Stereocontrol in Asymmetric γ-Lactam Syntheses from Imines and Cyanosuccinic Anhydrides

Abstract

Computations (SCS-MP2//B3LYP) reveal that the asymmetric synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds through a Mannich reaction between the enol form of the anhydride and the E-imine, followed by a transannular acylation. This new mechanistic picture accounts for both the observed reactivity and stereoselectivity. CH-O and hydrogen bonding interactions in the Mannich step and torsional steering effects in the acylation step are responsible for stereocontrol. It is demonstrated that this new mechanistic picture applies to the related reactions of homophthalic anhydrides with imines and presents new vistas for the design of a new reaction to access complex molecular architectures.

Dimerization and comments on the reactivity of homophthalic anhydride

“…Nucleophilic addition of the imine nitrogen acting as a nucleophile toward the (less reactive) C-1 carbonyl of HPA or its enol tautomer has been proposed, 2,22 but more recently, calculations have been reported that suggest that this pathway is too high in energy. 23 Concerted cycloaddition of imine with a diene-like enol of HPA ( 13 ) or its derived enolate have been considered, 24,25 but imines are normally regarded as weak dienophiles in a thermal Diels-Alder reaction, 26 and 1 reacts rapidly with 2 even at mild temperatures.…”

“…A concerted, cyclic, Mannich-like reaction 23 of the enol of HPA ( 13 ) accounts for the reactivity of imine 2 despite its low basicity and nucleophilicity (Scheme 5). A hydrogen bond between enol 13 as the donor and the imine nitrogen of 2 as the acceptor can organize the two coupling partners into a transition state geometry in which either the N -2,2,2-trifluoroethyl substituent of 2 lies over the HPA ring oxygen (a “boat”, 14 ), or the pyridine ring of 2 lies over the HPA C-1 carbonyl group (a “chair”, 15 ).…”

Stereochemistry and reactivity of the HPA-imine Mannich intermediate

“…Organization of the reaction components 2 and 3 by an intermolecular hydrogen bond 13,22 could take place in two different configurations (Scheme 2). The “boat” configuration ( 7 ) places the aryl group away from the benzo ring, and ought to be favored for small N-substituents R .…”

“…Despite earlier considerations of alternative mechanisms, 2,14,21 more recent analysis of the HPA-imine reaction seems to have settled on a two-step process centered on Mannich-type amino-anhydride intermediate 5 , 3,13,15,22 the stereochemistry of which translates to the C-3 and C-4 stereocenters of the THIQ product. Under certain conditions, elimination of amine from 5 to afford a Knoevenagel-type alkene product 6 has been observed.…”

“…Such compounds have seen application toward potential anticancer treatments, 6,,8,9 and include a new group of antimalarials from which a clinical candidate has recently emerged. 10,11,12 Synthetic 2,3 and computational 13,14 aspects of the HPA-imine reaction, formally a [4+2] cycloaddition of the enolized form of HPA ( 2 , Scheme 1), have been investigated extensively. A wide variety of solvents and additives have been shown to accommodate or modify the tranformation, which nonetheless occurs rapidly at modest temperatures even in the absence of added acid or base promoters.…”