Aldol and Mannich Reactions

These two transformations are powerful methods to form carbon-carbon bonds in synthetic organic chemistry, and L-Pro has proved a veiy good 

L-Pro was chosen as catalyst for the effective synthesis of flavanones from 2-hydro qracetophenones and aryl aldehydes. The transformation presumably occurs by the aldol condensation between both carbonyl 

The phase-transfer-catalyzed enantioselective direct aldol reactions of a glycine donor with aldehyde acceptors provide an ideal method for the simultaneous con- 

1 For reviews, see (a) T. Shioiri, A. Ando, M. Masui, T. Miura, T. Tatematsu, A. Bohsako, M. Higashiyama, C. Asakura. In M.E. Halpern (Ed.), Phase-Transfer Catalysis. ACS Symposium Series 659 American Chemical Society Washington, DC, 1997 Chapter 11, p. 136 (b) T. Ooi, K. Maruoka, Ace. Chem. Res. 2004, 37, 526. 

2 For recent reviews, see (a) T. Shioiri. In Y. Sasson, R. Neumann (Eds.), Handbook of Phase-Transfer Catalysis. Blackie Academic Professional London, 1997, Chapter 14 (b) M.J. O Donnell, Phases - The Sachem-Phase Transfer Catalysis Review 1998, Issue 4, p. 5 (c) M.J. O Donnell, Phases - The Sachem Phase Transfer Catalysis Review 1999, Issue 5, p. 5 (d) A. Nelson, Angew. Chem. 1999, 

Syntheses, 2nd edn. Wiley-VCH New York, 2000 Chapter 10 (g) M.J. O Donnell, Aldrichimica Acta 2001, 

Tatematsu, T. Shioiri, Tetrahedron Lett. 1993, 34, 1507. 

Although phase-transfer catalysed enantioselective direct aldol reactions of a glycine donor with aldehyde acceptors could provide an ideal method for the simultaneous construction of the primary structure and stereochemical integrity of p-hydrojy-a-amino acids, especially from the pharmaceutical viewpoint, the examples reported to date are very limited. In this regard, we have developed a direct aldol reaction of glycine Schiff base with a wide range of aliphatic aldehydes under mild phase-transfer conditions 

In combination wifh t-butyldimethylsilyl chloride, InClj catalyzes the aldol reaction between aldehydes and t-butyldimethylsilyl enol ethers in anhydrous organic solvents [140]. It has recently been found that the InCh-catalyzed Mukaiyama aldol reaction proceeds in water (Tab. 8.26) [141]. The reaction proceeds cleanly under almost neutral conditions to give /1-hydroxy ketones. The aqueous phase with IriClj can be reused. Water-soluble aldehydes such as glyoxylic acid and a commercial formaldehyde solution can be used directly for these reactions. 

In contrast with these results it has been claimed that hydrolysis of silyl enol 

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Sodeoka and co-workers have reported enantioselective aldol and Mannich reactions (Equations (106) and (J07)) 464,464a 464e Involvement of palladium enolates was confirmed by 111 NMR and ESI-MS spectrometry. /3-Keto esters (pronucleophiles) directly add to imines with high selectivity without preformation of silicon enolates (Equation (108)). 

Scheme 23 Transition states in aldol and Mannich reactions...

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

Odedra A, Seeberger PH (2009) 5-(Pyrrolidin-2yl)tetrazole-catalyzed aldol and Mannich reactions acceleration and lower catalyst loading in a continuous-flow reactor. Angew Chem Int Edit 48(15) 2699-2702... 

Multi-functional enantioselective catalysts for direct aldol and Mannich reactions have been prepared from (.S )-proline and 2,2/-diaminoBINAP.117... 

Scheme 2.1 The enamine catalytic cycle. An enamine derived from an amine- or amino acid-catalyst can react with a variety of electrophiles. The aldehyde and ketone reactants that form enamines and act as nucleophiles are often described as donors . Aldehyde and imine reactants that serve as electrophiles are described as acceptors for aldol and Mannich reactions, respectively. Ketones also serve as acceptors for aldol reactions.

