156928-09-5Relevant articles and documents
A stereoselective anti-aldol route to (3R,3aS,6aR)-hexahydrofuro[2,3-b] furan-3-ol: A key ligand for a new generation of HIV protease inhibitors
Ghosh, Arun K.,Li, Jianfeng,Perali, Ramu Sridhar
, p. 3015 - 3018 (2006)
A stereoselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, an important high affinity P2-ligand, in high enantiomeric excess (>99%) is reported. The synthesis features an ester-derived titanium enolate based highly stereoselective anti-aldol reaction as the key step. Georg Thieme Verlag Stuttgart.
Research and Development of an Efficient Synthesis of a Key Building Block for Anti-AIDS Drugs by Diphenylprolinol-Catalyzed Enantio- and Diastereoselective Direct Cross Aldol Reaction
Hayashi, Yumi,Aikawa, Toshiaki,Shimasaki, Yasuharu,Okamoto, Hiroaki,Tomioka, Yosuke,Miki, Takashi,Takeda, Masahiro,Ikemoto, Tetsuya
, p. 1615 - 1620 (2016)
An efficient method for synthesizing 1-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}oxy)pyrrolidine-2,5-dione (1), a key building block for HIV protease inhibitors, has been developed. A diphenylprolinol-catalyzed highly enantio- and diastereoselective cross aldol reaction of polymeric ethyl glyoxylate with an aldehyde was used as the key step. Acetalized aldol adduct was reduced with NaBH4 to give the diol intermediate in quantitative yield. The acetal exchange reaction followed by hydrogenation with Pd/C catalyst afforded 1′ in 95% yield over 2 steps. The condensation of 1′ with a carbonate gave crystalline 1 (>99/1 dr, > 99% ee) after single crystallization. This is a highly practical synthetic method since environmentally benign organocatalysis is utilized, the amount of catalyst is reduced to 3 mol %, and all of the intermediates before 1′ can be used without any purification.
Comparing the greenness and sustainability of three routes to an HIV protease inhibitor intermediate
Akakios, Stephanie Gina,Bode, Moira Leanne,Sheldon, Roger Arthur
, p. 3334 - 3347 (2021)
The greenness and sustainability of three different routes for the synthesis of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol (bis-furan alcohol), an advanced intermediate for a group of HIV protease inhibitors, including the FDA approved darunavir, used in antiretroviral (ARV) therapy, were compared. The method involved a comparison of (i) waste generated using theE-factor and relative to industrial benchmarks using the innovative Green Aspiration Level (iGAL) method, (ii) solvent usage on the basis of solvent intensity (SI) and properties according to the GSK solvent guide, and (iii) Green Motion scores according to the MANE methodology.
The efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol and its isomers
Kulkarni, Mukund G.,Shaikh, Yunnus B.,Borhade, Ajit S.,Dhondge, Attrimuni P.,Chavhan, Sanjay W.,Desai, Mayur P.,Birhade, Deekshaputra R.,Dhatrak, Nagorao R.,Gannimani, Ramesh
, p. 2394 - 2398 (2010)
The stereoselective synthesis of all the possible stereoisomers of bis-tetrahydrofyran alcohol, a ligand used for obtaining HIV protease inhibitors including Darunavir 1 and Brecanavir 2 has been achieved. A key intermediate 4-pentenal 5 was obtained by employing a Wittig olefination-Claisen rearrangement protocol from d-glyceraldehyde derivative 3 as a source of chirality. The 4-pentenal was readily converted in the bis-THF alcohol moiety in three steps.
Efficient synthesis of 3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol from glycolaldehyde
Canoy, Will L.,Cooley, Bob E.,Corona, John A.,Lovelace, Thomas C.,Millar, Alan,Weber, Aimee M.,Xie, Shiping,Zhang, Yong
, p. 1103 - 1106 (2008)
A one-step diastereoselective (up to 98:2) synthesis of the bis-furan alcohol of Darunavir and other HIV drug candidates has been achieved utilizing the novel cyclizatlon of glycolaldehyde and 2,3-dihydrofuran. The cycloaddition was catalyzed by a variety of catalysts including those formed from tin(II) triflate and common chiral ligands such as BINAP and Evans's box ligands. An efficient and unique enzymatic process enhanced the enantiomeric purity to provide the target in optically pure form.
