Cinchona alkaloid catalysis

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

Fig. 6.3 Wynberg s model of bifunctional cinchona alkaloid catalysis.

Wang Y, Liu XF, Deng L (2006) Dual-Function Cinchona Alkaloid Catalysis Catalytic Asymmetric Tandem Conjugate Addition-Protonation for the Direct Creation of Nonadjacent Stereocenters. J Am Chem Soc 128 3928... 

Domino Michael-cyclisation reaction catalysed by chiral cinchona alkaloid catalysis and silver catalysis. 

Scheme 7.57 Tandem Heck-dihydrotylation reaction catalysed by palladium, osmium, and tungsten catalysis and chiral cinchona alkaloid catalysis.

Scheme 7.65 Tandem Mannich-hydroamination reaction catalysed 1 chiral cinchona alkaloid catalysis and gold catalysis.

Michael donors and acceptors are common components in Brmsted base-mediated catalysis. Such transformations offer an uncomplicated route towards all-carbon quaternary stereocenters. In the most basic form, a,P-unsaturated aldehydes are highly reactive templates towards nucleophilic reactions. Under such conditions, mechanistic studies show no polymerization of the unsaturated aldehydes under cinchona alkaloid catalysis [10]. This absence of polymerization is a key mechanistic indicator that the quinucHdine nitrogen of the catalyst does not act as a nucleophilic promoter. Rather, the quinucHdine nitrogen acts, as predicted, in a Bronsted basic deprotonation-activation of various cyclic and acyclic... 

Wang Y, Liu X, Deng L. Dual-function cinchona alkaloid catalysis catalytic asymmetric tandem conjugate addition— protonation for the direct creation of nonadjacent stereocenters. J. Am. Chem. Soc. 2006 128(12) 3928-3930. 

The enantioselective hydrogenation of prochiral substances bearing an activated group, such as an ester, an acid or an amide, is often an important step in the industrial synthesis of fine and pharmaceutical products. In addition to the hydrogenation of /5-ketoesters into optically pure products with Raney nickel modified by tartaric acid [117], the asymmetric reduction of a-ketoesters on heterogeneous platinum catalysts modified by cinchona alkaloids (cinchonidine and cinchonine) was reported for the first time by Orito and coworkers [118-121]. Asymmetric catalysis on solid surfaces remains a very important research area for a better mechanistic understanding of the interaction between the substrate, the modifier and the catalyst [122-125], although excellent results in terms of enantiomeric excesses (up to 97%) have been obtained in the reduction of ethyl pyruvate under optimum reaction conditions with these Pt/cinchona systems [126-128],... 

In the second chapter, Hans Wynberg describes one facet—namely asymmetric catalysis—of the currently very active field of asymmetric synthesis. Wynberg and his co-workers have devised efficient asymmetric syntheses catalyzed by cinchona alkaloids. Several of these reactions are reviewed and rationalized by means of mechanistic models. 

The catalyst is a combination of a chemo-catalyst and a natural product taken from the cinchona alkaloids giving amazing results. In phosphine catalysed asymmetric catalysis these types of structures are lacking, as nature does not produce phosphines ( ) and the phosphines used in the early years of development of asymmetric homogeneous catalysis lacked the complexity of... 

Enantioselective hydrogenation of a-ketoesters on cinchona alkaloid-modified Pt/Al203 is an interesting system in heterogeneous catalysis [143-146], The key feature is that on cinchonidine-modified platinum, ethyl pyruvate is selectively hydrogenated to R-ethyl lactate, whereas on einchonine-modified platinum, S-ethyl pyruvate is the dominant product (Figure 16) [143]. 

In this chapter, we discuss recent (reported mainly during 2000-2005) asymmetric reactions catalyzed by chiral bases. Because practicality is an important factor in the present asymmetric catalysis, we restricted our discussion mainly to the reactions giving over 90% ee unless the conversion is novel. We notice, however, that there are many potentially useful and scientifically interesting reactions, in which enantioselectivity does not exceed the practical range at this moment. Chiral organic base (proline and cinchona alkaloids)-catalyzed reactions were discussed in Chapter 11 by Lelais and MacMillan. 

The advent of chiral Brpnsted base catalysis began with the recognition that the Cinchona alkaloids serve as excellent catalysts [7-12] and privileged structures... 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

---