91(P-18) Synthetic Study of Optically Active Manzamine B

Abstract

Since manzamine B (1) have been isolated from Okinawan marine sponge Haliclona sp. By Higa and co-workers in 1987, its pentacyclic structure involving large membered rings have been attractive as a synthetic target. While its interesting biological activities, such as cytotoxicity against P388 mouse leukaemia cells (IC_<50> 6μg/mL) and antitumor activity, have been reported, complete survey and further investigation have been prevented due to its limited availability. Herein, we report our synthetic approach of 1. Initially, we set the compound 7 as a key intermediate. In order to obtain 7 as an optically active form, asymmetric Diels-Alder reaction between 8 and aminodiene (9) using chiral-Cr-Salen complex was studied. After screening to reaction conditions, we have realized that 7a was obtained in 30% yield with up to 88% ee using carbamate-type aminodiene (9a). Amide-type aminodiene (9d) gave 7d in 37% with up to 81% ee, respectively. Next, construction of C-ring was investigated. Alkylation of formyl group of 7d, readily available by deprotection of N-allyl group with Pd (0), proceeded by Peterson reaction in 80% yield. After conversion of silyl enol ether to the corresponding ketal (23d), removal of N-chloroacetyl group was accomplished in pyridine under reflux conditions. Further transformation is currently under investigation.