Stabilization of Proline Enamine Carboxylates by Amine Bases

Abstract

As part of our ongoing studies to provide an experimental basis for the improved understanding of organocatalytic reaction mechanisms we present a study on the influence of amine bases on enamine intermediate stabilization in proline catalysis. The (partial) deprotonation of the proline acid function is displayed by characteristic shifts of certain proton resonances and is also manifested by an increase of the amount of enamine intermediate upon reaching a critical pK(aH). Strong bases, such as 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), allow for outstanding enamine stabilization in various solvents and, hence, permit the detection of enamine species that have been inaccessible until now (illustrated by the observation of minor amounts of Z enamines). The in situ NMR detection of a prolinate-DBUH(+) ion pair supports the well-documented reversal of enantioselectivity of proline-catalyzed aminations in the presence of amine bases by disabling the bifunctional activity and switching to a "simple" stereocontrol effect (as known from the Jørgensen/Hayashi-type diarylprolinol ethers). In addition, the possibility of attractive ionic interactions between both the iminium ion and prolinate enamines available in the presence of strong amine bases suggests promotion of the Mannich pathway in aldol reactions to mainly form condensation products.

A revisit to proline-catalyzed amination under basic conditions: Insight into the key intermediates and stereocontrolling transition state models for the reversal of enantioselectivity

“…Very recently, Gschwind and co-workers have explored the base-induced effect on the equilibrium among the key intermediates in proline-catalyzed reactions and the in situ NMR techniques have helped them to confirm the dominant existence of the prolinate-DBUH + ion pair (intermediate III in Scheme 2) under strong basic conditions [12]. They have proposed that the formation of the ion pair leads to the great stabilization of the active intermediate, and this ion-pair form should be the key nucleophile and responsible for the reversal of the enantioselectivity in amination.…”

“…For the enamine-mediated process in proline catalysis, the widely accepted Houk-List transition state model (TSA in Scheme 1), which underlines that the proton of the enamine carboxylic acid (intermediate I in Scheme 2) plays an essential role in directing the electrophile approaching the above face of s-trans-enamine in the stereocontrolling addition step, has been successfully employed to rationalize the stereoselectivity of various reactions [2,[13][14][15][16][17][18][19][20][21][22][23][24][25]. Recently, several experimental evidences have shown that the reactivity and selectivity of the proline-catalyzed transformations are sensitive to the basic additives [7][8][9]11,12]. For instance, in 2007, Seebach and Eschenmoser demonstrated the key role of the strong basic additive (such as DBU) in the generation of the pivotal reactive intermediate (enamine carboxylate anion, intermediate II shown in Scheme 2) and explained the observed stereoselectivity in proline-catalyzed aldol and Michael reactions under basic conditions by the proposed oxazolidinone pathway (or enamine carboxylate model, TSB in Scheme 1), in which the negatively charged enamine carboxylate constitutes the nucleophilic species and the carboxylate-assisted addition of the electrophile to the below face of the s-cis-conformation of enamine intermediate II yields more stable exo-oxazolidinone product [7].…”

“…They have proposed that the formation of the ion pair leads to the great stabilization of the active intermediate, and this ion-pair form should be the key nucleophile and responsible for the reversal of the enantioselectivity in amination. Therefore, sufficient experimental studies aiming at the identification of the active intermediates and the mechanism in proline catalysis under basic conditions have been reported [7][8][9]11,12]. On the other hand, the pioneering quantum mechanical investigations associated with basic conditions for proline-catalyzed aldol, amination, and Michael reactions have been performed by Sunoj et al [19][20][21].…”

“…Although various organocatalysts have been developed to reach high level of efficiencies and to widen the scope of substrates, proline, owing to its good performance in a broad range of asymmetric transformations such as aldol [4], Mannich [5], and amination reactions [6] etc., has been identified as a universal catalyst and is still the hot topic in the field of organocatalysis [1][2][3][4][5][6][7][8][9][10][11][12]. For the enamine-mediated process in proline catalysis, the widely accepted Houk-List transition state model (TSA in Scheme 1), which underlines that the proton of the enamine carboxylic acid (intermediate I in Scheme 2) plays an essential role in directing the electrophile approaching the above face of s-trans-enamine in the stereocontrolling addition step, has been successfully employed to rationalize the stereoselectivity of various reactions [2,[13][14][15][16][17][18][19][20][21][22][23][24][25].…”

Organocatalyzed Cascade Reaction in Carbohydrate Chemistry

“…It is supposed that DBU stabilizes the intermediately formed proline enamine. Support for this consideration is given by analysis of corresponding NMR-experiments [82]. This condensation process is followed by a stereoselective ketalization dictated by the configuration of the 2-hydroxy group of the carbohydrate (K).…”