Stereoselective and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol.
[reaction: see text] Two short and efficient synthesis routes have been developed for bis-THF-alcohol 2, a key building block of the investigational HIV protease inhibitor TMC114 (1). Using S-2,3-O-isopropylideneglyceraldehyde (4) as the source of chirality, both routes are based on a diastereoselective Michael addition of nitromethane to give predominantly the syn congeners 6 followed by a Nef oxidation and cyclization to afford lactone acetals 8, which are reduced and cyclized to give 2.
Quaedflieg
Peter J L M
PJ
DSM Pharma Chemicals, LS-ASC&D, PO Box 18, 6160 MD Geleen, The Netherlands. peter.quaedflieg@dsm.com
Kesteleyn
Bart R R
BR
Wigerinck
Piet B T P
PB
Goyvaerts
Nicolaas M F
NM
Vijn
Robert Jan
RJ
Liebregts
Constantinus S M
CS
Kooistra
Jaap H M H
JH
Cusan
Claudia
C
D003500:Cyclization; D000069454:Darunavir; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D013237:Stereoisomerism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C513052:hexahydrofuro(2,3-b)furan-3-ol; D000069454:Darunavir