HETEROCYCLES

Communication | Special issue | Vol. 88, No. 2, 2014, pp. 969-973
Received, 3rd August, 2013, Accepted, 28th August, 2013, Published online, 6th September, 2013.
DOI: 10.3987/COM-13-S(S)106

■ Improved Synthesis of the A-E Ring Segment of Ciguatoxin CTX3C

Kengo Shiroma, Hiroki Asakura, Tokihiro Tanaka, Hiroyoshi Takamura, and Isao Kadota*

Graduate School of Natural Sciences and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

The improved synthesis of the A-E ring segment of ciguatoxin CTX3C was performed via a highly convergent approach based on intramolecular allylation-RCM methodology.

Ciguatoxin CTX3C (1),1 one of the causative toxin of “ciguatera” seafood poisoning, was isolated from cultured dinoflagellate Gambierdiscus toxicus (Figure 1).2 The unique structural features and potent neurotoxicity of this molecule have attracted significant attention of synthetic chemists. 3,4 Herein, we wish to describe the improved synthesis of the A-E ring segment of ciguatoxin CTX3C as a part of the synthetic study of 1.

Previously, we reported the convergent synthesis of A-E ring segment of 1 as shown in Scheme 1.5,6 The ester 2, prepared from an AB ring carboxylic acid and E ring alcohol, was converted to α-chloroacetoxy ether 4 via the reaction with γ-methoxyallylstannane 3. The intramolecular allylation of 4 followed by ring-closing metathesis provided the A-E ring segment 5.7 In this paper, we wish to describe the improved synthesis of the A-E ring segment having a suitable side chain for the construction of the F ring moiety.

To improve the efficiency of the synthesis, we planed to perform the reaction of 3 with the AB ring moiety before the segment coupling. Selective tosylation of known diol 66b with TsCl/pyridine gave monotosylate 7 in 96% yield (Scheme 2). Reaction of the alcohol 7 with γ-methoxyallylstannane 3 in the presence of CSA provided the mixed acetal 8 as a mixture of diastereoisomers in 92% yield.8 Treatment of 8 with NaCN in DMSO afforded 9 in 92% yield. DIBAL-H reduction of the nitrile 9 followed by Pinnick oxidation of the resulting aldehyde gave carboxylic acid 10, which was subjected to the Yamaguchi esterification with the alcohol 11 to provide ester 12 in 87% overall yield.9 Treatment of 12 with TMSI/HMDS gave allylic stannane 13 in 86% yield.8 Modified Rychnovsky acetylation of the ester 13 provided the α-chloroacetoxy ether 4.10,11

We next examined the key reaction, intramolecular allylation of 4 (Table 1). In our previous work, the reaction was carried out with BF3·OEt2/MS4A in MeCN/CH2Cl2 to give a 4:1 mixture of the desired products 14 and its diasteroisomer 15 in 60% yield (entry 1).5 After several experiments, we found that the use of the conditions described in entry 2 gave better result. Thus, the reaction of 4 with MgBr2·OEt2/MS5A in toluene provided a 92:8 mixture of 14 and 15 in 85% overall yield. Although actual effects of the conditions used were not clear yet, it contributes to an improvement of the synthesis.

Further transformation was carried out as shown in Scheme 3. Ring-closing metathesis of 14 with the Grubbs’ catalyst 16 provided the pentacyclic ether 5 in 82% yield (Scheme 3).12 Thus, the key synthetic intermediate 5 was obtained in 39% overall yield by 10 steps from the diol 6. In our previous synthesis of 5 from 6, the overall yield was 11% by 13 steps. Removal of the benzylidene acetal of 5 with CSA in MeOH afforded 17 in 93% yield. Selective tosylation of the primary alcohol of 17 with TsCl/pyridine followed by TBS protection of the remaining secondary alcohol with TBSOTf/2,6-lutidine gave tosylate 18 in 83% overall yield. Treatment of 18 with NaCN in DMSO afforded nitrile 19 in 98% yield. Reduction of 19 with DIBAL-H followed by LiAlH4 provided alcohol 20. Removal of the TBS protective group of 20 with TBAF followed by selective protection of the remaining primary alcohol with TBDPSCl/Et3N/DMAP furnished the A-E ring segment 21 in 82% overall yield.

In conclusion, an improved synthesis of the A-E ring segment of ciguatoxin CTX3C (1) was performed by using a highly convergent synthetic strategy. Moreover, the key reaction steps, preparation of the α-chloroacetoxy ether 3 and its cyclization, were considerably optimized. Further studies towards the total synthesis of 1 are in progress in our laboratory.

ACKNOWLEDGEMENTS
This work was financially supported by The Research Foundation for Pharmaceutical Sciences, The Kurata Memorial Hitachi Science and Technology Foundation, and the Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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