Highly diastereo- and enantioselective catalytic synthesis of the bis-tetrahydrofuran alcohol of Brecanavir and Darunavir

An efficient highly diastereo- and enantioselective synthesis of the bis-tetrahydrofuran (bis-THF) alcohol of several HIV protease inhibitors, including Brecanavir and Darunavir, has been achieved utilizing an Evans Mukaiyama aldol reaction of (benzyloxy)acetaldehyde and a silyl ketene acetal. The lactone alcohol intermediate from the catalytic aldol reaction was reduced to a lactol. Palladium catalyzed hydrogenolysis removed the benzyl protection and promoted an in situ cyclization to form the epimer of the bis-THF alcohol in a 98:2 diastereomeric ratio and 97:3 enantiomeric ratio. The alcohol epimer was readily converted to the target in two steps by oxidation to a ketone followed by highly selective reduction to the bis-THF alcohol.

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(3S,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-olC6H10O3Er = 97:3 (chiral GC analysis)[α]D25=-29.6 (c 1.40, CHCl3)Source of chirality: asymmetric catalysis with [Cu((S,S)-phenyl-bis(oxazolinyl)pyridine)](SbF6)2Absolute configuration: (S,S)Absolute configuration: (3S,3aS,6aR)

(3aR,6aR)-Tetrahydrofuro[2,3-b]furan-3(2H)-oneC6H8O3Er = 97:3[α]D25=-151.9 (c 0.89, CHCl3)Source of chirality: asymmetric catalysis with [Cu((S,S)-phenyl-bis(oxazolinyl)pyridine)](SbF6)2Absolute configuration: (S,S)Absolute configuration: (3aR,6aR)

(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-olC6H10O3Er = 97:3[α]D25=-11.6 (c 0.73, MeOH)Source of chirality: asymmetric catalysis with [Cu((S,S)-phenyl-bis(oxazolinyl)pyridine)](SbF6)2Absolute configuration: (S,S)Absolute configuration: (3R,3aS,6aR)

(3S)-3-[(1S)-2-(Benzyloxy)-1-hydroxyethyl]dihydrofuran-2(3H)-oneC13H16O4Er = 97:3[α]D25=-8.0 (c 2.61, CHCl2)Source of chirality: asymmetric catalysis with [Cu((S,S)-phenyl-bis(oxazolinyl)pyridine)](SbF6)2Absolute configuration: (S,S)Absolute configuration: (S,S)