Enantiomerically pure synthesis of beta-substituted gamma-butyrolactones: a key intermediate to concise synthesis of pregabalin.
Chiral beta-substituted gamma-butyrolactones are known to be important intermediates for many biologically active compounds such as gamma-aminobutyric acid (GABA) derivatives and lignans. We have developed a general, convenient, and scalable synthetic method for enantiomerically pure beta-substituted gamma-butyrolactones, with either configuration, via nucleophilic cyclopropane ring opening of (1S,5R)- or (1R,5S)-bicyclic lactone followed by decarbethoxylation. The utility of our method was demonstrated by streamlined synthesis of pregabalin ((S)-3-isobutyl-gamma-aminobutyric acid), an anticonvulsant drug for the treatment of peripheral neuropathic pain.
Ok
Taedong
T
Department of Chemistry and School of Molecular Science (BK21), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea 305-701.
Jeon
Aram
A
Lee
Joohee
J
Lim
Jung Hak
JH
Hong
Chang Seop
CS
Lee
Hee-Seung
HS
D015107:4-Butyrolactone / Q000138:chemical synthesis* / Q000737:chemistry; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry; D018360:Crystallography, X-Ray; D000069583:Pregabalin; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis
D000927:Anticonvulsants; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D015107:4-Butyrolactone