Synthesis of the A-F Fragment of the Pacific Ciguatoxin CTX3C by Iterative Ring-Closing Metathesis and Tsuji-Trost Allylation

Abstract

The fully functionalized A-F fragment of the Pacific ciguatoxin CTX3C has been synthesized from a derivative of D-glucal, which serves as the B-ring. Rings A and C were introduced to either side of ring B by ring-closing diene and enyne metathesis (RCM). The seven-membered D-ring and eight-membered E-ring were assembled by iterative use of a six-step reaction sequence in which RCM was used for ring construction and Tsuji-Trost allylation was employed for subsequent stereoselective functionalization. The nine-membered F-ring was formed by use of an RCM reaction and bears the functionality required for attachment of the I-M fragment and subsequent closure of rings G and H.

Keywords: Tsuji-Trost allylation; ciguatoxin; iterative ring construction; polyether; ring-closing metathesis.

Figure 1

Representative Pacific ciguatoxins.

Figure 2

Disconnection of CTX3 C into the A−F fragment ii and the I−M fragment iii.

Scheme 1

Synthesis of the AB fragment from protected D‐glucal (1).

Scheme 2

Two routes for elaboration of the triflate 7 to give the ABC fragment 11.

Scheme 3

Functionalization of ring C to permit extension of the fused polycyclic ether array.

Scheme 4

Installation of ring D by sequential RCM and stereoselective palladium‐mediated Tsuji–Trost allylation.

Scheme 5

Installation of ring E by sequential RCM and stereoselective palladium‐mediated Tsuji–Trost allylation.

Scheme 6

Construction of ring F to complete the A−F fragment of CTX3C.