The efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol and its isomers

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.

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(3S,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-olC6H10O3[α]D28=-24.1 (c 1.1, CHCl3)Absolute configuration: (3S,3aS,6aR)Source of chirality: d-glyceraldehyde

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-olC6H10O3[α]D28=-11.2 (c 1.2, MeOH)Absolute configuration: (3R,3aS,6aR)Source of chirality: d-glyceraldehyde