36 抗腫瘍性化合物(-)-FR182877の不斉全合成(口頭発表の部)
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概要
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(-)-FR182877 was isolated from the fermentation broth of Streptomyces sp. No. 9885 by a research group of Fujisawa Pharmaceutical Company in 1998. This compound possesses an unprecedented hexacyclic ring system containing a bridgehead double bond as part of a vinylogous carbonate unit and 12 stereogenic centers, and exhibits microtubule stabilizing activity similar to that of Taxol. Hence, the complex structure and promising bioactivity of (-)-FR182877 have attracted considerable attention from synthetic chemists. Our synthetic approach began with the conversion of known aldehyde 8 to precursor 13 for the intramolecular Diels-Alder (IMDA) reaction. The IMDA reaction of the α,β-unsaturated aldehyde generated in situ from the corresponding acetal of 13 successfully provided the desired product 14 possessing the AB ring system as the single diastereomer. The CD ring system was constructed by the subsequent intramolecular hetero-Diels-Alder (IMHDA) reaction and the extensive studies suggested that the diastereoselectivity of the IMHDA reaction could be related to the E/Z geometry of alkene 16, which was generated in situ from 15. Consequently, we examined the IMHDA reaction of the substrate with the pure E-alkene to improve the diastereoselectivity. Horner-Wadsworth-Emmons reaction of 12 with 18E and subsequent reduction provide compound 19. Upon heating 19 in toluene, the stereoselective IMDA reaction occurred to afford the 20a as the major product. The cycloadduct was converted to the allyl alcohol 21, which was oxidized with MnO_2 to provide the corresponding aldehyde which in turn spontaneously underwent the intramolecular hetero-Diels-Alder (IMHDA) reaction in situ to afford the cycloadduct 23 as the sole product. Next, we examined the construction of the strained seven-membered ring moiety, and found that the intramolecular Heck reaction of compound 35 could only facilitate this transformation and afforded 36 incorporating the strained ABCDF ring system. The allylic alcohol 36 was successfully isomerized to the α-methyl ketone 38 with high diastereoselectivity, followed by the diastereoselective reduction, deprotection, and δ-lactone formation to accomplish the asymmetric total synthesis of (-)-FR182877. Starting from the C5 stereogenic center generated by the Evans aldol reaction, all other stereogenic centers have been successfully produced by asymmetric induction in this total synthesis.
- 天然有機化合物討論会の論文
- 2008-09-01
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