3-Isobutyl GABA

The story of the discovery of pregabalin (2) began in 1991, when Silverman and Taylor published a paper on the anticonvulsant effect of 3-alkyl GABA analogs (Silverman et ah, 1991). Out of this collection of compounds, 3-isobutyl GABA stood out as the most active analog in the series, which protected mice from seizures induced by corneal electroshock. 

Scheme 16.12. The original Silverman synthesis of ( + )-3-isobutyl GABA (43).

Many of the synthetic routes derived for pregabalin (2) before 2003 have relied on classical chiral resolution of either an intermediate or the final racemic 3-isobutyl GABA (43). In 2003, Jacobsen and co-workers published their work on a novel enantio-selective synthesis of pregabalin (2) (Sammis and Jacobsen, 2003). The Harvard group was able to promote conjugate addition of hydrogen cyanide into the unsaturated imide... 

Hydroformylation of 1,1-disubstituted allyl amides gives access to p -amino acids such as (S )-(-i-)-3-isobutyl-GABA (pregabalin). In 2005, the compound was launched in the United States by Pfizer (Lyrica ) for the treatment of central nervous system disorders and is one of the most prescribed drugs worldwide ( 1.8 billion in 2007). Today, several routes exist including kinetic resolution processes and enzymatic pathways [54]. The key step of an asymmetric catalytic approach recommended by Zhangs group [55] is the hydroformylation of an allyl phthahmide (Scheme 4.80). Under the conditions depicted in the scheme. 

Enna S. J (1981) GABA receptor pharmacology, functional considerations. Biochem Pharmacol. 30, 907-913 Felker P. (1978) Gas-hqmd chromatography of the heptafluorobutyric-O-isobutyl esters of ammo acids. J Chromatogr 153, 259-262 Fonnum F (1981) The Turnover of Transmitter Ammo Acids, With Special Reference to GABA, in Central Neurotransmitter Turnover (Pycock C J. and Tabener P V, eds.) University Press, Baltimore, pp 105-124... 

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