Biocatalytic processes for the preparation of substantially stereomerically pure fused bicyclic proline compounds

A method of preparing a substantially stereometrically pure compound according to structural formula II(a):

• including salts and hydrates thereof, wherein:
• A is O, CR1R2, —C═C—, or CH2—CH2—, wherein R1 and R2 are each independently selected from —H, —COOH, —X, —NH2, —CH2NHC(NH)NH2, —CX3, —CH3, —CH2CH3, and wherein X is selected from F, Cl, and Br;
• M and M′ may both be present or may both be absent and when both M and M′ are present M and M′ are the same and are selected from O and CR3R4 wherein R3 and R4 are H, or R3 or R4 of M and R3 or R4 of M′ form a methylene bridge;
• with the provisos that
• (a) when M and M′ are O, A is not O;
• and when A is O, M and M′ are not O;
• (b) A can be CH═CH— or CH2—CH2— when M and M′ are CR3R4;
• and
• (c) when M and M′ are CR3R4 and have one or more stereocenters, the stereocenters of M and M′ are of opposite stereochemistry;
• the method comprising contacting an amine compound according to structural formula I
• wherein A, M and M′ are as defined for structural formula II(a) and II(b), with oxygen in the presence of a monoamine oxidase enzyme with a co-factor under conditions in which the monoamine oxidase enzyme oxidizes the amine compound of structural formula I to a corresponding imine compound of structural formula II(a).

A method of preparing a mixture comprising a substantially enantiomerically pure aminosulfonate compound according to structural formula III(a) and a substantially enantiomerically pure aminosulfonate compound according to structural formula III(b):

• including salts and hydrates thereof, wherein:
• A is O, CR1R2, —C═C—, or CH2—CH2—, wherein R1 and R2 are each independently selected from —H, —COOH, —X, —NH2, —CH2NHC(NH)NH2, —CX3, —CH3, —CH2CH3, and wherein X is selected from F, Cl, and Br;
• M and M′ may both be present or may both be absent and when both M and M′ are present M and M′ are the same and are selected from O and CR3R4 wherein R3 and R4 are H, or R3 or R4 of M and R3 or R4 of M′ form a methylene bridge;
• with the provisos that
• (a) when M and M′ are O, A is not O;
• and when A is O, M and M′ are not O;
• (b) A can be CH═CH— or CH2—CH2— when M and M′ are CR3R4;
• and
• (c) when M and M′ are CR3R4 and have one or more stereocenters, the stereocenters of M and M′ are of opposite stereochemistry;
• the method comprising contacting an amine compound according to structural formula I
• wherein A, M and M′ are as defined for structural formula III with oxygen in the presence of a monoamine oxidase enzyme associated with a co-factor and with bisulfite under conditions which yield the mixture comprising a substantially enantiomerically aminosulfonate compound according to structural formula III(a) and a substantially enantiomerically aminosulfonate compound according to structural formula III(b).

A method of preparing a substantially enantiomerically pure aminonitrile compound according to structural formula IV(a):

• including salts and hydrates thereof, wherein:
• A is O, CR1R2, —C═C—, or CH2—CH2—, wherein R1 and R2 are each independently selected from —H, —COOH, —X, —NH2, —CH2NHC(NH)NH2, —CX3, —CH3, —CH2CH3, and wherein X is selected from F, Cl, and Br;
• M and M′ may both be present or may both be absent and when both M and M′ are present M and M′ are the same and are selected from O and CR3R4 wherein R3 and R4 are H, or R3 or R4 of M and R3 or R4 of M′ form a methylene bridge;
• with the provisos that
• (a) when M and M′ are O, A is not O;
• and when A is O, M and M′ are not O;
• (b) A can be CH═CH— or CH2—CH2— when M and M′ are CR3R4;
• and
• (c) when M and M′ are CR3R4 and have one or more stereocenters, the stereocenters of M and M′ are of opposite stereochemistry;
• the method comprising contacting an amine compound according to structural formula I
• wherein A, M and M′ are as defined for structural formula IV with oxygen in the presence of a monoamine oxidase enzyme associated with a co-factor and with bisulfite under conditions which yield a mixture comprising a substantially enantiomerically pure aminosulfonate compound according to structural formula III(a) and a substantially enantiomerically pure aminosulfonate compound according to structural formula III(b)
• and
• contacting the compounds according to structural formulae III(a) and III(b) with cyanide under conditions which yield the substantially enantiomerically pure aminonitrile compound according to structural formula IV(a).

