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. 2024 Jul 5;89(13):9569-9585.
doi: 10.1021/acs.joc.4c01057. Epub 2024 Jun 25.

Diastereoselective Synthesis of the HIV Protease Inhibitor Darunavir and Related Derivatives via a Titanium Tetrachloride-Mediated Asymmetric Glycolate Aldol Addition Reaction

Jordan M Witte  1 , Emmanuel Ayim  1 , Christopher J Sams  1 , Jasmine B Service  1 , Caitlyn C Kant  1 , Lillian Bambalas  1 , Daniel Wright  1 , Austin Carter  1 , Kelly Moran  1 , Isabella G Rohrig  1 , Gregory M Ferrence  1 , Shawn R Hitchcock  1
Affiliations

Diastereoselective Synthesis of the HIV Protease Inhibitor Darunavir and Related Derivatives via a Titanium Tetrachloride-Mediated Asymmetric Glycolate Aldol Addition Reaction

Jordan M Witte et al. J Org Chem. .

Abstract

Darunavir is a potent HIV protease inhibitor that has been established as an effective tool in the fight against the progression of HIV/AIDS in the global community. The successful application of this drug has spurred the development of derivatives wherein strategic regions (e.g., P1, P1', P2, and P2') of the darunavir framework have been structurally modified. An alternate route for the synthesis of darunavir and three related P1 and P1' derivatives has been developed. This synthetic pathway involves the use of a Crimmins titanium tetrachloride-mediated oxazolidine-2-thione-guided asymmetric glycolate aldol addition reaction. The resultant aldol adduct introduces the P1 fragment of darunavir via an aldehyde. Transamidation with a selected amine (isobutylamine or 2-ethyl-1-butylamine) to cleave the auxiliary yields an amide wherein the P1' component is introduced. From this stage, the amide is reduced to the corresponding β-amino alcohol and the substrate is then bis-nosylated to introduce the requisite p-nitrobenzenesulfonamide component and activate the secondary alcohol for nucleophilic substitution. Treatment with sodium azide yielded the desired azides, and the deprotection of the p-methoxyphenoxy group is achieved with the use of ceric ammonium nitrate. Finally, hydrogenation to reduce both the aniline and azide functionalities with concurrent acylation yields darunavir and its derivatives.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Darunavir (1) and related derivatives.
Figure 2
Figure 2
Synthetic pathways to darunavir (1).
Scheme 1
Scheme 1. Retrosynthetic Analysis of Darunavir
Scheme 2
Scheme 2. Synthesis of the Evans and Non-Evans syn-Glycolate Aldol Adducts 10
Scheme 3
Scheme 3. Synthesis of the γ-Azido-N-sulfonamide
Scheme 4
Scheme 4. Synthesis of Darunavir (1) and N-2-Ethylbutyl Darunavir (27)
Scheme 5
Scheme 5. Synthesis of the P1-Isopropyl Derivative 35
Scheme 6
Scheme 6. Origin of the P1-Neopentyl Darunavir Design
Scheme 7
Scheme 7. Synthesis of the Azido Neopentyl Darunavir Derivative
See this image and copyright information in PMC

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