Enantiomerically Pure Synthesis of β-Substituted γ-Butyrolactones:  A Key Intermediate to Concise Synthesis of Pregabalin

Abstract

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.

γ-Selective directed catalytic asymmetric hydroboration of 1,1-disubstituted alkenes

“…For example, CAHB of tert -butyl ester 7i using ligand ( S,S )- 6 affords lactone ( S ) -20 (78%, 91% ee); the latter has been used as a precursor to the anticonvulsant drug pregabalin. 19 Similarly, tert -butyl ester 21a gives ( R )- 22a (80%, 95% ee) and 21b gives ( R )- 22b (79%, 95% ee) using the catalyst with ( R,R )- 6 . With the enantiomeric ligand (i.e., ( S,S )- 6 ),CAHB-oxidation of 21c affords ( S )- 22c (75%, 92% ee).…”

Ring Opening of Donor–Acceptor Cyclopropanes with N-Nucleo­philes

“…The Lee group devised an approach to optically active β-substituted γ-butyrolactones by nucleophilic ring opening of enantiomerically pure cyclopropane 170. 158 The ring opening of 170 with the azide ion with no source of hydrogen ion present led to the formation of azidomethyl-substi- …”

Isolation and Asymmetric Total Synthesis of Perforanoid A

“…Tr eatment of the olefin with Jones reagent gave g-butyrolactone 15 in 75 %yield. [21] We then evaluated the allene-based PK reaction for the synthesis of 7 with the desired stereochemistries at C9 and C14. Both diastereomers of 16 were treated with LiCl in the presence of water in DMF at 130 8 8Ct oi nitiate decarboxylation, and allene 9 was obtained in 80 %y ield.…”