A method of preparing a substantially stereometrically pure amino acid compound according to structural formula VI:

• including salts thereof, wherein:
• A is O, CR1R2, —C═C—, or CH2—CH2—, wherein R1 and R2 are each independently selected from —H, —COOH, —X, —NH2, —CH2NHC(NH)NH2, —CX3, —CH3, —CH2CH3, and wherein X is selected from F, Cl, and Br;
• M and M′ may both be present or may both be absent and when both M and M′ are present M and M′ are the same and are selected from O and CR3R4 wherein R3 and R4 are H, or R3 or R4 of M and R3 or R4 of M′ form a methylene bridge;
• with the provisos that
• (a) when M and M′ are O, A is not O;
• and when A is O, M and M′ are not O;
• (b) A can be CH═CH— or CH2—CH2— when M and M′ are CR3R4;
• and
• (c) when M and M′ are CR3R4 and have one or more stereocenters, the stereocenters of M and M′ are of opposite stereochemistry;
• the method comprising contacting a substantially enantiomerically pure aminonitrile compound according to structural formula IV(a):
• wherein A, M and M′ are as defined for the amino compound of structural formula VI, with an acid and water under conditions in which the aminonitrile compound is converted to the substantially stereometrically pure amino acid compound according to structural formula VI.

A method of preparing a substantially stereometrically pure amino acid compound according to structural formula VI:

• including salts thereof, wherein:
• A is O, CR1R2, —C═C—, or CH2—CH2—, wherein R1 and R2 are each independently selected from —H, —COOH, —X, —NH2, —CH2NHC(NH)NH2, —CX3, —CH3, —CH2CH3, and wherein X is selected from F, Cl, and Br;
• M and M′ may both be present or may both be absent and when both M and M′ are present M and M′ are the same and are selected from O and CR3R4 wherein R3 and R4 are H, or R3 or R4 of M and R3 or R4 of M′ form a methylene bridge;
• with the provisos that
• (a) when M and M′ are O, A is not O;
• and when A is O, M and M′ are not O;
• (b) A can be CH═CH— or CH2—CH2— when M and M′ are CR3R4;
• and
• (c) when M and M′ are CR3R4 and have one or more stereocenters, the stereocenters of M and M′ are of opposite stereochemistry;
• the method comprising contacting a stereometrically pure bisulfite amine adduct compound according to structural formula III(a), substantially stereometrically pure bisulfite amine adduct compound according to structural formula III(b) or a mixture thereof
• with cyanide under conditions which yield the substantially stereometrically pure
• aminonitrile compound according to structural formula IV(a)
• wherein A, M and M′ are as defined for the amino compound of structural formula VI;
• and
• contacting the aminonitrile compound of structural formula IV(a) with an acid and water under conditions in which the aminonitrile compound is converted to the substantially stereometrically pure amino acid compound according to structural formula VI.

