Cascade Michael-aldol reaction

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.

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

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. 

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... 

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

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

The Michael-aldol cascade reaction of2-mercaptobenzaldehyde with a,/ -unsaturated A-acyl imides (293) (R = alkyl, Ar, hetero-Ar), giving rise to thiochromanes (294), has been attained using the thiourea derivative (295) as a chiral organocatalyst. The key factor here is the presence of the pyrazole moiety as H-bond acceptor, which facilitates the activation and contributes to a better organization of the transition state. 

---