Practical Access to 2-Alkylsuccinates through Asymmetric Catalytic Hydrogenation of Stobbe-Derived Itaconates

Abstract

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...

Unsymmetrical P-Chirogenic Bis(phosphane) Ligands: Their Preparation and Use in Rhodium-Catalyzed Asymmetric Hydrogenation

“…[1Ϫ5] Since DIOP was found to display high enantioselectivity in asymmetric hydrogenation catalyzed by rhodium complexes, it has been considered that C 2 -symmetrical bis(phosphane) ligands are endowed with superior catalytic properties. [6] A variety of C 2 -symmetrical ligands, such as DIPAMP, [7] BINAP, [8] DuPHOS, [9,10] BIPNOR, [11] and PennPHOS, [12] have indeed displayed superior asymmetric induction properties in an array of transition metal catalyzed reactions. On the other hand, it has also been shown that unsymmetrical bis(phosphane) ligands such as Josiphos, [13] Quinaphos, [14] Binaphos, [15] and others, [16,17] with different groups on the two phosphorus atoms, are effective for asymmetric hydrogenation in some cases.…”

Enantioselective Alkene Hydrogenation: Introduction and Historic Overview

“…DuPhos has been shown to be useful for the preparation of a-amino acid derivatives [222,[226][227][228][229][230][231][232][233][234][235][236][237][238][239][240][241], including b-branched examples that are not accessible with DIPAMP [222,242,243]. The catalyst system is also successful with enamides, enol acetates, unsaturated carboxylic, and itaconic acids [7,115,222,[244][245][246][247][248][249][250].…”

The Application of DuPHOS Rhodium(I) Catalysts for Commercial Scale Asymmetric Hydrogenation

“…This is demonstrated in the asymmetric hydrogenation of itaconic acid derivatives to give chiral succinates 17 (Fig. 11) [3]. This reaction is greatly accelerated by the presence of a sub-stoichiometric amount of base.…”

“…It is proposed that this facilitates the coordination of the resultant carboxylate group to the catalyst. A wide range of functionalities are tolerated as is the presence of E/Z isomers at the prochiral center [3]. On the contrary, itaconate derivatives with ester or amide functionalities on the b-carboxylate and the free a-carboxylic acid are not good substrates for rhodium DuPHOS catalysts, giving low conversion and selectivity.…”

“…Within the constraint of this geometric requirement a wide array of prochiral olefins have been demonstrated as suitable substrates for asymmetric hydrogenation with rhodium DuPHOS catalysts. Examples include enamides 2 [1,2], vinylacetic acid derivatives 3 [3], and enol acetates 4 [4].…”