Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
J Org Chem. 2013 May 3;78(9):4278-96. doi: 10.1021/jo400260m. Epub 2013 Apr 12.
A unified synthetic strategy to access (+)-irciniastatin A (a.k.a. psymberin) and (-)-irciniastatin B, two cytotoxic secondary metabolites, has been achieved. Highlights of the convergent strategy comprise a boron-mediated aldol union to set the C(15)-C(17) syn-syn triad, reagent control to set the four stereocenters of the tetrahydropyran core, and a late-stage Curtius rearrangement to install the acid-sensitive stereogenic N,O-aminal. Having achieved the total synthesis of (+)-irciniastatin A, we devised an improved synthetic route to the tetrahydropyran core (13 steps) compared to the first-generation synthesis (22 steps). Construction of the structurally similar (-)-irciniastatin B was then achieved via modification of a late-stage (-)-irciniastatin A intermediate to implement a chemoselective deprotection/oxidation sequence to access the requisite oxidation state at C(11) of the tetrahydropyran core. Of particular significance, the unified strategy will permit late-stage diversification for analogue development, designed to explore the biological role of substitution at the C(11) position of these highly potent tumor cell growth inhibitory molecules.
已实现一种通用的合成策略，用于获得（+）-irciniastatin A（又名 psymberin）和（-）-irciniastatin B，这两种细胞毒性次生代谢产物。该收敛策略的重点包括硼介导的醛醇缩合反应以形成 C(15)-C(17) 顺式-顺式三联体，试剂控制以形成四氢吡喃核的四个立体中心，以及后期的 Curtius 重排以安装酸敏感的手性 N，O-亚胺。完成了（+）-irciniastatin A 的全合成后，我们设计了一种改进的四氢吡喃核（13 步）合成路线，与第一代合成（22 步）相比有所改进。然后通过修饰后期（-）-irciniastatin A 中间体来构建结构相似的（-）-irciniastatin B，以实施化学选择性脱保护/氧化序列，从而在四氢吡喃核的 C(11)上获得所需的氧化态。特别重要的是，这种统一的策略将允许进行后期的多样化，以开发类似物，旨在探索这些高活性肿瘤细胞生长抑制剂分子在 C(11)位置取代的生物学作用。
