AMINO ALKYLPHOSPHINIC ACIDS AND DERIVED PEPTIDES

氨基酸类似物的合成， 取代羧酸基团一直是一个研究领域， 二十多年了。 这些类似物和衍生肽 结合它们，表现出多种生物学效应，如酶 抑制、除草活性和抗菌作用。 而 这些化合物中的大多数是天然存在的α- 在肽和蛋白质中发现的氨基酸， β和γ类似物。 在很大程度上，模拟开发 重点研究了二元膦酸[RP（O）（OH）2]。 直到最近， 对从单萜衍生的类似物的兴趣较少， 次膦酸[R2 P（O）OH]，尽管这些化合物似乎是 在结构上更类似于天然存在的氨基酸。 在这些 在已经研究的情况下，几种氨基烷基次膦酸和 结合它们的肽确实显示出抗菌和其他生物活性， 活动 因此，本项目的长期目标是综合 另外的氨基烷基次膦酸以及二肽和三肽 含有这些磷基氨基酸类似物。 该项目将侧重于修改现有的合成方法， 应用于以前未用作 模拟开发中的基板。 具体地说， 是三价酰胺酯[烷基烷基亚磷酰胺，RP（OR '）NR 112]， 其将使用商业上已建立的方法制备， 可用的前体。 这些amidoeters将与N- 在Arbuzov反应中与卤代烷基邻苯二甲酰亚胺反应，得到相应的 邻苯二甲酰亚胺磷酰胺。 用肼除去邻苯二甲酰基 并且乙酸也应当裂解所述聚合物的酸敏感性P-N键， 膦酰胺部分，从而产生所需的氨基烷基次膦酸 acids. 根据所用的具体邻苯二甲酰亚胺衍生物，α、β 或γ-氨基酸类似物。 将这些类似物与 适当保护的氨基羧酸和相关二肽， 偶联剂如二环己基碳二亚胺将提供 相应的二肽和三肽类似物。 氨基烷基次膦酸作为 以及含磷肽类似物将被测试以 确定预期生物活性的性质和程度， 这些化合物显示。

The synthesis of amino acid analogs wherein an acidic phosphorus unit replaces the carboxylic acid group has been an area of investigation for more than twenty years. These analogs, and the derived peptides incorporating them, exhibit a variety of biological effects such as enzyme inhibition, herbicidal activity and antibacterial action. While the majority of these compounds are analogs of the naturally occurring alpha- amino acids found in peptides and proteins, there has been some interest in beta and gamma analogs as well. To a large extent, analog development has focused on the dibasic phosphonic acids [RP(O)(OH)2]. Until recently, there had been less interest in analogs derived from the monobasic phosphinic acids [R2P(O)OH], even though these compounds would seem to be structurally more similar to the naturally occurring amino acids. In those cases which have been investigated, several aminoalkylphosphinic acids and peptides incorporating them do show antibacterial and other biological activity. Thus, the longterm objective of this project is the synthesis of additional aminoalkylphosphinic acids as well as the di- and tripeptides containing these phosphorous-based amino acid analogs. This project will focus on modifications of existing synthetic methods for application to phosphorus amides which have not previously been used as substrates in analog development. specifically, the amides to be employed are the trivalent amidoesters [alkyl alkylphosphonamidites, RP(OR')NR112], which will be prepared using established methods from commercially available precursors. These amidoesters will be combined with N- haloalkylphthalimides in an Arbuzov reaction to afford the corresponding phthalimidophosphinamides. Removal of the phthaloyl group with hydrazine and acetic acid should also cleave the acid sensitive P-N linkage of the phosphinamide moiety, thereby generating the desired aminoalkylphosphinic acids. Depending on the specific phthalimide derivative used, alpha, beta or gamma-amino acid analogs are obtained. Coupling of these analogs with suitably protected aminocarboxylic acids and related dipeptides by use of a coupling agent such as dicyclohexylcarbodiimide will afford the respective di- and tripeptide analogs. The aminoalkylphosphinic acids as well as the phosphorus-containing peptide analogs will be tested to ascertain the nature and degree of anticipated biological activity that these compounds exhibit.