R3)2)nNO2; R1 represents alkyl or alkenyl; R 2 represents alkyl, cycloalkyl or alkenyl; R3 independently represents 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 case H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl; R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and n is 1-10. 25. The compound of claim 24 characterized in that the compound represented by formula II is Q-IP, Q-PC, Q-AD, Q-(-)-MN, QD-(+)-MN, Q-AC, Q- Piv, Q-PH, Q-AN, Q-NT, Q-NT, Q-CN, Q-CH, Q-IB, Q-EF, Q-AA, Q-MP or Q-IPC. 26. A method for the production of a chiral, non-racemic compound from a prochiral substituted cyclic anhydride or a meso substituted cyclic anhydride, characterized in that it comprises the step of: reaction of a prochiral substituted cyclic anhydride or a meso substituted 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 degree of symmetry or a 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. 27. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted by succinic anhydride or substituted glutaric anhydride. 28. The method of claim 26, characterized in that said nucleophile is an alcohol. 29. The method of claim 26, characterized in that said nucleophile is a primary alcohol. 30. The method of claim 26, characterized in that said nucleophile is methanol or CF3CH2OH. 31. The method of claim 26, wherein said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ)2PHAL, (DHQD)2PHAL, (DHQ) 2PYR, (DHQD)2PYR, (DHQ)2AQN, (DHQD)2AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN or DHQD-PHN. 32. The method of claim 26, wherein said chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD)2AQN. 33. The method of claim 26, characterized in that said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB. 34. The method of claim 26, characterized in that said chiral, non-racemic tertiary amine catalyst is QD-PP. 35. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is 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)2PHAL, (DHQD)2PHAL, (DHQ)2PYR, (DHQD)2PYR, (DHQ) 2AQN, (DHQD)2AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN or DHQD-PHN. 36. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is 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)2PHAL, (DHQD)2PHAL, (DHQ)2PYR, (DHQD)2PYR, (DHQ) 2AQN, (DHQD)2AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN or DHQD-PHN. 37. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride, said nucleophile is methanol or CF3CH2OH; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ)2PHAL, (DHQD)2PHAL, (DHQ)2PYR, (DHQD)2PYR, (DHQ) 2AQN, (DHQD)2AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN or DHQD-PHN. 38. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is 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)2AQN. 39. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride, said nucleophile is a primate alcohol; and said chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD)2AQN. 40. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride, said nucleophile is methanol or CF:3CH2OH; and said chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD)2AQN. 41. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is 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. 42. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is 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. 43. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride, said nucleophile is methanol or CF3CH2OH; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB. 44. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride, said nucleophile is an alcohol; and said chiral, non-racemic tertiary amine catalyst is Q-PP. 45. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride, said nucleophile is a primary alcohol; and said chiral, non-racemic tertiary amine catalyst is Q-PP. 46. The method of claim 26, characterized in that said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride, said nucleophile is methanol or CF3CH2OH; and said chiral, non-racemic tertiary amine catalyst is Q-PP. 47. The method of claim 26, characterized in that said chiral, non-racemic tertiary amine catalyst is present in less than 30 mol% relative to said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride. 48. The method of claim 26, characterized in that said chiral, non-racemic tertiary amine catalyst is present in less than 20 mol% relative to said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride. 49. The method of claim 26, characterized in that said chiral, non-racemic tertiary amine catalyst is present in less than 10 mol% relative to said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride. 50. The method of claim 26, characterized in that said chiral, non-racemic compound has an enantiomeric excess greater than 50%. 