Bromolactamization: Key Step in the Stereoselective Synthesis of Enantiomerically Pure, cis‐Configured Perhydropyrroloquinoxalines. Issue 12 (5th July 2014)

• Record Type: Journal Article
• Authors: Schulte, Adrian; Situ, Xingci; Saito, Susumu; Wünsch, Bernhard
• Is Part Of: Chirality. Volume 26:Issue 12(2014:Dec.)
• Page Start: 793
• Page End: 800
• Publication Date: 2014-07-05
• Subjects: Chirality -- Periodicals; Pharmaceutical chemistry -- Periodicals; 541.22
• DOI: 10.1002/chir.22350
• Languages: English
• ISSNs: 0899-0042

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>Compounds based on the pyrroloquinoxaline system can interact with serotonin 5‐HT<sub>3</sub>, cannabinoid CB<sub>1</sub>, and μ‐opioid receptors. Herein, a chiral pool synthesis of diastereomerically and enantiomerically pure bromolactam (<italic>S</italic>, <italic>R, R, R</italic>)‐<bold>14A</bold> is presented. Introduction of the cyclohexenyl ring at the N‐atom of (<italic>S</italic>)‐proline derivatives <bold>8</bold> or methyl (<italic>S</italic>)‐pyroglutamate (<bold>12</bold>) led to the <italic>N</italic>‐cyclohexenyl substituted pyrrolidine derivatives <bold>4</bold> and <bold>13</bold>, respectively. All attempts to cyclize the (<italic>S</italic>)‐proline derivatives <bold>4</bold> with a basic pyrrolidine N‐atom via <named-content content-type="reactionType" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">[3 + 2] cycloaddition</named-content>, <named-content content-type="reactionType" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">aziridination</named-content>, or <named-content content-type="reactionType" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">bromolactamization</named-content> failed. Fast <named-content content-type="reactionType" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">aromatization</named-content> occurred during treatment of cyclohexenamines under halolactamization conditions. In contrast, reaction of a 1:1 mixture of diastereomeric pyroglutamates (<italic>S, R</italic>)‐<bold>13bA</bold> and (<italic>S, S</italic>)‐<bold>13bB</bold> with LiO<sup>t</sup>Bu and NBS provided the tricyclic bromolactam (<italic>S</italic>, <italic>R, R, R</italic>)‐<bold>14A</bold> with high diastereoselectivity from (<italic>S, R</italic>)‐<bold>13bA</bold>, but did not transform the diastereomer (<italic>S, S</italic>)‐<bold>13bB</bold>. The different behavior of the diastereomeric pyroglutamates (<italic>S, R</italic>)‐<bold>13bA</bold> and (<italic>S, S</italic>)‐<bold>13bB</bold> is explained by different energetically favored conformations. Chirality 26:793–800, 2014. © 2014 Wiley Periodicals, Inc.</p> </abstract>