Cascade reactions enantioselective organocatalytic

The triple Michael/Michael/aldol sequence developed by Enders shown in Scheme 7.8 can probably be considered as one of the most impressive demonstrations of the ability and power of enantioselective organocatalytic cascade reactions for the generation of molecular complexity from very simple and cheap starting materials." In this reaction, a nitroalkene, an enolizable aldehyde and an a,p-unsaturated aldehyde reacted with each other in the... 

Based on enantioselective epoxidation and subsequent ring opening and closing, the so-called Achmatowicz reaction was developed. This is an organocatalytic one-pot cascade for the annulation of a,(J-unsaturated aldehydes, hydrogen peroxide, p-carbonyl compounds and NBS, which furnish optically active 3-pyrones. Other chiral heterocycles were also assembled by organocatalytic cascade reactions using diaiylprolinol silyl ethers as catalysts. ... 

Recently, MacMillan reported a nine-step enantioselective total synthesis of (+)-minflensine via the key step reaction of organocatalytic Diels-Alder-cascade cyclization. Scheme 3.43 [58],... 

In recent years, several highly enantioselective organocatalytic two-component cascade reactions have been developed, leading to the synthesis of a five-member ring. 

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. 

One of the first highly enantioselective examples of multicomponent cascade reactions in orgnocatalysis was developed by Enders et al. [62] in 2006. In this report they describe an asymmetric organocatalytic triple cascade reaction for the construction of tetrasubstituted cyclohexenecarbaldehydes (93) starting from from enals (15), nitroalkenes (28), and enolizable aldehydes (94) (Scheme 10.27). In this work, they did the sequential creation of three bonds by a high enantioselective combination of enamine-iminium-enamine catalysis for a triple cascade reaction. 

In this chapter, the readers will be introduced in the different organocatalytic domino (or cascade) reactions that lead to the synthesis of C-C and C-heteroatom bonds. This type of reactions have found considerable applications in enantioselective heterocycle synthesis. The section has been organized by presenting first cascades initiated by a C-C bond formation and then presenting cascades initiated by a C-heteroatom bond formation. 

HongL, WangL, Sun WS, Wong KY, Wang R (2009) Organocatalytic AsymmetricEnede/-Crafts AUcylation/Cyclization Cascade Reaction of 1-Naphthols and a,P-Unsaturated Aldehydes An Enantioselective Synthesis of Chromanes and Dihydrobenzopyranes. J Org Chem 74 6881... 

Rueping M, Antonchick AR, Theissmann T (2006) A Highly Enantioselective Br0nsted Acid Catalyzed Cascade Reaction Organocatalytic Transfer Hydrogenation of Quinolines and Their Application in the Synthesis of Alkaloids. Angew Chem Int Ed 45 3683... 

New sulfur-containing spirocyclic scaffords were synthesized by two different enantioselective organocatalytic cascade reactions (13EJ07979). In the first synthesis, benzothiophene-2-one and an enal react in the presence of a secondary amine catalyst via a Michael-Aldol sequence to yield spiro-cyclo-hexenecarbaldehydes with excellent selectivities [20 1 diastereomeric ratios (dr) up to 20 1]. In the second reaction, the double Michael addition of ben-zothiophene-2-one to aromatic dieneones with primary amine catalysts yields the corresponding spiro-cyclohexanones with slighdy lower dr values. 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

D.-F. Yu, Y. Wang, P.-F. Xu, Tetrahedron 2011,67, iXl i-iTn. Organocatalytic enantioselective multicomponent cascade reaction facUe access to tetrahydropyridines with C3 all-carbon quaternary stereocenters. 

The first organocatalytic sulfa-Michael reaction of enals was reported by j0rgensen in 2005 [68]. In this report aliphatic and aromatic aldehydes reacted with several thiols in good yields and enantioselectivities under catalysis of 28. The products must be reduced immediately due to their fast epimerization at room temperature (Scheme 33.21). In this work, j0rgensen and coworkers also developed several multicomponent cascade reactions with good to excellent results. 

Organocatalysis have emerged recently as one of the cornerstones for the enanti-oselective synthesis of C-C or C-heteroatom bonds. Owing to the easy prediction of the stereochemical outcome of the reactions, iminium activation and specific Michael reactions is one of the most studied reaction types in organocatalysis. In the literature, we can find multiple approaches to the organocatalytic Michael reaction using different catalysts or nucleophiles, most of them with exceptional levels of stereoselectivity. Moreover, these simple additions to enals or enones have inspired multiple organocatalytic tandem and cascade reactions and, in our view, open up a new pathway for the enantioselective construction of complex scaffolds in one-pot procedures. 

Phosphoric acid 25a was successfully employed for mediating enantioselective synthesis of 1,3-disubstituted isoindolines from electrophilic bifunctional substrates (containing an imine and a Michael acceptor site) and indoles [33]. Catalyst 7a was used effectively in an organocatalytic asymmetric F-C alkylation/cyclization cascade reaction between 1-naphthols and a,(i-unsaturated aldehydes to give chro-manes in good yields and select vities (Scheme 3 5.18) [ 10]. Furthermore, 2-naphthols and p,y-unsaturated a-keto ester also reacted in a F-C alkylation/dehydration sequence, in the presence of a thiourea catalyst and a catalytic amount of concentrated sulfuric acid, affording optically active naphthopyran derivatives [54]. 

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. 

Rueping M, Antonchick AP, Theissmann T. A highly enantioselective Brpnsted acid catalyzed cascade reaction organocatalytic transfer hydrogenation of quinolines and their application in the synthesis of alkaloids. Angew. Chem. Int. Ed. 2006 45 3683-3686. 

In the intensively studied field of multicomponent reactions (MCRs), one can highlight several interesting cascades involving successive C-N and C-C bond formations. It is important to note that, although the majority of these sequences such as the Hantzsch, the Biginelli, or the Mannich reactions are known for more than one century, their organocatalytic enantioselective versions have been disclosed only very recently. 

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