Journal
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Volume 24, Issue 9, Pages 1700-1706Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.0c00320
Keywords
asymmetric catalysis; ketoreductase; statin; tert-butyl (R)-3-hydroxyl-5-hexenoate; pilot-plant-scale synthesis
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Funding
- National Natural Science Foundation of China [21801047]
- Shanghai Sailing Program [18YF1402100]
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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.
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