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，但没有一种具有普遍性和广泛适用性。 α-氨基膦酸是一种重要的分子结构，因为它们可以在酶抑制剂中用作α-氨基酸类似物。 酶活性的抑制可用于许多疾病状态的治疗目的。目前的建议使用已建立的不对称合成方法，结合容易的立体选择性Curtius重排，以提供快速和容易获得手性α-烷基-α-氨基膦酸。 然后，α-烷基-α-氨基膦酸准备好掺入肽结构中，其将模拟天然酶底物。这种方法的应用，二苯基α-氨基膦酸酯，已知的丝氨酸蛋白酶抑制剂的不对称合成，将进一步证明这种方法的实用性。将对立体化学纯的二苯基α-氨基膦酸酯进行酶抑制试验，以分析这些α-氨基酸类似物中α-位置的立体化学的重要性。

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.