253265-97-3Relevant articles and documents
The Chiron Approach to (3 R,3 aS,6 aR)-Hexahydrofuro[2,3- b]furan-3-ol, a Key Subunit of HIV-1 Protease Inhibitor Drug, Darunavir
Ghosh, Arun K.,Markad, Shivaji B.,Robinson, William L.
, p. 1216 - 1222 (2020/12/22)
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-isopropylidene-protected glycofuranoside, and a Baeyer-Villiger oxidation of a tetrahydrofuranyl-2-aldehyde derivative. This optically active ligand alcohol was converted to darunavir efficiently.
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 (2017/11/30)
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.
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 (2016/09/23)
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.
