PRODUCTION OF CHIRAL AMINOALCHOLS

手性邻氨基醇是合成许多重要药物的重要中间体。然而，它们的合成仍然是一个重大的合成挑战。以合理的成本控制同时含有醇基和氨基的碳手性中心的立体化学是成功生产这些重要化学中间体的关键。目前，还没有广泛适用的路线来高产率和高立体化学纯度地生产手性邻氨基醇。这项研究将开发一种生产手性邻氨基醇的通用方法，该方法依赖于立体选择性的醇脱氢酶催化的转化，一步引入两个手性中心，具有高产率和立体选择性。在对整个细胞的初步研究中，已经表明存在多种酶系统会引起竞争反应，从而降低立体化学纯度。使用分离的脱氢酶有可能生产任何单一的高立体化学纯度的非对映异构体。这种方法的经济性依赖于有效的辅因子回收。在第一阶段，我们计划确定使用立体选择性乙醇脱氢酶和甲酸脱氢酶进行辅因子循环的反应的可行性，为生产各种手性邻氨基醇奠定基础。拟议的商业应用：生产现有和新医药产品的关键中间体

Chiral vicinal aminoalcohols are important intermediates in the synthesis of many important pharmaceutical compounds. However, their synthesis remains a significant synthetic challenge. Gaining control over the stereochemistry of chiral centers at carbons bearing both the alcohol and amino groups at reasonable cost is the key to the successful production of these important chemical intermediates. Currently, no broadly-applicable route exists for the production of chiral vicinal aminoalcohols in high yield and with high stereochemical purity. The proposed research will develop a general method for the production of chiral vicinal aminoalcohols that relies on a stereoselective alcohol dehydrogenase-catalyzed conversion to introduce two chiral centers in a single step, with high yield and stereoselectivity. In preliminary work with whole cells, it has been shown that multiple enzyme systems present give rise to competing reactions that lower stereochemical purity. The use of an isolated dehydrogenase offers the potential to produce any single diastereomer in high stereochemical purity. The economics of this method depend upon efficient cofactor recycling. In Phase 1 we plan to establish the feasibility of a reaction using a stereoselective alcohol dehydrogenase coupled with formate dehydrogenase for cofactor recycling, laying the foundation for the production a variety of chiral vicinal aminoalcohols. PROPOSED COMMERCIAL APPLICATIONS: Production of key intermediates for existing and new pharmaceutical products