Stereoselective Synthesis of the C10-C18 Fragment of Iriomoteolide-3a

Abstract

An efficient synthesis of the highly stereogenic centered C10-C18 fragment of iriomoteolide-3a has been accomplished. Key steps include Sharpless asymmetric dihydroxylation and epoxidation for generation of the desired stereocenters.In 2008, Tsuda and co-workers isolated a potent cytotoxic macrolide, iriomoteolide-3a (1, Figure 1), from a marine benthic dinoflagellate Amphidinium sp. (strain HYA024), which was monoclonally separated from sea sand collected off Iriomote Island, Japan. 1 Iriomoteolide-3a (1) is a 15-membered macrolide having a novel carbon framework comprising eight stereogenic centers including an allyl epoxide, four hydroxy groups and two methyl branches. Compound 1 represents a unique and novel 15-membered macrolide class compared to the other known 15-membered macrolides. Further, the initial in vitro screening showed that iriomoteolide-3a (1) and its 7,8-Oisopropylidene derivative 2 ( Figure 1) exhibit potent cytotoxicity against human B lymphocyte DG-75 and Raji cells in the low nanomolar range. The unique structural features of iriomoteolide-3a coupled with its potent cytotoxicity have attracted the attention of synthetic organic chemists. In 2009, Nevado and co-workers reported the first total synthesis of 1 along with biological evaluation of its analogues. 2 At the same time, we demonstrated the synthesis of the macrocyclic core of iriomoteolide-3a. 3 Later, the total synthesis of 7,8-O-isopropylidene iriomoteolide-3a was accomplished by Zhao and co-workers, 4 while synthesis of the C1-C9 fragment of 2 has been reported by Chang. 5 Figure 1 Structure of iriomoteolide-3a and its 7,8-O-isopropylidene derivativeIn continuation of our work on the synthesis of macrolides, including iriomoteolide-3a, 3,6 we initiated an alternative strategy towards various analogues of 1 for biological evaluation. In this paper, we report the synthesis of the C10-C18 fragment, a key subunit of iriomoteolide-3a (1) having five stereocenters. As shown in Scheme 1, our synthetic strategy for iriomoteolide-3a is convergent and involves a late-stage assembly of macrocyclic core 3 and side chain 4. The macrocycle 3 can be obtained from epoxy subunit 5 and sulfone 6 through a Julia-Kocienski olefination (C9-C10 bond formation) followed by Yamaguchi macrolactonization. The formation of the C9-C10 bond in all earlier approaches was accomplished using ring-closing metathesis. Scheme 1 Retrosynthetic analysis of iriomoteolide-3aThe synthesis of epoxy segment 5 (C10-C18 fragment) was carried out as shown in Scheme 2, starting from propane-1,3-diol (7). Monoprotection of diol 7 as the tert-butyldiphenylsilyl ether provided compound 8 in 98% yield. Swern oxidation of alcohol to aldehyde followed by Grignard reaction with vinylmagnesium bromide afforded the allyl alcohol 9 in 86% yield over two steps. 7 Treatment of 9 with triethyl orthoacetate in the presence of propanoic acid at 140°C for four hours gave the γ,δ-unsaturated ester 10 via ortho-Claisen rearrangement. 8 At this stage, the requisite chiral dihydroxy functionali...