Asymmetric synthetic study of macrolactin analogues

Abstract

We designed two aromatic analogues 1a and 1b of macrolactin A with expectation of enhancing biological activity and metabolical stability. As a result of retrosynthetic analysis of these compounds 1a– b , two synthetic strategies have been examined. The first strategy includes the enantioselective addition of nonadienyl anion, derived from 3 , to aldehyde 4 as a key step. The second one includes epimerization of ynone 7 to ( E, E)-conjugated dienone 31 and subsequent diastereoselective hydride-reduction of 31 . Although the former route furnished no desired target, the latter one was revealed to work well for the synthesis of 1 . Unfortunately, the aimed (2 Z,4 E)-analogue 1a could not be synthesized due to an epimerization of the (2 Z)-olefin into the (2 E)-olefin. However, these methods could be applied to the total asymmetric synthesis of the (2 E,4 E)-analogue 1b . Overall, control of all of the four stereocenters was achieved by means of asymmetric and diastereoselective reactions without using any chiral natural sources.