It is also worth noting that B3LYP and related functionals provide very poor reaction energetics for the aldol and Mannich reactions. The more modem functionals, such as M06-2x and the long-range-corrected functionals CAM-B3LYP and LC-(oPBE, perform much better, with mean errors of less than 2 kcalmol" ... 

Enantioselective aldol and Mannich reactions and related transformations can be efficiently performed with several zirconinm catalysts. Addition of 1-naphtol to ethyl pyruvate mediated with the chiral (diboma-Cp)ZrCl3 complex is reported with an appreciable level of enantioselectivity. ... 

General comments about the Michael reaction procedures are analogous to those developed in the aldol and Mannich reactions.For example, the O-TMS-protected diphenylprolinol compound 20 in cooperation with benzoic acid catalyses the asymmetric Michael addition of aldehydes to nitroalkenes, in a simple, practical and efficient procedure. Benzoic acid promotes the rapid formation of the enamine intermediate and the reaction takes place in the highly concentrated organic phase of the aqueous biphasic system. 

LLC networks containing catalytic headgroups have also been shown to be useful for heterogeneous Lewis acid catalysis. The Sc(III)-exchanged cross-linked Hu phase of a taper-shaped sulfonate-functionalized LLC monomer has been shown to be able to catalyze the Mukaiyama aldol and Mannich reactions [115] with enhanced diastereoselectivity. This Sc(III)-functionalized Hu network affords condensation products with syn-to-anti diastereoselectivity ratios of 2-to-l, whereas Sc(III) catalysts in solution or supported on amorphous polymers show no reaction diastereoselectivity at all. 

Aldol and Mannich reactions. Formation of cyclopentenones is readily achieved by a twofold Mukaiyama aldol reaction between l,3-bis(trimethylsiloxy)-1,3-dienes and 1,2-diketones. ... 

The ability of L-Pro to promote aldol and Mannich reactions has also been exploited with chiral starting materials wherein L-Pro is not controlling the stereochemical outcome of the product, but rather substrate control is operative. The efficiency of the procedure prevents the use of other similar catalysts for these transformations. As an illustration, aldol and Mannich reactions have been employed to prepare carbapenem derivatives with potential value for the preparation of new antibacterial agents (Scheme 2.11). 

The regio- and the stereoselectivity of proline-catalyzed a-electrophilic substitution of carbonyl compounds can therefore be successfully explained by the oxazolidinone model, although the diastereoselectivity of the aldol and Mannich reactions was not taken into account in Seebach s discussion. Moreover, the model also could explain the autoinductive effects observed by Blackmond in the proline-catalyzed nitroso aldol and a-amination reactions of aldehydes [29, 31], by simply assuming that the oxazolidinone product acts as a base in the rate-determining enamine formation step. Kinetic resolution of proline, leading to chirality amplification effects, would be accounted for by the greater thermodynamic stability of the matched oxazolidinone product. In fact, the formation of Seebach s oxazolidi-nones, rather than enamines or iminium ion intermediates, from ketones and proline in DMSO solution had been described by List et al. in 2004 [23], but they concluded that this was a parasitic equilibrium leading to an unproductive intermediate. On the other hand, the product oxazolidinone in the proline-catalyzed a-amination of... 

This reaction was one of the first asymmetric produce concise, elegant solutions for the direct aldol and Mannich reactions. The most closely related work reported in the literature at the time is a single report by... 

A. S. Demir, S. Basceken, Tetrahedron Asymmetry 2013, 24, 515-525. Study of asymmetric aldol and Mannich reactions catalyzed by proline-thiourea host-guest complexes in nonpolar solvents. 

Although the number of successful applications of primary amino acids in stereoselective organocatalysis is far fewer than for the secondary amine, a few interesting examples are worth pointing out. The diversity of primary amino acids in aldol and Mannich reactions has been reviewed recently [48]. Several primary amino acids, such as alanine, valine, tryptophan, and threonine have been used as orga-nocatalysts. For instance, Barbas and coworkers have demonstrated the use of a L-threonine catalyzed protocol towards the synthesis of syn-l,2-diols through direct aldol reaction between a-hydroxyketones and para-nitrobenzaldehyde (Figure 17.13) [49]. 

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