Asymmetric Total Synthesis of Herbarumin III: Introduction of the syn-1,3-Diol Moiety from an Optically Pure Hydroxy Epoxide Resolved by HKR

Abstract

Herbarumin III (1) isolated from the fermentation broth and mycelium of the fungus Phoma herbarum displays significant phytotoxic effects against seedlings of A. hypochondriacus. The herbarumin macrolides (1-3, Figure 1) interact with bovin-brain calmodulin and inhibit the activation of the calmodulin-dependent enzyme cAMP phosphodiesterase. Construction of the 10-membered lactone ring and the streocontrol of syn-1,3-diol unit are two major issues in the total synthesis of herbarumin III (1). In the previous total synthesis of 1, the 10-membered lactone ring was synthesized by ring-closing metathesis (RCM) reaction and Yamaguchi’s lactonization method. Asymmetric synthesis of the syn-1,3-diol moiety have been achieved using chiral pool methods, chemoenzymatic method, and asymmetric allylation/Sharpless epoxidation method. Herein, we would like to report an asymmetric total synthesis of herbarumin III (1) starting from an enantiomerically pure hydroxy epoxide generated by using Jacobsen’s hydrolytic kinetic resolution (HKR) method to install the syn-1,3-diol moiety. Retrosynthetically (Scheme 1), the macrolactone ring of 1 could be constructed by RCM reaction at the final stage and the corresponding diene 4 would be prepared from alcohol 6 and 5-hexenoic acid (5). The syn-1,3-diol moiety of 6 could be introduced by using a nucleophilic epoxide opening reaction of epoxide 7. The starting epoxide 7 is prepared from (–)-8 that we have prepared previously by using Jacobsen’s hydrolytic kinetic resolution (HKR) method. Removal of double bond in 8 by catalytic hydrogenation followed by treatment with dimethylsulfonium methylide yields the syn-1,3-diol moiety 9 in good yield (Scheme 2). Protection of the allylic alcohol using ethyl vinyl ether (EVE) in the presence of PPTS (pyridinium para-toulenesulfonate) in dichloromethane gives 10