Smith Amos B, Lin Qiyan, Doughty Victoria A, Zhuang Linghang, McBriar Mark D, Kerns Jeffrey K, Boldi Armen M, Murase Noriaki, Moser William H, Brook Christopher S, Bennett Clay S, Nakayama Kiyoshi, Sobukawa Masao, Lee Trout Robert E
Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, PA, 19104.
Tetrahedron. 2009 Aug 15;65(33):6470-6488. doi: 10.1016/j.tet.2009.04.001.
Evolution of a convergent synthetic strategy to access (+)-spongistatin 2 (2), a potent cytotoxic marine macrolide, is described. Highlights of the synthesis include: development of a multicomponent dithiane-mediated linchpin union tactic, devised and implemented specifically for construction of the spongistatin AB and CD spiro ring systems; application of a Ca(II) ion controlled acid promoted equilibration to set the thermodynamically less stable axial-equitorial stereogenicity in the CD spiroketal; use of sulfone addition/Julia methylenation sequences to unite the AB and CD fragments and introduce the C(44)-C(51) side chain; and fragment union and final elaboration to (+)-spongistatin 2 (2) exploiting Wittig olefination to unite the advanced ABCD and EF fragments, followed by regioselective Yamaguchi macrolactonization and global deprotection. Correction of the CD spiro ring stereogenicity was subsequently achieved via acid equilibration in the presence of Ca(II) ion to furnish (+)-spongistatin 2 (2). The synthesis proceeded with a longest linear sequence of 41 steps.
本文描述了一种用于合成强效细胞毒性海洋大环内酯类化合物（+）-海绵他汀2（2）的收敛性合成策略的演变。该合成的亮点包括：开发了一种多组分二硫烷介导的关键连接策略，该策略是专门为构建海绵他汀AB和CD螺环系统而设计和实施的；应用Ca（II）离子控制的酸促进平衡来设置CD螺环酮中热力学上较不稳定的轴向-赤道立体化学；使用砜加成/朱莉娅亚甲基化序列来连接AB和CD片段并引入C（44）-C（51）侧链；以及利用维蒂希烯烃化反应将高级ABCD和EF片段连接起来，随后进行区域选择性山口大环内酯化和全局脱保护，从而将片段连接并最终合成（+）-海绵他汀2（2）。随后通过在Ca（II）离子存在下进行酸平衡来校正CD螺环的立体化学，以得到（+）-海绵他汀2（2）。该合成以最长41步的线性序列进行。
