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Efforts toward a convenient and scalable process for the synthesis of a novel CXCR antagonist 1 are described, with a specific focus on a chiral key intermediate. Two generations of a racemic route have been developed for short-term deliveries, and a stereoselective process has been devised for longer term plans. Key steps involved an enzymatic resolution of racemic tetrahydrothiophene-2-carboxylic acid to install the (2R) stereocenter, the mild and efficient preparation of a sterically hindered sulfinimine under a nitrogen flow, and its stereoselective reduction to set up the (1S) amine stereocenter. The process has been scaled-up to multikilogram scale for the racemic approach, and the stereoselective route was demonstrated on multigram scale.

An improved process for tert-butanesulfinyl ketimines formation using titanium(IV) alkoxides is described. This new protocol gives better results especially for sterically hindered ketones compared to classical conditions where titanium(IV) isopropoxide is found to be only moderately effective. We found that removal of isopropanol or ethanol from the reaction mixture either under a nitrogen flow or under vacuum dramatically increased reaction rate, extent of conversion, and yield of the reaction. This methodology has been exemplified on several substrates reported in the literature to be difficult.

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