Aldol reaction Proline-catalysed

For ipsenol, Benjamin List published in 2001 a synthesis starting from 3-meth-ylbutanal and acetone. [206] The enantioselective aldol reaction is catalysed by proline to yield the hydroxy-ketone with an enantiomeric excess of 73 %. After protection of the alcohol function, the enol triflate is formed regioselectively. The vinyl substituent is introduced by means of a StiUe coupling, and followed by deprotection. 

In direct nitroso aldol reactions of a-branched aldehydes, an L-prolinamide (50) catalyses to give a-hydroxyamino carbonyl compounds which are otherwise dis- favoured ees up to 64% were found.149 Another prolinamide derivative gives similar results in a nitrosobenzene reaction.150 For proline-catalysed cases involving highly substituted cyclohexanones, DFT calculations have highlighted the roles of electro- static and dipole-dipole interactions in the level of de achieved.151 (g)... 

Hartree-Fock and density functional theory (DFT) calculations have been used to probe the enantioselectivity of the direct aldol reaction of acetone and 2,2-dimethyl-propanal, catalysed by (S)-proline, in DMSO solution.107... 

Direct intermolecular aldol reactions, catalysed by proline, between tetrahydro-4H-thiopyranone (25) and racemic aldehydes exhibit enantiotopic group selectivity and dynamic kinetic resolution, with ee% of >98% in some cases.109... 

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>. 

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 proline-catalysed aldol reaction of tetrahydrothiopyran-4-one with l,4-dioxa-8-thiaspiro[4.5]decane carboxaldehydes in wet DMSO is highly diastereo- and enantio-selective. The adducts have potential as tetrapropionate synthons <05OLl 181>. 

The Robinson annelation The proline-catalysed aldol reaction Reactions with hydroxy-acetone Conjugate addition... 

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 proline-catalysed aldol reaction (chapter 26) of the heterocyclic ketone 177 with benzal-dehyde gave the an//-aldol 178. Reduction by the Prasad method (chapter 21) gave the anti,anti-diol 179 and so, by desulfurisation with Raney Ni, the anti,anti-Aio 179. The reduction could be controlled by the neighbouring chiral centre but the Prasad method uses 1,3-control by chelation with BEt2 and external axial delivery of nucleophilic hydride from NaBH4 181. This is 1,3-control via a cyclic intermediate.29... 

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. 

The proline-catalysed aldol reaction of tetrahydro-4/f-thiopyran-4-one with aldehydes, which is accelerated by water <04SL1891>, gives the anti adducts with high diastereo- and enantioselectivity DMSO is the solvent of choice for aliphatic aldehydes and moist DMF for aromatic examples (Scheme 23). Desulfurisation of these thiopyrans with Raney-Ni gives products equivalent to aldol products derived from pentan-3-one <04TL8347>. 

This proline-catalysed aldol proceeds via initial formation of an enamine with the donor component. This enamine then reacts with the re-face of the acceptor through a closed-transition state, as depicted in Figure 7.4, to give the anti-product as the major diastereomer. The proline also activates the acceptor by hydrogen bonding within this ensemble and thus plays a bifunctional role in the reaction. The resulting iminium ion is then hydrolysed to close the catalytic cycle. 

Figure 7.4 Catalytic cycle of the proline catalysed aldol reaction...

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. 

Interactive mechanism for the proline-catalysed ant/selective aldol reaction... 

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. ... 

In the case of propionaldehyde, a range of aldehyde acceptors are applicable with good yields and selectivities. The scope includes allq l-derived aldehydes (80-88% yield, 97-99% ee) and one aryl-derived aldehyde (81% yield, 99% ee). The relevance of this discovery was proven soon after by the same group, by applying the intermolecular, proline-catalysed aldol reaction as part of a two-step synthesis of carbohydrates (Scheme 5.9). The... 

Scheme 5.8 Proline-catalysed direct aldehyde cross-aldol reaction.

Although a seemingly simple transformation, the mechanism for the proline-catalysed aldol reaction and for other related addition reactions has been the source of much scientific debate and discussion over the last decade. Some issues of contention have included understanding the complex equilibria governing intermediate formations, the stereochemical... 

Another issue is the formation of oxazolidinones, which has been the subject of study by several research groups and is considered to be part of a parasitic equilibrium for proline-catalysed aldol reactions. More recent studies have indicated that this parasitic equilibrium may not be true, and that reversible oxazolidinone formation may help keep proline in solu-tion. Figure 5.3 illustrates a generalised mechanism for proline catalysis involving enamine intermediates. As aforementioned, the formation of oxazolidinones may or may not be part of a parasitic equilibrium. 

In terms of stereochemical considerations, proline-catalysed aldol reactions are proposed to occur via a metal-free Zimmerman-Traxler transition state, which has been supported by computational studies indicating that this is the most energetically favourable and consistent in predicting stereochemical outcomes. ... 

Interestingly, the reaction outcome can be improved in terms of yield and enantioselectivity by applying high pressure to the reaction conditions, albeit at levels unreachable with standard to-date technical equipment. Entirely aldehyde-based versions of the proline-catalysed Mannich reaction are also possible and provide access to q n-y-amino alcohols after subsequent reduction in excellent enantioselectivities (Scheme 5.12). To avoid the favoured cross-aldol or self-Mannich side reactions of the aldehyde, propionaldehyde needed to be added slowly to the reaction mixture. 

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. 

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, ... 

The intermolecular aldol reaction of ketones with aldehydes has been intensively investigated since the seminal discovery of the i-proline catalysed process.Most of the modified organocatalysts, successively reported for this fundamental reaction, were amide derivatives of i-proline, able to work at lower loading in more environmentally friendly media and displaying better stereocontrol (Chapter 5). 

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. 

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