Practical synthesis of the bicyclic darunavir side chain: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol from monopotassium isocitrate
Moore, Gary L.,Stringham, Rodger W.,Teager, David S.,Yue, Tai-Yuen
, p. 98 - 106 (2017)
A practical synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol?a key intermediate in the synthesis of darunavir?from monopotassium isocitrate is described. The isocitric acid salt, obtained from a high-yielding fermentation fed by sunflower oil, was converted in several steps to a tertiary amide. This amide, along with the compound's ester functionalities, was reduced with lithium aluminum hydride to give, on acidic workup, a transient aminal-triol. This was converted in situ to the title compound, the bicyclic acetal furofuranol side chain of darunavir, a protease inhibitor used in treatment of HIV/AIDS. Key to the success of this process was identifying an optimal amide that allowed for complete reaction and successful product isolation. N-Methyl aniline amide was identified as the most suitable substrate for the reduction and the subsequent cyclization to the desired product. Thus, the side chain is produced in 55% overall yield from monopotassium isocitrate.
A Concise One-Pot Organo- and Biocatalyzed Preparation of Enantiopure Hexahydrofuro[2,3-b]furan-3-ol: An Approach to the Synthesis of HIV Protease Inhibitors
Kanemitsu, Takuya,Inoue, Mizuho,Yoshimura, Nono,Yoneyama, Kazutoshi,Watarai, Rie,Miyazaki, Michiko,Odanaka, Yuki,Nagata, Kazuhiro,Itoh, Takashi
, p. 1874 - 1880 (2016)
A simple and efficient one-pot synthesis of enantiopure hexahydrofuro[2,3-b]furan-3-ol, a crucial component of HIV-1 protease inhibitors, was developed. The one-pot process involves an organocatalytic condensation followed by an enzymatic optical resolution. The condensation of 1,2-dihydrofuran and glycolaldehyde was achieved using Schreiner's thiourea catalyst (1 mol-%). A subsequent lipase-catalyzed kinetic resolution gave the target alcohol with >99 % ee. To demonstrate the practicality of this method, Darunavir, an HIV-1 protease inhibitor used to treat multi-drug-resistant HIV, was synthesized.
Highly diastereo- and enantioselective catalytic synthesis of the bis-tetrahydrofuran alcohol of Brecanavir and Darunavir
Black, David M.,Davis, Roman,Doan, Brian D.,Lovelace, Tom C.,Millar, Alan,Toczko, Jennifer F.,Xie, Shiping
, p. 2015 - 2019 (2008)
An efficient highly diastereo- and enantioselective synthesis of the bis-tetrahydrofuran (bis-THF) alcohol of several HIV protease inhibitors, including Brecanavir and Darunavir, has been achieved utilizing an Evans Mukaiyama aldol reaction of (benzyloxy)acetaldehyde and a silyl ketene acetal. The lactone alcohol intermediate from the catalytic aldol reaction was reduced to a lactol. Palladium catalyzed hydrogenolysis removed the benzyl protection and promoted an in situ cyclization to form the epimer of the bis-THF alcohol in a 98:2 diastereomeric ratio and 97:3 enantiomeric ratio. The alcohol epimer was readily converted to the target in two steps by oxidation to a ketone followed by highly selective reduction to the bis-THF alcohol.
An Efficient Synthesis of the Bicyclic Darunavir Side Chain Using Chemoenzymatic Catalysis
Charnock, Simon J.,Finnigan, James D.,Hyster, Todd K.,Lim, Jesmine,Riehl, Paul S.
, (2022/03/03)
Herein, we describe a chemoenzymatic synthesis of the bicyclic fragment of Darunavir. A ketoreductase was identified using metagenomic mining to catalyze a highly enantio- and diastereoselective dynamic kinetic resolution of a β-ketolactone. Subsequent lactone reduction with diisobutylaluminum hydride and phase transfer cyclization affords the bicyclic acetal fragment in 39% yield over four steps.
METHODS FOR MAKING DARUNAVIR P2-LIGAND PRECURSORS
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, (2022/02/28)
A method for making an optically active P2-ligand precursor comprising converting D-xylose or a derivative thereof or D-glucose or a derivative thereof to the optically active P2-ligand precursor.
