Asymmetric domino reactions

In 2005, Ricci and coworkers published the first organocatalytic enantio-selective Friedel-Crafts allylation of indoles with nitroalkenes utilising simple thiourea 66. In general, moderate yields and enantioselectivities were observed for this difficult transformation, utilising 20 mol% catalyst 

In 2006, Berkessel and coworkers reported a new and improved iso-phoronediamine-derived bisthiourea organocatalyst for the asymmetric Morita-Baylis-Hillman reaction. Employing 20 mol% of catalyst 67 and N,iV,iV, iV -tetramethylisophoronediamine (TMIPDA) as base under neat reaction conditions, the adduct of 2-cyclohexen-l-one with cyclohex-anecarbaldehyde was obtained in 75% yield and 96% enantiomeric excess 

Seheme 19.81 Enantioselective nitro-Michael reaction employing thiourea 69. 

Berkessel, H. Groger, Asymmetric Organocatalysts, ed. A. Berkessel, H. Groger, Wiley-VCH, Weinheim, 2005. 

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The asymmetric domino reactions between 2-mercaptobenzaldehyde and a,fi-unsaturated aldehydes proceed with excellent chemo- and enantio-selectivities in the presence of (99) (20 mol%) as organocatalyst to afford 2//-l-benzothiopyrans (98) in high yields with 91-98% ee.145... 

Diastereo- and enantio-selective cascade of Michael addition and lactonization between various silyl enolates derived from phenyl carboxylates and -unsaturated ketones were successfully carried out by using an efficient organic catalyst, a cinchoni- dine-derived chiral quaternary ammonium phenoxide. In this asymmetric domino reaction, the corresponding tnms-3,4-dihydropyran-2-oncs were obtained in high yields with almost complete diastereoselectivities and good to excellent enantioselectivities.161... 

The asymmetric domino reaction between 2-mercaptobenzaldehyde and a,f)-unsaturated aldehydes proceeds with excellent chemo- and enantio-selectivities to afford 2-substituted 3-formyl-2//-l bcnzothiopyrans, products of a formal Baylis-Hillman reaction, when the. 9-proline derived catalyst 407 is employed (Scheme 123) <2006TL8547>. 

Scheme 2.49 Enders three-component catalytic asymmetric domino reaction.

Pellissier H. Asymmetric domino reactions. Part B Reactions based on the use of chiral catalysts and biocatalysts. Tetrahedron 2006 62 2143-2173. 

Asymmetric domino reactions based on the use of chiral auxiliaries 06T1619. 

Scheme 4.8 Au-catalyzed asymmetric domino reactions reported by Zhang.

The aza-Morita-Baylis-HiUman reaction is known to be a useful and atom-economical C-C bond-forming reaction of electron-deficient alkenes with imines usually catalyzed by Lewis bases [202]. It formally involves a sequence of reactions including a Michael addition, a Mannich reaction, a proton transfer, and a retro-Michael reaction ( -elimination). Although there are many reports in the field of the enantioselective aza-Morita-Baylis-Hilhnan reaction, only rare examples of asymmetric domino reactions initiated by this reaction have been reported. In 2010, Sasai et al. [203] developed the first organocatalyzed asymmetric domino aza-Morita-Baylis-Hillman/aza-Michael reaction of a,p-unsaturated carbonyl compounds with N-tosylimines, allowing an easy access to chiral cis-1,3-disubstituted isoindolines as single diastereomers. The process was induced by a Hg-BINOL-derived catalyst and provided these products in high yields and enantioselectivities, as shown in Scheme 10.18. 

In 2007, Chen, Deng, and co-workers [42] reported the first asymmetric domino reaction catalysed by primary amines. A primary amine derived from quinine catalyzed a Michael-Michael-retro-Michael cascade, where the two reagents (64 and 65) act alternatively and selectively as the Michael donor and acceptor under readily controllable conditions. The corresponding cyclohexenones 66 were obtained in good yields and excellent stereoselectivities (Scheme 10.20). However, an extra step was sometimes necessary in order to push the reaction and thus to obtain the cyclic products. In this case, the initial Michael adduct was treated with benzylamine and TEA to render the cycloadduct. 

On the other hand, several groups have also recently developed asymmetric domino reactions through relay catalysis with combinations of organocatalysts with ruthenium catalysts. For example. You et al. demonstrated in 2009 that ruthenium catalyst could be compatible with Bronsted acid catalyst. They reported a practical and economical synthesis of chiral tetrahydropyrano[3,4-b]indols and tetrahydro-p-carbolines by the combination of ruthenium-catalysed olefin cross-metathesis and a chiral phosphoric acid-catalysed Friedel-Crafts alleviation reaction, as shown in Scheme 7.41. This domino reaction allowed the use of readily available materials to highly enantioselectively construct synthetically valuable polycyclic indole frameworks in enantioselectivity of up to 94% ee. 

ASYMMETRIC DOMINO REACTIONS USING CHIRAL CARBOHYDRATE DERIVATIVES 3... 

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