Deployment of Sulfinimines in Charge-Accelerated Sulfonium Rearrangement Enables a Surrogate Asymmetric Mannich Reaction

Abstract

β-Amino acid derivatives are key structural elements in synthetic and biological chemistry. Despite being a hallmark method for their preparation, the direct Mannich reaction encounters significant challenges when carboxylic acid derivatives are employed. Indeed, not only is chemoselective enolate formation a pitfall (particularly with carboxamides), but most importantly the inability to reliably access α-tertiary amines through an enolate/ketimine coupling is an unsolved problem of this century-old reaction. Herein, we report a strategy enabling the first direct coupling of carboxamides with ketimines for the diastereo- and enantioselective synthesis of β-amino amides. This conceptually novel approach hinges on the innovative deployment of enantiopure sulfinimines in sulfonium rearrangements, and at once solves the problems of chemoselectivity, reactivity, and (relative and absolute) stereoselectivity of the Mannich process. In-depth computational studies explain the observed, unexpected (dia)­stereoselectivity and showcase the key role of intramolecular interactions, including London dispersion, for the accurate description of the reaction mechanism.

Transfer freier Aminogruppen via α‐Aminierung von Carbonylen

“…Ladungsbeschleunigte Sulfoniumumlagerungen haben sich als nützliche Strategie für die Knüpfung von C−C und C−N Bindungen erwiesen [8] . Kürzlich beschrieb unsere Gruppe erfolgreich eine direkte Kupplung von Amiden und Sulfiniminen, die die Synthese von β‐Aminoamiden via einer [3,3]‐sigmatropen Sulfoniumumlagerung ermöglicht [8i] . Basierend auf diesen Ergebnisse stellten wir die Hypothese auf, dass die Umsetzung von tert ‐Butylsulfinamid [9] ( 1 ) mit einem geeigneten Vinylkation (I) [10, 11] in der Bildung einer neuen C−N Bindung resultieren und so einen direkten Zugang zur Einführung einer primären Aminogruppe in einem Schritt ermöglichen sollte.…”

Multicatalysis protocol enables direct and versatile enantioselective reductive transformations of secondary amides

“…During the past decade, considerable advancements on the direct transformations of amides have been achieved (14)(15)(16)(17)(18) either via the electrophilic activation of amides (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) or via catalytic partial reduction of amides (32)(33)(34)(35)(36)(37)(38)(39)(40). However, very few examples of the asymmetric transformations of amides have been reported (41)(42)(43)(44), and those involving the catalytic asymmetric reductive transformation of the amide group itself is even more scarce (42,43). Recently, we disclosed the catalytic asymmetric reductive cyanation and phosphonylation of secondary amides using iridium/chiral thiourea relay catalysis (42).…”

One-Step Asymmetric Construction of 1,4-Stereocenters via Tandem Mannich-Isomerization Reactions Mediated by a Dual-Functional Betaine Catalyst

“…Accordingly, considerable efforts have been devoted to the development of asymmetric methods for the construction of these motifs . Particularly, using metal-based chiral Lewis acids as catalysts, various asymmetric vinylogous Mannich reactions have been developed, yielding chiral amino butenolides with 1,2-stereocenters (Scheme C). − However, efficient constructions of amino butenolides with remote 1,4-stereocenters remains an unmet challenge.…”