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. 2025 Jan 10;90(1):471-478.
doi: 10.1021/acs.joc.4c02380. Epub 2024 Dec 16.

A New Synthesis of Enantiopure Amine Fragment: An Important Intermediate to the Anti-HIV Drug Lenacapavir

Anand H Shinde  1 , Ramakrishna Sayini  1 , Piyal Singh  1 , Justina M Burns  1 , Saeed Ahmad  1 , G Michael Laidlaw  1 , B Frank Gupton  1 , Douglas A Klumpp  1 , Limei Jin  1
Affiliations

A New Synthesis of Enantiopure Amine Fragment: An Important Intermediate to the Anti-HIV Drug Lenacapavir

Anand H Shinde et al. J Org Chem. .

Abstract

Herein, we describe a new seven-step approach to prepare (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine ((S)-4) from the inexpensive 2-(3,5-difluorophenyl)acetic acid. The key steps in the sequence include (1) the Weinreb amide-based ketone synthesis to provide an entry point to the core structure; (2) simple functional group transformations to afford the racemic amine 4-rac; and (3) dynamic kinetic resolution (DKR) to access the chiral amine (S)-4. This seven-step process delivered the enantiopure amine (S)-4 in an overall isolated yield of approximately 15%. The process was demonstrated on a decagram scale, and the process requires no chromatographic purifications. Single-crystal X-ray crystallography measurements verified the chiral amine structure and absolute configuration.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Retrosynthetic disconnections for lenacapavir and its simpler constituents for chemical synthesis.
Scheme 1
Scheme 1. Methods for the Synthesis of Fragment A and Related Conversions
(a) Resolution approach to (S)-4-mandelate (Reproduced from ref (11). Available under a Creative Commons Attribution 4.0 International License); (b) Enzymatic approach to (S)-4 (Reproduced from ref (12) Copyright [2024] American Chemical Society).
Scheme 2
Scheme 2. Reported Transformations of Ketone 8 to Chiral Amine and Derivatives
Scheme 3
Scheme 3. Synthesis of Mesylate 11 from Ketone 8
Scheme 4
Scheme 4. Synthesis of Enantiopure Free Amine (S)-4
Figure 2
Figure 2
X-ray structure of (S)-4 (confirmed (S)-absolute configuration of the chiral amine center).
Scheme 5
Scheme 5. Decagram-Scale Demonstration of Synthesis of Chiral Amine (S)-4
See this image and copyright information in PMC

References

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