Asymmetric aldol reactions proline catalysed

Novel organic molecules derived from L-proline and amines or amino alcohols, were found to catalyse the asymmetric direct aldol reaction with high efficiency. Notably those containing L-proline amide moiety and terminal hydroxyl group could catalyse direct asymmetric aldol reactions of aldehydes in neat acetone with excellent results[1]. Catalyst (1), prepared from L-proline and (IS, 2Y)-diphcnyl-2-aminoethanol, exhibits high enantioselectivities of up to 93% ee for aromatic aldehydes and up to >99% ee for aliphatic aldehydes. 

An alternate approach to the direct asymmetric Mannich reaction uses enan-tiomericaUy pure organocatalysts. L-Proline and derivatives, applied with much success to the catalytic asymmetric aldol reaction (see Section 7.1), also function as effective catalysts in the Mannich reaction. The mechanism of this process is similar to the L-proline-catalysed aldol reaction involving conversion of the donor into an enamine and proceeds via a closed six-membered transition state similar to that depicted in Figure 7.4. However, in contrast to the L-proline-catalysed aldol reaction, the sy -Mannich adduct is the major diastereomer formed and the si rather than the re-face of the acceptor undergoes attack, as depicted in Figure 7.5. 

Ellman and coworkers have shown that chiral sulfinate 14 can catalyse asymmetric aldol reactions of acetone, whereas proline itself gave poor results. However, more active and selective catalysts are prolinamides with general structure 16 containing two or more stereocentres in the molecule, and based on ot-alkylbenzylamines ISa," chiral (3-amino alcohols (16b-d, 16e-f, axially chiral amino hydroxyl-2,2 -binaphtyl amide 16i, ... 

Recently, Bazito with coworkers have reported that a 4-TBSO-proline 29-catalysed asymmetric aldol reaction of acetone with 4-nitrobenzaldehyde can run in supercritical (sc) CO2 or sc-COj/IL green solvent systems with a poor yield and low enantiomeric excesses. The moderate catalytic performance of 29 in SC-CO2 may be attributed to the known capability of primaiy and secondary amines to generate carbamic acid salts with CO2, which hamper the catalytic process. 

In 2001 Barbas III et al. reported the amino acid-catalysed direct asymmetric aldol reaction between ketones and aldehydes. Using the benchmark condensation reaction between acetone and p-nitro-benzalde-hyde, the authors tested many different amino acids as organocatalysts, including (5 )-ot-2-methyl-proline 7a (Scheme 11.2). In this reaction however 7a proved to be much less reactive than (S)-proline (1), as well as slightly less enantioselective. Compound 7a was also found to be less efficient than 1 in the direct organocatalytic asymmetric a-oxidation of cyclohexanone with iodosobenzene, as reported by Cordova et ah in 2005 (Scheme 11.3). ... 

Based on the observations and quantum mechanical calculations for proline-catalysed asymmetric aldol reactions Li and coworkers synthesised a series of L-proline-hased dipeptides for the direct asymmetric aldol reaction between substituted aldehydes and acetone in DMSO. Dipeptide 31 was successfully employed yielding the desired adducts in excellent yield and good to excellent enantioselectivity. Additionally, PGME 5000 was used as a surfactant additive in catalytic amounts, since prior reports showed an acceleration of aldol reactions hy such additives Xheme 13.20b). 

The group of Zhang designed a series of L-proline-based dipeptides eom-prising a C-terminal amino-piperidyl pyridine moiety (Scheme 13.22a). The asymmetric aldol reaction between various aldehydes and cyelie ketones, catalysed by peptide 34 in 10 mol% loading, was performed in brine since... 

In the area of organocatalysis, proline has been utilised in various asymmetric reactions including direct asymmetric aldol reactions. Some such proline-catalysed aldol reactions, however, have serious limitations with respect to reactivity and selectivity. Although these problems were overcome through the development of new catalysts derived from proline, there is still an urgent need for structurally and electronically novel catalysts due to the difficulty in appropriate modification of proline. In this context, we have designed and prepared artificial amino acid catalyst (S)-l having a binaphthyl backbone as a frequently utilised chiral unit in asymmetric catalysts. ... 

