Practical Manufacture of 4-Alkyl-4-aminocyclohexylalcohols Using Ketoreductases

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The diastereoselective preparation of cis- or trans-4-substituted-4-aminocyclohexyl alcohols by conventional chemical processes reported in the literature requires long synthetic sequences and is not amenable to scale-up. In the past decade, ketoreductases (KREDs) have emerged as a powerful approach for the preparation of chiral secondary alcohols from prochiral ketones. This paper describes the diastereoselective preparation at the kilo scale of cis-allyl N-(4-hydroxy-1-methyl-cyclohexyl)carbamate (6a) via ketoreductase transformation. The methodology was also applicable to a set of different analogous cyclic ketones.