Patent EA-002192-B1 (EA)
Title: Efficient enantioselective addition reaction using an organozinc reagent
Inventor: CHEN CHENG YI
IPC: C07C215/68
Filed: 1998-05-12
Abstract: 1. A process for the preparation of a compound of formula I:   or its enantiomer, wherein A is: (a) C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl, unsu bstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, CO2-C1-C6-alkyl, C3-C7-cycloalkyl, or C1-C6-alkoxy; (b) phenyl, biphenyl, or naphthyl, unsubstituted or substituted with one to four substituents selected from R<1>, R<2>, R<3>, and R<4>; R<1>, R<2>, R<3>, and R<4> are independently: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, aryl, CO2-C1-C6-alkyl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, or C1-C6-alkoxy, such that C1-C6-alkyl is unsubstituted or substituted with aryl, aryl is defined as phenyl, biphenyl, or naphthyl, unsubstituted or substituted with C1-C6-alkyl, C1-C6-alkoxy, NO2, or halo (Cl, Br, F, I); R<5> is: (a) H, (b) C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, CO2-C1-C6-alkyl, C3-C7-cycloalkyl, or C1-C6-alkoxy; (c) C1-C4-perfluoroalkyl, R<6> is: C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, CO2-C1-C6-alkyl, C3-C7-cycloalkyl or C1-C6-alkoxy; comprising the steps of: a) adding slowly a dialkylzinc in a solvent or neat, to a first chiral additive, comprising one or more exchangeable protons or alternatively, to a mixture of a first chiral additive comprising one or more exchangeable protons and a second additive, in a solvent under an inert atmosphere at a temperature of about -78 degree C to about 50 degree C to form a chiral zinc complex or a second additive containing chiral zinc complex; b) adding a second additive to a chiral zinc complex, and heating the reaction mixture to about 10 degree C to about 70 degree C to form a second additive containing chiral zinc complex, where the first chiral additive bears one and only one exchangeable proton, or alternatively, where the first chiral additive bears more than one exchangeable proton, or the second additive was added in step a), then this addition step is skipped; c) mixing chiral zinc complex or the second additive containing chiral zinc complex with an organometallic reagent of formula, R<6>M, where M is: Li, Na, K, Zn, MgX1, CuX1, or B(Xl)2; and X1 is Cl, Br, I, F, or CF3SO2; in a solvent at a temperature range of-20 degree C to about 60 degree C to form a chiral organozinc complex; and d) mixing a carbonyl-containing compound of formula:   optionally dissolved in a solvent with the solution of the chiral organozinc complex under an inert atmosphere at a temperature of about -20 degree C to about 60 degree C for about 1 hour to about 72 hours. 2. The process as recited in Claim 1, for the preparation of a compound of formula I:   or its enantiomer, wherein A is: (a) C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2 NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, CO2-C1-C6-alkyl, C3-C7-cycloalkyl, or C1-C6-alkoxy; (b) phenyl, biphenyl, or naphthyl, unsubstituted or substituted with one to four substituents selected from R<1>, R<2>, R<3>, and R<4>; R<1>, R<2>, R<3>, and R<4> are independently: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, aryl, CO2-C1-C6-alkyl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, or C1-C6-alkoxy, such that C1-C6-alkyl is unsubstituted or substituted with aryl, aryl is defined as phenyl, biphenyl, or naphthyl, unsubstituted or substituted with C1-C6-alkyl, C1-C6-alkoxy, NO2, or halo (C1, Br, F, I); R<5> is: (a) H, (b) C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, CO2-C1-C6-alkyl C3-C7-cycloalkyl, or C1-C6-alkoxy; (c) C1-C4-perfluoroalkyl, R<6> is: C2-C6-alkenyl, or C2-C6-alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, CO2-C1-C6-alkyl, C3-C7-cycloalkyl