HETEROCYCLES

Communication | Special issue | Vol. 86, No. 2, 2012, pp. 997-1001
Received, 3rd September, 2012, Accepted, 20th September, 2012, Published online, 27th September, 2012.
DOI: 10.3987/COM-12-S(N)117

■ Synthesis of the E Ring Segment of Ciguatoxin CTX3C via the Negishi Coupling of Cyclic Ketene Acetal Triflate

Kengo Shiroma, Hiroyoshi Takamura, and Isao Kadota*

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

Abstract

Stereocontrolled synthesis of the E ring segment of ciguatoxin CTX3C was performed via the Negishi coupling of cyclic ketene acetal triflates. Transformation of 8-membered lactones to the corresponding ketene acetal triflates was found to be affected by the protective groups of the substrates.

Ciguatoxin CTX3C (1),1 isolated from cultured dinoflagellate Gambierdiscus toxicus, is a causative toxin of “ciguatera” seafood poisoning (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 a stereocontrolled synthesis of the E ring segment via the Negishi coupling of a cyclic ketene acetal triflate as a part of the synthetic study of 1.

Previously, we reported the synthesis of cyclic ethers via the Negishi coupling5 of cyclic ketene acetal triflates prepared from the corresponding lactone and PhNTf2/KHMDS6 as shown in Scheme 1. Thus, the reaction of the ketene acetal triflate 3, prepared from ε-lactone 2 with PhNTf2/KHMDS, with zinc homoenolate 4 in the presence of Pd(PPh3)4 provided 7-membered cyclic enol ether 5 in 83% yield for the two steps.7 The reaction was successfully applied to the synthesis of the DE and GH ring segments of gambierol and the C ring of brevetoxin B.7,8 Encouraged by these results, we attempted to apply this methodology to the synthesis of E ring segment of CTX3C (1).

The synthesis of the 8-membered lactone 13 was prepared according to the reported procedure.9 Protection of 1,6-hexanediol 6 with TBDPSCl/imidazole gave alcohol 7 (Scheme 2). Oxidation of 7 with SO3·py/DMSO/Et3N followed by Wittig reaction of the resulting aldehyde with Ph3P=CHCO2Me afforded α,β-unsaturated ester 8. Reduction of 8 with DIBAL-H gave the corresponding allylic alcohol, which was subjected to Sharpless asymmetric epoxidation to furnish epoxy alcohol 9 in 59% overall yield. Treatment of 9 with benzoic acid and Ti(OiPr)4 afforded the benzoate 10,10 which was treated with K2CO3 in MeOH, and the resulting triol was protected with PhCH(OMe)2/CSA to give the benzylidene acetal 11 in 70% overall yield. Removal of the TBDPS protection of 11 using TBAF, followed by stepwise oxidation with TEMPO and NaClO2 provided carboxylic acid 12. Lactonizaton of 12 under Yamaguchi conditions provided 13 in 35% overall yield.11 The lactone 13 obtained was then treated with PhNTf2/KHMDS. However, unfortunately, the reaction gave a complex mixture containing a trace amount of the desired cyclic ketene acetal triflate 14.12,13 To improve this process, we next examined the effect of the protective group of the substrates.
Table 1 summarizes the results of the reactions using various substrates.14 Compared with the case of 13 (entry 1), the reaction was slightly improved when 4-methoxybenzylidene acetal was used as a protective group giving the product 16 in 10% yield. A reasonable yield was obtained by the reaction of 17 having an acetonide protection (entry 3). The desired cyclic ketene acetal triflate 18 was obtained in 79% yield. On the other hand, no reaction took place with bis-TBS ether derivative 19 (entry 4). Although the reason is not clear yet, the changing the protective group would affect on the conformation of the 8-membered lactone ring to stabilize the resulting potassium enolate.

The cyclic ketene acetal triflate 18 obtained was then subjected to the key C-C bond formation. Thus, the Negishi coupling of 18 was carried out with zinc homoenolate 4 in the presence of PdCl2(o-Tol3P)28 to give cyclic enol ether 21 in 70% yield. Reduction of the ester 21 with LiAlH4, followed by protection of the resulting alcohol with TBDPSCl/imidazole provided the corresponding silyl ether, which was subjected to the hydroboration with thexylborane and oxidation to afford hydroxyl cyclic ether 22 as a single stereoisomer in 34% overall yield. The cis-relationship of the two alkyl groups on the ether ring was confirmed by 1H NMR analysis and NOE experiments. The Dess-Martin reaction of the alcohol 22 and subsequent Ito-Saegusa oxidation16 of the resulting ketone gave enone 23 in 72% overall yield. Stereoselective reduction of the enone 23 was performed by using NaBH4/CeCl3 to furnished a 5:1 mixture of the desired E ring segment 24 and its diastereomer in 97% combined yield. The coupling constants, JHa,Hb = 9.0 Hz, clearly indicated the trans-relationship of Ha and Hb protons.

In conclusion, the stereocontrolled synthesis of the E ring segment of ciguatoxin CTX3C was achieved by using the Negishi coupling of an 8-membered cyclic ketene acetal triflates. Although the details are not clear yet, the effect of the protective groups on the triflation reaction is of interest. Further studies towards the total synthesis of 1 are in progress in our laboratories.

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

References

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