Aldol asymmetric cascade reaction

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

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. 

Enders et al. [54] developed an asymmetric organocatalytic domino reaction of y-nitroketones 83 and enals. The reaction, catalyzed by compound VII, renders the final cyclohexene 84 via a Michael-Aldol cascade reaction followed by dehydration, with moderate yields and diastereoselectivities and good enantioselectivities (Scheme 10.23). Two years later, the same research group reported a related reaction starting from 2-(nitromethyl)benzaldehyde [55]. The reaction proceeds via a domino nitroalkane-Michael-aldol condensation reaction that leads to the final 3,4-dihydronaphthalenes in excellent yields and enantioselectivities. 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

SCHEME 2.11 Phosphoric add-catalyzed asymmetric cascade aldol-reduction reaction. 

SCHEME 2.46 Asymmetric synthesis of spiro-3,3 -cyclopropyl oxindoles via a Michael-aldol cascade reaction. 

The most impressive result of the catalytic Michael-aldol cascade is the kinetic resolution of the racemic cyclopentenone 458 shown in Sch. 64. The reaction is performed with 10 mol % (S)-ALB to give the tandem Michael-aldol adduct 459 in 97 % ee and 75 % yield based on malonate 390f. Asymmetric induction in 459 was measured after dehydration of the hydroxyl group, as was done for 451. Clearly, this demonstrates the viability of this new asymmetric strategy for the synthesis of a variety of fully functionalized prostaglandins. 

Enders described a fascinating organocatalytic one-pot asymmetric synthesis of tricyclic compounds using a triple-cascade/Diels-Alder reaction sequence. Combination of dieneal 110 with enal 111 and nitro alkene 112 in the presence of a chiral amine catalyst results in a Michael/Michael/aldol condensation sequence to yield cycloaddition precursor 113. Cooling the reaction mixture and addition of a Lewis acid promotes the desired intramolecular Diels-Alder reaction to selectively afford the highly functionalized tricyclic target 114. ... 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

D. B. Ramachary, M. Kishor, Org. Biomol. Chem. 2010, 8, 2859-2867. Direct catalytic asymmetric synthesis of highly functionalized tetronic acids/tetrahydro-isobenzofuran-1, 5-diones via combination of cascade three-component reductive alkylations and Michael-aldol reactions. 

It has been widely demonstrated that aldolases are important biocatalysts for the asymmetric carbon-carbon bond formation. This is because they possess the unique characteristics by which they can build up new polyfunctional molecular frameworks through the assembly of simple molecules. Particularly important in this point is to design biocatalytic cascade carboligation reactions by a sequential or one-pot combination of independent aldol additions catalyzed by different... 

Later, Ramachary and Sakthidevi reported for the first time the organo-catal)Aic cascade approach to the asymmetric synthesis of functionalised chromans via Barbas-List aldol-acetalisation reaction, as depicted in Scheme 2.28. The reaction of acetone with 2-hydro ybenzaldehyde under trans-4-OH-L-proline-catalysis in NMP as solvent furnished the corresponding aldol/lactol intermediate which upon treatment with p-TSA in methanol in one-pot furnished the selectively frans-2-metho y-2-methyl-chroman-4-ol in 55% yield and 77% ee, as shown in Scheme 2.28. 

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