N-trityl- and N-phenylfluorenyl-N-carboxyanhydrides and their use in dipeptide synthesis
N-trityl- and N-phenylfluorenyl-N-carboxyanhydrides and their use in dipeptide synthesis
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DOI：
10.1021/jo981860p
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发表时间：
1999-04-02
影响因子：
3.6
通讯作者：
Rapoport, H
中科院分区：
文献类型：
--
作者：
Sim, TB;Rapoport, H
n -羧酸酐（Leuchs ' anhydries, NCAs）一度被认为是合成肽的灵丹妙药。它们很容易一步制备，废液可以忽略不计，它们在室温下与氮亲核试剂快速偶联，偶联副产物是二氧化碳。然而，它们的价值很快就显现出来了。同样的特性使它们具有吸引力，它们的极端反应性，限制了它们的使用，除了一个明显的例外，核糖核酸酶的合成。伴随这种反应性的是固有的不稳定性和聚合倾向，以及对映体完整性的一些损失。在试图克服这些缺陷时，NCA的氮被额外的tosyl2和nitrophenylsulfonyl取代，但几乎没有改善。最有希望的结果是最近在氮上加入一个烷氧羰基，形成氨基保护的nca （UNCA）。虽然这种修饰确实克服了它们的不稳定性和聚合倾向，但在肽合成过程中对映体的纯度仍有很大损失，而且对碱基也有一定的不稳定性。我们已经通过制备n -三烷基ncas （TNCAs）和n -苯基氟酰ncas （PFNCAs）解决了这些问题。我们的目的是增加稳定性，主要是抑制任何外映异构化，即在r -氨基上取代三烷基或苯基氟烯基残基的既定效果。7
The N-carboxyanhydrides (Leuchs’ anhydrides, NCAs) at one time appeared to be the panacea for peptide synthesis. They are easily prepared in one step with negligible waste stream, they couple rapidly at room temperature with nitrogen nucleophiles, and the coupling byproduct is carbon dioxide. Their value, however, was quickly adumbrated. The same quality that made them attractive, their extreme reactivity, limited their use, with one notable exception, the synthesis of ribonuclease. 1 Accompanying this reactivity is an inherent instability and propensity for polymerization, as well as some loss in enantiomeric integrity.In attempting to overcome these deficiencies, the nitrogen of the NCA was additionally substituted with tosyl2 and nitrophenylsulfonyl groups3 with little improvement. The most promising results were achieved recently with an alkoxycarbonyl group added to the nitrogen, forming the urethane-protected-NCA (UNCA). 4 While this modification does overcome their instability and tendency to polymerize, there still remains a significant loss of enantiomeric purity during peptide synthesis5 and some instability to base. 6 We have addressed these problems by preparing the N-trityl-NCAs (TNCAs) and the N-phenylfluorenyl-NCAs (PFNCAs). Our intent was to increase stability and, primarily, to inhibit any epimerization, a well-established effect of substitution of a trityl or phenylfluorenyl residue on the R-amino group. 7