Crimmins Michael T, Katz Jason D, Washburn David G, Allwein Shawn P, McAtee Laura F
Department of Chemistry, Venable and Kenan Laboratories of Chemistry, University of North Carolina at Chapel Hill, 27599-3290, USA.
J Am Chem Soc. 2002 May 22;124(20):5661-3. doi: 10.1021/ja0262683.
The total synthesis of spongistatin 1 (1) and spongistatin 2 (2) has been achieved through an advanced-stage intermediate. The synthesis is highlighted by a highly convergent assembly of the four key fragments (the C1-C15 AB fragment 2, the C16-C28 CD fragment 3, the C29-C43 EF fragment 4, and the C44-C51 side chain 5) at a very advanced stage of the synthesis with minimal functional group interconversion. The CD fragment 3 functions as the central building block to which the other fragments are attached. The synthesis of the AB and CD spiroketal fragments is accomplished through the addition of a metalated gamma-pyrone to a beta-alkoxy aldehyde followed by spiroketalization. The EF subunit was assembled with high diastereoselectivity relying on asymmetric aldol reactions of chlorotitanium enolates of N-propionyl oxazolidinethiones and a double diastereoselective boron aldol to join the E and F fragments. Wittig coupling of the CD and EF fragments followed by a diastereoselective aldol reaction between the CDEF ketone and an AB aldehyde set the stage for attachment of the C44-C51 side chains and final macrolactonization and deprotection.
海绵他汀1（1）和海绵他汀2（2）已通过一个高级中间体实现了全合成。该合成的亮点在于在合成的非常高级阶段以最少的官能团转化对四个关键片段（C1 - C15的AB片段2、C16 - C28的CD片段3、C29 - C43的EF片段4和C44 - C51侧链5）进行高度汇聚组装。CD片段3作为核心构建块，其他片段连接其上。AB和CD螺缩酮片段的合成是通过将金属化的γ - 吡喃酮加到β - 烷氧基醛上然后进行螺缩酮化来完成的。EF亚基以高非对映选择性进行组装，依赖于N - 丙酰基恶唑烷硫酮的氯钛烯醇盐的不对称羟醛反应以及一个双非对映选择性硼羟醛反应来连接E和F片段。CD片段与EF片段的维蒂希偶联，随后CDEF酮与AB醛之间进行非对映选择性羟醛反应，为连接C44 - C51侧链以及最终的大环内酯化和脱保护奠定了基础。
