Michael/aldol cascade

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. 

The intermediate enolate formed in a Michael reaction normally undergoes protonation to give the ketone product. However, in the presence of an aldehyde, a Michael/Aldol cascade can occur. Using the racemic Michael acceptor (11.41), Shibasaki has demonstrated an enantioselective and diastereoselective Michael/Aldol cascade involving the malonate nucleophile (11.42) and the aldehyde (11.43). The process also involves a kinetic resolution of the starting material. Not only is this a remarkable example of several aspects of stereoselectivity, the product (11.44) is a useful prostaglandin precursor. 

Scheme 1.1 Enantioselective Michael/aldol cascade reaction generating a quaternary stereocenter.

Scheme 7.8 Enantioselective triple Michael/Michael/aldol cascade reaction developed by Enders.

Scheme 7.9 Triple Michael/Michael/aldol cascade followed by one-pot intramolecular Diels-Alder reaction.

Scheme 7.10 Triple Michael/Michael/aldol cascade using 2-cyanoacrilates or alkyli-deneoxindoles as highly active electrophiles.

Hetero-Michael/aldol cascade reactions have been studied by several research groups using ort/zo-substituted benzaldehydes as functionalized reagents. In this context, different benzo-fused heterocyclic architectures have... 

Scheme 7.50 Sxilfa-Michael/aldol cascade for the synthesis of tetrahydrothiophenes.

Scheme 7.53 Sulfa-Michael/aldol cascade using ketones as internal electrophiles.

Scheme 7.57 Oxa-Michael/Michael/Michael/aldol cascade reaction for the synthesis of cyclohexenecarbaldehydes.

On the other hand, a triple Michael/Michael/Aldol cascade sequence has been developed for the synthesis of highly substituted cyclohexanes starting from dimethylmalonate, an a,p-unsaturated aldehyde and a nitroalkene in which H-bonding catalysis and iminium activation were jointly employed for the simultaneous activation of the two Michael acceptors involved in the... 

Recently, there has been considerable progress in the synthesis of nitrogen-containing heterocycles based on (ox)indole skeleton. Oxindole derivatives serve as useful reaction partners in various domino transformations. Michael addition of aliphatic aldehydes to electron-deficient olefinic oxindole motifs gave chiral intermediates, which were further combined with diverse activated olefins or imines to afford spirocyclic oxindoles with high molecular complexity (Scheme 8.27). Spiro-oxindole derivatives were also assembled by a Michael/Michael/aldol cascade of oxindole and two equivalents of enal. " ... 

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. 

The construction of polyheterocycHc spirotetrahydrothio derivatives via a sulfa-Michael/aldol cascade reaction appeared in the literature in the year 2014 (14TL6335).The authors were attraaed to tetrahydrothiophenes due to their ability to serve as building blocks in many pharmaceutical agents and natural products. Previously, methods for preparing tetrahydrothiophenes lacked generality and efficiency. These workers were able to prepare titled compounds by the reaction of various chalcones with 1,4-dithane-2,5-diol under mild conditions. A few examples are shown below.The latter reaction showed excellent diasteroselectivity in the presence of a chiral phase transfer catalyst. 

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. 

SCHEME 14.15. Enantioselective synthesis of tetiahydrothiophenes through sulfa-Michael-aldol cascade process between 2-mercaptoacetophenone and a,P-unsaturated aldehydes. 

SCHEME 14.17. Enantioselective synthesis of thiochromenes through sulfa-Michael-aldol cascade process using cycloalkenones, promoted hy different prolinol-derived catalysts. 

A BINAP-derived bifunctional thiophosphoramide gives >98% del>99% ee in Michael addition of cyclohexanones to both aryl- and alkyl-substituted nitroolefins. Imidazolylmethyl ketones undergo one-pot Michael-aldol cascade reactions with Q ,/3-unsaturated aldehydes in DCM at 20 °C using the simple organocatalyst, prolinol... 

Overview of Michael/Aldol Cascade Strategy for the Synthesis of Cardenolides... 

A rare Diels-Alder/aza-Michael/aldol cascade allows the formation of tetracyclic pyridocarbazoles derivatives from 3-vinylindoles and o,p-unsaturated aromatic aldehydes (Scheme 7.33) [51]. In this triple cascade, six stereogenic centers are formed, as well several new C-C bonds and one C-N bond, all with great efficiency and high stereoselectivities. 

Domino Sequences Involving Oxindoles as Pronucleophiles Another commonly used approach for the synthesis of spirooxindoles relies on the use of simple oxindoles as pronucleophiles with several Michael acceptors. For example, we developed a highly enantioselective methodology for the synthesis of spirooxindoles by a Michael-Michael-aldol cascade (Scheme 10.19) [30]. Simple 2-oxindole (58) undergoes two consecutive Michael reactions with enals 16 catalyzed by the Jprgensen-Hayashi catalyst I. Next, an intramolecular aldol reaction catalyzed by the same catalyst takes place to afford, after dehydration, the corresponding spirooxindoles 59. 

In the process, activation of a,P-unsaturated aldehydes by a chiral organocatalyst produces iminiums which trigger a Michael-aldol cascade process to afford intermediates which undergo spontaneous dehydration to give oc,p-unsaturated aldehydes 129. 

A thia-Michael/aldol cascade [92] of ot,P-unsaturated aldehydes with 3-mercapto a-carbonyl esters or l,4-dithiane-2,5-diol and aza-Michael/aldol reactions of a,P-unsaturated aldehydes with indole-2-carbaldehydes or pyrroles [93] was also developed. 

In 2011, a novel construction of bispirooxindoles in a Michael-aldol cascade was developed by Tan et al. In the presence of 20mol% of the novel multifunctional thiourea catalyst 162, 3-substituted oxindoles 160 and methyleneindolinones 161 smoothly underwent domino Michael-aldol reaction to give bispirooxindole derivatives 163 bearing three quaternary stereocenters with high enantio- and diaslereo-selective purity (Scheme 2.44) [63]. 

SCHEME 243 Chiral thiourea-catalyzed Michael-aldol cascade reaction. 

SCHEME 2.AA Asymmetric synthesis of bispirooxindoles via a Michael—aldol cascade. 

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

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