Biomimetic Transannular Oxa-Conjugate Addition Approach to the 2,6-Disubstituted Dihydropyran of Laulimalide Yields an Unprecedented Transannular Oxetane
Biomimetic Transannular Oxa-Conjugate Addition Approach to the 2,6-Disubstituted Dihydropyran of Laulimalide Yields an Unprecedented Transannular Oxetane
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DOI：
10.1021/jo8023494
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发表时间：
2009-02-20
影响因子：
3.6
通讯作者：
Boddy, Christopher N.
中科院分区：
文献类型：
--
作者：
Houghton, Stephen R.;Furst, Laura;Boddy, Christopher N.
2,6-二取代二氢吡喃是许多生物活性聚酮化合物的共同特征，包括抗癌海洋聚酮化合物月桂马内酯。虽然月桂马利特的许多未表征的生物合成途径可以被自信地假设，但反式 2,6-二取代二氢吡喃的生物合成起源却不能。我们假设大环月桂马内酯前体中的跨环氧杂合物加成可能是 2,6-二氢吡喃的起源。为了检验这一假设，我们构建了一个模型，其中包含氧杂合物加成介导的二氢吡喃形成的关键官能团。在酸介导的条件下，该模型进行区域特异性氧杂合物加成，产生稳定的反式氧杂环丁烷作为唯一的区域异构体。没有检测到所需的更稳定的二氢吡喃。由于氧杂环丁烷的环应变和预期的容易开环的逆-氧杂-缀合物加成，这种前所未有的区域特异性是出乎意料的。该氧杂环丁烷对酸性和碱性条件稳定，许多文献中的无环氧杂环丁烷也可以进行类似的逆氧杂合物加成。虽然氧杂环丁烷动力学稳定性的来源尚未确定，但它可能能够通过氧杂合物加成来构建一般的氧杂环丁烷。由于硬氧亲核试剂和软活化多烯酸酯亲电试剂之间的几何轨道排列不良和软硬不相容性，无法生成更稳定的二氢吡喃区域异构体。这些因素不利于通过氧杂缀合物加成来破坏缀合。基于这些结果，我们提出二氢吡喃的形成并不像我们所提出的那样发生在完整的聚酮化合物大环上，而是发生在不断增长的聚酮化合物链上的聚酮化合物生物合成过程中。
2,6-Disubstituted dihydropyrans are a common feature in many bioactive polyketides, including the anticancer marine polyketide laulimalide. While much of the uncharacterized biosynthetic pathway for laulimalide can be confidently postulated, the biosynthetic origins of the trans 2,6-disubstituted dihydropyran cannot. We hypothesize that a transannular oxa-conjugate addition in a macrocyclic laulimalide precursor could be the origin of the 2,6-dihydropyran. To test this hypothesis, we constructed a model containing the key functional groups for oxa-conjugate addition-mediated dihydropyran formation. Under acid-mediated conditions, the model under went regiospecific oxa-conjugate addition producing a stable trans oxetane as the only regioisomer. The desired, more stable dihydropyran was not detected. This unprecedented regiospecificity is unexpected due to the ring strain of the oxetane and the anticipated facile ring opening retro-oxa-conjugate addition. The oxetane is stable to acid and basic conditions, as are a number of literature acyclic oxetanes that could undergo similar retro-oxa-conjugate addition. While the source of the oxetane kinetic stability is yet to be characterized, it may enable general oxetane construction via oxa-conjugate addition. The more stable dihydropyran regioisomer could not be generated due to poor geometrical orbital alignment and hard-soft incompatibility between the hard oxygen nucleophile and the soft activated polyenoate electrophile. These factors disfavor the breaking of conjugation by oxa-conjugate addition. Based on these results we propose that dihydropyran formation does not occur on completed polyketide macrocycles as we had proposed but rather during polyketide biosynthesis on the growing polyketide chain.