A commercial synthesis of the antiglaucoma agent, travoprost 2, is described. A total of 22 synthetic steps are required to provide the single enantiomer prostanoid, with the longest linear sequence being 16 steps from 3-hydroxybenzotrifluoride. The route is based upon a cuprate-mediated coupling of the single enantiomer vinyl iodide 13 and the tricyclic ketone 5, of high stereochemical purity, to yield the single isomer bicyclic ketone 15. A Baeyer-Villiger oxidation provides the lactone 16 as a crystalline solid, thus limiting the need for chromatographic purification. DIBAL-H reduction, Wittig reaction, esterification, and silyl group deprotection complete the synthesis of travoprost.

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All four diastereoisomers of 4-hydroxypipecolic acid were prepared in a form conveniently protected for drug discovery applications with the use of industrially scaleable methodology. Resolution of the racemic starting material using proprietary acylases followed by an acyliminium ion cyclisation gave diastereomeric mixtures of 4-formyloxypipecolic acid, which were differentiated using an enzyme-catalysed hydrolysis. The products were separated by partition, and by following a sequence of straightforward chemical steps, the individual stereoisomers of the protected 4-hydroxypipecolates were crystallized to optical purity in 100 g quantities.

2′,3′-Dideoxy-5-fluoro-3′-thiacytidine [(-)-FTC], the active ingredient in the antiviral drug emtricitabine (Emtriva), was prepared by a bioresolution process using cholesterol esterase immobilized on Accurel PP to resolve optical isomers of racemic FTC butyrate. Cholesterol esterase was immobilized at 1.9-kg scale. Recycling studies were carried out with racemic FTC butyrate that indicated a high degree of immobilized cholesterol esterase stability resulting in 15 successive cycles of use (14 recycles). Racemic FTC butyrate (∼8 kg, 200 g/L) was resolved with immobilized cholesterol esterase using a 1-pentanol/ potassium dihydrogen phosphate buffer-solvent system to give (-)-FTC‚HCl (98% ee, 2.17 kg, 31% molar yield based on racemic FTC butyrate).