This paper describes a new convergent approach to the synthesis of an HIV protease inhibitor which was designed to be suitable in long acting formulations. Unique features in the synthesis include an asymmetric hydrogenation as well as enzymatic reduction of a key chloro ketone intermediate, to set the threo stereochemistry in the corresponding epoxide and the diastereoselective coupling of the latter with the zinc enolate of a suitable functionalized amide derivative.

Biocatalytic processes are of increasing importance in the production of chiral alcohols which are important building blocks in the synthesis of chemical catalysts, liquid crystals, agrochemicals and pharmaceuticals. Methods for the synthesis of chiral alcohols can be subdivided into three general classes: traditional (such as classic racemic resolution, chromatography, chiral pool synthesis), asymmetric chemical, and biological (enzymes, whole microbial cells) methods. The last can also be applied to the more traditional methods. Enzymatic techniques are attracting a growing interest as green catalysts because of the different advantages they offer, as compared to other methods: high selectivity, high product purity, mild reaction conditions, competitive production costs, and excellent catalyst availability. In this contribution we give an overview of the biocatalytic approaches for the manufacture of chiral alcohols. To our knowledge there are currently about five major enzyme groups applied for the synthesis of chiral alcohols. The first one reduces carbonyl functional groups (ketones) to enantiopure secondary alcohols (dehydrogenases or reductases). The second group forms alcohols by introduction of molecular oxygen with concomitant one or two electron reduction (mono‐ and dioxygenases). The third group forms alcohols by addition of water to unsaturated carbon carbon double bonds (hydratases) whereas the fourth one forms alcohols by nucleophilic addition of small molecules such as HCN at carbonyl groups which usually also results in a new C–C bond formation (hydroxynitrile lyases and aldolases). The last major group of enzymes discussed herein belongs to the traditional methods mentioned above and resolves racemic chiral alcohols by reacting with only one enantiomer in a racemic mixture (hydrolases). In a selection of case studies we demonstrate the high level of importance that biocatalytic processes have already gained in the industrial manufacture of chiral alcohols. There are numerous processes available that have been or still are operated in multi‐tonne scale. By solving the drawback of cofactor requirements and regeneration for a range of enzymes, especially in the area of asymmetric reduction, the dehydrogenases and oxygenases are now commonly used for commercial processes and are in several cases superior to whole‐cell microbial processes. The highly competitive nature of enzymatic processes compared to whole‐cell (fermentation) and chemical approaches is demonstrated with the example of the manufacture of optically active ethyl ( R )‐3‐hydroxybutyrate.

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