Enantio- and Diastereoselective Intermolecular Stetter Reaction of Glyoxamide and Alkylidene Ketoamides

Abstract

A triazolinylidine carbene catalyzed intermolecular Stetter reaction of glyoxamide and alkylidene ketoamides has been developed. 1,4-dicarbonyl products are afforded in good to excellent yields, enantioselectivities and diastereoselectivities. Further derivatization of the products affords useful intermediates for organic synthesis.The Stetter reaction, 1 the N-heterocyclic carbene (NHC) catalyzed addition of aldehydes to Michael acceptors, is a prototypical example of the emerging class of catalyzed umpolung reactions. 2 Following a seminal early report by Enders and Teles, 3 we 4 and others 5 have extensively investigated the asymmetric intramolecular Stetter reaction. The asymmetric intermolecular Stetter, on the other hand, has remained a much more significant challenge. 6 In 2008, Enders reported an asymmetric intermolecular Stetter reaction of aromatic aldehydes and chalcones proceeding in good yield and modest modest selectivities. 7 Concurrently, we reported the enantioselective intermolecular Stetter reaction of glyoxamides 1 with alkylidene malonates 2 (eq 1). 8(1) Supporting Information Available Detailed experimental procedures and spectral data for all new compounds, nOe of 12, and X-ray structures of 11 and 22. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2010 July 2. A shortcoming of the use of alkylidene malonates 2 is the need for the second ester group. We considered that the use of alkylidene ketoacid derivatives would provide an opportunity to incorporate synthetically useful substituents on the second carbonyl (eq 2). However, the reaction would generate mixtures of diastereomers, a situation that could be rectified through the use of alkylidene ketoamides. We have already demonstrated that the protonation event in the asymmetric Stetter is highly diastereoselective 4d and it has been welldocumented that tertiary β-ketoamides, bearing a stereocenter between the carbonyls, are configurationally stable due to strong A 1,3 strain in the enolate. 9 Interestingly, catalytic asymmetric transformations that generate ketoamide stereocenters are surprisingly rare. 10

Stetter Reactions of Unsaturated 1‐Acyl‐1H‐pyrroles

“…[25] Non-enolisable aromatic and glyoxal aldehydes have been employed with highly activated Michael acceptors including α,β-unsaturated ketones, diester alkylidenes, nitroalkenes and ketoamide alkylidenes to give the desired 1,4-dicarbonyl products in good yields. [26][27][28][29][30] At present, there are only a few reports of enolisable aldehydes and unsaturated esters being coupled in good yield using intermolecular Stetter reactions. [31,32] We were highly gratified to observe that the 1acylpyrrole unit enabled the intermolecular Stetter reaction to proceed smoothly (Scheme 8).…”

Bis(amino)cyclopropenylidenes as Organocatalysts for Acyl Anion and Extended Umpolung Reactions

“…The use of simple β‐alkyl substituted ketone acceptors in the Stetter reaction also represents a significant challenge. The more electrophilic β‐alkyl nitroolefins18 and alkylidene malonates17b, 19 have been employed, but these acceptors do not provide direct access to the ubiquitous and useful 1,4‐diketone motif. Gratifyingly, the Stetter reaction between methyl p ‐formylbenzoate and enone 14 provided an excellent yield of the addition product under the catalysis of bis(amino)cyclopropenium salt 3 (Scheme ).…”

Highly Enantioselective Intermolecular Stetter Reaction of Simple Acrylates: Synthesis of α‐Chiral γ‐Ketoesters

“…Otherwise all Michael acceptors require a second activating group for adequate reactivity. Key contributions were again made by Rovis and co‐workers, who focused on the use of alkylidenemalonates and ketoamides 3b,d…”