Direct Coupling of Pyrroles with Carbonyl Compounds: Short Enantioselective Synthesis of (S)‐Ketorolac

Abstract

Nicht aktivierte C(sp2)‐ und C(sp3)‐Atome werden bei der beschriebenen Kupplung von Pyrrolen mit Carbonylverbindungen (Ketonen, Amiden, Estern, Lactonen, Lactamen) verknüpft (siehe Schema). Eine intramolekulare Variante dieser neuen Methode machte den nichtsteroidalen entzündungshemmenden Wirkstoff (S)‐Ketorolac in einer kurzen enantioselektiven Synthese zugänglich. Zudem werden Überlegungen zum Mechanismus dieser Reaktion vorgestellt.

Room Temperature Copper‐Catalyzed 2‐Functionalization of Pyrrole Rings by a Three‐Component Coupling Reaction

“…in the addition of a pyrrole unit to the α‐carbon of enolizable carbonyl compounds (e.g. ketones, esters, amides, latones, or lactams) in the presence of a stoichiometric Cu II species 10. However, the possibility that the unbound pyrrole unit (no coordination to copper) directly attacks the ketenimine intermediate cannot be ruled out at the moment.…”

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

“…[139] A mechanistic investigation revealed that the first step in the mechanism likely involves deprotonation of the indole and enolization of the carbonyl group by LiHMDS to generate the copper(II)-chelate species 161.…”

From Conjugated Tertiary Skipped Diynes to Chain‐Functionalized Tetrasubstituted Pyrroles

“…[15] In particular, tetrasubstituted pyrroles 5 can be considered as hybrid scaffolds [16] comprising a structurally privileged pyrrole ring and a naturally occurring a-hydroxy acid motif. [17] The hybrid features five points of diversity (two chemodifferentiated ester groups, two chemodifferentiated R groups and one N À R 1 group) and two differentiated points for complexity generation, one in the ring (sp 2 -linking point; C4-H) and the other in the chain (sp 3 These hybrid structures are usually synthesized by Friedel-Crafts reaction between the substituted pyrrole and the corresponding alkyl glyoxylate. [18,19] In recent years, a number of important organometallic methodologies for the synthesis of pyrroles from alkyne-containing materials have been developed.…”