Michael/aldol condensation

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

J0rgensen has also reported a sequential Michael/Michael/aldol condensation for the three component coupling of malonitrile 111 and a,P-unsaturated aldehydes that involves two iminium ion catalysed Michael additions followed by an intramolecular aldol condensation (Scheme 43) [170]. Using diarylprolinol ether 55 (10 mol%) in a concentrated toluene solution of malonitrile 111 and 3 equivalents of a,P-unsaturated aldehyde the reaction products can be isolated in just 1 8 h (57-89% yield 97-99% ee). The atom efficiency of this three component reaction is remarkable and the ability to prepare these complex products under... 

Scheme 43 Multicomponent Michael/Michael/aldol condensation reaction...

J. A. Bacigaluppo, M. I. Colombo, M. D. Preite, J. Zinczuk, E. A. Ruveda, The Michael-Aldol Condensation Approach to the Constmction of Key Intermediates in the Synthesis of Terpenoid Natural Prod-ucts, Pure Appl. Chem. 1996, 68, 683. 

The assembly of the cyclohexene derivatives D should be feasible via an organocatalyzed domino Michael/Michael/aldol condensation sequence starting from a linear aldehyde A, a nitroalkene B and an a,(->-unsaturated aldehyde C. 

The horizontal approach for the DEF synthon was more rewarding due to its simplicity and more importantly due to its straightforwardness. The easily obtainable acetylene precursor 107 underwent synchronous Michael-aldol condensation reaction with dimethyl acetone dicarboxylate to give 108 which was smoothly transformed into 86a (Scheme 22). 

Chiral cyclohexene derivatives were also constructed by an asymmetric four-component quadruple domino reaction initiated by oxa-Michael addition of alcohols to acrolein. The other two components were another equivalent of acrolein and a nitroalkene. Enders has shown that cyclohexene derivatives can also be assembled by a domino reaction of y-nitroketones and enals. Domino Michael/aldol condensation of 5-oxoalkanals and a,p-unsaturated aldehydes afforded densely functionalised cyclohexenes. Combination of unsaturated aldehydes with unsaturated p-ketoesters resulted in the formation of chiral cyclohexene derivatives via a Michael/ Morita-Baylis-Hillman sequence (Scheme 8.21). ... 

In 2010, Enders and co-workers developed a quadruple cascade AFC/ Michael/Michael/aldol condensation reaction of indoles, acrolein, and nitroalkenes under the catalysis of diphenylprolinol TMS-ether catalyst (S)-104 following an iminium/enamine/iminium/enamine activation sequence (Scheme 6.42). " The reaction provided a straightforward and efficient entry to 3-(cyclohexenylmethyl)-indoles 105 bearing three stereogenic centers in moderate to excellent yields (23-82%) and excellent stereoselectivity (91 9->95 5 dr and 94->99% ee). 

Through a domino oxa-Michael-aldol condensation reaction, a range of 2-substituted 3-formyl-2E/-chromenes were prepared from salicylaldehydes and a,p unsaturated aldehydes catalyzed by a diphenylperhydro indoUnol... 

Having precursor 407 in hand. Brooks et al. were able to synthesize anguidine (376) in a further 17 steps. Thus, precursor 407 was converted into enamine 409, which was hydrolyzed to hydroxymethylene derivative 410. Michael reaction with butanone afforded the exo product 411. Followed by an intramolecular Michael aldol condensation, enone 412 was obtained, which was methylated to the allyl alcohol 413 using methyl iodide. Subsequent reduction with Ufliium aluminum hydride led to tetraol 414. This was converted to the triacetate and selectively deprotected to diol 415. Acid-catalyzed cycUzation and protection of the free OH group afforded the trichothecene skeleton 416. Afterwards, the acetal 416 was deprotected and the ketone was reacted in a Wittig reaction to the olefin, which was treated with TBAF to afford compound 417. Epoxidation with /n-CPBA, followed by acetylatiOTi and final mono-deprotection, afforded the trichothecene, anguidine (376) (Scheme 8.4). 

Fukumoto and coworkers [45, 46] have observed a threefold domino SN/Michael/aldol condensation reaction on treatment of an acetylcyclopropane... 

The combination of an imine derived from the reaction of acrolein organocatalyst 1 with simple indoles 84 and nitroalkenes 85 affords the 3-(cyclohexenylmethyl)-indoles 86 (Scheme 7.16) [59]. In this reaction, the indole 84 initiates the Friedel-Crafts-type reaction followed by a Michael reaction with nitroalkenes 85 to the intermediate 87. From this process, a hydrolysis takes place and the resulting compound enters another catalytic cycle involving a Michael/aldol condensation reaction similar to those reported previously. 

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... 

Scheme 7.36 Domino oxa-Michael-aldol condensation reactions.

Scheme 7.39 Erase s domino oxa-Michael-aldol condensation.

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. 

Enders et al. [75] developed a synthesis of polyfunctionalized 3-(cyclohex-enylmethyl)-indoles 125 via a quadruple domino Friedel-Crafts-type Michael-Michael-aldol condensation reaction, in 2010. This cascade sequence is initiated by a Friedel-Crafts reaction of indole (126) by an iminium activation mode to the enal, followed sequentially by an enamine- and an iminium-mediated Michael addition. After an intramolecular aldol-condensation, four C-C bonds are formed and the domino product is constructed bearing three contiguous stereogenic centers (Scheme 10.34). 

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. ... 

Relying, as in the previous studies, on the capability of secondary amine catalysts to activate both nucleophile and electrophile, Enders assembled a quadruple domino Friedel-Crafts-type/Michael/Michael/aldol condensation sequence, affording an efficient and direct asymmetric synthesis of polyfunctionalized 3-(cyclohexenylmethyl)-indoles 172 with moderate to high yields (Scheme 2.55) [82]. 

SCHEME 2.55 Enders s Friedel-Crafts-type/Michael/Michael/Aldol condensation domino sequence. 

SCHEME 2.79 Oxa-Michael/Michael/Michael/aldol condensation on the first total synthesis of (+)-conicol 232. 

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. 

Hong and coworkers have demonstrated the three-component organocatalytic oxa-Michael-Michael-Michael-aldol condensation of a,p-unsaturated aldehyde 84 with 2-(( )-2-nitrovinyl)benzene-l,4-diol (83), as the key step in the total synthesis of (+)-conicol 89 (Schane 6.11) [31],... 

The reaction started with the tandem oxa-Michael-Michael reaction of 83 and 84 to give 87 in 76% yield and greater than 99% ee. The following Michael-aldol condensation with 4,4-dimethoxy-but-2-enal 85 works nicely in 69% yield and also excellent enantioselectivity. The obtained hexahydro-6//-benzo[c]chromene 88 is a highly functionalized intermediate in the total synthesis of (+)-conicol 89. The two-step reaction could be achieved in one pot from 83 and 84, without isolation of the intermediate 87, with a 55% overall isolated yield of 88. 

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