Synthesis of (-)-(R)-pyrrolam a and studies on its stability: a caveat on computational methods.
Synthesis of (-)-(R)-pyrrolam a and studies on its stability: a caveat on computational methods.
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DOI：
10.1021/jo049460r
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发表时间：
2004-08
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影响因子：
--
通讯作者：
Rhett T. Watson;V. Gore;K. Chandupatla;R. Dieter;J. Snyder
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文献类型：
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作者：
Rhett T. Watson;V. Gore;K. Chandupatla;R. Dieter;J. Snyder
以N-叔丁氧羰基吡咯烷为起始原料，经α-（N-氨甲酰基）烷基铜酸酯乙烯化反应、N-叔丁氧羰基脱保护、环合，经三步反应合成了（-）-（R）-吡咯烷胺A。一锅脱保护-环化程序导致吡咯烷A及其双键异构体的混合物。这些异构化事件可以通过使用两步程序来规避。为了指导方面的实验，一系列的计算能量评估和化学位移预测进行了分子力学，半经验，从头算和密度泛函方法。双键异构体的相对稳定性，通过实验估计，挑战了一些计算方法，只有MP2模型与其适度的电子相关接近匹配的实验数据。MP2方法进一步应用于吡咯烷A与其异构体9之间的双键迁移的不寻常方面。在纯样品上的反应（1至9）是不可逆的，没有外消旋化，并且氧化铝介导的平衡伴随着对映体过量的完全损失。的不可逆性的来源被追溯到中间体二烯醇阴离子的不对称电荷分布。分析最终导致吡咯烷能量表面的半定量草图。
The asymmetric synthesis of (-)-(R)-pyrrolam A was achieved in three operations from N-Boc pyrrolidine via an alpha-(N-carbamoyl)alkylcuprate vinylation reaction followed by N-Boc deprotection and cyclization. One-pot deprotection-cyclization procedures led to mixtures of pyrrolam A and its double bond isomers. These isomerization events could be circumvented by use of a two-step procedure. To guide aspects of the experiments, a series of computational energy evaluations and chemical shift predictions were performed with molecular mechanics, semiempirical, ab initio, and density functional methods. The relative stabilities of the double bond isomers, as estimated by experiment, challenged a number of computational methods, and only the MP2 model with its moderate degree of electron correlation came close to matching the experimental data. The MP2 method was further applied to an unusual aspect of the double bond migration between pyrrolam A and its isomer 9. The reaction (1 to 9) on neat samples is irreversible without racemization, and the alumina-mediated equilibration is accompanied by complete loss of enantiomeric excess. The source of the irreversibility was traced to asymmetric charge distribution in the intermediate dienolate anion. The analysis ultimately led to a semiquantitative sketch of the pyrrolam energy surface.