ASYMMETRIC SYNTHESIS OF ALPHA AMINO PHOSPHONIC ACIDS

该提案旨在开发一种高效、实用的α-氨基膦酸不对称合成方法。已经开发了几种方法，但没有一种方法找到普遍、广泛的适用性。α-氨基膦酸是一种重要的分子结构，因为它们可以作为酶抑制剂中的α-氨基酸类似物。抑制酶活性可用于许多疾病的治疗目的。目前的方案采用成熟的不对称合成方法，结合简单、立体选择性的Curtius重排反应，提供了快速、容易地获得手性α-烷基-α-氨基膦酸的途径。然后，α-烷基-α-氨基膦酸准备好并入模拟天然酶底物的多肽结构中。将该方法应用于丝氨酸蛋白酶抑制剂α-氨基磷酸二苯酯的不对称合成，将进一步证明该方法的实用性。将对立体化学纯的二苯基α-氨基膦酸酯进行酶抑制测试，以分析在这些α-氨基酸类似物中α-位立体化学的重要性。

The proposal seeks to develop an efficient and practical method for the asymmetric synthesis of alpha-aminophosphonic acids. Several methods have been developed, but none has found general, widespread applicability. Alpha-Aminophosphonic acids are an important molecular structure because they can serve as alpha- amino acid analogues in enzyme inhibitors. Inhibition of enzyme activity can be used for therapeutic purposes in many disease states. The current proposal uses established asymmetric synthetic methods combind with the facile, stereoselective Curtius rearrangement to provide quick and easy access to chiral alpha- alkyl-alpha-aminophosphonic acids. The alpha-alkyl-alpha- aminophosphonic acids are then ready for incorporation into peptide structures which would mimic natural enzyme substrates. The application of this methodology to the asymmetric synthesis of diphenyl alpha-aminophosphonates, known serine protease inhibitors, will further demonstrate the utility of this method. The stereochemically pure diphenyl alpha-aminophosphonates will be tested for enzyme inhibition to analyze the importance of the stereochemistry at the alpha-position in these alpha-amino acid analogues.