Candidaantarctica Lipase B mediated kinetic resolution: A sustainable method for chiral synthesis of antiproliferative β-lactams.

• Published in: European Journal of Medicinal Chemistry
• Main Authors: McLoughlin, Eavan C, Twamley, Brendan, O'Boyle, Niamh M
• Format: Article in Journal/Newspaper
• Language: English
• Published: Elsevier Science 2024
• Subjects: Antiproliferative; Beta-lactams; Biocatalysis; Chiral resolution; Enantiomers; Lipase; Antarc*; Antarctica
• Online Access: https://doi.org/10.1016/j.ejmech.2024.116692; https://pubmed.ncbi.nlm.nih.gov/39068864

Biocatalysis is a valuable industrial approach in active pharmaceutical ingredient (API) manufacturing for asymmetric induction and synthesis of chiral APIs. Herein, we investigated synthesis of a panel of microtubule-destabilising antiproliferative β-lactam enantiomers employing a commercially available immobilised Candida antarctica lipase B enzyme together with methanol and MTBE. The β-lactam ring remained intact during chiral kinetic resolution reactions, plausibly due to a bulky N-1 phenyl substituent on the β-lactam ring substrate. The predominant reaction mediated by CAL-B was methanol catalysed conversion of the β-lactam 3-acetoxy substituent to a 3-hydroxyl group, with preferential methanolysis of the 3S, 4S enantiomer. The unreacted substrate underwent progressive enantioenrichment to the 3R, 4R enantiomer. Substitution patterns on the B ring C3 meta position of the β-lactam scaffold greatly affected the rate of reaction. Halo substituents (fluoro-, chloro- and bromo-) reduced the rate of conversion compared to unsubstituted analogues, which in turn increased enantiomeric excess (ee). Ee values up to 86 % for the 3S, 4S 3-hydroxyl enantiomer were achieved. A double resolution approach for unreacted substrate yielded high ee values (>99 %) for the 3R, 4R 3-acetoxy enantiomer. CAL-B mediated methanolysis is a more sustainable method for resolution of racemic antiproliferative β-lactams compared to a previous technique of chiral diastereomeric resolution. Yields of β-lactams obtained using CAL-B are far superior than previously described, which will facilitate progression toward pre-clinical and clinical development. Biocatalysis is a useful tool in the toolbox of the medicinal chemist.