Development of a Scalable Synthetic Route to (1R,5R)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one: An Important Intermediate in the Synthesis of Lenacapavir

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2025-02-26 DOI:10.1021/acs.oprd.4c00527

Aline Nunes De Souza, Nagaraju Sakkani, Daryl Guthrie, Rajkumar Lalji Sahani, John M. Saathoff, Samuel R. Hochstetler, Justina M. Burns, Saeed Ahmad, G. Michael Laidlaw, B. Frank Gupton, Douglas A. Klumpp, Limei Jin

引用次数: 0

Abstract

(1R,5R)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one is used in the asymmetric synthesis of lenacapavir. Herein, we report an enantioselective synthesis of this important chiral intermediate from the inexpensive commodity (R)-epichlorohydrin. This synthetic method comprises 6 steps, including a 4-step telescoped bicyclic ketone synthesis, I₂-promoted hydroxylation, and an Albright–Goldman oxidation. This sequence affords (1R,5R)-2,2-dimethoxybicyclo[3.1.0]hexan-3-one in an overall 25% isolated yield as an enantiomerically pure compound. The entire process has been successfully demonstrated on a hundred-gram scale.

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.