22 リベロマイシンBの全合成(口頭発表の部)
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Reveromycins are novel polyketide-type antibiotics isolated from Streptmyces sp. and inhibit the signal transduction pathway associated with EGF receptors. The characteristic structural features involve spiroketal core having a hemi-succinate, two unsaturated side chains ending in carboxilic acids, and two alkyl groups. The potent biological activity and the unique structure attracted the attention of synthetic organic chemists, and the first total synthesis of 2 was recently achieved by Theodorakis et al. We have already reported the stereoselective synthesis of 6,6-spiroketal system in 1, and elucidated the absolute configuration through the synthesis. Here, we report the stereoselective total synthesis of reveromycin B (2). Our synthetic strategy involved the Wittig reaction, Horner-Wadsworth-Emmons reaction and one-pot Julia coupling reaction for construction of the unsaturated side chains. The spiroketal core was provided by acetylide coupling reaction between Weinreb amide 3 and alkyne 4, which were prepared from epoxides 8 and 15, respectively. Exo-cyclization of the epoxide 8 followed by regioselective oxidation gave the sterically hindered lactone 12, which was efficiently converted into the Weinreb amide 3 via aminolysis using Me_2AlCl-MeNHOMe・HCl. (Z)-Selective Homer-Wadsworth-Emmons reaction of aldehyde 15 using Still's reagent afforded alkenyl oxirane 16. Pd-HCO_2H reduction of 16 proceeded regio- and stereoselectively to give the desired anti-alcohol 17 which was converted into the alkyne 4 by silylation, oxidative cleavage of olefin, and Colvin rearrangement. The coupling reaction of 3 and 4 using nBuLi following by hydrogenation afforded ketone 22, which was treated with TsOH to give the thermodynamically stable spiroketal 23. After succination of 25, deprotection of TES group, and TPAP oxidation, the resulting aldehyde 28 was subjected to the Horner-Wadsworth-Emmons reaction with phosphonate 21 to give the (E, E)-diene 29 exclusively. The Wittig reaction of 37 gave the α,β- unsaturated aldehyde 38 which was reduced with ZnBH_4 to afford allyl alcohol 39. The subsequent Mitsunobu reaction using 2-mercaptobenzothiazole and Mo(VI) catalyzed oxidation gave sulfone 41, which was coupled with aldehyde 36 in the presence of LiHMDS to afford the (E)-olefin 42. Deprotection of TES group in 42 followed by Dess-Martin oxidation provided aldehyde which was subjected to the Wittig reaction with a neutral phosphorane to give the protected reveromycin B (44). Finally, successive desilylation and deallylation gave reveromycin B (2), which was identical (^1H-NMR, ^<13>C-NMR, [α]_D, IR, HRMS) with the natural product.
- 天然有機化合物討論会の論文
- 1999-09-01
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