Development of a Scalable Synthetic Route to (1 <i>R</i> ,5 <i>R</i> )-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one: An Important Intermediate in the Synthesis of Lenacapavir
(1<i>R</i>,5<i>R</i>)-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 (<i>R</i>)-epichlorohydrin. This synthetic method comprises 6 steps, including a 4-step telescoped bicyclic ketone synthesis, I<sub>2</sub>-promoted hydroxylation, and an Albright-Goldman oxidation. This sequence affords (1<i>R</i>,5<i>R</i>)-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.
Authors
- Douglas A. Klumpp (ORCID: https://orcid.org/0000-0001-5271-699X)
- G. Michael Laidlaw
- Rajkumar Lalji Sahani (ORCID: https://orcid.org/0000-0002-0868-4684)
- Sakkani Nagaraju (ORCID: https://orcid.org/0000-0002-2326-0548)
- limei jin (ORCID: https://orcid.org/0009-0009-8036-2004)
- John M. Saathoff (ORCID: https://orcid.org/0000-0002-9860-3840)
- B. Frank Gupton (ORCID: https://orcid.org/0000-0002-8165-1088)
- Justina M. Burns (ORCID: https://orcid.org/0009-0006-9555-1586)
- Samuel R. Hochstetler
- Aline Souza
- Saeed Ahmad (ORCID: https://orcid.org/0000-0002-4187-2767)
- Daryl Guthrie (ORCID: https://orcid.org/0000-0002-7961-5918)
Institutions
- Virginia Commonwealth University (US)
- Association for Language Learning (GB)
Publication Details
- Journal
- Organic Process Research & Development
- Published
- 2025-02-26
- DOI
- https://doi.org/10.1021/acs.oprd.4c00527
- Citations
- 1
- Primary Topic
- Traditional and Medicinal Uses of Annonaceae
- Type
- article
- Field-Weighted Citation Impact
- 1.11