Autocatalytic process for the synthesis of chiral propargylic alcohols

A process for the preparation of a compound of formula

• or mirror image
• wherein R1 is selected from the group consisting of hydrogen, C1-6-alkyl and (C1-6-alkoxy) carbonyl, any alkyl or alkoxy optionally being substituted with one or more halogen atoms,
• R2 is selected from the group consisting of aryl, aralkyl, C1-6-alkyl and (1′—R3)—C3-6-cycloalkyl wherein R3 is hydrogen, methyl or ethyl, any of said aryl, aralkyl, alkyl is optionally substituted with one or more halogen atoms, and
• A is selected from the group consisting of C1-20-alkyl, C3-6-cycloalkyl, aryl and aralkyl, any of said cycloalkyl, aryl and aralkyl is optionally annellated to one or more further 5 to 7 membered carbocyclic or heterocyclic rings, and/or any of said alkyl, cycloalkyl, aryl and aralkyl is optionally substituted with one or more halogen atoms, cyano, C1-6-alkyl, C3-6-cycloalkyl, —NR4R5, —SR6 and/or —OR7, and wherein said alkyl and cycloalkyl substituent attached to A is optionally substituted with one or more halogen atoms, and wherein R4 and R5 independently are hydrogen or C1-6-alkyl, or wherein R4 is hydrogen and R5 is C2-7-acyl or (C1-6-alkoxy)carbonyl, wherein each acyl and alkoxy in R5 is optionally substituted with one or more halogen atoms, or wherein R4 and R5 together with the nitrogen atom form a 5 to 7 membered heterocyclic ring, or wherein R4 and R5 together are ═CH-aryl, the aryl moiety optionally being substituted with one or more halogen atoms, —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2 or C1-6-alkyl, or R4 and R5 together are ═CH—N(C1-6-alkyl)2, and wherein R6 is C1-6-alkyl, optionally substituted with one or more halogen atoms, and wherein R7 is hydrogen or C1-6-alkyl, optionally substituted with one or more halogen atoms, or
• wherein A and R1 together form a 5 to 7 membered carbocyclic or heterocyclic rings, optionally substituted with one or more halogen atoms, cyano, C1-6-alkyl, C3-6-cycloalkyl, —NR4R5, —SR6 and/or —OR7, wherein R3, R4, R5, R6 and R7 are as defined above,
• said process comprising the steps of
• (i) preparing a mixture of a zinc(II) catalyst, an initial amount of the compound of formula I in a molar ratio to the zinc(II) catalyst from 0.1:1 to 2:1, and optionally a further chiral auxiliary in a molar ratio to the zinc(II) catalyst of 0.1:1 to 3:1, and
• (ii) adding to said mixture
• (a) a compound of formula
• wherein A and R1 are as defined above, and
• (b) a base, and
• (c) a compound of formula
• wherein R2 is as defined above,
• at a temperature from −78 to 30° C., and
• (iii) heating the mixture obtained in step (ii) to 10 to 50° C. until completion of the reaction,
• to obtain the compound of formula I.