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-5-hexenoate ((R)-2a) (96.2% yield, >99.9% enantiomeric excess (ee)). This newly developed biocatalytic process alleviates the cryogenic conditions (−40 °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.

中文翻译：

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实用的生物催化合成叔丁基（R）-3-羟基-5-己烯酸酯的开发：他汀侧链的关键中间体

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。他汀类药物的使用大大延长了人们的生活，并改善了他们的生活质量。他汀类药物的更有效，立体选择性和可持续合成的开发一直是最重要的。在本研究中，通过筛选酮还原酶（KRED）和优化反应，我们成功地在中试规模上通过KRED-06催化了酮酯1a的高立体选择性还原，而无需添加外源NADP ⁺，产生了3.21 kg对映体纯叔丁基（[R）-3-羟基-5-己烯酸（（[R ） - 2a中）（96.2％的收率，> 99.9％的对映体过量（ee））。这种新开发的生物催化工艺减轻了我们在第一代使用NaBH ₄和（l）-酒石酸合成（R）-2a时使用的低温条件（−40°C）。加上我们先前建立bromocarbonate的合成图3a经由一釜非对映选择性羧化/的bromocyclization（[R ）-图2a，我们已经开发了一种新颖，实用的合成路线，以他汀类药物的侧链，具有很大的潜力可实施到工业生产他汀类药物的。