Deracemization of Amino Acids

描述(申请人提供)：非天然氨基酸(UAA)正日益成为重要的医药中间体，在许多当前和未来的药物中有应用。由于UAA几乎总是需要作为纯立体异构体，所以手性合成比最常用的拆分方法更受欢迎。在第一阶段中，演示了一锅法生产L对映体的工艺。在该方法中，D-L-氨基酸混合物的D-对映体用D-氨基酸氧化酶选择性地氧化成相应的2-酮酸。然后，通过L氨基酸转氨酶或L氨基酸脱氢酶将2-酮酸立体选择性地胺化成L氨基酸。这在一步反应中完成，中间体不需要分离，也不需要保护基团或衍生化。产率和对映体超额值接近100%。该方法适用范围广，适用于各种UAA产品。在一些被研究的酶上使用定向进化来创造更有活性的酶突变体。在第二阶段，将进一步确定和优化去消解进程的特点。将对一些酶进行定向进化，以创造具有增强活性和更广泛底物专一性的突变体。此外，还将对氨基酸去消旋化制备纯D-对映体进行研究。这两种制备L或D-对映体的方法都将在100克的重要商业目标上进行演示。

DESCRIPTION (provided by applicant): Unnatural amino acids (UAAs) are increasingly becoming important pharmaceutical intermediates, with applications in a number of current and future drugs. Since UAAs are almost always required as pure stereoisomers, a chiral synthesis is preferred over the resolution methods that are most commonly employed. In Phase I the single-pot deracemization process to make the L-enantiomer was demonstrated. In this method the D-enantiomer of a D,L-amino acid mixture is selectively oxidized to the corresponding 2- ketoacid using a D-amino acid oxidase. The 2-ketoacid is then stereoselectively aminated to the L-amino acid by an L-amino acid transaminase or an L-amino acid dehydrogenase. This is accomplished in a reaction single step, intermediates need not be isolated nor is it necessary for protecting groups or derivatization. Yields and enantiomeric excess values approach 100 percent. This method has a broad scope and will be applicable to a wide range of UAA products. Directed evolution was used on a number of the enzymes investigated to create more active enzyme mutants. In Phase II the deracemization process will be further characterized and optimized. Directed evolution will be performed on a number of the enzymes to create mutants with enhanced activity and broader substrate specificity. In addition, the deracemization of amino acids to make the pure D-enantiomer will be investigated. Both methods, for making the pure L- or D-enantiomer will be demonstrated on the 100 gram scale for important commercial targets.