Zinc (d)-Tartrate Catalyzed Asymmetric Epoxide Ring Opening: Access to Enantioenriched β-Hydroxy Thiols and ADC Linker Compounds

We report a zinc (d)-tartrate catalyzed asymmetric ring opening of epoxides with thiols, affording β-hydroxy sulfides with high enantioselectivity up to 98:2 er after crystallization. The process enables fast reaction in 10–15 min under continuous flow conditions and demonstrates efficient catalyst recyclability over multiple cycles. The implementation of a dual-purpose thiol methyl 3-mercaptopropanoate provides a cost-effective strategy for enantiomeric enrichment via crystallization, eliminating enzymatic resolution. Overall, this methodology represents a practical platform for chiral β-hydroxy sulfides synthesis for antibody-drug conjugates (ADC).

• Karmakar A¹
• Revu O¹
• Vasilev M¹
• Li J¹
• Chen A¹
• Popuri S¹
• Shingare RD¹
• Mamunooru M¹
• Gangu AS¹
• Sirasani G¹
• Maguire RJ²
• Qu B¹
• Martinelli M³
• Senanayake CH¹

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• ²Cybrexa Therapeutics, 5 Science Park, 395 Winchester Avenue, New Haven, Connecticut 06511, United States
• ³Exelixis Inc., 1851 Harbor Bay Parkway, Alameda, California 94502, United States

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