38 Reveromycin Aの全合成(口頭発表の部)

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Reveromycins A-D (1-4) are novel polyketide-type antibiotics isolated from the genus Streptomyces as inhibitors of mitogenic activity induced by the epidermal growth factor (EGF) in a mouse epidermal keratinocyte. The characteristic structural features of reveromycins include a 6,6- or a 5,6-spiroketal system bearing a hemisuccinate, two unsaturated side chains and two alkyl groups. Their strong biological activity as potential drugs and their synthetically challenging, unique structure have attracted the attention of synthetic organic chemists and the total synthesis of reveromycin B (2) has been independently accomplished by three groups. We now report the first asymmetric total synthesis of reveromycin A (1), which is the major and most bioactive compound of the reveromycins. Our retrosynthetic analysis of reveromycin A (1) is as follows. The unsaturated left and right side chains should be produced by the Horner-Wadsworth-Emmons reaction, Julia coupling, and Wittig reactions during the later stage due to their instabilities. The construction of the hemisuccinate of the C18 tert-hydroxyl group might be achieved by acylation under high pressure. The main problem should be the construction of the 6,6-spiroketal core 5 in which the C18 tert-hydroxyl group and C19 side chain are axially oriented. The inherent instability of the 6,6-spiroketal system in 5 may cause some difficulties during the synthetic studies, e.g., easy transketalization of 5 (X=H) into the stable 5,6-spiroketal 7, transformation of 5 into the undesired 6,6-spiroketals 6 in the unnatural form via an equilibration. The construction of 5 could be achieved by the intramolecular ketalization of the ketone 8, which would be synthesized via the coupling reaction of the Weinreb amide 9 and alkyne 10. The coupling reaction of 9 and the lithio derivative of 10 followed by hydrogenation furnished the saturated ketone 11, which was treated with CSA to give the 6,6-spiroketals 12 in the natural form and 13 in 54% and 27% yields, respectively. Deprotection of the MTM group in 12 with MeI-NaHCO_3 proceeded to afford the alcohol 16. Succinylation of 16 with mono-allyl succinate and DCC at 1.5GPa efficiently proceeded to give the succinate 17. Desilylation of 17 followed by the Dess-Martin oxidation gave the aldehyde, which was subjected to the Horner-Wadsworth-Emmons reaction with (EtO)_2P(O)CH_2C(Me)=CHCO_2Allyl to give the (E,E)-dienoic esters 18. Deprotection of the MPM group in 18 with DDQ afforded the alcohol 19. The 6,6-spiroketal 13 in the unnatural form was converted into the desired 19 via the treatment of the alcohol 21 with CSA. The treatment of alcohol 23 derived from 19 with 2-mercaptobenzothiazole under the modified Mitsunobu conditions with TMAD and n-Bu_3P gave the sulfide which was subjected to the Mo(VI)-mediated oxidation to give the sulfone 24. The one-pot Julia olefination of 24 and the aldehyde 28 stereoselectively produced the (6E,8E)-diene 25. Deprotection of TES group in 25 followed by Dess-Martin oxidation provided aldehyde which was subjected to the Wittig reaction with a neutral phosphorane to give the protected reveromycin A (27). Finally, successive deallylation with Pd(Ph_3P)_4-Ph_3P and desilylation with TBAF in DMF gave reveromycin A (1), which was identical with the natural product.
2000-10-01

38 Reveromycin Aの全合成(口頭発表の部)

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