A method of preparing a substantially enantiomerically pure compound according to structural formula V:

• including salts thereof, wherein:
• R5 is (C1-C6)alkyl;
• A is O, CR1R2, —C═C—, or CH2—CH2—, wherein R1 and R2 are each independently selected from —H, —COOH, —X, —NH2, —CH2NHC(NH)NH2, —CX3, —CH3, —CH2CH3, and wherein X is selected from F, Cl, and Br;
• M and M′ may both be present or may both be absent and when both M and M′ are present M and M′ are the same and are selected from O and CR3R4 wherein R3 and R4 are H, or R3 or R4 of M and R3 or R4 of M′ form a methylene bridge;
• with the provisos that
• (a) when M and M′ are O, A is not O;
• and when A is O, M and M′ are not O;
• (b) A can be CH═CH— or CH2—CH2— when M and M′ are CR3R4;
• and
• (c) when M and M′ are CR3R4 and have one or more stereocenters, the stereocenters of M and M′ are of opposite stereochemistry;
• the method comprising contacting a substantially stereometrically pure amino acid compound according to structural formula VI
• wherein A, M and M′ are as defined for the amino acid compound of structural formula V with an acid and a compound selected from the group consisting of R5—OH and R5OC(O)CH3 under conditions in which the amino acid compound according to structural formula VI is converted to the substantially enantiomerically pure aminoester compound according to structural formula V.

A method of preparing a substantially stereometrically pure amino ester compound according to structural formula V:

• including salts thereof, wherein:
• R5 is (C1-C6)alkyl, A is O, CR1R2, —C═C—, or CH2—CH2—, wherein R1 and R2 are each independently selected from —H, —COOH, —X, —NH2, —CH2NHC(NH)NH2, —CX3, —CH3, —CH2CH3, and wherein X is selected from F, Cl, and Br;
• M and M′ may both be present or may both be absent and when both M and M′ are present M and M′ are the same and are selected from O and CR3R4 wherein R3 and R4 are H, or R3 or R4 of M and R3 or R4 of M′ form a methylene bridge;
• with the provisos that
• (a) when M and M′ are O, A is not O;
• and when A is O, M and M′ are not O;
• (b) A can be CH═CH— or CH2—CH2— when M and M′ are CR3R4;
• and
• (c) when M and M′ are CR3R4 and have one or more stereocenters, the stereocenters of M and M′ are of opposite stereochemistry;
• the method comprising contacting a stereometrically pure bisulfite amine adduct compound according to structural formula III(a), substantially stereometrically pure bisulfite amine adduct compound according to structural formula III(b) or a mixture thereof.
• with cyanide under conditions which yield the substantially stereometrically pure aminonitrile compound according to structural formula IV(a)
• wherein A, M and M′ are as defined for the amino compound of structural formula VI;
• and
• contacting the aminonitrile compound of structural formula IV(a) with an acid and an alcohol under conditions in which the aminonitrile compound is converted to the substantially stereometrically pure amino ester compound according to structural formula V.

A method of preparing a substantially stereometrically pure amino amide compound according to structural formula VII:

• including salts thereof, wherein:
• A is O, CR1R2, —C═C—, or CH2—CH2—, wherein R1 and R2 are each independently selected from —H, —COOH, —X, —NH2, —CH2NHC(NH)NH2, —CX3, —CH3, —CH2CH3, and wherein X is selected from F, Cl, and Br;
• M and M′ may both be present or may both be absent and when both M and M′ are present M and M′ are the same and are selected from O and CR3R4 wherein R3 and R4 are H, or R3 or R4 of M and R3 or R4 of M′ form a methylene bridge;
• with the provisos that
• (a) when M and M′ are O, A is not O;
• and when A is O, M and M′ are not O;
• (b) A can be CH═CH— or CH2—CH2— when M and M′ are CR3R4;
• and
• (c) when M and M′ are CR3R4 and have one or more stereocenters, the stereocenters of M and M′ are of opposite stereochemistry;
• the method comprising contacting a stereometrically pure bisulfite amine adduct compound according to structural formula III(a), substantially stereometrically pure bisulfite amine adduct compound according to structural formula III(b) or a mixture thereof
• with cyanide under conditions which yield the substantially stereometrically pure aminonitrile compound according to structural formula IV(a)
• wherein A, M and M′ are as defined for the amino compound of structural formula VI;
• and
• contacting the aminonitrile compound of structural formula IV(a) with an acid under conditions in which the aminonitrile compound is converted to the substantially stereometrically pure amino amide compound according to structural formula VII.