Practical Synthesis of the Bicyclic Darunavir Side Chain: (3 R,3a S,6a R)-Hexahydrofuro[2,3- b]furan-3-ol from Monopotassium Isocitrate

Abstract

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.

Scheme 1. Literature Process from Potassium Isocitrate to (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol

Scheme 2. Optimization of the Synthetic Process from Isocitrate to (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol

Figure 1

Impurities of hemiester 4, amide 5b, 7, and 8.