Pioneering works on the proline-catalysed direct asymmetric aldol reactions, see (a) U. Eder, G. Sauer and R. Wiechert, Angew. Chem., Int. Ed.,... 

On the other hand, a number of asymmetric aldol reactions have been performed in the last year in the presence of variously substituted prolines as the organocatalysts. As an example, Zhao et al. reported excellent results for the cross-aldol reaction of cyclohexanone with p,y-unsaturated keto esters catalysed by a tra i-siloxy-L-proline (Scheme 2.3). This practical and highly efficient protocol could be extended to other ketones, albeit with lower enantioselectivities (<93% ee). 

The reaction of salicylaldehydes with a,P-unsaturated compounds which can lead to chromenes, chromans and other heterocycles has been reviewed <07OBC1499> and details of their reaction with allenic esters and ketones have been published <07CEJ3701>. A proline-catalysed benzoic acid-promoted asymmetric synthesis of chromene-3-carbaldehydes involves a domino oxa-Michael - aldol reaction with a,P-unsaturated aldehydes the ee range is 83-98% (Scheme 11) <07CEJ574>. 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

The L-proline-catalysed asymmetric aldol condensation between acetone (147) and various aldehydes has been efficiently promoted by applying high pressure (0.2 GPa). In these processes acetone is used as both reactant and solvent. As shown in Scheme 7.37, all of the reactions give the desired aldol products in high yield, except the reaction between acetone and isovaleral-dehyde the highest ee values are obtained with cyclohexyl- and naphthy-laldehydes (Scheme 7.37). 

The asymmetric Robinson annelation relies on an intramolecular aldol reaction to create the new chiral centre. More recently List19 and MacMillan20 have used proline 58 to catalyse intermolecular aldol reactions with nearly as good results. Acetone and isobutyraldehyde 89 can be condensed to give a single enantiomer of the aldol 90 in excellent yield and ee providing 30% proline is used as catalyst. 

The scope of this chapter does not allow nor attempt a comprehensive account of all developed processes to date. A detailed summary, in particular of aldol, Mannich, or ot-functionalisation reactions, can be found in excellent reviews written on the topic." Barbas and List reported an asymmetric, direct, intermolecular aldol reaction of acetones and aldehydes (Scheme 5.4), presumably via enamine formation of proline and acetone. As compared to its metal-catalysed alternatives, no preformation of the respective enolate is required, a mode of action that mimics metal-free aldolase enzymes. ... 

Organocatalysed aldol reaction has been extensively studied after being rediscovered in 2000 when List et al. developed the first proline-catalysed asymmetric direct intermolecular reaction. The aldol process is defined as the reaction of two carbonyl compounds to produce p-hydrojq carbonyl derivatives, and many combinations of starting compounds could be envisaged, but the most studied are summarised in Scheme 6.1. 

Barbas and researchers identified that the diamine la TFA salt can catalyse the asymmetric intermolecular direct aldol reactions of a,a-dialkylaldehydes with aromatic aldehydes (Scheme 9.2). The bifunctional catalytic system exhibited excellent reactivity to give products with moderate diastereo- and enantioselectivities. Notably, L-proline is an ineffective catalyst for this class of aldol reactions. The re-face attack of an enamine intermediate on an aryl aldehyde was proposed, causing the observed stereochemistry. 

OH) with aldehydes 9 in the homogeneous conditions (DMF or DMSO) (Scheme 10.1). Furthermore, PEG-supported catalyst 20a could be recovered by precipitation from the DMF solution with ether and reused in the same reactions without reduction of enantiomeric excesses of products 10 (R = OH). It also appeared applicable to asymmetric iminoaldol (Mannich) reactions to afford p-aminoketones 16 (R = Ar) (Scheme 10.3) and to the enantioselective Michael/aldol cascade reaction resulting in the S3mthesis of Wieland-Mischler ketone 28b, an important precursor of some other natural compounds (Scheme 10.6). Diastereo- and enantioselectivities of these reactions were close to the corresponding data for proline-catalysed reactions. 

