Catalytic Asymmetric Radical-Mediated Three-Component Piancatelli-Type Rearrangement of Furylalkenes

Abstract

As one of the most fundamental rearrangement reactions, the classical Piancatelli reaction mainly relies on the use of α-furylcarbinols and is initiated by an acid-promoted dehydroxylation process and limited to a two-component manner. In this work, the first asymmetric radical-mediated three-component Piancatelli-type rearrangement of furylalkenes with diverse carbon-centered radical precursors and anilines is developed via the combination of copper­(I) or photoredox catalysis with chiral Brønsted acid and unchiral Lewis acid catalysis. This protocol features a wide substrate scope and high functional group tolerance and provides expedient access toward a broad spectrum of densely functionalized fluoroalkyl-containing cyclopentenones bearing α-quaternary carbon stereocenters in high yields with high enantioselectivities and diastereoselectivities (>70 examples, up to 95% yield, 96% ee, and >20/1 dr). The synthetic utility has been demonstrated by product derivations and applying onto the late-stage functionalization of valuable drug targets or natural products. Mechanistic studies revealed that the diastereoselectivity of the rearrangement reaction was controlled by Dy­(III)-accelerated Z/E isomerization of the Piancatelli intermediates and the chiral Brønsted acid-catalyzed 4π-electrocyclization of pentadienyl carbocation intermediates was both a rate- and enantio-determining step.

Retro-Aza-Piancatelli Rearrangement Triggered Cascade Reaction of Methyl Furylacrylates with Anilines to Access Cyclopenta[b]pyrrolidinones

“…9a More recently, we developed the radicalmediated Piancatelli-type rearrangement of furyl-substituted terminal alkenes with diverse fluoroalkyl radical precursors and anilines. 10 Of note is that the resulted major 5-alkyl-5-aryl-4-(arylamino)cyclopentenone products generally show a cisrelationship between the C4-amino and C5-aryl group.…”

“…Nevertheless, it is important to note that all these reactions have almost exclusively relied on furfuryl alcohols to generate the key furanoxonium ion intermediates via an acid-catalyzed dehydration process (Scheme a). The discovery of novel strategies and/or employing other furan derivatives for the generation of functionalized furanoxonium ion intermediates to trigger the Piancatelli reaction is highly desirable, but still less developed. , In this context, Read de Alaniz reported the ring opening-initiated aza-Piancatelli reaction using furyl-substituted donor–acceptor cyclopropanes (CPs) as novel precursors (Scheme b) . More recently, we developed the radical-mediated Piancatelli-type rearrangement of furyl-substituted terminal alkenes with diverse fluoroalkyl radical precursors and anilines .…”

“…The discovery of novel strategies and/or employing other furan derivatives for the generation of functionalized furanoxonium ion intermediates to trigger the Piancatelli reaction is highly desirable, but still less developed. , In this context, Read de Alaniz reported the ring opening-initiated aza-Piancatelli reaction using furyl-substituted donor–acceptor cyclopropanes (CPs) as novel precursors (Scheme b) . More recently, we developed the radical-mediated Piancatelli-type rearrangement of furyl-substituted terminal alkenes with diverse fluoroalkyl radical precursors and anilines . Of note is that the resulted major 5-alkyl-5-aryl-4-(arylamino)­cyclopentenone products generally show a cis -relationship between the C4-amino and C5-aryl group.…”

“…Subsequent acid-promoted nucleophilic addition by the aniline via intermediate II to generate intermediate III and further upon furan ring opening/isomerization delivers the pentadienyl carbocation IV . Conrotatory 4π electrocyclization of IV furnishes the major cis -adduct and minor trans -adduct, which is consistent with the previous reports. , Although only minor trans -adduct can undergo lactamization, a retro -aza-Piancatelli rearrangement of major cis -adduct to minor trans -adduct proceeds smoothly, thus significantly increasing the yield of the desired lactam product.…”

Quaternary carbon construction through Piancatelli rearrangement: easy access to spirocyclopentenones

“…Of late, this reaction has been explored to build an asymmetric version of the reaction as well as libraries of new scaffolds. 12,13 We have earlier developed a domino Piancatelli rearrangement/Friedel–Crafts alkylation approach of indole-tethered furfuryl alcohols to access bridged cycloocta[ b ]indole cores of alkaloids. 9 b…”