Enantioenriched BCP Benzylamine Synthesis via Metal Hydride Hydrogen Atom Transfer/Sulfinimine Addition to [1.1.1]Propellane

Russell Shelp; Rohan R Merchant; Jonathan M E Hughes; Patrick J Walsh

doi:10.1021/acs.orglett.1c03681

Enantioenriched BCP Benzylamine Synthesis via Metal Hydride Hydrogen Atom Transfer/Sulfinimine Addition to [1.1.1]Propellane

Org Lett. 2022 Jan 14;24(1):110-114. doi: 10.1021/acs.orglett.1c03681. Epub 2021 Dec 15.

Authors

Russell Shelp¹, Rohan R Merchant², Jonathan M E Hughes³, Patrick J Walsh¹

Affiliations

¹ Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, United States.
² Department of Discovery Chemistry, Merck & Co., Inc., South San Francisco, California 94080, United States.
³ Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States.

PMID: 34908426
DOI: 10.1021/acs.orglett.1c03681

Abstract

The stereoselective synthesis of bicyclo[1.1.1]pentane (BCP) benzylamine derivatives from [1.1.1]propellane and mesityl sulfinimines via metal hydride hydrogen atom transfer (MH HAT) is reported. Medicinally relevant heterocyclic BCP methanamines are prepared with high diastereoselectivity. The strategic impact of the method is demonstrated via the streamlined synthesis of the BCP analogue of a key levocetirizine intermediate. Mechanistic evidence for a competitive H₂ evolution pathway and the importance of controlled silane addition during reaction initiation are disclosed.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.