Toward the synthesis of norzoanthamine: Complete fragment assembly
Toward the synthesis of norzoanthamine: Complete fragment assembly
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DOI：
10.1021/jo070165r
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发表时间：
2007-06-22
影响因子：
3.6
通讯作者：
Tanner, David
中科院分区：
文献类型：
--
作者：
Juhl, Martin;Monrad, Rune;Tanner, David
设想复杂的海洋生物碱去甲虫胺（2）由三个关键的结构单元组装而成：C-1-C-5片段A、C-6-C-10片段B和C-11-C-24片段C。以（R）-γ-羟甲基-γ-丁内酯为起始原料，经14步反应合成了片段A，总收率为33%。片段B由PMB保护的4-戊炔醇分两步制备，产率为76%。C-11-C-24片段C由（S）-香芹酮经（R）-异香芹酮经18步反应制得（总收率6%）。目标分子的整个碳骨架（C-1-C-24）的会聚立体选择性合成通过以下组装实现。衍生自C-11-C-24片段C的烯基碘20通过这两种空间要求非常高的偶联配偶体的高产率Stille偶联反应偶联到片段B（C-6-C-10），得到关键的Diels-Alder前体24。分子内Diels-Alder反应以优异的产率和非对映选择性顺利进行，生成三环反-反-反式全氢菲基序的去甲虫胺（C-6-C-24）。锂化片段A（C-1-C-5）和醛40（C-6-C-24）之间的最终片段偶联也已成功完成，提供了天然产物的整个碳框架。
The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building blocks: the C-1-C-5 fragment A, the C-6-C-10 fragment B, and the C-11-C-24 fragment C. The synthesis of fragment A was achieved in 14 steps and 33% overall yield from (R)-gamma-hydroxymethyl-gamma-butyrolactone. Fragment B was made in two steps from PMB-protected 4-pentynol in 76% yield. The C-11-C-24 fragment C was made from (S)-carvone via (R)-isocarvone in 18 steps (6% overall yield). The convergent stereoselective synthesis of the entire carbon framework (C-1-C-24) of the target molecule was achieved via the following assemblage. Alkenyl iodide 20 derived from the C-11-C-24 fragment C was coupled to fragment B (C-6-C-10) through a high-yielding Stille coupling reaction of these two sterically very demanding coupling partners, affording the key Diels-Alder precursor 24. The intramolecular Diels-Alder reaction proceeded smoothly in excellent yield and diastereoselectivity, generating the tricyclic trans-anti-trans perhydrophenanthrene motif of norzoanthamine (C-6-C-24). The final fragment coupling between lithiated fragment A (C-1-C-5) and aldehyde 40 (C-6-C-24) has also been successfully accomplished affording the entire carbon framework of the natural product.