Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture
Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture
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DOI：
10.1126/science.1188934
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发表时间：
2010-07-16
期刊：
影响因子：
56.9
通讯作者：
Hughes, Gregory J.
中科院分区：
文献类型：
--
作者：
Savile, Christopher K.;Janey, Jacob M.;Hughes, Gregory J.
药物合成可以大大受益于与酶催化相关的选择性增益。在这里，我们报告了一种有效的生物催化过程，以取代最近实施的铑催化的不对称烯胺氢化的抗糖尿病化合物西他列汀的大规模生产。从一种具有催化机制以进行所需化学反应但对前西格列汀酮缺乏任何活性的酶开始，我们应用底物步移、建模和突变方法来创建具有合成手性胺的边际活性的转氨酶;然后通过定向进化进一步工程化该变体以用于生产环境中的实际应用。所得的生物催化剂显示出广泛的适用性，对手性胺的合成，以前只能通过决议。这项工作强调了生物催化的成熟，以实现高效，经济和环境友好的制药工艺。
Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.