The Chiron Approach to (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol, a Key Subunit of HIV-1 Protease Inhibitor Drug, Darunavir

Abstract

We describe an enantioselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol which is a key subunit of darunavir, a widely used HIV-1 protease inhibitor drug for the treatment of HIV/AIDS patients. The synthesis was achieved in optically pure form utilizing commercially available sugar derivatives as the starting material. The key steps involve a highly stereoselective substrate-controlled hydrogenation, a Lewis acid catalyzed anomeric reduction of a 1,2-O-isopropylideneprotected glycofuranoside, and a Baeyer−Villiger oxidation of a tetrahydrofuranyl-2-aldehyde derivative. This optically active ligand alcohol was converted to darunavir efficiently.

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

“…This drug was initially approved by the FDA in 2006 and the European Directorate for the Quality of Medicines and Health Care (The European Pharmacopoeia) in 2007 and fully approved in 2008 due to its high efficacy in combating HIV infection . The successful application of darunavir in combination therapies has inspired the pursuit of improved syntheses of darunavir − and syntheses of derivatives with the potential for even greater potency (Figure ). − In this context, the seminal efforts of Ghosh and coworkers laid the foundation for structural aspects of darunavir and the domains where the structure could be modified.…”

Micro-total process system machine (μ-TPSM) for rapid synthesis of antiretroviral darunavir

“…Many reported studies have employed batch processes for the synthesis of darunavir APIs. 13,14 The batch processes involve the collection of consecutive batches of intermediate and then moving to the next step that requires maintenance of expensive storage inventory and is labour intensive, which increases the production cost. 32 Compared to the batch process, the alternative integrated continuous process using small diameter tubing arranged in solenoid form consumes less space and enables inline quenching, extraction and purification, thereby decreasing labour intensity and improving safety.…”

“…Even then, the use of noble metals for the catalysis step couldn't be avoided. 13,14 As a result, the high price and limited availability of the noble metal catalyst reduced the accessibility of the antiretroviral API to common people. 15 Besides, batch production carried out at different locations further increased the production time, transportation charges and carbon dioxide emission resulting in an overpriced, labour intensive process causing a disturbance in the prospective chain supply.…”

“…Many reported studies have employed batch processes for the synthesis of darunavir APIs. 13,14 The batch processes involve the collection of consecutive batches of intermediate…”

Accessing HIV-1 Protease Inhibitors through Visible-Light-Mediated Sequential Photocatalytic Decarboxylative Radical Conjugate Addition–Elimination–Oxa-Michael Reactions

“…A few methods were also developed for its one-carbon higher homologues . On the other hand, multistep synthetic routes have often been adopted to obtain the HIV-1 protease inhibitors III – V wherein the bicyclic Cp-THF skeleton has been constructed by either intramolecular radical cyclization , or intramolecular oxa-Michael reaction of predesigned substrates. We earlier developed highly stereoselective nucleophilic conjugate addition of Grignard reagents to 4- O -Boc-cyclopent-2-enone ( R )- 1a in the presence of copper wherein the addition took place anti to the OBoc group to furnish diastereo- and enantiomerically pure cyclopentenones (Scheme a) .…”