98(P-44) アセチレンコバルト錯体を活用したシガトキシンの合成研究(ポスター発表の部)

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Ciguatoxin 1B (CTX 1B, 1) is one of the most toxic marine natural products causing seafood poisoning "ciguatera". Several synthetic groups have been involved toward the total synthesis of CTX due to its remarkable structural complexity, biological activity and limited availability from nature. The first success in a total synthesis of CTX-3C was reported by Hirama et al. in 2001. During the course of our synthetic studies toward 1, we have developed new methodologies including (i) construction of medium-size (7-9) ether rings via acetylene cobalt complexes in highly stereoselective syn-trans mode, (ii) reductive decomplexation into cis-olefins or vinylsilanes, (iii) ring-opening reactions of cyclic α,β-epoxysilanes into allyl alcohols and (iv) stereoselective heteroconjugate additions. Scheme 1 exhibits retrosynthetic analysis toward 1, where the A, F, G ring cyclization would be achieved at the last stage from 2 that would be synthesized through a coupling between acetylide 3 (Segment L) and aldehyde 4 (Segment R). On the basis of this analysis, we synthesized 18 as a model of the E'FGH ring (Scheme 3). Acetylene cobalt complex 14 was treated with TsOH to effect the F ring cyclization to give 15. The condition under high-pressure hydrogenation made it possible to convert the acetylene cobalt complex moiety into ketone, which was treated with BF_3-OEt_2 in the presence of Et_3SiH to afford the E'FGH ring 18. Synthesis of Segment L was accomplished via acetylene cobalt complex and vinylsilane as shown in Scheme 5. The construction of E ring was proceeded by the following steps as used in that of D ring: carbon chain elongation through the acetylide of 29, cobalt complexation, cyclization, hydrosilylation, epoxidation via iodolactonization of 33, Peterson reaction to Z-enyne 36, opening of epoxysilane and finally Mitsunobu reaction to afford Segment L3. We have recently been exploring a highly convergent synthesis of Segment R4 that would be synthesized from Segment R1, R2 and R3 (Scheme 6). The heteroconjugate addition of 40 to 39 provided the adduct as an exclusive product via a β-chelation as shown in 46 (Scheme 7 and 9). Acetylene cobalt complex 51 was treated with BF_3.OEt_2 and then followed by Sharpless dihydroxylation and spiroketalization with HF・Py to give the JKLM ring 54. Making a success of synthesis of Segment R4 via Sonogashira coupling and I, H ring cyclization, we will set out the last stage of total synthesis of ciguatoxin 1 (Scheme 10).
天然有機化合物討論会の論文
2002-09-01

98(P-44) アセチレンコバルト錯体を活用したシガトキシンの合成研究(ポスター発表の部)

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