The cinchona alkaloid-mediated opening of prochiral cyclic anhydrides in the presence of methanol leading to optically active hemiesters is described. Very structurally diverse anhydrides are converted into their corresponding methyl monoesters, and either enantiomer can be obtained with up to 99% ee by using quinine or quinidine as directing additive. After the reaction, the alkaloids can be recovered almost quantitatively and reused without loss of enantioselectivity. Additionally, a catalytic protocol which permits the substoichiometric use of quinidine in the presence of easily accessible pentamethylpiperidine (pempidine) is presented.

The useful combination of high catalytic activity and high enantioselectivity is provided by rhodium catalysts based on a new class of FerroTANE ligands when employed in the hydrogenation of itaconate derivatives (see scheme). Reactions performed at S/C ratio of 20 000 are complete within 3 h and directly afford valuable 2‐alkylsuccinamide products in up to 99 % enantiomeric excess.

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A convenient highly enantioselective methanolysis of cyclic meso-anhydrides only requires one equivalent cinchona alkaloid and low temperature. Both enantiomers can be easily obtained with up to 98% ee by using either quinine or quinidine.As yet, numerous enzymatic 2 and nonenzymatic 3-7 methods for the desymmetrization of meso-dicarboxylic acid derivatives have been developed. Although a few catalytic versions are known 3,7b most transformations of this kind require stoichiometric amounts of chiral reagents such as alcohols, 4 amines, 5 amino alcohols, 6 or titanium reagents (Ti-TADDOLates) 7a to accomplish high enantiotopic differentiation. In addition they suffer from moderate stereoselection, use of sophisticated enantiomerically pure compounds or complex reaction conditions. Given the findings of Aitken et al. 3a-b and Oda and coworkers 3c-d we developed a new stoichiometric method employing inexpensive and readily available cinchona alkaloids and methanol. With this convenient metal free procedure cyclic meso-anhydrides are easily transferred to their corresponding methyl monoesters with very high enantiomeric excess (ee) in excellent yield.In our initial studies, we screened the use of various cinchona alkaloids for the methanolysis 8 of anhydride 1. The highest enantiomeric excess for methyl monoester 2 was observed in reactions with commercially available quinidine. Quinidine derivatives, other chiral amino alcohols and tertiary amines gave lower asymmetric induction. Quinine, the pseudo-enantiomer of quinidine, provided the best stereoselection for the preparation of ent-2.Searching for the optimal reaction conditions we first examined the effect of the alkaloid amount on the enantioselectivity of the ring opening. Using anhydride 1 as test substrate we found that the enantiomeric excess of the product increased when larger quantities of the alkaloid were employed. The highest asymmetric induction was observed in reactions with one equivalent of quinidine. Thus, in toluene solution at ambient temperature (2R,3S)-2 was formed in 83% yield having 78% ee. It is noteworthy that more alkaloid did not lead to further improvement.Since the reaction medium often affects chemical transformations, 12 we also studied the influence of the solvent polarity on the ring-opening of 1. When the desymmetrization was performed in benzene or tetrachloromethane the highest asymmetric inductions were obtained. The enantiomeric excess still remained high when the solvent system toluene/CCl 4 1:1 was employed.Lowering the temperature also had a positive effect on the stereoselectivity. Eventually, the best results were obtained in reactions run at -50 °C in toluene/CCl 4 mixtures, using 1.1 eq. of the alkaloids. Thus, use of quinidine led to the formation of methyl monoester 2 with 98% ee. 9 Its enantiomer, ent-2, was obtained with the same enantiomeric excess using quinine as promoter. After acidic extraction of the reaction mixture no further purification of the crude methyl monoesters by chromatography or recrystallization...