51. The method of claim 26, characterized in that said chiral, non-racemic compound has an enantiomeric excess greater than 70%. 52. The method of claim 26, characterized in that said chiral, non-racemic compound has an enantiomeric excess greater than 90%. 53. The method of claim 26, characterized in that said chiral, non-racemic compound has an enantiomeric excess greater than 95%. 54. A method for the production of a chiral, non-racemic compound from a prochiral cyclic anhydride or a meso cyclic anhydride, characterized in that it comprises 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 said meso cyclic anhydride comprises an internal degree of symmetry or a point of symmetry or both; thereby producing a chiral, non-racemic compound; wherein said catalyst is represented by formula I: [image] where R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, -(C (R3)2)nC(O)R5, -C(C(R3)2)nC≡CR6, -(C(R3)2)nOPO(CR5)2, -(C(R5)2)nOR5, -( C(R3)2)nN(R5)2, -(C(R3)2)nSR6 or –(C(R3)2)nNO2; R 1 represents alkyl or alkenyl; R 2 represents alkyl, cycloalkyl or alkenyl; R3 independently represents 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; R5 represents, independently of each case, H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl; R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and n is 1-10. 55. The method of claim 54, characterized in that R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -( C(R3)2)nCN, -(C(R3)2)nC(O)R5, or -(C(R3)2)nC≡CR6. 56. The method of claim 54, characterized in that R1 is ethyl. 57. The method of claim 54 characterized in that R1 is -CH=CH2. 58. The method of claim 54 characterized in that R is -C(O)R2. 59. The method of claim 54 characterized in that R is -C(O)R 2 and R 2 is alkyl. 60. The method of claim 54 characterized in that R is (C(R3)2)nCO2R4. 61. The method of claim 54 characterized in that R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2. 62. The method of claim 54 characterized in that R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2, n is 1. 63. The method of claim 54 characterized in that R is (C(R3)2)nCO2R4 and R4 is cycloalkyl. 64. The method of claim 54 characterized in that R is –CH2CO2R4 and R4 is cycloalkyl. 65. The method of claim 54 characterized in that R is -CH2CO2R4, R4 is cyclohexyl, and R1 is -CH=CH2. 66. The method of claim 54 characterized in that R is -CH2CO2R4, R4 is (-)-menthyl, 1-adamantyl, isobornyl, (-)-isopinocamphyl, or (+)-phenyl; and R 1 is -CH=CH 2 . 67. The method of claim 54 characterized in that R is (C(R3)2)nC(O)N(R5)2. 68. The method of claim 54 characterized in that R is -CH2C(O)N(R3)2 and R1 is -CH=CH2. 69. The method of claim 54 characterized in that R is -CH2C(O)NH-1-adamantyl and R1 is -CH=CH2. 70. The method of claim 54 characterized in that R is -(C(R3)2)nCN. 71. The method of claim 54 characterized in that R is -CH2CN and R1 is -CH=CH2. 72. The method of claim 54 characterized in that R is (C(R3)2)nC(O)R5. 73. The method of claim 54 characterized in that R is -CH2C(O)R5 and R5 is alkyl. 74. The method of claim 54 characterized in that R is CH2C(O)C(CH3)3 and R1 is -CH=CH2. 75. The method of claim 54 characterized in that said catalyst is QD-IP, QD-PC, QD-AD, QD-(-)-MN, QD-(+)-MN, QD-AC, QD-Piv, QD -PH, QD-AN, QD-NT, QD-NT, QD-CN, QD-CH, QD-IB, QD-EF, QD-AA, QD-MP or QD-IPC. 76. The method of claim 54 characterized in that the compound is QD-IP, QD-(-)-MN or QD-AD. 77. The method of claim 54 characterized in that said nucleophile is an alcohol. 78. The method of claim 54 characterized in that said nucleophile is a primary alcohol. 79. The method of claim 54 characterized in that said nucleophile is methanol or CF3CH3OH. 80. The method of claim 54 characterized in that said prochiral cyclic anhydride or meso cyclic anhydride is substituted succinic anhydride or substituted glutaric anhydride. 81. The method of claim 54 characterized in that said catalyst is present in less than 70 mol% relative to said prochiral cyclic anhydride or meso cyclic anhydride. 