Intramolecular N-to-S or N-to-O acyl shifts in peptides are of fundamental and practical importance, as they constitute the first step in protein splicing and can be used for the synthesis of thioester-modified peptides required for native chemical ligation. It has been stated that the nucleophile must be positioned anti to the carbonyl oxygen, as in a cis amide. Despite the importance of such reactions, an understanding of this geometric restriction remains obscure. Here we argue that the empirical requirement for positioning the nucleophile is a stereoelectronic effect arising from the ease of approach of the nucleophile to a carbonyl group, not ground-state destabilization. DFT calculations on model amides support our explanation and indicate a significant decrease in both the transition-state energy and the activation energy for a cis amide. However, the approach of the nucleophile must be anti not only to the carbonyl oxygen but also to the nitrogen. The direction of approach is expressed by a new, modified Bürgi–Dunitz angle. Our data shed light on the mechanisms of acyl shifts in peptides, and they explain why a cis peptide might be required for protein splicing. The further implications for acyl shits in homoserine and homocysteine peptides and for aldol condensations are also considered.

中文翻译：

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接近控制。肽中 N-to-S 和 N-to-O 酰基转移的几何约束的立体电子起源†

肽中的分子内 N-to-S 或 N-to-O 酰基转移具有基本和实际重要性，因为它们构成蛋白质剪接的第一步，可用于合成天然化学连接所需的硫酯修饰肽。据说亲核试剂必须与羰基氧相反，如顺式酰胺。尽管这种反应很重要，但对这种几何限制的理解仍然模糊不清。在这里，我们认为定位亲核试剂的经验要求是立体电子效应，这是由于亲核试剂易于接近羰基，而不是基态不稳定。对模型酰胺的 DFT 计算支持我们的解释，并表明顺式酰胺的过渡态能量和活化能均显着降低。然而，亲核试剂的接近必须不仅对羰基氧而且对氮是反的。进场方向由一个新的、修改后的 Bürgi-Dunitz 角表示。我们的数据揭示了肽中酰基转移的机制，它们解释了为什么顺式蛋白质剪接可能需要肽。还考虑了对高丝氨酸和高半胱氨酸肽中的酰基粪便以及醛醇缩合的进一步影响。