Quinidine catalysis

Phase-transfer catalysis has been widely been used for asymmetric epoxidation of enones [100]. This catalytic reaction was pioneered by Wynberg et al., who used mainly the chiral and pseudo-enantiomeric quaternary ammonium salts 66 and 67, derived from the cinchona alkaloids quinine and quinidine, respectively [101-105],... 

BQC is derived from quinine, which is a member of the cinchona family of alkaloids. Ammonium salts derived from quinidine, a diastereomer of (1) at the hydroxyl substituent, have been used less frequently in catalysis than BQC. Quini-dinium salts often give rise to products with enantioselectivity opposite to that from (1). Other related compounds, such as those derived from cinchonine and cinchonidine (which lack the methoxy substituent on the quinoline nucleus), have found application in organic synthesis. The cinchona alkaloids, as well as salt derivatives in which the benzyl group bears various substituents, have also been studied. Results from polymer-bound catalysts have not been promising. ... 

Chiral Catalysis. Brucine has been utilized as chiral catalyst in a variety of reactions. For example, its incorporation into a polymer support provides a chiral catalyst for performing enan-tioselective benzoin condensations. It has also been used as a chiral catalyst in the asymmetric synthesis of (I )-malic acid via the corresponding p-lactone, which results from the asymmetric cycloaddition of chloral and ketene (eq 12). Though brucine yields malic acid with 68% ee, quinidine was found to be a more selective catalyst (98% ee). 

As mentioned in the previous section, nowadays, readily available and inexpensive cinchona alkaloids with pseudoenantiomeric forms, such as quinine and quinidine or cinchonine and cinchonidine, are among the most privileged chirality inducers in the area of asymmetric catalysis. The key feature responsible for their successful utility in catalysis is that they possess diverse chiral skeletons and are easily tunable for diverse types of reactions (Figure 1.2). The presence of the 1,2-aminoalcohol subunit containing the highly basic and bulky quinuclidine, which complements the proximal Lewis acidic hydroxyl function, is primarily responsible for their catalytic activity. 

From a variety of X-ray crystal studies (e.g., didehydro-QCI/QCD and didehydro-quinidine), we have established that alkyne quinuclidines are twisted consistently less than the vinyl and ethyl analogues. Overall torsion angles, that is, the sum of the three torsion angles, vary from 26 to 49° compared with up to 65° for ethyl and 60° for ethenyl derivatives, respectively (Figure 12.3). Fine-tuning of nitrogen polarity (and basicity), which may be important for catalysis and perhaps pharmacological activity, is thus possible ([28] R. Wartchow, personal communication). 

An alternate to the use of Lewis acids is the employment of amine catalysts in the MBH reaction. Hatakeyama and coworkers have used the quinidine (7.164) as a catalyst in the MBH reaction of both aromatic aldehydes such as ben-zaldehyde (7.17) and aliphatic aldehydes with the acrylate (7.165). In all cases ees are high (91-99%), but yields are moderate. This amine has also been applied to the catalysis of the aza-Bayhs-HiUman reaction of methylvinyl ketone (MVK) and methyl acrylate with N-tosylarylaldimines giving the product with high ee. ... 

Asymmetric cycloaddition of ketene to chloral catalyzed by quinidine gives an (R)-product which on hydrolysis undergoes inversion of the absolute configuration to (S)-malic acid, and vice versa for catalysis by quinine. This reaction allows convenient access to either enantiomer of malic acid (Kilenyi and Aitken, 1992). 

The Plaquevent group achieved a new and efficient method for the approach to both enantiomers of methyl dihydrojasmonate 47 by asymmetric Michael addition under solid-liquid phase-transfer catalysis. The main advantages of their procedure are the solvent-free system and the creation of two contiguous stereogenic centres in one step. The authors proposed a plausible mechanism with a transition state composed of substrate 45 and catalyst, quinine-, or quinidine-derived PTC catalyst (48a, 49a), in which hydrogen bonding ensures the proximity of the reactive centres and significantly stabilises the transition state (Scheme 16.14). ... 

The mechanism of enamine catalysis has been established the enamine is the active form of nucleophile. Other modes of activation are less developed and are limited to a certain group of donors and acceptors. Quinidine was found to catalyze the reaction of hydroxyacetone with aldehydes to yield the desired 5y -aldols with moderate diastereoselectivity and low enantioselectivity [169]. This represents the first example of a tertiary amine catalyzing the direct aldol reaction. Even (3, y-unsaturated a-keto ester 154 was successfidly coupled with protected hydroxyacetone 51 in the presence of 20 mol% of 9-amino-9-deoxy-cpi-cinchonine 155 and a small amount of TEA (Scheme 3.27). 

Most reports on organocatalytic sulfa-Michael reactions are based on Br0nsted base catalysis, in order to activate pro-nucleophiles containing a S H or a Se—H bond. The early works, appeared in the lates 1970s, featured natural cinchona alkaloids 1-4 as basic catalysts (Figure 14.1). In their seminal works, Wynberg and co-workers employed less than 1 mol% of quinine 1 as chiral catalyst for the conjugated addition of arenethiols to 2-cyclohexen-l-ones. The enantiocontrol was unsatisfactory with benzyhnercaptan [6]. The quasi-enantiomeric catalyst quinidine 2 furnished the... 

Later, an enantioselective one-pot tandem Mannich-hydroamination reaction was reported by Liu and co-workers on the basis of a sequential organo- and gold catalysis.The proeess involved propargylated malonitrile and oxindole imine derivatives as substrates and employed a chiral cinchona alkaloid, such as a quinidine phenol derivative, to induce the enantioselective Mannich reaction and a gold catalyst, such as XPhosAuNTfa... 

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