82. The method of claim 54 characterized in that said catalyst is present in less than 40 mol% relative to said prochiral cyclic anhydride or meso cyclic anhydride. 83. The method of claim 54 characterized in that said catalyst is present in not less than 10 mol% in relation to said prochiral cyclic anhydride or meso cyclic anhydride. 84. The method of claim 54 wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 50%. 85. The method of claim 54 wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 70%. 86. The method of claim 54 wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 90%. 87. The method of claim 54 wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 951. 88. The method of claim 54 characterized in that R is -CH2CO2R4; R 4 is (-)menthyl, 1-adamantyl, isobornyl, (-)isopinocampyl, or (+)-phenyl; R 1 is -CH=CH 2 ; and the specified nucleophile is an alcohol. 89. The method of claim 54 characterized in that R is -CH2CO2R4; R4 is (-)mentyl or 1-adamantyl; R 1 is -CH-CH 2 ; and the specified nucleophile is an alcohol. 90. The method of claim 54 characterized in that R is -CH2CO2R4; R4 is (-)mentyl or 1-adamantyl; R 1 is -CH=CH 2 ; and said nucleophile is methanol or CF3CH2OH. 91. A method for producing a chiral, non-racemic compound from a prochiral cyclic anhydride or meso cyclic anhydride, comprising the step of: reactions of prochiral cyclic anhydride or meso cyclic anhydride with a nucleophile in the presence of a catalyst; wherein said prochiral cyclic anhydride or meso cyclic anhydride comprises an internal degree of symmetry or a point of symmetry or both; thereby producing a chiral, non-racemic compound; wherein said catalyst is represented by formula II: [image] R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2),CN, -( C(R3)2)nC(O)R5, -C(C(R3)2)nOCR6, -(C(R3)2)nOPO(OR5)n-(C(R3)2)nOR5, -(C( R3)2)nN(R5)2, -(C(R3)2)nSR5 or -(C(R3)2)nNO2; R 1 represents alkyl or alkenyl; R 2 represents alkyl, cycloalkyl or alkenyl; R3 independently represents H, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, arain, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde or ester; R4 represents cycloalkyl, -CH(R:3)2, alkenyl, alkynyl, aryl or aralkyl; R5 represents, independently of each case, H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl; R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and n is 1-10. 92. The method of claim 91, characterized in that said catalyst is Q-IP, Q-FC, 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. 93. The method of claim 91, characterized in that the nucleophile is an alcohol. 94. The method of claim 91 characterized in that the nucleophile is a primary alcohol. 95. The method of claim 91 characterized in that the nucleophile is methanol or CF3CH2OH. 96. The method of claim 91 characterized in that said prochiral cyclic anhydride or meso cyclic anhydride which is substituted succinic anhydride or substituted glutaric anhydride. 97. The method of claim 91 wherein said catalyst is present in less than about 70 mol% relative to said prochiral cyclic anhydride or mesocyclic anhydride. 98. The method of claim 91 wherein said catalyst is present in less than about 40 mol% relative to said prochiral cyclic anhydride or mesocyclic anhydride. 99. The method of claim 91 wherein said catalyst is present in less than about 10 mol% relative to said prochiral cyclic anhydride or mesocyclic anhydride. 100. The method of claim 91 wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 50%. 101. The method of claim 91 wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 70%. 102. The method of claim 91 wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 90%. 103. The method of claim 91 wherein said chiral, non-racemic compound has an enantiomeric excess greater than about 95%. 104. The method of claim 91 characterized in that R is -CH2CO2R4, R4 is (-) menthyl, 1-adamantyl, isobornyl, (-)-isopinocamphyl, (+)-phenyl; R 1 is -CH=CH 2 ; and the specified nucleophile is an alcohol. 105. The method of claim 91 characterized in that R is -CH2CO2R4, R4 is (-) menthyl or 1-adamantyl; R 1 is -CH-CH 2 ; and the specified nucleophile is an alcohol. 