52(P14) SmI_2による効率的な中員環閉環反応(ポスター発表の部)

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Highly oxygenated diterpenoids such as grayanotoxin (1), kalmanol (2), vinigrol (3), taxol (4), ingenol ester (5) has been found among some of the best known biologically active natural products. Total synthesis of these diterpenes has stood for over 20 years as a major challenge for organic chemists. We started the program directed toward the total synthesis of these diterpenes with the aim at exploring a general and flexible synthetic method for the stereoselective formation of highly functionalized carbocycles via the reductive coupling reactions mediated by samarium(II) iodide (SmI_2). In conjunction with our program directed toward the total synthesis of vinigrol (3), we synthesized the 8-6 fused ring system of this diterpene through the efficient cyclization of the 8-membered ring using an SmI_2 induced Barbier coupling. Treatment of the aldehyde 6 with SmI_2 in the presence of HMPA cleanly allowed the 8-membered ring closure reaction to furnish the cyclooctanol 7 relevant to the 8-6 fused ring system of 3 in quantitative yield. Subsequent to this study, we have developed a general, efficient, and convenient method for construction of medium ring carbocycles utilizing SmI_2-mediated Barbier reaction. It was found that the introduction of a conformational constrain greatly enhances the ability of acyclic precursors to undergo the SmI_2-promoted Barbier-type cyclization of medium rings. Various 8- and 9-membered carbocycles are assembled with high efficiency via this protocol. For example, when the aldehyde 8 was treated with SmI_2 in the presence of HMPA at room temperature, the 8-membered ring annulation reaction instantaneously proceeded to form the 8-6 fused ring 9 in quantitative yield. In a similar manner, the aldehydes 10 and 12 are good substrates for the SmI_2-mediated cyclizations and afforded the 8-5 trans-fused ring 11 and 8-5 cis-fused ring 12, respectively. The ketones 14, 16, and 18 were also subjected to the same reductive couplings with SmI_2. The cyclization reactions took place quite well providing the 8-6 fused rings 15, 17, and 19, respectively. The almost quantitative yields of the cyclooctanols 7, 9, 11, 13, 15, 17, and 19 are remarkable in view of the difficulties normally encountered during the cyclization of 8-membered rings. Nine-membered rings are also readily accessible by the SmI_2-induced Barbier couplings. Treatment of the one-carbon homologated aldehydes 20, 22, and 24 with SmI_2 under the same conditions led to the 9-6 fused ring 21, 9-5 trans-fused ring 23, and 9-5 cis-fused ring 25, respectively, in good yields. The 9-6 fused rings 27 and 29 were also constructed in high yields through the same reductive cyclization reactions of the homologous ketones 26 and 28, respectively. The reaction is operationally quite simple. Particularly noteworthy is the fact that these 8- and 9-membered carbocycles were obtained in excellent yields under non-high-dilution conditions. The optimum reaction conditions for the couplings involved the addition of a 0.1M solution of SmI_2-HMPA in THF to a 0.1M solution of the starting material in THF at room temperature. In all cases, reactions were completed within seconds after SmI_2-HMPA was added. Apparently, the annulation reaction by the SmI_2-promoted Barbier reaction is among the most convenient entries into medium-sized rings.
天然有機化合物討論会の論文
1997-07-20

52(P14) SmI_2による効率的な中員環閉環反応(ポスター発表の部)

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