Stereoselective photochemical 1,3-dioxolane addition to 5-alkoxymethyl-2(5H)-furanone: synthesis of bis-tetrahydrofuranyl ligand for HIV protease inhibitor UIC-94017 (TMC-114).
A convenient synthesis of (3R,3aS,6aR)-3-hydroxyhexahydrofuro[2,3-b]furan, a high-affinity nonpeptidal ligand for HIV protease inhibitor UIC-94017, is described. This inhibitor is undergoing advanced clinical trials. The synthesis utilizes a novel stereoselective photochemical 1,3-dioxolane addition to 5(S)-benzyloxymethyl-2(5H)-furanone as the key step. The requisite furanone derivative was prepared in high enantiomeric excess by an immobilized lipase-catalyzed selective acylation of (+/-)-1-(benzyloxy)-3-buten-2-ol and a ring-closing olefin metathesis with Grubbs' catalyst. Optically active bis-THF was converted to protease inhibitor 2 (UIC-94017).
Ghosh
Arun K
AK
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,Chicago, Illinois 60607, USA. arunghos@uic.edu
Leshchenko
Sofiya
S
Noetzel
Marcus
M
D002384:Catalysis; D000069454:Darunavir; D004148:Dioxolanes / Q000737:chemistry*; D005663:Furans / Q000138:chemical synthesis*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D008024:Ligands; D015394:Molecular Structure; D013237:Stereoisomerism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C494001:(3R,3aS,6aR)-3-hydroxyhexahydrofuro(2,3-b)furan; D004148:Dioxolanes; D005663:Furans; D017320:HIV Protease Inhibitors; D007202:Indicators and Reagents; D008024:Ligands; D013449:Sulfonamides; D000069454:Darunavir