Enantioselective cinchona-based chiral modifiers

Among the various strategies [34] used for designing enantioselective heterogeneous catalysts, the modification of metal surfaces by chiral auxiliaries (modifiers) is an attractive concept. However, only two efficient and technically relevant enantioselective processes based on this principle have been reported so far the hydrogenation of functionalized p-ketoesters and 2-alkanons with nickel catalysts modified by tartaric acid [35], and the hydrogenation of a-ketoesters on platinum using cinchona alk oids [36] as chiral modifiers (scheme 1). 

The efficiency with which modified Cinchona alkaloids catalyze conjugate additions of a-substituted a-cyanoacetates highlights the nitrile group s stereoselective role with the catalyst. Deng et al. [60] utilized this observation to develop a one-step construction of chiral acyclic adducts that have non-adjacent, 1,3-tertiary-quatemary stereocenters. Based on their mechanistic studies and proposed transition state model, the bifimctional nature of the quinoline C(6 )-OH Cinchona alkaloids could induce a tandem conjugate addition-protonation reaction to create the tertiary and quaternary stereocenters in an enantioselective and diastereoselective manner (Scheme 18). 

Substituted aliphatic and aromatic a-keto ethers (see Figure 2.7) are also amenable to enantioselective hydrogenation catalyzed by cinchona-modified Pt catalysts [34], However, as opposed to the achiral ketones discussed above, kinetic resolution is observed for these chiral substrates. At conversions of 20-42%, ee values of 91-98% were obtained when starting with a racemic substrate. While the very high initial ee values were impressive, it was also dear that this method with yields of less than 50% and gradually decreasing ee values is of little preparative value. The obvious solution was to attempt dynamic kinetic resolution in the presence of a base. Indeed, with OH -activated Amberlites dynamic kinetic resolution was observed. Both (R,S)-2-methoxy cyclohexanol and (R,S)-2-methoxy-l,2-diphenyl ethanol can be obtained... 

The development of the first highly enantioselective cyanocarbonation of prochiral ketones promoted by a chiral base catalyst, such as a cinchona alkaloid derivative, was reported by Tian and Deng in 2006. " Importantly, the reaction complemented known enzyme- and transition metal based methods in substrate scope via its unique ability to promote highly enantioselective cyanocarbonation of sterically hindered simple dialkyl ketones. Mechanistic studies provided experimental evidence to shed significant light on the asymmetric induction step in which the modified cinchona alkaloid acted as a chiral nucleophilic catalyst. Moreover, experimental evidence supported the mechanistic proposal that the enantioselectivity determination step in the cyanocarbonation was a DKR of the putative intermediates G and H via asymmetric transfer of the alkoxycarbonyl group (Scheme 2.105). 

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