Asymmetric Biginelli Reactions

Simple phenyl substituents at the 3,3 -positions were sufficient to achieve high levels of enantiocontrol, which is in contrast to the substitution effect of many other BINOL phosphate-catalyzed reactions. Indeed, increasing the size of the 3,3 -sub-stituents resulted in both decreased yields and enantioselectivities. The synthetic utility of the catalytic asymmetric Biginelli reaction was demonstrated by the preparation of the active pharmaceutical ingredient monastrol (110a) in two steps... 

Gong LZ, Chen XH, Xu XY (2007) Asymmetric organocatalytic biginelli reactions a new approach to quickly access optically active 3,4-dihydropyrimidin-2-(lH)-ones. Chem Eur J 13 8920-8926... 

Huang YJ, Yang FY, Zhu CJ (2005) Highly enantioseletive biginelli reaction using a new chiral ytterbium catalyst Asymmetric synthesis of dihydropyrimidines. J Am Chem Soc 127 16386-16387... 

Wu YY, Chai Z, Liu XY, Zhao G, Wang SW (2009) Synthesis of substituted 5-(Pyrrohdin-2-yl) tetrazoles and their application in the asymmetric Biginelli reaction. Eur J Org Chem 904-911. 

Chen XH, Xu XY, Liu H, Cun LF, Gong LZ (2006) Highly enantioselective organocatalytic Biginelli reaction. J Am Chem Soc 128 14802-14803 Cordova A (2004) The direct catalytic asymmetric mannich reaction. Acc Chem Res 37 102-112... 

Scheme 11.19 Asymmetric Biginelli reaction catalysed by sulfonimides 22 and 23.

A novel, efficient, and recyclable asymmetric l-glycyl-3-methyl imidazolium chloride-copper(II) complex [Gmim]Cl-Cu(ll) was studied as a heterogeneous catalyst for the enantioselective Biginelli reaction (Karthikeyan et al 2013). The reaction was conducted under air atmosphere and solvent-free conditions, and the desired cyclized products were conveniently obtained in high yields with excellent enantioselectivities (up to 98% ee) (Scheme 4.60). 

The Biginelli reaction has also been the focus of an increased interest in the area of asymmetric organocatalysis especially for the development of more efficient procedures and rendering new chiral examples of this process [41]. Great improvements have been reached in this field [42, 43] compared with those obtained in the chiral metal version that has been little explored [37, 38]. 

Y. Huang, F. Yang, C. Zhu, J. Am. Chem. Soc. 2005, 127, 16386-16387. Highly enantioselective Biginelli reaction using a new chiral ytterbium catalyst asymmetric synthesis of dihydropyrimidines. 

For a recent pivotal review, see M. M. Heravi, S. Asadi, B. M. Lashkariani, Mol. Divers 2013,17, 389-407. Recent progress in asymmetric Biginelli reaction. 

The same catalyst (93) was applied with success to the first organocatalytic multi component asymmetric Biginelli reaction providing medicinally relevant chiral 3,4-dihydropyrimidini-2-(l//)-ones (94) (Scheme 29)7 Chiral acid-catalyzed inverse electron-demanding aza Diels-Alder reaction of aldimines (95) with electron-rich alkenes (Scheme 30). A new catalyst salt (96) that consist of an achiral ammonium ion and chiral phosphate anion has been developed that catalyzes highly... 

Table 13.23 Catalytic asymmetric three component biginelli reactions promoted by chiral Yb catalyst...

Sohn and colleagues [31] evaluated the use of L-proline esters (CAT-21, Table 4) in the Biginelli reaction. They also investigated the mechanism of CAT-21 asymmetric catalysis in such reactions. Initially, they evaluated three possible pathways that could influence the enantioselectivity observed for this reaction (Figure 7). One of these pathways involves the condensation of the aldehyde with mea leading to the formation of a chiral acyl imine. In this sense, the... 

In 2011, Li used a chiral calixarene (CAT-31) to perform an asymmetric version of the Biginelli reaction (Table 6). CAT-31 produced the Biginelli adducts in moderate yields and enantioselectivities (54% 44% ee). As possible additives, a piperidine-TFA salt and p-toluic acid were used to provide the Biginelli adducts in 42% yield and 68% ee. The monomer did not efficiently promote enantioselectivity in these reactions. From all tested aldehydes, those with substituents in the metfl-position had a better ee (80-98%), while those with substituents in the para-position had a lower ee (20-69%). The proposed mechanism by the authors involved the enamine intermediate, which interacts with the calixarene cavity in some manner, as confirmed by NMR experiments [42]. 

D.Z. Xu, H. Li, Y. Wang, Highly enantioselective Biginelli reaction catalyzed by a simple chiral primary amine catalyst asymmetric synthesis of dihydropyrimidines. Tetrahedron 68 (2012) 7867-7872. 

Furthermore, multicomponent reactions, as represented by Ugi reaction and Biginelli reaction, are attractive strategies for the selective construction of complex organic molecules from several simple starting materials in a single operation. Recently, Wang and Zhu et al. reported asymmetric synthesis of 5-(l-hydroxyalkyl)tetrazoles 60 from aldehydes, isocyanide, and hydrazoic acid via chiral salen-organoaluminum complex 59 catalyzed asymmetric Passerlni-type reaction (Scheme 43) [76]. 

Very similar results have also been reported with the use of sulfur ylides as donor molecules [179]. With regard to the asymmetric Biginelli reaction [180] and mulhcomponent coupling reachons [181] using 30 or its analog as a catalyst, only references are given here. 

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