op6b00377_si_001.pdf (6.01 MB)
Practical Synthesis of the Bicyclic Darunavir Side Chain: (3R,3aS,6aR)‑Hexahydrofuro[2,3‑b]furan-3-ol from Monopotassium Isocitrate
journal contribution
posted on 2016-12-14, 00:00 authored by Gary L. Moore, Rodger W. Stringham, David S. Teager, Tai-Yuen YueA practical synthesis
of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ola
key intermediate in the synthesis of darunavirfrom 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.
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side chainproduct isolationMonopotassium Isocitratetitle compoundsunflower oilisocitric acid saltMethyl aniline amidePractical Synthesisprotease inhibitorbicyclic acetal furofuranol side chainsynthesisBicyclic Darunavir Side Chainmonopotassium isocitratefuran -3-olHIVlithium aluminum hydridedarunaviracidic workup
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