ASYMMETRIC SYNTHESIS OF ALPHA AMINO PHOSPHONIC ACIDS

该提案旨在开发一种高效实用的不对称合成-氨基膦酸的方法。已经开发了几种方法，但没有一种具有普遍、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。抑制酶活性可用于治疗许多疾病状态。目前的建议使用已建立的不对称合成方法，结合简单的立体选择性Curtius重排，以提供快速和容易的手性-烷基-氨基膦酸。然后，α -烷基- α -氨基膦酸就可以被掺入模拟天然酶底物的肽结构中。将该方法应用于已知丝氨酸蛋白酶抑制剂二苯基α -氨基膦酸盐的不对称合成，将进一步证明该方法的实用性。立体化学纯二苯基α -氨基膦酸盐将进行酶抑制测试，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.