Organocatalytic aldol-Michael reactions

Scheme 15 Use of organocatalytic aldol-Michael reactions to tetrahydrofurans by McQuade etal. [13]...

Scheme 2.63. Organocatalytic synthesis of 2-271 by a domino O-nitroso-aldol/Michael reaction.

One of the first synthetically useful organocatalytic C-N bond forming cycloaddition reaction came with the work of Yamamoto et al. [125] reported in 2004. Based on enamine activation, they developed the tandem 0-nitroso aldol/Michael reactions of cyclic enones to generate nitroso Diels-Alder adducts in moderate yields and high enantioselectivities (Scheme 11.44). 

Enantioselective organocatalytic conjugate additions such as Michael and aldol reactions have been intensely studied under new catalysts. However, only a few organocatalyzed Michael reactions have been developed. The reaction involves construction of a new C-N bond that is very attractive for syntheses of molecules with biological properties. 

Application of an organocatalytic domino Michael addition/intramolecular aldol condensation to the preparation of a series of important heterocycles has recently received much attention [158] with methods being disclosed for the preparation of benzopyrans [159-161], thiochromenes [162-164] and dihydroquinolidines [165, 166]. The reports all use similar conditions and the independent discovery of each of these reactions shows the robust nature of the central concept. A generalised catalytic cycle which defines the principles of these reports is outlined in Fig. 10. Formation of iminium ion 102 is followed by an intermolecular Michael addition of an oxygen, sulfur or nitrogen based nucleophile (103) to give an intermediate... 

Scheme 42 Organocatalytic domino Michael/aldol/intramolecular S 2 reactions...

The first organocatalytic intermolecular asymmetric aldol reaction was reported by List and coworkers in 2000 [23]. The aldol reaction between acetone and a variety of aldehydes was accomplished in excellent yields and high levels of e-nantioselectivity. For example, the aldol product of the coupling with o-butyral-dehyde was formed in 97 % yield and 96 % ee ((1), Scheme 4.10). The remarkable levels of selectivity sparked massive interest in the field of proUne-catalysed aldol, Michael and Mannich reactions. Later that year MacMillan reported a phenylalanine-derived catalyst (35) for the Diels-Alder reaction of a-P-unsaturated aldehydes with up to 94 % ee ((2), Scheme 4.10) [24]. Many further applications of... 

An organocatalytic (j0rgensen-Hayashi catalyst 1) domino Micliael/Michael/aldol condensation was used to prepare a hexahydronaphtlialenone (+)-121 m route to the natural product (+)-galbulin (Scheme 7.22). In this case, it was proposed that an iminium salt 118 (activated from the re face) and an enamine species 117 were preformed. Following a kinetic asymmetric transformation (KAT) of the racemic precursor 115, the intermediate 119 is first formed through an intermolecular Michael reaction. A second intramolecular Michael reaction occurs and the intermediate 120 forms, and finally an acid-initiated aldol condensation... 

Domino Processes with the Aldol Reaction as Subsequent Step 279 Table 8.6 Organocatalytic domino Michael/aldol reaction by Jorgensen et at. [23b]. 

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. 

P. Kotame, B.-C. Hong, J.-H. Liao, Tetrahedron Lett. 2009, 50, 704—707. Enantioselective synthesis of the tetrahydro-6//-benzo[c]chromenes via domino Michael-aldol condensation control of five stereocenters in a quadruple-cascade organocatalytic multi-component reaction. 

For other example of the use of same type of catalyst, in the obtainment of indole derivatives, see D. Enders, C. Wang, M. Mukanova, A. Greb, Chem. Commun. 2010, 46, 2447-2449. Organocatalytic asymmetric synthesis of polyfunctionalized 3-(cyclohexenyhnethyl)-indoles via a quadruple domino Friedel-Crafts-type/Michael/Michael/aldol condensation reaction. 

Wang, J., Li, H., Xie, H., Zu, L., Shen, X., Wang, W. (2007). Organocatalytic enantioselective cascade Michael-aldol condensation reactions efficient assembly of densely function-aUzed chiral cyclopentenes. Angewandte Chemie International Edition, 46, 9050-9053. 

Bor-Cherng, H., Nitin, S. D., Che-Sheng, H., Ju-Hsiou, L. (2010). Sequential organocatalytic Stetter and Michael-Aldol condensation reaction asymmetric synthesis of fuUy substituted cyclopentenes via a [I -l- 2 -I- 2] annulation strategy. Organic Letters, 12, 4812-4815. 

Jhuo, D.-H., Hong, B.-C., Chang, C.-W., Lee, G.-H. (2014). One-pot organocatalytic enantioselective Michael-Michael-Aldol-Henry reaction cascade. A facile entry to the steroid system with six contiguous stereogenic centers. Organic Letters, 16, 2724-2727. 

In what can be regarded as the earliest evidence for the participation of enamines in a proline-catalyzed aldol reaction and its in situ detection was provided by Metzeger and coworker. A combination of high-resolution MS/MS and ESI-MS methods could detect the condensahon product between prohne and acetone [9]. Furthermore, the evidence was strongly in favor of enamine as compared to the isomeric oxazolidinone. In a subsequent study, Seebach and coworkers using NMR and IR studies proposed that an oxazolidinone intermediate plays a vital role in asymmetric organocatalytic Michael reactions. Evidence for participation of bicychc as well as spirocyclic oxazolidinones in proline-catalyzed reachons was presented [10]. 

The asynunetric organocatalytic triple cascade reaction for the synthesis of telrasu-bstituted cyclohexene carbaldehydes developed by Enders et al. (Scheme 1.30) [40] is a milestone of organocatalytic cascade reactions. This three-component domino reaction proceeds by way of a catalyzed Michael-Michael-aldol condensation sequence affording products in good to moderate yields (25 to 58%). Notably, four stereogenic centers are formed with high diastereoselectivity and complete enantioselectivity. 

A similar organocatalytic quadruple domino Friedel-Crafts/Michael/Michael/ aldol condensation reaction initiated by Friedel-Crafts reaction of indole to acrolein was also developed by Enders et al. [48], as well as a microwave-assisted qnadruple cascade organocatalytic Michael/Henry condensation/Michael/aldol condensation anploying acetaldehyde and nitroalkenes as substrates [49]. 

Another impressive example of dienamine-iminium cascade catalysis was developed during the total synthesis of a-tocopherol 59 by Liu et al. [31]. This natural product is a member of the vitamin E family and possesses remarkable biological activity. The key step in the total synthesis of this natural product involved an organocatalytic aldol/oxa-Michael cascade reaction for construction of the core... 

Pulkkinen J, Aburel PS, Halland N, Jprgensen KA. Highly enantio and diastereoselective organocatalytic domino Michael-aldol reactions of (3-diketone and (3-ketosulfone nucleophiles with a,(3-unsaturated ketones. Adv. Synth. Catal. 2004 346(9-10) 1077-1080. 

Ramachary, D.B. Barbas, C.R III (2004) Towards Organo-Click Chemistry Development of Organocatalytic Multicomponent Reactions Through Combinations of Aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen Cycloaddition Reactions. Chemistry A European Journal, 10, 5323-5331. 

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