Stereoselective Synthesis of trans-3-Amino-2,2,4,4-tetramethylcyclobutanol

A highly trans-diastereoselective synthesis of the useful synthon tert-butyl(3-hydroxy-2,2,4,4-tetramethylcyclobutyl)carbamate was accomplished by ketoreductase (KRED) catalysis with ∼98:2 dr. Herein, we describe its development from inexpensive 2,2,4,4-tetramethylcyclobutane-1,3-dione, evolving from a poorly selective and stoichiometric oxime reduction to an efficient sequence of chemo- and biocatalytic reactions. The utility of this process, which also resulted in a 10-fold improvement in process mass intensity (PMI), was demonstrated on scale en route to a fragment of the investigational androgen receptor degrader GDC-2992.