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-protei nogenic amino acid that is an essential component of the didemnins, th e present synthesis does not require the intermediacy of the expensive amino acid D-allo-isoleucine, the starting material being commerciall y available enantiopure (S) -2methyl-1-butanol. Steps in the sequence include catalytic asymmetric epoxidation, regioselective titanium-prom oted opening of an epoxy alcohol with an ammonia equivalent, stereospe cific generation of an N-Boc-amino epoxide and its nucleophilic openin g by a cyanide anion, Application of this method has permitted the ena ntioselective preparation of isostatine methyl ester and, for the firs t time, of isostatine amide, both in fully protected form.