Organocatalytic Enantioselective Formal Conjugate Addition of a Hydroxymoyl Anion to α,β‐Unsaturated Aldehydes

Abstract

In memory of our colleague and friend Rafael SuauThe conjugate addition reaction is a fundamental transformation in organic chemistry. The wide variety of reagents amenable to participate as Michael donors or acceptors makes this reaction extremely versatile, allowing the preparation of many different classes of highly functionalized compounds in a very easy and reliable way. Moreover, the conjugate addition reaction also occurs very often with the concomitant generation of one or more stereocenters and, in this context, intense research has focused on the development of catalytic enantioselective approaches for carrying out this important reaction in a stereocontrolled way.[1] Although most of the methodologies reported to date involve the use of transition-metal catalysts, several organocatalytic enantioselective variants of the conjugate addition reaction have been developed in the last few years;[2] many of which have performed excellently with regard to chemical efficiency and stereocontrol. On the other hand, many research groups have also directed their attention to finding novel reactivity patterns applied to the conjugate addition reaction by using umpoled reagents, [3] which have expanded the array of compounds which can be used as Michael donors or acceptors, to further increase the scope of this methodology. In particular, the enantioselective conjugate addition of acyl or formyl anions to a,b-unsaturated carbonyl compounds or related derivatives entails a particular interest because this transformation allows the preparation of 1,4-dicarbonyl compounds, which are classically much more difficult to access by standard C À C bond forming reactions than the corresponding 1,3-or 1,5-dicarbonyl compounds.[4] However, despite the enormous potential of the oxime moiety and the key role played by this functional group in plenty of organic reactions, the development of umpoled reagents that behave as hydroxymoyl anion equivalents remains unexploited.In fact, even for the related case of the conjugate addition of acyl/formyl anion equivalents, enantioselective versions for this particular transformation under metal-free conditions are very scarce (see Scheme 1). For example, the Stetter reaction using N-heterocyclic carbenes (NHC) as catalysts can be an extremely effective approach for the formal enantioselective conjugate addition of acyl anions, [5] but it is ineffective when trying to use formaldehyde as the Michael donor.For the particular case of the conjugate addition of a formyl anion equivalent, there is only one single example related to an enantioselective organocatalytic version; this involves the use of N,N-dialkylhydrazones as Michael donors, which undergo conjugate addition to b,g-unsaturated a-ketoesters under chiral Brønsted-acid catalysis to give moderate levels of enantioselection.[6] Another relevant example involves oxazol-5A C H T U N G T R E N N U N G (2 H)-ones as aryloyl anion equivalents in the conjugate addition to enoylphosphonates, [7] which also relies on Brønsted-acid catalysis. In...

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New Approach to Oximes through Reduction of Nitro Compounds Enabled by Visible Light Photoredox Catalysis

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