or C1-C6-alkoxy; comprising the steps of: a) adding slowly a dialkylzinc in a solvent or neat, to a first chiral additive in a solvent under an inert atmosphere at a temperature of about -78 degree C to about 50 degree C to form a chiral zinc complex; b) adding a second additive to a chiral zinc complex, and heating the reaction to about 10 degree C to about 70 degree C to form a second additive containing chiral zinc complex, where the first chiral additive bears one and only one exchangeable proton; c) mixing the second additive containing chiral zinc complex with an organometallic reagent of formula, R<6>M, where M is: Li, Na, K, Zn, MgXl, CuX1, or B(X1)2; and X1 is Cl, Br, I, F, or CF3SO2; in a solvent at a temperature range of-20 degree C to about 60 degree C to form a chiral organozinc complex; and d) mixing a carbonyl-containing compound of formula:   optionally dissolved in a solvent with the solution of the chiral organozinc complex under an inert atmosphere at a temperature of about -20 degree C to about 60 degree C for about 1 hour to about 72 hours. 3. The process as recited in Claim 1, for the preparation of a compound of formula I:   or its enantiomer, wherein A is: (a) C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, CO2-C1-C6-alkyl, C3-C7-cycloalkyl, or C1-C6-alkoxy; (b) phenyl, biphenyl, or naphthyl, unsubstituted or substituted with one to four substituents selected from R<1>, R<2>, R<3>, and R<4>; R<1>, R<2>, R<3>, and R<4> are independently: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, aryl, CO2-C1-C6-alkyl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, or C1-C6-alkoxy, such that C1-C6-alkyl is unsubstituted or substituted with aryl, aryl is defined as phenyl, biphenyl, or naphthyl, unsubstituted or substituted with C1-C6-alkyl C1-C6-alkoxy, NO2, or halo (C1, Br, F, I); R<5> is: (a) H, (b) C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, CO2-C1-C6-alkyl C3-C7-cycloalkyl, or C1-C6-alkoxy; (c) C1-C4-perfluoroalkyl, R<6> is: C2-C6-alkenyl, or C2-C6-alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, CO2-C1-C6-alkyl, C3-C7-cycloalkyl or C1-C6-alkoxy; comprising the steps of: a) adding slowly a dialkylzinc in a solvent or neat to a mixture of a first chiral additive bears one and only one exchangeable proton and a second additive, in a solvent under an inert atmosphere at a temperature of about -78 degree C to about 50 degree C to form a second additive containing chiral zinc complex; b) mixing the second additive containing chiral zinc complex with an organometallic reagent of formula, R<6>M, where M is: Li, Na, K, Zn, MgX1, CuX1, or B(X1)2; and X1 is Cl, Br, I, F, or CF3SO2; in a solvent at a temperature range of-20 degree C to about 60 degree C to form a chiral organozinc complex; and c) mixing a carbonyl-containing compound of formula:   optionally dissolved in a solvent with the solution of the chiral zinkorganozinc complex under an inert atmosphere at a temperature of about -20 degree C to about 60 degree C for about 1 hour to about 72 hours. 4. The process as recited Claim 1, wherein the first chiral additive has the formula:   or its enantiomer or diastereomer, and the substituents are defined as: R<9> and R<10> are independently: OH, NH2, NHR<17>, N(R<17>)2, or   R<7>, R<8>, R<11> and R<12> are independently: (a) H, (b) CF3, (c) CN, (d) CONH2, (e) CONH(C1-C6-alkyl), (f) CON(C1-C6-alkyl)2, (g) CO2-C1-C6-alkyl, (h) C3-C7-cycloalkyl, (i) C1-C6-alkyl C2-C6-alkenyl, or C2-C6-alkynyl, unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of: halo (Cl, Br, F, I), CF3, CN, NO2, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2 CONH2, CONH(C1-C6-alkyl), CON(C1-C6-alkyl)2, NHCONH2, NHCONH(C1-C6-alkyl), NHCON(C1-C6-alkyl)2, CO2-C1-C6-alkyl C3-C7-cycloalkyl, C1-C6-alkoxy; (j) R<7> and R