Cinchona enantioselective protonation

In this chapter, all research works directly in relation with enantioselective protonations mediated by cinchona alkaloids are exemplified by schemes. Several publications related to this type of chemistry, but not using cinchona alkaloids, are mentioned for comparison purposes but are not illustrated. Therefore, the reader can easily differentiate the studies involving cinchona alkaloids from other publications of interest for a better overall view of the research field. 

Since the seminal work of Lucette Duhamel [3] in 1976 describing what is the first direct asymmetric protonation of an enolate (in fact its enamine analogue), it is only in 1992 that Takeuchi et al. successfully used a cinchona alkaloid for the enantioselective protonation of a particular samarium enediolate under mild conditions [4], Samarium diodide reduced benzil 1 into the corresponding enediolate 2, which was then enantioselectively protonated by quinidine 3 at room temperature, affording (R)-benzoin 4 in 91% ee (Scheme 7.3). The presence of molecular oxygen was necessary to obtain high selectivities. However, the procedure was not catalytic as 3 equiv of quinidine 3 were needed. Moreover, only one substrate was described showing the limits of this procedure. 

Recently, Levacher and coworkers developed the first organocatalytic enantioselective protonation of silyl enol ethers S using readily available cinchona alkaloids [5]. 

Despite the obvious potential of cinchona alkaloids as bifunctional chiral catalysts of the nucleophilic addition/enantioselective protonation on prochiral ketenes, no further contribution has appeared to date and only a few papers described this asymmetric reaction with other catalysts [13], When the reaction is carried out with soft nucleophiles, the catalyst, often a chiral tertiary amine, adding first on ketene, is covalently linked to the enolate during the protonation. Thus, we can expect an optimal control of the stereochemical outcome of the protonation. This seems perfectly well suited for cinchona analogues and we can therefore anticipate successful applications of these compounds for this reaction in the near future. 

Despite the importance of the Michael addition in organic synthesis, the tandem conjugate addition/enantioselective protonation has been little explored [14] and only a few publications have involved cinchona alkaloids as bifunctional catalysts B for controlling the configuration of the chiral carbon created during protonation (Scheme 7.9). 

Pracejus and coworkers reported the first Michael addition/enantioselective protonation mediated by cinchona alkaloids [15]. The authors put a special emphasis on the requirement of using chiral P-N,N-dialkylamino alcohol to achieve significant inductions. The addition of benzyl thiol 16 on 2-phthalimidoacrylate 17 catalyzed by 5 mol% of quinidine 3 gave the best selectivity (Scheme 7.10). 

Overall, cinchona alkaloids, which are already powerful (organo)catalysts in most major chemical reactions, will be expected to be major players in the enantioselective protonations of enols/enolates. This will persuade the synthetic chemist to incorporate these methodologies with confidence in total syntheses. 

Another group of cinchona alkaloids lacks the 6 -mclhoxy group. Cinchonine (7) and its diastereomer cinchonidine (5) are commercially available and have been used as catalysts in the addition of zinc alkyls to aldehydes (Section D. 1.3.1.4.). Cinchonidine and dihydrocin-chonidine (6) were used to modify the surface of platinum catalysts used in the enantioselective reduction of z-oxo esters to a-hydroxy esters (see Section D.2.3.1. for such applications). Dihydrocinchonidine may conveniently be obtained by catalytic reduction of the double bond of cinchonidine, e.g., with nickel and hydrogen7. Cinchonidine also acts as a catalyst in the enantioselective formation of C-S and C-Se bonds by the addition of thiols and selenols to activated alkenes, such as 1-nitroalkenes (Sections D.5. and D.6.). Another application is the enantioselective protonation of kelenes (SectionD.2.I.). 

