Spongipyran synthetic studies. Evolution of a scalable total synthesis of (+)-spongistatin 1
详细信息 查看全文
- 作者：Amos B. Smith III ; Chris Sfouggatakis ; Christina A. Risatti ; Jeffrey B. Sperry ; Wenyu Zhu ; Victoria A. Doughty ; Takashi Tomioka ; Dimitar B. Gotchev ; Clay S. Bennett ; Satoshi Sakamoto ; Onur Atasoylu ; S
- 刊名：Tetrahedron
- 出版年：2009
- 出版时间：15 August 2009
- 年：2009
- 卷：65
- 期：33
- 页码：6489-6509
- 全文大小：1474 K
文摘
Three syntheses of the architecturally complex, cytotoxic marine macrolide (+)-spongistatin 1 (1) are reported. Highlights of the first-generation synthesis include: use of a dithiane multicomponent linchpin coupling tactic for construction of the AB and CD spiroketals, and their union via a highly selective Evans boron-mediated aldol reaction en route to an ABCD aldehyde; introduction of the C(44)–C(51) side chain via a Lewis acid-mediated ring opening of a glucal epoxide with an allylstannane to assemble the EF subunit; and final fragment union via Wittig coupling of the ABCD and EF subunits to form the C(28)–C(29) olefin, followed by regioselective Yamaguchi macrolactonization and global deprotection. The second- and third-generation syntheses, designed with the goal of accessing 1 g of (+)-spongistatin 1 (1), maintain both the first-generation strategy for the ABCD aldehyde and final fragment union, while incorporating two more efficient approaches for construction of the EF Wittig salt. The latter combine the original chelation-controlled dithiane union of the E- and F-ring progenitors with application of a highly efficient cyanohydrin alkylation to append the F-ring side chain, in conjunction with two independent tactics to access the F-ring pyran. The first F-ring synthesis showcases a Petasis–Ferrier union/rearrangement protocol to access tetrahydropyrans, permitting the preparation of 750 mg of the EF Wittig salt, which in turn was converted to 80 mg of (+)-spongistatin 1, while the second F-ring strategy, incorporates an organocatalytic aldol reaction as the key construct, permitting completion of 1.009 g of totally synthetic (+)-spongistatin 1 (1). A brief analysis of the three syntheses alongside our earlier synthesis of (+)-spongistatin 2 is also presented.