Cinchona-catalyzed Mannich reactions

Soon after, the groups of Ricci [35] and Schaus [36] also employed a-amidosulfones as stable imine precursors in cinchona-catalyzed Mannich reactions. Ricci and coworkers reported [35] that, under PTC conditions (toluene/aqueous K2C03) using 75 as a catalyst (1 mol%), both the aliphatic and aromatic a-amido p-tolylsulfones 76 reacted with the malonates to afford the Mannich adducts 77 with high levels of enantioselectivity (85-99% ee) (Scheme 8.25). The subsequent decarboxylation/ transesterification of 77 gave the corresponding [3-amino acid derivatives without any alternation of the optical purities. The chiral dihydropyrimidones 80 were also successfully synthesized by Schaus and coworkers via the cinchonine catalyzed... 

Mannich Reaction Carbamate-protected alkyl imines are important building blocks in the synthesis of chiral alkyl amines. However, they are usually unstable, and most of them cannot be prepared in pure form. As the optimal substitutes, a-amido sulfones 142 were first used in the PTC-catalyzed enantioselective aza-Henry reaction in 2005 [57]. Subsequently, Song et al. reported a chiral Cinchona alkaloid thiourea (130b)-catalyzed Mannich reaction with in situ generation of... 

In addition to chiral PTCs, cinchona-based thioureas have also been proved to serve as catalysts for nitro-Mannich reactions. In 2006, Ricci and coworkers first reported that the quinine-based thiourea 40 (20mol%) can catalyze the aza-Henry reaction between nitromethane and the N-protected imines 93 derived from aromatic aldehydes [40]. N-Boc-, N-Cbz-, and N-Fmoc protected imines gave the best results in terms of the chemical yields and enantioselectivities (up to 94% ee at —40°C) (Scheme 8.30). 

Another catalytic application of chiral ketene enolates to [4 + 2]-type cydizations was the discovery of their use in the diastereoselective and enantioselective syntheses of disubstituted thiazinone. Nelson and coworkers described the cyclocondensations of acid chlorides and a-amido sulfones as effective surrogates for asymmetric Mannich addition reactions in the presence of catalytic system composed of O-TM S quinine lc or O-TMS quinidine Id (20mol%), LiC104, and DIPEA. These reactions provided chiral Mannich adducts masked as cis-4,5 -disubstituted thiazinone heterocycles S. It was noteworthy that the in situ formation of enolizable N-thioacyl imine electrophiles, which could be trapped by the nucleophilic ketene enolates, was crucial to the success of this reaction. As summarized in Table 10.2, the cinchona-catalyzed ketene-N-thioacyl-imine cycloadditions were generally effective for a variety of alkyl-substituted ketenes and aliphatic imine electrophiles (>95%ee, >95%cis trans) [12]. 

The enantioselective vinylogous Mannich reaction of siloxyfurans with ketimines catalyzed by a cinchona alkaloid amide/Cu(OAc)2 combination afforded furan-2(5fJ)-one containing contiguous tetra- and trisubstituted stereocenters with high selectivity (13AGE5557). 

The dual activation mode of the aforementioned cinchona alkaloid-derived thiourea catalysts proved to be highly effective in catalyzing the asynunetric Mannich reaction, among other transformations. These findings prompted the development of new, more simple bifunctional chiral catalysts that are predominately based on tra 5 -l,2-diaminocy-clohexane. For example, the application of the thiourea catalyst 120, which was developed by Takemoto and coworkers, afforded upon the reaction of Af-Boc-protected imines with diethyl malonate the desired chiral amines in good chemical yields (up to 91%) and enantioselectivities (98% ee) (Scheme 11.23) [81]. The catalytic mechanism presumably involves deprotonation and coordination of the active carbonyl compound by the chiral tertiary amine moiety. The formed enolate then attacks the si-face of the... 

SCHEME 11.21 Bifunctional cinchona aUcaloid/thiourea-catalyzed asymmetric Mannich reaction. 

Cinchona alkaloids with a thiourea group have also been applied for the asymmetric preparation of amino acid derivatives. Recent examples include an asymmetric Mannich reaction leading to P-amino ester derivatives with a benzoxazole moiety [77] and the formation of P-amino esters with a benzothiazole group [78]. The latter reaction was catalyzed efficiently by a C9 thiourea derivative (26) with a 2,6-dichloro-4-(trifluoromethyl)phenyl group connected to the thiourea group as shown in Scheme 6.34. 

Very recently. Song, Yang, and coworkers described a domino Mannich reaction catalyzed by a chiral thiourea derivative of a cinchona alkaloid (111 in Figure 42.5). They showed how amino-benzoxazoles 128 are viable amine components for the imine formation with aldehydes 127 in three-component Mannich reactions (Scheme 42.28) [70]. 

Zhang HL, Syed S, Barbas CFI. Highly enantio- and diaster-eoselective Mannich reactions of glycine Schiff bases with in situ generated A-Boc-imines catalyzed by a cinchona alkaloid thiourea. Org. Lett. 2010 12(4) 708-711. 

Later Schaus and co-workers used the cinchona alkaloid-derived thiourea catalyst 60 to catalyze the nucleophilic addition of both nitroalkanes (not shown) and dimethyl malonate to the Al-carbamoyl protected imines 46b, 61a-d to produce the corresponding Mannich adducts 62 in excellent yields and high enantioselectivities (Scheme 5.30) [41], The level of selectivity observed in these reactions is indicative of a catalyst-associated complex with a high degree of coordination. Modelling... 

The influence of pressure on organic reactions catalyzed by chiral metal-free organic molecules was studied for selected asymmetric Michael, Baylis-Hillman, aldol, Mannich, Friedel-Crafls, and Diels-Alder reactions-the essential part of this work was done in Japan. In the early stages of those investigations the high-pressure technique was applied to reactions catalyzed by cinchona alkaloids and in most cases low or moderate enantioselectivities were observed. Since 2002 some examples of high-pressure reactions catalyzed by proUne, thioureas, and modified cinchona alkaloids have appeared. 

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