35 (-)-Apicularen Aの全合成(口頭発表の部)

抄録

Kunze et al. reported the isolation of (-)-apicularen A (1) from a variety of strains of the myxobacterial genus Chondromyces in 1998. Subsequently, the gross structure of 1 including the relative and absolute stereochemistry was determined. Biological studied revealed 1 to be highly cytostatic to a wide range of human cancer cell lines with IC_<50> values in the range of 0.23 to 0.68 nM. In addition, recent reports indicated that 1 exhibited antiangiogenesis properties, induced apoptosis produced nitric oxide, and acted as a noverl specific V-ATPase inhibitors. From structural point of view, 1 is characterized by a number of motifs such as a trans-tetrahydropyran ring embedded in a 12-membered salicylate macrolactone, and four stereogenic centers within the macrolactone core which bears a higyly unsaturated N-acylenamine side chain. Because of its fascinationg molecular architecture and potent biological activity, 1 has been targeted by a number of synthetic research groups. To date, four total syntehses of 1, have been achieved along with four formal total synrtheses. In this presentation, we wish to present a novel stereoselective approach for the synthesis of 1. The key features of this total synthesis included (i) assembling of (E)-iodoalkene and substituted heptanal by Nozaki-Hiyama-Kishi coupling; (ii) stereospecific synthesis of trans-2,6-disubstituted dihydropyran 6 by using Pd(II)-catalyzed 1,3-chirality transferred reaction from triol 7; (iii) Yamaguchi macrolactonization of the seco acid to construct 12-membered lactone ring with dihydropyran bridge; (iv) regio- and stereo-selective introduction of hydroxy group at C-11 position of 5 by oxymercuration and reductive demercuration; (v) stereospecific CuI-mediated coupling of 2 with (2Z,4Z)-heptadienemide 3 under the mild conditions.