Michael addition to enals

Heteroaromatic compounds are also suitable nucleophiles in the Michael additions to enals catalysed by prolinol silyl ethers. Hayashi and coworkers demonstrated that oxazolinones can add effectively to enals (Scheme S.lSa)." Indole also added effectively to a,p-unsaturated aldehydes (Scheme 8.13b). Also, enantioselective Michael addition of simple 3(2H)-furanones to a,(3-unsaturated aldehydes has been described (Scheme 8.13c). ... 

FIGURE 2.15. Stereochemical outcome of the amine-catalyzed Michael addition to enals. 

SCHEME 11.17. Enantioselective aza-Michael additions to enals catalyzed by imidazoU-dinone 33. 

Despite this early success, it was not until 2006 that MacMillan reported the first highly enantioselective intermolecular aza-Michael addition to enals [51]. In this work, MacMillan reported the use of N-sUyloxycarbamates as nucleophiles. The N-O functionality would increase the nucleophilicity at the nitrogen center via the a-effect, while the carbamate functionality would decrease the basicity of the... 

The first organocatalytic oxo-Michael addition to enals was reported by Jot-gensen in 2007 [65], Jorgensen used as a suitable nucleophile benzaldehyde oxime, which reacts with enals with catalysis by 28. The resulting product, reduced directly to the alcohol due its UabiUty, was obtained in excellent yields and enan-tioselectivities (Scheme 33.20). The oxime moiety can easily be cleaved to afford the 1,3-diols without loss of enantiomeric purity. However, aromatic enals turned out to be unreactive in this transformation. 

The first report regarding phospha-Michael additions to enals was made independently and at the same time by the research groups of Melchiorre [71] and... 

Despite the great interest in chiral phosphines and the success in the phospha-Michael addition to enals, only one example of an organocatalytic phospha-Michael reaction to enones can be found in the Uterature. 

Prolines.1 The complex 2 undergoes base-catalyzed (CH,ONa) Michael addition to a,p-enals and -enones. Reaction of 2 with acrolein furnishes a dihydro-pyrrole-2-carboxylic acid which is reduced to (S)-proline. 

Other compounds with sufficiently acidic C-H protons can serve as pronucleophiles in Michael additions to a,p-unsaturated aldehydes. Li, Wang and coworkers showed that arylmethanes bearing electron-withdrawing substituents underwent Michael addition to various enals mediated hy prolinol silyl ethers. Catalyst screening revealed that triethylsilyl catalyst Clb was the most efficient one (Scheme 8.10). Independently, Jorgensen and coworkers have also described benzylation of unsaturated aldehydes with toluenes. ... 

Pou and Moyano reported another example of an aza-Michael/cyclisation sequence. Jang and coworkers also realised tandem nitromethane and TEMPO addition to enals, as well as a quadruple cascade of a,p-unsaturated aldehydes, nitromethane and TEMPO using Cla catalyst and a copper salt. ... 

On the other hand, Wang and co-workers [28, 29] made two important contributions to the synthesis of cyclopentene derivatives. Both reactions were initiated with a carbo-conjugated addition of malonates derivatives. The first one was a double Michael addition between enals and 7-malonate-a,(3-imsaturated esters catalyzed by XII rendering the final cyclopentanes with three stereogenic centers in good yields (87-92%) and excellent stereoselectivities (84—99% ee) [28]. As for the second one, Wang and co-workers focus on the synthesis of cyclopentenes. This reaction was based on a Michael-aldol sequence followed by dehydration, between aromatic enals and dimethyl 2-oxoethylmalonate [29]. A set of densely functionahzed chiral cyclopentenes were synthesized in high yields (63-89%) and excellent enantiose-lectivities (91-97% ee) (Scheme 10.13). 

The NHC activation turned out to be relevant for the preparation of enantioen-riched and highly functionalized 5-carbon synthons such as nitroesters anti-51 (Scheme 12.24) or syn-58 (Scheme 12.25) [30,31,32]. First, the imidazolinium precatalyst was shown to be useful for the formation of the homoenolate derived from enal, which could subsequently react through Michael addition to p-nitrostyrene. 

Organocatalysis have emerged recently as one of the cornerstones for the enanti-oselective synthesis of C-C or C-heteroatom bonds. Owing to the easy prediction of the stereochemical outcome of the reactions, iminium activation and specific Michael reactions is one of the most studied reaction types in organocatalysis. In the literature, we can find multiple approaches to the organocatalytic Michael reaction using different catalysts or nucleophiles, most of them with exceptional levels of stereoselectivity. Moreover, these simple additions to enals or enones have inspired multiple organocatalytic tandem and cascade reactions and, in our view, open up a new pathway for the enantioselective construction of complex scaffolds in one-pot procedures. 

The field of organocatalyzed Michael addition has rapidly evolved to reach its maturity as exemplified by the number of applications of the most classic reactions in total synthesis. It is not surprising that the methodologies first developed with enantioselectivities in a practical range and with broad scope were the first ones widely accepted and used by the synthetic community. The best examples are the addition of aldehydes to methyl vinyl ketone, iminium nucleophilic carbon addition to enals, or phase-transfer-catalyzed addition to vinyl ketones. 

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