106. The method of claim 91 characterized in that R is -CH2CO2R4, R4 is (-) menthyl or 1-adamantyl; R 1 is -CH=CH 2 ; and said nucleophile is methanol or CF3CH2OH. 107. Kinetic resolution method, characterized in that it includes the step: reactions of racemic cyclic anhydride with alcohol in the presence of a catalyst represented by formula I: [image] R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, -(C (R3)2)nC(O)R5, -C(C(R3)2)nC≡CR6, (C(R3)2)nOPO(OR5)2, -(C(R3)2)nOR5, -(C (R3)2)nN(R5)2, -(C(R3)2)nSR5 or -(C(R3)2)nNO2; R 1 represents alkyl or alkenyl; R 2 represents alkyl, cycloalkyl or alkenyl; R3 independently represents 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, selenether, ketone, aldehyde or ester; R 4 represents cycloalkyl, -CH(R 3 ) 2 , alkenyl, alkynyl, aryl or aralkyl; R5 represents, independently of each case, H, alkyl, alkenyl, aryl, cycloalkyl, or aralkyl; R 6 represents optionally substituted alkyl, alkenyl, aryl, or aralkyl; and n is 1-10; and when the above kinetic resolution method is completed or terminated, each unreacted cyclic anhydride has an enantiomeric excess greater than zero and an enantiomeric excess of the product is greater than zero. 108. The method of claim 107 characterized in that R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C (R3)2)nCN, -(C(R3)2)nC(O)R5 or -(C(R3)2)nC≡CR6. 109. The method of claim 107 characterized in that R1 is ethyl. 110. The method of claim 107 characterized in that R1 is -CH=CH2. 111. The method of claim 107 characterized in that R1 is -C(O)R2. 112. The method of claim 107 characterized in that R is -C(O)R 2 and R 2 is alkyl. 113. The method of claim 107 characterized in that R is -(C(R3)2)nCO2R4. 114. The method of claim 107 characterized in that R is -(C(R3)2)nCO2R4 and R4 is -CH(R3)2. 115. The method of claim 107 characterized in that R is {C(R3)2)nCO2R4 and R4 is -CH(R3)2, n is 1. 116. The method of claim 107 characterized in that R is -(C(R3)2)nCO2R4 and R4 is cycloalkyl. 117. The method of claim 107 characterized in that R is -CH2CO2R4 and R4 is cycloalkyl. 118. The method of claim 107 characterized in that R is -CH2CO2R4 and R4 is cycloalkyl; and R 1 -CH=CH 2 . 119. The method of claim 107 characterized in that R is -CH2CO2R4 and R4 is (-)-menthyl, 1-adamantyl, isobornyl, (-)-isopinocamphyl, or (-)-phenyl; and R 1 is -CH=CH 2 . 120. The method of claim 107 characterized in that R is (C(R3)2)nC(O)N(R5)2. 121. The method of claim 107 characterized in that R is CH2C(O)N(R5)2 and R1 is -CH=CH2. 122. The method of claim 107 characterized in that R is -CH2C(O)NH-1-adamantyl and R1 is -CH=CH2. 123. The method of claim 107 characterized in that R is -C(R3)2)nCN. 124. The method of claim 107 characterized in that R is -CH2CN and R1 is -CH=CH2. 125. The method of claim 107 characterized in that R is -(C(R3)2)nCOR5. 126. The method of claim 107 characterized in that R is CH2C(O)R5 and R5 is alkyl. 127. The method of claim 107 characterized in that R is CH2C(O)C(CH3)3 and R1 is -CH=CH2. 128. The method of claim 107 characterized in that 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. 129. The method of claim 107 characterized in that said catalyst is QD-IP, QD-(-)-MN or QD-AD. 130. The method of claim 107 characterized in that said alcohol is a primary alcohol. 131. The method of claim 107 characterized in that said nucleophile is methanol or CF3CH2OH. 132. Kinetic resolution method, characterized in that it includes the step: reactions of racemic cyclic anhydride with alcohol in the presence of a catalyst represented by formula II: [image] R represents -C(O)R2, -(C(R3)2)nCO2R4, -(C(R3)2)nC(O)N(R5)2, -(C(R3)2)nCN, -(C (R3)2)nC(O)R5, -C(C(R3)nC≡CR6, (C(R3)2)nOPO(OR5)2, -(C(R3)2)nOR5, -(C(R3 )2)nN(R5)2, -(C(R3)2)nR5 or –((R3)2)nNO2; R 1 represents alkyl or alkenyl; R 2 represents alkyl, cycloalkyl or alkenyl; R3 represents independently for each case 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 case 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 kinetic resolution method is completed or terminated, each unreacted cyclic anhydride has an enantiomeric excess greater than zero and the enantiomeric excess of the product is greater than zero. 133. The method of claim 132 characterized in that 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. 134. The method of claim 132 characterized in that said alcohol is a primary alcohol. 135. The method of claim 132 characterized in that said nucleophile is methanol or CF3CH2OH.