Concise synthesis of the A/BCD-ring fragment of gambieric acid A.

Haruhiko Fuwa,Makoto Sasaki,Ryo Fukazawa

doi:10.3389/fchem.2014.00116

Abstract

Gambieric acid A (GAA) and its congeners belong to the family of marine polycyclic ether natural products. Their highly complex molecular architecture and unique biological activities have been of intense interest within the synthetic community. We have previously reported the first total synthesis, stereochemical reassignment, and preliminary structure–activity relationships of GAA. Here we disclose a concise synthesis of the A/BCD-ring fragment of GAA. The synthesis started from our previously reported synthetic intermediate that represents the A/B-ring. The C-ring was synthesized via an oxiranyl anion coupling and a 6-endo cyclization, and the D-ring was forged by means of an oxidative lactonization and subsequent palladium-catalyzed functionalization of the lactone ring. In this manner, the number of linear synthetic steps required for the construction of the C- and D-rings was reduced from 22 to 11.

Highlights

In 1992, Nagai, Yasumoto, and co-workers reported the isolation of gambieric acid A (GAA, 1) and its natural congeners, gambieric acids B–D (GAB–GAD, Figure 1) (Nagai et al, 1992a,b)
Our synthesis and NMR spectroscopic analysis of a series of suitably designed A/B-ring model compounds of Gambieric acids (GAs) strongly indicated that the absolute configuration of the polycyclic ether domain of GAs needs to be unambiguously established through total synthesis (Fuwa et al, 2008a, 2009a)
We describe a concise synthesis of the A/BCD-ring fragment 2 of Gambieric acid A (GAA), wherein the C-ring was constructed by using an oxiranyl anion coupling/6-endo cyclization sequence (Mori et al, 1997a,b, 1998) and the D-ring was forged via an oxidative lactonization and subsequent palladium-catalyzed functionalization of the derived lactone

Summary

Introduction

In 1992, Nagai, Yasumoto, and co-workers reported the isolation of gambieric acid A (GAA, 1) and its natural congeners, gambieric acids B–D (GAB–GAD, Figure 1) (Nagai et al, 1992a,b). Our synthesis entailed convergent assembly of the A/BCD- and F GHIJ-ring fragments, i.e., 2 and 3, respectively, by means of Suzuki–Miyaura coupling (Miyaura and Suzuki, 1995; Sasaki and Fuwa, 2008; Suzuki, 2011) to give the endocyclic enol ether 4, followed by closure of the E- and F-rings via a stereoselective allylation of a thioacetal (Suga et al, 2014) and a ring-closing metathesis (Hoveyda and Zhugralin, 2007), respectively, to construct the nonacyclic polyether core 5 (Figure 2).

Results

Conclusion