Brønsted-Acid-Catalyzed (3+2)-Cycloannulation of In-Situ-Generated 3-Methide-3H-pyrroles: Asymmetric Synthesis of Cyclopenta[b]pyrroles

Abstract

An organocatalytic, highly enantioselective addition of cyclic enamides to in-situ-generated 3-methide-3H-pyrroles with subsequent cyclization and elimination has been developed. This protocol represents a novel and straightforward route toward polycyclic cyclopenta­[b]­pyrroles with high yields and excellent enantioselectivity. Central to the success is the formation of a chiral, hydrogen-bonded 3-methide-3H-pyrrole upon phosphoric-acid-catalyzed dehydration of the starting 1H-pyrrol-3-yl carbinol that reacts with the enamide in a stepwise cycloannulation process.

Asymmetric Brønsted Acid Catalyzed Cycloadditions of ortho-Quinone Methides and Related Compounds

“…Scheme 28 BINOL-phosphoric acid-catalyzed (3+2)-cycloaddition of pyrrole-3carbinols 86 and enamides 39. 62 Preliminary results suggest that other electronrich alkenes may react with pyrrolyl-3-methides as well. Thus, under thoroughly optimized conditions pyrrole-3-carbinols are converted into cyclopenta [b]pyrroles upon reaction with 3-alkyl-2-styrenyl indoles with good yields and excellent diastereo-and enantiostereoselectivity.…”

“…(Scheme 28). 62 This process has been shown to be not limited to -aryl-substituted pyrrolyl-3-methides, but…”

“…Scheme 28 BINOL-phosphoric acid catalyzed [3+2]-cycloaddition of pyrrole-3-carbinols 86 and enamides 3962 …”

Recent Advances in Metal‐ and Organocatalyzed Asymmetric Functionalization of Pyrroles

“…Then the subsequent intramolecular Friedel-Crafts reaction of the C-2 position of pyrroles with the iminium ion followed by elimination of the enamide deliver the corresponding product 180 a (Scheme 65). [135]…”

“…A chiral phosphoric acid-catalyzed enantioselective [3 + 2] cyclo-annulation of cyclic enamides to in situ generated 3methide-3H-pyrroles has been realized by Schneider's group in 2020 (Scheme 65). [135] By introducing 10 mol% of C-42 as the catalyst, a wide variety of polycyclic cyclopenta [b]pyrroles 180 were synthesized from 1H-pyrrol-3-yl carbinol 178 and N-acetyl cyclic enamides 179 in moderate to excellent yield with excellent enantioselectivity. Substitution at the C-5 position of the pyrrole core by esters and amide-containing substrates with different steric demands was well established by this methodology.…”