Cinchona derivative

He et al. elaborated on the concept of cinchona derivatives and produced the ligands 9-amino(9-deoxy)epiquinine (96a) and epicinchonine (96b) (Scheme 4.44) [87]. The amines were tested with both Rh and Ir precursors for the ATH of ketones in PrOH/KOH. The best results were achieved using 96b as the ligand and [lr(cod)Cl]2 as the metal precursor, and for isobutyrophenone the conversion and enantioselectivity were obtained in 90 and 97% ee, respechvely. Later it was shown that the Ir complex of 9-amino(9-deoxy)epicinchonine 96b could be recovered in high yields with dilute HCl. The yields (90-94%) and enanhoselectivities of 1-phenylethanol (93-95% ee) were maintained with small variahons after six cycles [88]. 

Hypersensitivity or idiosyncrasy to quinidine or other cinchona derivatives manifested by thrombocytopenia, skin eruption or febrile reactions myasthenia gravis history of thrombocytopenic purpura associated with quinidine administration digitalis intoxication manifested by arrhythmias or AV conduction disorders complete heart block left bundle branch block or other severe intraventricular conduction defects exhibiting marked QRS widening or bizarre complexes complete AV block with an AV nodal or idioventricular pacemaker aberrant ectopic impulses and abnormal rhythms due to escape mechanisms history of drug-induced torsade de pointes history of long QT syndrome. 

While the oxygenation of alkenes represents the lion s share of methodology development, new and improved protocols for the [C=0 + C] approach to epoxides have also been reported. For example, the phase-transfer-catalyzed asymmetric Daizens reaction using the chiral Cinchona derivative 41 afforded spirocyclic epoxide 52 in good to excellent yields and fair to good ee s <99T6375>. 

The most promising results are offered by trifluoromethyl aminoalcohols as chiral ligands (entry 10). Cinchona alkaloids in the presence of pyridine (entry 7) and cinchona-derived surfactants (entry 6), which provide an asymmetric micellar microenvironment in aqueous solvents, are also worthy of note. 

Deng and co-workers have also applied the cinchona derivatives to the kinetic resolution of protected a-amino acid N-carboxyanhydrides 51 [48]. A variety of alkyl and aryl-substituted amino acids may be prepared with high se-lectivities (krei=23-170, see Scheme 10). Hydrolysis of the starting material, in the presence of the product and catalyst, followed by extractive workup allows for recovery of ester, carboxylic acid, and catalyst. The catalyst may be recycled with little effect on selectivity (run 1, krei=114 run 2, krei=104). The reaction exhibits first-order dependence on methanol and catalyst and a kinetic isotope effect (A MeOH/ MeOD=l-3). The authors postulate that this is most consistent with a mechanism wherein rate-determining attack of alcohol is facilitated by (DHQD)2AQN acting as a general base. 5-Alkyl 1,3-dioxolanes 52 may also... 

TABLE 10.2. Reactions with First- and Second-Generation Cinchona-Derived Catalysts... 

A number of other types of compounds have been used as chiral catalysts in phase-transfer reactions. Many of these compounds embody the key structural component, a P-hydroxyam-monium salt-type structure, which has been shown to be crucial to the success of the above described cinchona-derived quats. Although they have not been as successful as the cinchona catalysts, the ephedra-alkaloid derived catalysts (see 20, 22, 23 and 25 in Charts 3 and 4) have been used effectively in several reactions. In general, quats with chirality derived only from a single chiral center, which cannot participate in a multipoint interaction with other reaction species, have not been effective catalysts [80]. 

A caution has been noted for chiral PTC alkylations involving alkyl halides that can be easily reduced. Attempted alkylation of 35 with (bromomethyl)cyclooctatetraene with a chiral cinchona-derived catalyst gave only racemic product [20]. 

Promising examples of the catalytic asymmetric Darzens condensation, which yields an epoxide product via carbon-carbon and carbon-oxygen bond formation, have been reported recently by two groups (Scheme 10.11). Toke and co-workers used crown ether 24 in the reaction to form the a,P-unsaturated ketone 78 [38b] with 64% ee, whereas the Shioiri group used the cinchona-derived salt 3a [52], which resulted in 78 with 69% ee. The latter authors propose a catalytic cycle involving generation of a chiral enolate in situ from an achiral inorganic base... 

Lygo and Wainwright recently reported a detailed study of the asymmetric phase-transfer mediated epoxidation of a variety of acyclic a,P-unsaturated ketones of the chalcone type. The third-generation cinchona-derived quats (8c and 7c), related to those discussed earlier in the alkylation section and Scheme 10.4, gave the best inductions (89% ee, 88 to 89, Scheme 10.13 and 86% ee for the pseudoenantiomeric catalyst 7c to give, as product, the enantiomer of 89). 

Cinchona-Derived Chiral Phase-Transfer Catalysts for Amino Acid Synthesis... 

In particular, it is not only the cinchona alkaloids that are suitable chiral sources for asymmetric organocatalysis [6], but also the corresponding ammonium salts. Indeed, the latter are particularly useful for chiral PTCs because (1) both pseudo enantiomers of the starting amines are inexpensive and available commercially (2) various quaternary ammonium salts can be easily prepared by the use of alkyl halides in a single step and (3) the olefin and hydroxyl functions are beneficial for further modification of the catalyst. In this chapter, the details of recent progress on asymmetric phase-transfer catalysis are described, with special focus on cinchona-derived ammonium salts, except for asymmetric alkylation in a-amino acid synthesis. 

Silyl enolates are useful carbon nucleophiles in the asymmetric tandem Michael addition and lactonization (Scheme 3.3). Mukaiyama recently reported that cinchona-derived ammonium phenoxides act as activators (nucleophilic catalysis), to give highly stereocontrolled products [18-20]. In a typical PTC manner, most of the... 

Cinchona-Derived Chiral Poly(Phase-Transfer Catalysts) for Asymmetric Synthesis... 

Figure 4.2 Origin of stereoselectivity of cinchona-derived quaternary ammonium salts.

The development of polymeric cinchona-derived PTCs was triggered by the group of Jew and Park in 2001 [8]. The group paid particular attention to the fact that the cinchona alkaloids have demonstrated great utility in the Sharpless asymmetric dihydroxylation. Especially, it was noted that the significant improvements in both stereoselectivity and scope of the asymmetric dihydroxylation were achieved when the dimeric ligands of two independent cinchona alkaloid units attached to heterocyclic spacers were used, such as (DHQ)2-PHAL or (DHQD)2-PYR (Figure 4.4) [9]. 

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