A Straightforward, Highly Stereoselective Synthesis of Protected Isostatine Derivatives

A novel strategy for the synthesis of isostatine derivatives has been developed. Contrary to previous approaches to isostatine, a non‐proteinogenic amino acid that is an essential component of the didemnins, the present synthesis does not require the intermediacy of the expensive amino acid D‐allo‐isoleucine, the starting material being commercially available enantiopure (S)‐2‐methyl‐1‐butanol. Steps in the sequence include catalytic asymmetric epoxidation, regioselective titanium‐promoted opening of an epoxy alcohol with an ammonia equivalent, stereospecific generation of an N‐Bocamino epoxide and its nucleophilic opening by a cyanide anion. Application of this method has permitted the enantioselective preparation of isostatine methyl ester and, for the first time, of isostatine amide, both in fully protected form.