In analogy with the above-mentioned amine-catalysed aldol reactions, our binaphthyl-based amino sulfonamide catalysts showed unique reactivity and selectivity in the asymmetric Mannich reaction of aldehydes. For instance, the Mannich reaction of propanal with an a-imino ester catalysed by (S)-3 gave the antr-Mannich adduct as a major diastereomer, while the syn-Mannich adduct was obtained in the proline-catalysed reaction first reported by the Barbas group (Scheme 17.8). ... 

Among a wide variety of chiral organocatalysts that have been used in the asymmetric Mannich reaction, one of the most widely used remains proline itself, which generally provided excellent enantioselectivities for the Mannich products arisen from either three-component, one-pot reactions or reactions of preformed imines with aldol donors. While these reactions were mostly performed at a catalyst loading of 10mol %, Mannich reactions of enolisable aldehydes and ketones with imines catalysed by (i )-3-pyrrolidinecarboxylic... 

Hydroformylation of olefins has been established as an important industrial tool for the production of aldehydes. In recent years, novel asymmetric tandem reactions have included a rhodium-catalysed enantioselective hydroformylation. In this context, in 2007 Abillard and Breit ° and Chercheja and Eilbracht independently reported a novel domino hydroformylation-aldol reaction catalysed by an achiral rhodium catalyst and L-proline catalyst (Scheme 7.49). Possibly owing to the fact that proline is hard but the rhodium catalyst is soft, the proline can be compatible with the rhodium catalyst to allow this domino reaction to be achieved. By fine adjustment of the hydroformylation rate to that of the L-proline-catalysed aldol addition, the undesired homodimerisation of the aldehyde could be avoided. As a result, by in situ hydroformylation reaction, the donor aldehyde of a... 

The combination of organocatalysts and enzymes remains rare, and the first examples of asymmetric tandem reactions catalysed by this type of catalyst combination have been described only recently. For example in 2004, Cordova et al. worked out a one-pot procedure involving L-proline as catalyst in the first step of the reaction and the enzyme Amano I (lipase extracted from Pseudomonas cepacia) in the second step. As shown in Scheme 9.1, the aldol reaction between an aldehyde and acetone occurred to give the corresponding intermediate p-hydroxy ketone, which was subsequently submitted to kinetic resolution by treatment with the enzyme, affording the corresponding almost enantiopure acetate in moderate yields. 

Extensive molecular dynamic simulations of proline-catalysed asymmetric aldol condensation of propionaldehyde in water have revealed that the stereoselectivity can be attributed to differences in transition-state solvation pattems. " The hydrogen bond concept has been applied to design new proline-based organocatalysts. " 4-Hydroxyproline derivatives bearing hydrophobic groups in well-defined orientations have been explored as catalysts in water an advantage of aromatic substituents syn to the carboxylic acid moiety has been attributed to a stabilizing transition-state hydrophobic interaction and this is supported by quantum mechanics (QM) calculations. " Catalysts and solvents were screened for reaction between cyclohexanone andp-nitrobenzaldehyde. 

A desymmetrizing aldol reaction of 3-substituted cyclobutanones with aryl aldehydes in CH2CI2 has been promoted with dr up to 99 1 and ee < 99% stereodirected by N-phenylsulfonyl (5)-proline. Proline-based di- and tri-amides have also been used effectively to catalyse asymmetric aldol condensation and the importance of each chiral centre of the catalyst has been discussed. 

Even though the use of (S)-proline (1) for the synthesis of the Wieland-Miescher ketone, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaetion, was reported in the early 1970s, aminocatalysis - namely the catalysis promoted by the use of chiral second-aiy amines - was rediscovered only thirty years later. The renaissance of aminocatalysis was prompted by two independent reports by List et al. on the asymmetric intermolecular aldol addition catalysed by (S)-proline (1) and by MacMillan et al. on the asymmetric Diels-Alder cycloaddition catalj ed by a phenylalanine-derived imidazolidinone 2. These two reactions represented the archetypical examples of asymmetric carbonyl compound activation, via enamine (Figure ll.lA) and iminium-ion (Figure 11.IB), respectively. 

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