Cyclohexanone aldol reaction, stereoselectivity

A DFT study found a corresponding TS to be the lowest energy.167 This study also points to the importance of the solvent, DMSO, in stabilizing the charge buildup that occurs. A further computational study analyzed the stereoselectivity of the proline-catalyzed aldol addition reactions of cyclohexanone with acetaldehyde, isobu-tyraldehyde, and benzaldehyde on the basis of a similar TS.168 Another study, which explored the role of proline in intramolecular aldol reactions, is discussed in the next section.169... 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

First, chemoselective (Chapter 24) conjugate addition of the silyl ketene acetal on the enone is preferred to direct aldol reaction with the aldehyde. Then an aldol reaction of the intermediate silyl enol ether on the benzaldehyde follows. The stereoselectivity results, firstly, from attack of benzalde-hyde on the less hindered face of the intermediate silyl enol ether, which sets the two side chains trans on the cyclohexanone, and, secondly, from the intrinsic diastereoselectivity of the aldol reaction (this is treated in some detail in Chapter 34). This is a summary mechanism. 

The stereoselective chelation-controlled aldol reaction of unsubstituted lithium ester enolates with (7 s)-2-(p-tolylsulfinyl) cyclohexanone A (Figure 16) led to a high enantio-face differentiation (> 90 < 10), while the simple diastereoselection was rather low for prochiral enolates567. The role of the lithium cation acting as a template is here essential, since sodium, potassium, HMPA or even added ZnCl2 resulted in decreased yield and selectivity. 

The hydrophobicity-driven association of reactant molecules in aqueous solution has even been found in aldol reactions. The trimethylsilyl ether of cyclohexanone adds to benzaldehyde in aqueous solution at 20 °C in the absence of a catalyst to give aldol addition products with a synlanti stereoselectivity opposite to that of the acid-catalyzed reaction carried out in dichloromethane [746]. 

The degree of stereoselectivity of aldol reactions of simple cyclohexanone enolates has been a subject of some confusion. For cyclohexanone itself, it has been reported that reaction of the lithium enolate with benzaldehyde gives Ae two isomeric aldols (Scheme 1) in ratios of 52 48 in THF at -78 C and 50 50 in dimethoxyethane at -20 C. On the other hand, Seebach reports ratios of 79 21 at -78 C and 85 15 at -150 C. ° Hirama and coworkers reinvestigated the reaction of the lithium enolate of cyclohexanone with benzaldehyde (Scheme 1) and found anti.syn ratios of about 82 18 at -78 C. The ratio is... 

Stotter has reported a study that suggests that the low stereoselectivity sometimes observed in aldol reactions of cyclohexanones results from significant aldolate equilibration. As shown in equation (63), the lithium enolate of l-azabicyclo[2.2.2]octan-3-one reacts with benzaldehyde to give, after normal... 

The attachment of proline and proline derivatives to dendrons was a further strategy used to attempt their recycling (Fig. 4.37). Thus, compact and expanded dendrimers functionalized with prolinamide units at the periphery such as system 189 were used in the aldol reaction of cyclopentanone and cyclohexanone with p-nitrobenzaldehyde, with a possible dendritic effect that inaeased the stereoselectivities observed with simple A -benzylproUnamide and G1 dendron 189 [271]. 

The proline-catalyzed aldol reaction of cyclohexanone (57) with 4-nitrobenzal-dehyde (2a) in DMSO affords the desired aldol anti-SSa with good yield but rather low stereoselectivity (Scheme 3.15) [14]. However, the addition of water led to an increase both in the yield and enantioselectivity, though the reaction rate remained [17]. 

In the same context, Trombini et al. developed other organocatalysts of this type bearing an imidazolium. Under solvent-free conditions, these catalysts were shown to be highly efficient at a remarkably low catalyst loading of 0.1 mol % to induce excellent stereoselectivities in the aldol reaction of cyclohexanone with aldehydes in the presence of water (Scheme 2.8). Moreover, exceptionally high values of TON (up to 930) were achieved in the case of the most reactive aromatic aldehydes. 

Interestingly, the stereoselectivity of reactions of cyclohexanone vith iso-butyraldehyde and benzaldehyde vere first predicted by using density functional theory calculations on models based on Houk s calculated transition state of the Hajos-Parrish-Eder-Sauer-Wiechert reaction [125]. The transition states of inter- and intramolecular aldol reactions are almost super-imposable and readily explain the observed enantiofacial selectivity. Relative transition state energies vere then used to predict the diastereo- and enan-tioselectivity of the proline-catalyzed reactions of cyclohexanone vith iso-butyraldehyde and benzaldehyde. The predictions are compared vith the experimental results in Scheme 4.30. The good agreement clearly validates the theoretical studies, and provides support for the proposed mechanism. Additional density functional theory calculation also support a similar mechanism [126, 127]. 

Enol stannanes of cyclohexanone and propiophenone have been indicated to take part in r/treo-selective aldol reactions with benzaldehyde at low temperatures e.g. —78 °C), but to be erythro-seAsciiwe at higher temperatures ca 45 °C). Two complementary methods have been described for stereoselection in aldol-type reactions. Whilst a-mercurio-ketones show eryr/wo-selection in their reactions with aldehydes in the presence of boron trifluoride diethyl etherate, pre-formed lithium enolates and aldehydes, in the presence of simple trialkyl-boranes, lead to mixtures that are rich in the more stable threo-d do product. Aldol-type products arise from 1,3-alkyl migrations of alk-l-enyl alkyl acetals and ketals, in a reaction that is catalysed by boron trifluoride diethyl etherate (Scheme 52). Diastereoselection is possible, since (.E)-alkenyl acetals give the... 

Houk and coworker have examined the stereoselectivily in a series of amino acids in an intramolecular aldol reaction using the DFT(B3LYP) computational tool [51]. They attributed increased conformational flexibility in the stereoselective bond forming transition state as the origin of the lower enantiomeric excess noted with acyclic primary amino acids. Himo, Cordova, and coworkers have used density functional theory computations to examine the stereocontroUing transition states for the (S)-alanine catalyzed intermolecular aldol reaction between cyclohexanone and para-nitrobenzaldehyde [52]. In a very recent study, Houk, Mahrwald, and coworkers compared the transition states of an asymmetric aldol reaction... 

Stereoselectivities of aldol reactions of trimethoxysilyl enol ethers catalysed by lithium binaphthoate are greatly affected by the presence of water, which may induce a change from anti- to iyn-adduct formation for those derived from cyclohexanone, for example. " Direct anti- and regio-specific aldol reactions of cyclododecanone with 0 benzaldehyde in NaOH/MeOH have provided building blocks for helical construction of supramolecules. ... 

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