A Concise Enantioselective Formal Synthesis of the Second-Generation Oral Contraceptive Levonorgestrel

Le résumé fourni par la source

A concise formal synthesis of levonorgestrel (LNG) precursor, a natural 18a-homoestrone, 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one, is described, in which the steroid core of LNG is formed by enantioselective CRED bioreduction of prochiral secodione followed by Torgov cyclization as the key steps. Almac’s proprietary CRED enzymes were screened against secodione and several enzymes with excellent stereoselectivity for the required (13 R ) absolute configuration at the C-13 asymmetric center were identified. The best performing enzyme, CRED-BW, under optimized conditions gave the desired (13 R,17 S )-chiral secol with outstanding stereoselectivity (>99% ee, >99% de) and excellent conversion (99%). The scalability of the CRED protocol was demonstrated on >100 g batches without any loss in efficiency and optical purity. Optimization and scale-up of Torgov cyclization were carried out using chiral acetate in the presence of catalytic amounts of p -TsOH·H 2 O to provide Torgov diene of high diastereomeric purity in 90% isolated yield. In addition, this synthesis features highly selective transformations such as regio- and diastereoselective Pd-catalyzed hydrogenation and ammonia-free Birch reduction applied to chiral Torgov diene and trans -fused 14,15-dihydroacetate at scale. Finally, our approach enables the regio- and stereoselective syntheses of levonorgestrel key precursor on a multigram scale, showing great potential for industrial applications.

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