A Total Synthesis of Norhalichondrin B

Abstract

Keywords natural products; pyrans; polyethers; metathesisThe halichondrin family of marine polyethers, first defined by the isolation and structure elucidation of norhalichondrin A by Uemura and co-workers in 1985, now numbers ~ 15 compounds.[1] The structures of the halichondrins, as exemplified by norhalichondrin B (Figure 1) are characterized by a 53-55 carbon backbone that is defined by two domains: the spiroketal containing C31-C53/55 region and a C1-C30 macrolactone that also contains a 2,6,9-trioxatricyclo[3.3.2.0 3,7 ]decane. The structures, in conjunction with impressive levels of cytotoxicity, have attracted significant scientific attention [2,3] highlighted by the total syntheses of halichondrin B and norhalichondrin B by Kishi in 1992, [3,5] and the current efforts of Eisai Pharmaceuticals to establish E7389,[6] a truncated analog of the macrolactone, as an anti-cancer therapeutic. In this communication we describe our studies that have culminated in the total synthesis of norhalichondrin B.Our overall plans are defined in Figure 1, and involve a late stage Horner-Wadsworth-Emmons coupling of C40-C53 domain, 2 with phosphonate 3. Phosphonate 3 can be traced back to C1-C13 domain 5 and C12-C38 domain 4. In the forward sense, we envisioned that these two domains would be connected by a combination of cross-metathesis and macrolactonization as the key reactions. The C12-C38 domain 4 could be further dissected to arrive at pyranopyran 6 and the C14-C26 THF-ring containing domain 7.[7] Pyran 2 and pyranopyran 6 would ultimately be prepared by the application of our recently reported furan→pyranone conversion, [8] and pyranopyran 5 would arise from a tandem ring-opening-ring-closing metathesis of an oxabicyclo[3.2.1]octene. [9]

Synthesis of 5,6- and 6,6-Spirocyclic Compounds

“…Recently, this approach has been exploited in the synthesis of norhalichondrin B 235 [126] (Scheme 57). Additionally, an oxa-Michael strategy has been used by Brimble et al [127] for the synthesis of bis(benzannulated)-spiroacetals 238 (Scheme 58).…”

“…Wulff et al [131] have reported a tandem desymmetrization/oxa-Michael addition in their studies toward the spiroacetal Scheme 57 Oxa-Michael approach towards norhalichondrin B [126] portion of didemnaketal A (Scheme 60). Sharpless asymmetric dihydroxylation of the meso bis-enone 248 and in situ hemiacetalization followed by conjugate addition gave the singly anomeric spiroacetal 251 as the only product.…”

The Halichondrins and E7389

“…45 The overall plans for the synthesis are summarized in Figure 9. The completion of the synthesis was planned around a late-stage HornerWadsworth-Emmons coupling of C1-C39-containing phosphonate 149 with the C40-C53 domain aldehyde 147, followed by spiroketal formation.…”

Asymmetric Domino Reactions Based on the Use of Chiral Substrates

“…Moreover, the same authors have reported the total synthesis of the biologically active natural product norhalichondrin B, which also involved a domino ring-opening-ring-closing metathesis of a chiral highly functionalised ether under very similar conditions, providing the corresponding chiral key pyranopyran in 71% yield, as shown in Scheme 1.58. 96 A novel asymmetric approach to a densely functionalised lactarane skeleton in enantiomerically pure form, involving a domino ring-opening-ring closing metathesis of a chiral norbornene derivative, was reported by Ghosh et al, in 2008. 97 As shown in Scheme 1.59, the reaction of a chiral auxiliary with ethylene in the presence of a first-generation Grubbs' catalyst afforded the corresponding enantiopure hydroazulene derivative in 65% yield as a single product.…”