Synthesis of Enantiopure 8-Aminomethylindolizines from Glutamine by Stereoelectronically Controlled Cationic Cyclization

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Starting from natural glutamine the synthesis of the 8aminomethylindolizine (4b) was accomplished.The construction of the ring system was performed by employing a cationic 6-exoπ-cyclization of an intermediate aziridinium salt.Transformation of the N,N-dibenzyl protected amine (4b) into the pharmacologically relevant target compound ( 11) is also describcd.The exploitation of cationic π-cyclizations in the construction of a variety of ring systems has been the object of intense studies in the field of heterocyclic chemistry. 1Employing N-pyrrole-terminated cyclization precursors this strategy gives access to tetrahydroindolizines and tetrahydropyrrolo[1 ,2-a]azepines. 2,3 As a part of our ongoing efforts to design selective dopamine D2/D3 autoreceptor agonists 4 which are of potential interest for the treatment of schizophrenia and cocaine craving, 5 we used cationic π-cyclizations for the construction of enantiomerically pure 6-and 7-dipropylaminotetrahydroindolizines revealing highly interesting receptor binding profiles. 6The ex-chiral pool synthesis of the 7-amino regioisomers was performed by chemoselective functionalization of asparagine (Asn), incorporation of a pyrrole moiety by Paal-Knorr reaction to furnish la and O-activation of the side chain. 7Since we were aware that sulfonylation of N,N-dibenzyl protected 1 ,2-amino alcohols and subsequent intermolecular nucleophilic substitution can result in rearrangements through aziridinium intermediates, 8 we elucidated the structure of the product very carefully.In fact, a 6-endo process leading to the indolizine (3a) was observed exclusively.5-Exo attack of 2a to give the pyrrolizine derivative (4a) could not bc detected.As an extension of our studies, we intended to investigate the synthesis of the homologous 1 ,2-amino alcohol (1b) which should bc available from natural glutamine (Gln).After O-activation the cyclization behavior of the resulting aziridinium derivative (2b) should be examined.