The enantioselective protonation of silyl enol ethers, such as (12.39), by a catalyst has been achieved using 2 mol% of the proton source (12.40). The acidity of (12.40) is enhanced by coordination to a Lewis acid. The silyloxy group is activated by fluoride ion and up to 99% ee in the asymmetric protonation of a-aryl substituted cyclic silyl enol ethers such as (12.39) has been obtained using a Lewis acidic BINAP. / F complex.In a similar vein, silyl enol ethers of tetralones and indanones undergo asymmetric protonation with moderate to good ee using catalytic quantities of hydrogen fluoride salts of cinchona alkaloids in the presence of acyl fluorides and ethanol, which act as a stoichiometric source of HE 28... 

Catalytic enantioselective protonation of a-oxygenated ester enolates has been achieved via a phospha-Brook rearrangement, using a simple phosphite and a cinchona catalyst the process converts R R-C=0 R R C H-0P(0)(0Ar)2." ... 

Early in the 1960s, Pracejus and co-workers reported on the first enantioselective protonation of ketene through an alcoholysis of disusbstituted ketene 58a in the presence of cinchona alkaloid derivative Q (Scheme 31.20). Remarkably, high levels of selectivity were obtained when the methanolysis of methylphenylketene was conducted at 110°C in the presence of 1 mol% of 0-acetyl quinine Q. The enantioselection of the reaction was found to be highly temperature dependent indeed, at —40°C, racemic ester 59a was obtained. The authors explained this... 

Poisson T, Dalla V, Marsais F, Dupas G, Oudeyer S, Levacher V. Organocatalytic enantioselective protonation of silyl enolates mediated by cinchona alkaloids and a latent source of HP. Angew. Chem. Lnt. Ed. 2007 46 7090-7093. 

Claraz A, Leroy J, Oudeyer S, Levacher V. Catalytic enantioselective protonation of enol trifluoroacetates by means of hydrogenocarbonates and cinchona alkaloids. J. Org. Chem. 2011 76 6457-r6463. 

Quite surprisingly, whereas the chemistry of silyl enolates is considered as one of the cornerstones in organic synthesis, only a few papers have been devoted to organocatalytic enantioselective protonation of this class of substrates. The first organocatalyzed process was reported by Levacher et al. [33] by making use of cinchona alkaloids as catalysts and a latent source of hydrogen fluoride. The mechanism postulated by the authors is illustrated in Scheme 3.38. Basically, the reaction between benzoyl fluoride and ethanol in the presence of a catalytic amount of... 

Scheme 3.39 Enantioselective protonation of silyl enolates by means of cinchona alkaloids and a latent source of hydrogen fluoride...

Scheme 3.40 Mechanism for the enantioselective protonation of silyl enolates using cinchona alkaloids and carboxylic acids...

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

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). 

The use of compounds with activated methylene protons (doubly activated) enables the use of a mild base during the Neber reaction to 277-azirines. Using ketoxime 4-toluenesulfonates of 3-oxocarboxylic esters 539 as starting materials and a catalytic quantity of chiral tertiary base for the reaction, moderate to high enantioselectivity (44-82% ee) was achieved (equation 240). This asymmetric conversion was observed for the three pairs of Cinchona alkaloids (Cinchonine/Cinchonidine, Quinine/Quinidine and Dihydro-quinine/Dihydroquinidine). When the pseudoenantiomers of the alkaloid bases were used, opposite enantioselectivity was observed in the reaction. This fact shows that the absolute configuration of the predominant azirine can be controlled by base selection. 

In this chapter, we review the enantioselective proto nation of enols/enolates where the asymmetry is brought by cinchona alkaloids, either the natural products or some analogues. The cinchona alkaloids may act as a direct protonating agent of enolates or as an acid-base bifunctional catalyst by first deprotonating the substrate to generate the enolate and then, as an acid, by reprotonating the carbanion. 

Next to Muzart s work, Baiker and coworkers reinvestigated the reaction parameters of the palladium-catalyzed EDP of cyclic [i-kcto esters in the presence of various chiral proton sources including cinchona alkaloids [31]. When working with benzyl ester 55a as model compounds, they demonstrated the crucial effect of the solvent on the enantioselectivity of the reaction. In the palladium-catalyzed debenzylation of 55a carried out at room temperature with hydrogen, the highest conversions but the lowest enantioselectivities were achieved in protic polar solvents... 

---