From C-glycosides to fused polycyclic ethernatural products

Abstract

A highly efficient and flexible approach to fused polycyclic ethers that couples the synthesis of C-glycosides with enol ether-olefin ring closing metathesis (RCM) and/or acid mediated cyclizations has been presented. We have developed a single flask, enol ether oxidation, carbon-carbon bond forming approach to the generation of C-glycosides. We have been successful in the formation of both alpha- (Table 1.11) and beta- (Table 1.10) C-glycosides from a single glycosyl donor (glycal anhydride). Both Schrock's Mo catalyst 123 and the 2nd generation Grubbs' Ru catalyst 124 have been used in enol ether-olefin RCM reactions to generate alpha-substituted enol ethers. PPTS, pyridine, and heat have been effective in generating alpha-unsubstituted enol ethers. Our ability to couple the formation of C-glycosides with RCM or acid mediated cyclizations directed our attention to the use of this strategy in the synthesis of fused polycyclic ether natural products. We initially targeted the synthesis of hemibrevetoxin B (2). We have completed a formal total synthesis of ±-hemibrevetoxin B to Mori intermediate 167 in 21 overall steps and in 3.9% yield from the Danishefsky-Kitahara diene 74. Our success in the formal total synthesis of hemibrevetoxin B gave us great confidence to pursue the synthesis of gambierol 6. We have synthesized the A-D ring system 283 in 20 steps and in 4.2% overall yield. The FG ring system 302 was synthesized in 9 steps and in 13% overall yield. We have been successful in the generation of C-glycosides and have been able to apply them in the formation of fused polycyclic ether natural products.