Bromolactamization : Key Step in the Stereoselective Synthesis of Enantiomerically Pure, cis ‐Configured Perhydropyrroloquinoxalines

Compounds based on the pyrroloquinoxaline system can interact with serotonin 5‐HT 3 , cannabinoid CB 1 , 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. Chirality 26:793–800, 2014 . © 2014 Wiley Periodicals, Inc.