Organocatalysis Michael-aldol reactions

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... 

Hong BC, Lin CW, Liao WK, Lee GH (2013) Sequential asymmetric catalysis in Michael-Michael-Michael aldol reactions merging organocatalysis with photoredox catalysis in a one-pot enantioselective synthesis of highly functionalized decalines bearing a quaternary carbon stereocenter. Org Lett 15 6258-6261... 

Cobb, A.J.A., Shaw, D.M., Longbottom, D.A., Gold, J.B. and Ley, S.V. (2005) Organocatalysis with proline derivatives improved catalysts for the asymmetric Mannich, nitro-Michael and aldol reactions. Org. Biomol. Chem., 3, 84. 

Other reviews deal with aldol additions of group 1 and 2 enolates,103 direct catalytic asymmetric aldol reactions catalysed by chiral metal complexes,104 the exploitation of multi-point recognition in catalytic asymmetric aldols,105 and recent progress in asymmetric organocatalysis of aldol, Mannich, Michael, and other reactions.106... 

Since the discovery of proline-catalyzed enantioselective aldol reactions, an extensive research program to explore chiral secondary amine catalysts has been pursued. Several polymer-supported chiral amines have been synthesized for aldol, Mannich, and related reactions. Polystyrene is a popular solid phase for use in place of silica gel in the proline-based organocatalysis. In contrast, silica gel displays a slightly acidic character and has a hydrogen-bond donor or acceptor, which may change the catalytic activity and chiral space of the organocatalyst. Flow enantioselective aldol [158-161], Mannich [162], Michael [163], and related reactions... 

In conclusion, Kappe s group demonstrated the absence of any differences between conventional and microwave heating in proline-catalyzed Mannich and aldol reactions as well as no evidence for specific or non-thermal microwave effects. In all cases, in contrast to the previous literature reports, the results obtained with microwave irradiation could be reproduced by conventional heating at the same reaction temperature and time in an oil bath. The differences observed in previous publications could be a result of incorrect temperature measurements [36]. After Kappe s [35] publication several articles appeared in the literature concerning the application of microwaves in asymmetric organocatalysis, mostly in aldol and Michael type reactions operating via enamine as well as iminium catalysis. 

Later, the cascade three-component organocatalysis was applied in the first enantioselective total synthesis of (-l-)-coni-col (Scheme 21.34). The synthesis was achieved via a key step reaction involving the organocatalytic domino oxa-Michael-Michael-Michael-aldol condensation of 2-( )-2-nitro-vinyl)benzene-l,4-diol 148, 3-methylbut-2-enal 145, and ( )-4,4-dimethoxybut-2-enal 150. The successful synthesis further expands the realm of the reactant of this three-component reaction beyond 3-arylacrylaldehyde to the a, 3-unsaturated aldehydes bearing a y-H. 

During the past decades, the scope of Lewis acid catalysts was expanded with several organic salts. The adjustment of optimal counter anion is of significant importance, while it predetermines the nature and intensity of catalytic Lewis acid activation of the reactive species. Discovered over 100 years ago and diversely spectroscopically and computationally investigated [131-133], carbocations stiU remain seldom represented in organocatalysis, contrary to analogous of silyl salts for example. The first reported application of a carbenium salt introduced the trityl perchlorate 51 (Scheme 49) as a catalyst in the Mukaiyama aldol-type reactions and Michael transformations (Scheme 50) [134-142]. 

Notz W, Tanaka F, Barbas CF (2004) Enamine-based organocatalysis with proline and diamines the development of direct catalytic asymmetric aldol, Mannich, Michael, and Diels-Alder reactions. Acc Chem Res 37(8) 580-591... 

Notz, W., Tanaka, F., Barbas, C. F., III. Enamine-Based Organocatalysis with Proline and Diamines The Development of Direct Catalytic Asymmetric Aldol, Mannich, Michael, and Diels-Alder Reactions. Acc. Chem. Res. 2004, 37, 580-591. 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

Carbocations were discovered over 100 years ago and have been investigated in diverse ways both spectroscopically and computationally [86-88]. Although as cations they can possess strong Lewis acidic character, carbocations remain seldom represented in organocatalysis, unlike the analogous of silyl salts, for example, discussed above. The first catalytic application of a carbenium salt, the trityl perchlorate 35 (Figure 16.7), was reported for Mukaiyama aldol-type reactions and Michael transformations (Scheme 16.29) [89-97]. 

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