Hydrogen proline-catalyzed reactions

In the (S)-proline-catalyzed aldol reactions, the addition of a small amount of water did not affect the stereoselectivities [6]. However, a large amount of water often resulted in products with low enantiomeric excess water molecules interrupt the hydrogen bonds and ionic interactions critical for the transition states that lead to the high stereocontrol. For example, in the (S)-proline-catalyzed aldol reaction of acetone and 4-nitrobenzaldehyde in DMSO, the addition of 10% (v/v) water to the reaction mixture reduced the ee-value from 76% (no water) to 30% [6]. Note that the addition of a small amount of water into (S)-proline-catalyzed reactions often accelerates the reaction rate, and the addition of water should be investigated when optimizing these reactions [61]. 

There are many other examples of highly efficient catalytic asymmetric syntheses. These include the asymmetric dihydroxylation of alkenes and certain homogeneous catalyzed hydrogenations. The latter will be discussed in the context of redox reactions in Sections 17.3.2 and 17.4.7. Further examples for catalytic asymmetric syntheses also mentioned in this book are the proline-catalyzed cyclohexenone annulations in Figure 12.19. 

Computational studies suggest that the mechanism of the proline catalyzed aldol cyclization is best described by the nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide. A metal-free partial Zimmerman-Traxler-type transition state involving a chair-like arrangement of enamine and carbonyl atoms and the participation of only one proline molecule has been established [118,119]. On the basis of density functional theory (DFT) calculations Cordova and co-workers [120,121] have studied the primary amino acid intermolecular aldol reaction mechanism. They demonstrated that only one amino acid molecule is involved in the... 

Two different models were proposed by Ley for the 2b-catalyzed reaction which should also be of application for the cases of proline 1 and proline-tetrazole catalysts 2a, both of them in good agreement with the observed absolute configuration of the final Michael adducts (Figure 2.2). One proposal involved the possibility of the tetrazole moiety acting as a bulky substituent which directed the income of the electrophile by the less hindered face of the enamine intermediate in the most stable pseudo-rrarw conformation. Alternatively, the formation of a hydrogen-bonded transition state was also proposed, in this case with the participation of the pseudo-cj5 enamine conformer. This second pathway was afterwards estimated to be the energetically most favored one by DFT calculations. ... 

Moyano, Rios, and co-workers [38] have shown that the beneficial effect of hydrogen-bond donors in proline-catalyzed aldol reactions in nonpolar solvents [39] is due both to the facilitation of proline solubilization by formation of an oxazolidinone with the ketone and to the stabilization of the iminium carboxylate zwitterionic form that is the direct precursor of the reactive enamine intermediate,... 

This contribution will be divided according to activation mechanisms used to achieve the targeted transformation and the reaction type itself. However, some caution is necessary. As already shown in the case of the proline-catalyzed inter-molecular aldol reaction (Scheme 4), 12 can be considered to act as a bifunctional catalyst. Therefore, a strict classification according to just one single activation mechanism will not always be possible and very often activation modes like e.g. enamine formation are accompanied with additional interactions, such as e.g. hydrogen bonding. 

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... 

Use of proline-catalyzed five-component cascade olefmation/Diels-Alder/ epimerization/olefination/hydrogenation reactions of enones, aryl aldehydes, alkyl cyanoacetates, and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99% de) with excellent yields (70 to 75%) was also reported (Scheme 1.20) [23]. 

SCHEME 1.21 Mechanism proposed for proline-catalyzed olefination-hydrogenation reactions. 

Gryko and coworkers studied the influence of an acid additive in the aldol reaction catalyzed by a proline derivative equipped with an existing hydrogen bonding... 

Similar equipment for applications on the laboratory scale has been reported (and has recently been commercialized) (69-72). Most of the reported applications had the aim of investigating kinetics of chemical reactions as indicated by changes in liquid-phase concentrations. The equipment can typically be used at elevated temperatures and pressures. Applications to heterogeneous catalytic reactions include investigations of the enantioselective hydrogenation of exocyclic a,p-unsaturated ketones catalyzed by Pd/C in the presence of (A)-proline (73) and the esterification of hexanoic acid with octanol catalyzed by a solid acid (the resin Nafion on silica) (74). 

The development of chiral peptide-based metal catalysts has also been studied. The group of Gilbertson has synthesized several phosphine-modified amino adds and incorporated two of them into short peptide sequences.[45J,71 They demonstrated the formation of several metal complexes, in particular Rh complexes, and reported their structure as well as their ability to catalyze enantioselectively certain hydrogenation reactions.[481 While the enantioselectivities observed are modest so far, optimization through combinatorial synthesis will probably lead to useful catalysts. The synthesis of the sulfide protected form of both Fmoc- and Boc-dicyclohexylphosphinoserine 49 and -diphenylphosphinoserine 50 has been reported, in addition to diphenylphosphino-L-proline 51 (Scheme 14).[49 To show their compatibility with solid-phase peptide synthesis, they were incorporated into hydrophobic peptides, such as dodecapeptide 53, using the standard Fmoc protocol (Scheme 15).[451 For better results, the phosphine-modified amino acid 50 was coupled as a Fmoc-protected dipeptide 56, rather than the usual Fmoc derivative 52.[471 As an illustrative example, the synthesis of diphe-nylphosphinoserine 52 is depicted in Scheme 16J45 ... 

Diastereoselective fluoro-functionalization of proline derivatives produces fluorinated prolines. Both enantiomerically pure 4-trifluoromethyl and 4-difluoromethyl prolines 268 and 270 have been prepared (see Scheme 9.57) [85]. The key reaction for the stereo-controlled synthesis is diastereoselective Pd-catalyzed hydrogenation of 267 and 269. 

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