Unexpected synthesis of conformationally restricted analogues of gamma-amino butyric acid (GABA): mechanism elucidation by electrospray ionization mass spectrometry.
From previous results with lower homologues, dehydroiodination of the three alkenyl-beta-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 gamma-amino ester moiety, and are therefore conformationally restricted analogues of gamma-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.
Ferraz
Helena M C
HM
Institute of Chemistry, University of São Paulo-USP, São Paulo SP, 05508-900, Brazil. hmferraz@iq.usp.br
Pereira
Fernando L C
FL
Gonçalo
Erika R S
ER
Santos
Leonardo S
LS
Eberlin
Marcos N
MN
D020650:Combinatorial Chemistry Techniques; D003517:Cyclopentanes / Q000138:chemical synthesis*; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
D003517:Cyclopentanes; D005680:gamma-Aminobutyric Acid