Stereoselective Synthesis of the I-L Fragment of the Pacific Ciguatoxins.

J Stephen Clark,Michael Popadynec

doi:10.3390/toxins12120740

Abstract

The I–L ring system found in all the Pacific ciguatoxins has been prepared from a tricyclic precursor in a highly stereoselective manner. Subtle differences in the reactivity of the enones present in the seven- and eight-membered rings of the tricyclic ether starting material have been exploited to allow selective protection of the enone in the eight-membered ring. Subsequent distereoselective allylation of the seven-membered ring has been accomplished by a palladium-mediated Tsuji-Trost reaction. The K-ring methyl and hydroxyl groups have been installed in a highly stereoselective manner by sequential conjugate reduction and enolate oxidation reactions. Ring L has been constructed by a use of a novel relay ring-closing metathesis reaction to complete the tetracyclic framework, which possesses the functionality necessary for elaboration of rings I and L and the introduction of ring M.

Highlights

We have reported a novel bidirectional ring-closing metathesis (RCM) approach to the synthesis of the tricyclic I–K fragment of P-CTX3-C from a simple monocyclic precursor and present the results of studies concerning its elaboration to give an I–L fragment that can serve as an advanced intermediate for the preparation of the terminal fragment of any of the Pacific ciguatoxins [24]
In previous work concerning the synthesis of the I–M fragment of P-CTX-3C and related ciguatoxins, we have demonstrated that the tricyclic sub-unit 1 can be prepared from a simple tetrahydropyranyl precursor by double ring-closing metathesis (RCM) and that subsequent bidirectional functionalisation of the diketone 1 is possible by sequential double allyl enol carbonate formation and double palladium-mediated Tsuji-Trost allylation (Scheme 1) [24,25]
The synthesis of the I–L ring system of the Pacific ciguatoxins has been accomplished in 10 steps starting from the tricyclic bis-enone 1

Summary

Introduction

The ciguatoxins are a family of large and structurally complex fused polycyclic ether natural products of marine origin. More than 30 other ciguatoxins have been isolated from marine dinoflagellates or from fish and marine organisms that accumulate the toxins by predation. The ciguatoxins can be grouped as Pacific, Caribbean or Indian according the ocean or sea where samples containing each toxin were first collected [3,4,5,6]. Pacific ciguatoxins are the most numerous and well-characterised of the ciguatoxins and this group accounts for more than three quarters of the ciguatoxins that are known [4,5,6]. Four Caribbean ciguatoxins have been characterized—C-CTX-1 and

Methods

Results

Conclusion