title: Bromolactamization: key step in the stereoselective synthesis of enantiomerically pure, cis-configured perhydropyrroloquinoxalines.
abstract: Compounds based on the pyrroloquinoxaline system can interact with serotonin 5-HT3 , cannabinoid CB1 , and μ-opioid receptors. Herein, a chiral pool synthesis of diastereomerically and enantiomerically pure bromolactam (S,R,R,R)-14A is presented. Introduction of the cyclohexenyl ring at the N-atom of (S)-proline derivatives 8 or methyl (S)-pyroglutamate (12) led to the N-cyclohexenyl substituted pyrrolidine derivatives 4 and 13, respectively. All attempts to cyclize the (S)-proline derivatives 4 with a basic pyrrolidine N-atom via [3 + 2] cycloaddition, aziridination, or bromolactamization failed. Fast aromatization occurred during treatment of cyclohexenamines under halolactamization conditions. In contrast, reaction of a 1:1 mixture of diastereomeric pyroglutamates (S,R)-13bA and (S,S)-13bB with LiO(t) Bu and NBS provided the tricyclic bromolactam (S,R,R,R)-14A with high diastereoselectivity from (S,R)-13bA, but did not transform the diastereomer (S,S)-13bB. The different behavior of the diastereomeric pyroglutamates (S,R)-13bA and (S,S)-13bB is explained by different energetically favored conformations.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Schulte
authors.forename: Xingci
authors.initials: X
authors.lastname: Situ
authors.forename: Susumu
authors.initials: S
authors.lastname: Saito
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D060326:Chemistry Techniques, Synthetic; D005971:Glutamates / Q000737:chemistry; D007769:Lactams / Q000737:chemistry*; D047029:Lactams, Macrocyclic / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011392:Proline; D011759:Pyrrolidines; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D005971:Glutamates; D007769:Lactams; D047029:Lactams, Macrocyclic; D011759:Pyrrolidines; D011810:Quinoxalines; D011392:Proline; C032519:pyrrolidine
keywords: bromolactamization; cis-configured perhydroquinoxaline; kinetic resolution; proline; pyroglutamate; stereoselectivity