Unexpected Synthesis of Conformationally Restricted Analogues of γ-Amino Butyric Acid (GABA):  Mechanism Elucidation by Electrospray Ionization Mass Spectrometry

• Published in: Journal of organic chemistry 2005-01, Vol.70 (1), p.110-114
• Main Authors: Ferraz, Helena M. C, Pereira, Fernando L. C, Gonçalo, Érika R. S, Santos, Leonardo S, Eberlin, Marcos N
• Format: Article
• Language: English
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Chemistry; Combinatorial Chemistry Techniques; Cyclopentanes - chemical synthesis; Exact sciences and technology; gamma-Aminobutyric Acid - analogs & derivatives; gamma-Aminobutyric Acid - chemical synthesis; gamma-Aminobutyric Acid - chemistry; Mass spectrometry; Molecular Structure; Organic chemistry; Preparations and properties; Reactivity and mechanisms; Spectrometry, Mass, Electrospray Ionization - methods; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo048309e

From previous results with lower homologues, dehydroiodination of the three alkenyl-β-enamino esters 3a−c was expected to provide six-membered N-heterocyclic products. The reactions of 3a−c with triethylamine are found to lead, however, to the unexpected stereoselective synthesis of the trisubstituted cyclopentane derivatives 4a−c, as confirmed by IR and NMR spectroscopy. Cyclopentanes 4a−c bear two chiral centers and a γ-amino ester moiety, and are therefore conformationally restricted analogues of γ-amino butyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system. Use of electrospray ionization mass (ESI-MS) and tandem mass spectrometry (ESI-MS/MS) allowed the key iminium ion intermediates 5a−c +, as well as the protonated molecules of both the reactant and final products, [3a−c + H] + and [4a−c + H] + , to be intercepted and structurally characterized. From these findings a mechanism for this unexpected but synthetically attractive and efficient stereoselective reaction is proposed.