Asymmetric conjugate addition-aldol

The asymmetric conjugate additions with thiol nucleophiles was further expanded to 2-mercaptobenzaldehydes [98]. Wang had previously developed a domino Michael-aldol reaction promoted by Cinchona alkaloids, and now illustrated the utihty of cyclohexane-diamine bifunctionalized catalysts for the domino... 

Scheme 3.22 Rhodium-catalyzed asymmetric intramolecular conjugate addition-aldol reaction [40],...

In a recent study of asymmetric conjugate addition, Simon Woodward and co-workers8 required a series of enones 43. Some they made with lithium enolates 41 of ketones or esters 40 added to aldehydes to give the aldols 42 that were dehydrated to the enones 43 with concentrated HC1. 

Florhydral has the methyl group p to the aldehyde. One possible approach is an asymmetric conjugate addition, but again asymmetric reduction of the acid (or allyhc alcohol) is preferable, since the required alkene is easy to make by aldol chemistry. Here we show one example with the acid and one with the alcohol, but either are possibihties in both cases. 

In this chapter, remarkable advances in the research devoted to peptide catalysed alcohol esterifications, 1,4-conjugate additions, aldol reactions, Strecker synthesis, asymmetric cyanohydrin synthesis and alkene epoxida-tion are discussed. 

Since the introduction of the first peptide organocatalyst in the 1980s, a considerable number of new peptide frameworks have been developed that are able to effectively catalyse several important transformations including alcohol esterifications, 1,4-conjugate additions, aldol reactions, Strecker synthesis, asymmetric cyanohydrin synthesis and alkene epoxidation are discussed. A few successful examples of solid-supported peptides and reactions in ball milling under solvent-free conditions have been demonstrated. These methods combine the advantages of being economically and environmentally friendly processes. 

Transition metal enolate complexes have been prepared with most or all transition metals, and the enolate ligands have been shown to adopt a variety of bonding modes. Bofli early and late transition metal enolate complexes are intermediates in a number of important catalytic processes. Early transition metal enolates are important intermediates in asymmetric aldol reactions that exploit the Lewis acidic character of early metals. Late transition metal enolates are intermediates in aldol and Michael addition processes, -Saegusa oxidations,Heck-type processes, catalytic asymmetric conjugate additions, - and cross coupling of enolate nucleophiles. - ... 

A plausible mechanism was proposed based on the mechanistic studies performed by Hayashi for Rh-catalyzed asymmetric conjugate addition (Scheme 105) (184). Hydroxorhodium species Q-I is generated in situ from [Rh(COD)Cl]2 and KOH transmetallation with Aryl boronic acid gives the Rh complex Q-II. Conjugate addition to the enone gives the intermediate Q-HI, which is followed by Aldol cyclization to furnish intermediate Q-IV. Hydrolysis gives the product 234... 

The asymmetric conjugate addition with thiol nucleophiles was demonstrated using 2-mercaptobenzaldehydes. The utiUty of the same chiral cyclohexane-diamine catalysts 35 mediated the domino Michael-aldol of 2-sulfanylbenzaldehydes with maleimides (Scheme 13.10) [28]. The products of the reaction consist of fused heterocycles in high yield and high enantiomeric ratios. The stereochemical outcome sheds insight into the proposed mechanism whereby the catalyst simultaneously activates the thiol group via the cyclohexyl tertiary amine while the maleimide is stabihzed by the thiourea component... 

Yamamoto and coworkers described a highly enantioselective asymmetric domino 0-nitroso aldol-conjugate addition seqnence using cyclic enones 221 and aromatic nitroso compounds 222 as depicted in Scheme 36 [346]. A related reaction with imines was also reported by Cdrdova and coworkers (Scheme 37) [228]. 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

The conjugate addition of (K)-N-methyl-N-a-methylbenzyl amide 33 to tert-butyl cinnamate 34, followed by an asymmetric aldol reaction and subsequent N-oxidation/Cope elimination afforded the -substituted homochiral Baylis-Hillman product 39 in good yield (Scheme 7) [37]. This chemistry requires the use of stoichiometric rather than catalytic amounts of the chiral base. 

The enantioselective conjugate addition of tetrahydropyran-4-ones and their thio analogues to nitrostyrene is achieved using proline-based catalysts <06JA9624>, as is the asymmetric aldol reaction of these substrates with benzaldehydes (Scheme 27) <06JOC8198>. 

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