Development of a Practical, Biocatalytic Synthesis of tert-Butyl (R)-3-Hydroxyl-5-hexenoate: A Key Intermediate to the Statin Side Chain
Development of a Practical, Biocatalytic Synthesis of tert-Butyl (R)-3-Hydroxyl-5-hexenoate: A Key Intermediate to the Statin Side Chain
复制标题
(R)-3-羟基-5-己烯酸叔丁酯的实用生物催化合成方法的开发：他汀类药物侧链的关键中间体
DOI：
10.1021/acs.oprd.0c00320
复制
发表时间：
2020-09-18
影响因子：
3.4
通讯作者：
Chen, Fener
中科院分区：
文献类型：
--
作者：
Hu, Chen;Liu, Minjie;Chen, Fener
HMG-CoA还原酶抑制剂，他汀类药物，是最有效和最畅销的降胆固醇药物之一。他汀类药物的使用极大地延长了人们的寿命，提高了他们的生活质量。开发更有效、立体选择性和可持续的他汀类药物合成仍然至关重要。在本研究中，通过对酮还原酶（KRED）的筛选和反应优化，我们在中试规模上成功地进行了KRED-06催化的酮酯1a的高度立体选择性还原，而不添加外源NADP（+），产生3.21 kg对映体纯的（R）-3-羟基-S-己烯酸叔丁酯（（R）-2a）。（96.2%产率，>99.9%对映体过量（ee））。这种新开发的生物催化工艺简化了我们使用NaBH 4和（L）-酒石酸合成（R）-2a的第一代工艺中采用的低温条件（-40 ℃）。结合我们先前建立的通过（R）-2a的非对映选择性羧化/溴环化合成溴碳酸酯3a的方法，我们开发了一种创新的、实用的他汀侧链合成路线，具有很大的潜力可用于他汀类药物的工业生产。
The HMG-CoA reductase inhibitors, statins, are one of the most effective and bestselling cholesterol-lowering drugs. The use of statins has greatly extended people's lives and improved the quality of their life. Development of a more efficient, stereoselective, and sustainable synthesis of statins is continuingly of utmost importance. In the present study, through screening of ketoreductases (KREDs) and reaction optimization, we have successfully performed a highly stereoselective reduction of ketoester 1a catalyzed by KRED-06 at a pilot-plant scale without the addition of exogenous NADP(+), generating 3.21 kg of enantiomerically pure tert-butyl (R)-3-hydroxyl-S-hexenoate ((R)-2a) (96.2% yield, >99.9% enantiomeric excess (ee)). This newly developed biocatalytic process alleviates the cryogenic conditions (-40 degrees C) employed in our first-generation synthesis of (R)-2a using NaBH4 and (L)-tartaric acid. Coupled with our previously established synthesis of bromocarbonate 3a via a one-pot diastereoselective carboxylation/bromocyclization of (R)-2a, we have developed an innovative, practical synthesis route to statin side chain, possessing great potential to be implemented into industrial production of statins.