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Enantiomerically enriched 2-substituted succinic acid derivatives of general structure 2 have attracted great interest recently because of their utility as chiral building blocks and peptidomimetics in the design of pharmaceuticals, flavors and fragrances, and agrochemicals with improved properties. [1] Asymmetric catalytic hydrogenation of b-substituted itaconic acid derivatives (1) potentially offers one of the most convenient and practical routes to this class of compounds. No such catalyst system has yet been developed for the highly enantioselective synthesis of a diverse range of valuable 2alkylsuccinates of type 2.While asymmetric catalytic hydrogenation of the parent itaconates (1; R 3 , R 4 H) to 2-methylsuccinate derivatives has been accomplished with considerable cogency, [2] the ability to hydrogenate b-substituted itaconate derivatives with high enantioselectivities has remained challenging. Of the few examples documented thus far only b-phenyl and b-1naphthylitaconate derivatives have been hydrogenated with reasonably high enantioselectivity, and then only when the substrates 1 were employed as the pure E-geometric isomer. [3] The curtailed effectiveness of known asymmetric hydrogenation catalysts is particularly apparent when R 3 or R 4 , or both, of 1 is an alkyl group. Yet even less success has been reported for asymmetric hydrogenation of b,b-disubstituted itaconate derivatives (1; R 3 , R 4 =H), where the highest enantioselectivity recorded to date is 78 % ee. [4] We herein describe a broadly effective catalyst system that permits highly enantioselective hydrogenation of a wide array of b-substituted itaconate derivatives of type 1. Both b-aryl and b-alkyl substituents are tolerated, and the substrates may be employed as crude E/Z-isomeric mixtures. Moreover, a series of b,b-disubstituted itaconate derivatives have been hydrogenated with high enantioselectivites. A practical process has been developed for the production and isolation of enantiomerically pure 2-alkylsuccinates from crude products derived from the Stobbe recation.Most convenient access to either b-substituted or b,bdisubstituted itaconate derivatives involves a base-promoted Stobbe condensation reaction between dialkylsuccinates and aldehydes or ketones, respectively. [5] Unfortunately, the Stobbe condensation reaction typically leads to a mixture of E and Z isomeric itaconate products, which often are contaminated with varying quantities of deconjugated isomer (for example 3). The presence of geometric isomers can cause complications since the (E)-and (Z)-itaconate derivatives are likely to be hydrogenated with vastly different rates and enantioselectivites. [6, 7] Accordingly, separation of the (Z)-itaconate derivative from the favored E isomer typically is necessary prior to hydrogenation with most current catalysts. Moreover, the presence of isomerized substrate 3 in the mixture is potentially detrimental since any hydrogenation of this material necessarily will afford a racemic succinate product.We initially surveyed a...

A greatly improved process has been developed for synthesis of the glutarate derivative 2, a key intermediate required for Pfizer's drug candoxatril. The cationic (R,R)-Me-DuPHOS-Rh catalyst was found to allow highly efficient and enantioselective hydrogenation of a unique carboxylate substrate (5) to afford the desired product in >99% ee and high yield (95%). The robust nature of the process was validated on a 12 kg reaction scale. A novel mechanism for the hydrogenation process is proposed. Through use of a labile eta(6)-benzene-Rh-Me-DuPHOS complex, the postulated catalytic intermediates have been synthesized by independent means. Detailed spectroscopic analyses of these intermediates corroborate the mechanistic hypotheses. Interconversion of these key catalytic intermediates has been demonstrated.

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Mit weniger als 1 Mol‐% eines chiralen Vanadium‐Katalysators und wäßrigem H2O2 als Oxidationsmittel können unter einfachsten Reaktionsbedingungen Sulfide zu optisch aktiven Sulfoxiden (mit bis zu 85% ee) umgesetzt werden [Gl. (a)]. R, R′  Alkyl, Aryl .