Cinchona protonation

En route to the total synthesis of cinchona alkaloid meroquinene, a Hoffmann-La Roehe group took advantage of the Hofmann-Loffler-Freytag reaetion to funetionalize the ethyl side ehain in piperidine 49 to give ehloroethylpiperidine 51 via the intermediaey of protonated aminyl radieal 50. °... 

Japanese workers (50,51) were the first to observe optical activity in the addition of thiols to electron-poor olefins (eq. [9]) The e.e. was not determined, but these observations led us to attempt using a cinchona alkaloid as the catalyst in the addition of thiophenol to cyclohexenone. The reaction lends itself admirably to a scope, limitations, and mechanism study, and the results have been published in detail (19). An important mechanistic difference between the addition of the dodecanethiol to isopropenyl methyl ketone and the addition of thiophenol to a cyclohexenone (eq. [1]) lies in the sequence of chirality-producing steps. In the former case, chirality is produced when the proton adds to the a-caibon atom of the ketone—after thiol addition has taken place. In the latter... 

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 development of predictive transition state models for the interpretation of selectivity data pertaining to the use of cinchona alkaloid derivatives in all the processes described above is challenging due to the complex conformational behaviour of these natural scaffolds (for example, it is well known that 0-acylated quinidines undergo major conformational changes upon protonation) [223]. Consequently, hypotheses regarding the details of chirality transfer in these systems are notably absent. 

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. 

Fluorination of cinchona alkaloids has also been investigated. For instance, fluorination of quinine acetate under similar superacidic conditions (HF—SbFs/CHCls) affords a mixture of difluorocompounds in the 10 position that are ephners in 3 (60% yield, 1 1 ratio). This reaction involves a mechanism similar to the one described earlier (protonation, isomerization of carbenium ions, and Cl— F exchange). Curiously, when the reaction is performed on quinine itself, fluorination does not occur and an unprecedented rearrangement takes place (Figure 4.51). ... 

Moreover, bulk MIP was prepared [56] exhibiting diastereoselectivity for cinchona alkaloids. In the presence of MIP in solution, the cinchonidine fluorescence emission was hypsochromically shifted with the increase of the cinchonide concentration. That is, maximum of the fluorescence emission was at 390 nm in the absence of cinchonidine whereas it was at 360 nm at higher concentrations of cinchonidine. When cinchonidine was examined in the absence of MIP or in the presence of NIP, there was no spectral shift or this shift was negligibly small. This shift has been explained on the basis of protonation of the nitrogen atoms present in the cinchonidine structure. 

Addition of the thiophenolate anion to the / -carbon atom of the enone is the chirality-determining step it is, at the same time, rate-determining. The transition state is a ternary complex comprising the catalytic base in the protonated form, the thiophenolate anion, and the enone. The last is activated to nucleophilic attack by hydrogen-bonding to the catalysts / -hydroxy group. The chiral cinchona bases thus act as bifunctional catalysts. 

Later, the same group showed that a racemic open chain benzyl p-ketoester was also converted to the corresponding optically active ketone according to a similar procedure using cinchona alkaloids 21 or 22 as a chiral proton source [23],... 

Undoubtedly, the modification of the structure of the cinchona alkaloid also has a significant effect on its conformational behavior in solution esters [17] and 9-0-carbamoyl derivatives [21] exist as a mixture of two major anti-closed and anti-open conformers, while C9 methyl ethers prefer an anti-closed arrangement in noncoordinating solvents [17]. Here again, protonation provides the anti-open conformation as the sole stable form [16b]. In addition to the solvent polarity, many other factors such as intermolecular interactions are also responsible for the complex conformational behavior of cinchona alkaloids in solution. 

The group of Park and Jew developed the efficient reaction systems for the preparation of optically active a-alkylserine and a-alkylcysteine derivatives (Scheme 6.15) [40], The group developed the oxazoline-based substrate for serines 52a and the thiazoline-based substrate 52b for cysteines, respectively. The oxazoline and thiazoline moieties fulfilled a dual function the activation of the a-proton and the protection of both the amino and the side chain hydroxy groups. The ortho-biphenyl derivatives 52a and 52b were specifically designed for the cinchona PTC 54, and solid cesium hydroxide monohydrate was chosen as an optimal base. The PTC 29 was also found to be as effective as the PTC 54 for the asymmetric alkylation of 52a. 

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. 

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]. 

Pracejus also studied the tandem nucleophilic addition/diastereoselective protonation of optically pure (S)-phenylethylamine on phenylmethylketene [11], With the aim of synthesizing amino acids and their derivatives, Calmes and coworkers reinvestigated the reaction of prochiral ketenes (generated in situ from acid chorides in the presence of a tertiary amine) with (R)-pantolactonc, an a-hydroxylactone [12], The authors have shown that the diastereoselectivity is dependent on the base used. Particularly, triethylamine and quinuclidine afforded complementary results and the diasteromeric ratios observed with quinuclidine suggest that the high stereoselections could be observed in nucleophilic additions to prochiral ketenes in the presence of cinchona alkaloids. 

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). 

The hydrogenolysis/decarboxylation/asymmetric protonation reaction cascade of acyclic benzyl P-oxo-esters such as 47 catalyzed by Pd/C with H2 in the presence of a catalytic amount of cinchonine 43 afforded the (S)-ketone 48 with enantioselec-tivities up to 75% ee, similar to previous results obtained with other P-amino alcohols. The reaction was carried out at room temperature in a short reaction time [28]. The best solvent for both yield and ee was ethyl acetate, compared with acetonitrile and THF. Comparative performances of cinchona alkaloids with other commonly used P-aminoalcohols are displayed on Scheme 7.22. 

Access to optically active 2-fluoro-l-tetralone 53 was achieved using the same palladium-mediated cascade reaction [30]. The catalytic enantioseiective decarbox-ylative protonation of 2-fluoro benzyl P-keto ester 54 in the presence of 30 mol% of quinine 20 afforded enantioenriched (S)-tetralone 53 in 65% ee (Scheme 7.24). The reaction was very sensitive to the nature of the palladium catalyst used. Furthermore, a minor amount of defluorinated product was observed. Several other cinchona derivatives were tested including analogues of cinchonine described by Brunner in organocatalytic EDP (see Section 7.5.3), but these chiral inductors afforded low selectivities (<30% ee). 

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... 

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