Identification of a Robust Carbonyl Reductase for Diastereoselectively Building syn-3,5-Dihydroxy Hexanoate: a Bulky Side Chain of Atorvastatin,Organic Process Research & Development

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Identification of a Robust Carbonyl Reductase for Diastereoselectively Building syn-3,5-Dihydroxy Hexanoate: a Bulky Side Chain of Atorvastatin
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2017-07-20 00:00:00 , DOI: 10.1021/acs.oprd.7b00194
Xu-Min Gong ₁ , Gao-Wei Zheng ₁ , You-Yan Liu _{2,

3} , Jian-He Xu ₁

Affiliation

t-Butyl-6-cyano-(3R,5R)-dihydroxyhexanoate is an advanced chiral precursor for the synthesis of the side chain pharmacophore of cholesterol-lowering drug atorvastatin. Herein, a robust carbonyl reductase (LbCR) was newly identified from Lactobacillus brevis, which displays high activity and excellent diastereoselectivity toward bulky t-butyl 6-cyano-(5R)-hydroxy-3-oxo-hexanoate (7). The engineered Escherichia coli cells harboring LbCR and glucose dehydrogenase (for cofactor regeneration) were employed as biocatalysts for the asymmetric reduction of substrate 7. As a result, as much as 300 g L^–1 of water-insoluble substrate was completely converted to the corresponding chiral diol with >99.5% de in a space–time yield of 351 g L^–1 d^–1, indicating a great potential of LbCR for practical synthesis of the very bulky and bi-chiral 3,5-dihydroxy carboxylate side chain of best-selling statin drugs.

中文翻译：

用于非对映选择性构建辛-3,5-二羟基己酸酯的稳健羰基还原酶的鉴定：阿托伐他汀的大体积侧链

叔丁基-6-氰基-（3 R，5 R）-二羟基己酸酯是一种先进的手性前体，用于合成降胆固醇药物阿托伐他汀的侧链药效团。在本文中，从短乳杆菌中新鉴定出一种强健的羰基还原酶（Lb CR），它对高密度的叔丁基6-氰基-（5 R）-羟基-3-氧代己酸叔丁酯具有很高的活性和非对映选择性（7）。具有Lb CR和葡萄糖脱氢酶（用于辅因子再生）的工程化大肠杆菌细胞被用作生物催化剂，用于不对称还原底物7。结果，多达300 g L ^–1的水不溶性底物以351 g L ^–1 d ^–1的时空产率被完全转化为相应的手性二元醇，de > 99.5％de，表明了巨大的潜力的Lb的CR对非常笨重和实际合成双向的畅销他汀类药物-手性3,5-二羟基羧酸侧链。

更新日期：2017-07-21

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