Open AccessPractical Synthesis of the Bicyclic Darunavir Side Chain: (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol from Monopotassium Isocitrate
Author(s) -
Gary L. Moore,
Rodger W. Stringham,
David S. Teager,
TaiYuen Yue
Publication year - 2016
Publication title -
organic process research and development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 109
eISSN - 1520-586X
pISSN - 1083-6160
DOI - 10.1021/acs.oprd.6b00377
Subject(s) - darunavir , chemistry , amide , side chain , furan , bicyclic molecule , dabco , lithium aluminium hydride , yield (engineering) , aminal , stereochemistry , combinatorial chemistry , organic chemistry , octane , human immunodeficiency virus (hiv) , materials science , medicine , family medicine , viral load , antiretroviral therapy , metallurgy , polymer
A practical synthesis of (3 R ,3a S ,6a R )-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.