Cinchona optimization

The most common chiral auxiliaries are diphosphines (biphep, binap and analogues, DuPhos, ferrocenyl-based ligands, etc.) and cinchona and tartaric acid-derived compounds. It is clear that the optimal chiral auxiliary is determined not only by the chiral backbone (type or family) but also by the substituents of the coordinating groups. Therefore, modular ligands with substituents that can easily be varied and tuned to the needs of a specific transformation have an inherent advantage (principle of modularity). 

Much work [42] has been devoted to cinchona alkaloid modified Pd and Pt catalysts in the enantioselective hydrogenation of a-keto esters such as ethyl pyruvate (Scheme 5.11). Optimal formulation and conditions include supported Pt, the inexpensive (—)-cinchonidine, acetic acid as solvent, 25 °C and 10-70 bar H2. Presently, the highest e.e. is 97.6% [to (R)-ethyl lactate]. 

Coenegracht et al. [3] have introduced a four solvent system to compose mobile phases for the separation of the parent alkaloids in different medicinal dry plant materials, like Cinchona bark and Opium. Through the use of mixture designs and response surface modeling an optimal mobile phase was found for each type of plant material. These new mobile phases resulted in equally good or better separations than obtained by the procedures of the Pharmacopeias. Although separations were as predicted, the accuracy of the quantitative predictions needed to be improved. 

As (—)-cinchonidine-derived ammonium salts have been mainly used as chiral PTCs in monomeric cinchona-PTCs via the asymmetric alkylation of 1, and have generally shown better results than those of others [e.g., derived from (+)-cinchonine, (—(-quinine, and (+)-quinidine], the Park-Jew group primarily prepared (—) -cinchonidine derivatives to identify both the optimal linker and best relationship of attachment for the two cinchona units, and to compare catalytic efficiency with that of monomeric cinchona-PTCs. 

By screening solvent and inorganic bases to establish the optimal reaction conditions for dimeric chiral PTCs, a toluenexhloroform (7 3, v/v) solvent system and a 50% aqueous KOH base were found to afford the best enantioselectivity and chemical yield within a reasonable reaction time. As dimeric cinchona-PTCs are very poorly soluble in toluene (one of the popular solvents in asymmetric alkylation), this might act as an obstacle for the catalyst to show its maximum ability. However, the addition of chloroform to toluene provided better results due to an improved solubility of the dimeric PTC. This difference in ability to dissolve the dimeric PTC might be heavily associated not only with the reaction rate but also with the chemical/ optical yield. However, the use of chloroform alone proved to be inadequate as an optimal solvent [10]. 

During the search for the optimal dimeric PTC for this epoxidation, the Park-Jew group found an interesting result, namely that the functional groups of 9-0 H and 6 -OMe in the cinchona unit, along with 2-F group in the phenyl linker, were critical factors for high enantioselectivity of the reaction (Scheme 4.16). 

The intramolecular alkylation of the enolate derived from phenylalanine derivatives 22a,b to form P-lactams 23a,b has also been achieved using Taddol as a chiral phase-transfer catalyst (Scheme 8.11) [23]. In this process, the stereocenter within enantiomerically pure starting material 22 is first destroyed and then regenerated, so that the Taddol acts as a chiral memory relay. Taddol was found to be superior to other phase-transfer catalysts (cinchona alkaloids, binol, etc.) in this reaction, and under optimal conditions (50 mol % Taddol in acetonitrile with BTPP as base), P-lactam 23b could be obtained with 82% et. The use of other amino acids was also studied, and the... 

Continuous reactors are not always beneficial to achievement of good reactor performance (Woltinger, 2002) in the asymmetric opening of meso-anhydrides, due to product inhibition of the cinchona alkaloid catalyst the conversion and enantiomeric excess decreased rapidly during a continuous reaction. Even optimization of reaction parameters to decrease residence time to a very low value (1 h) did not improve the situation sufficiently. In contrast, performing the reaction in repetitive batch mode allowed a modest 60% e.e. to be sustained over 18 cycles. 

Three structural elements in the cinchona molecule were identified to affect rate and ee of the enantioselective hydrogenation of a-keto acid derivatives (i) an extended aromatic moiety, (ii) the substitution pattern of the quinuclidine (the absolute configuration at C8 controls the sense of induction N-alkylation yields racemate), and (iii) the substituents at C9 (OH or MeO is optimal larger groups reduce the enantioselectivity). 

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. 

Among the several screened cinchona derivatives, (DHQ)2AQN 6 was selected for a full optimization of the conditions (solvent and temperature). The reaction was carried out in DMF with a combination of benzoyl fluoride and ethanol as a latent source of HF. Enantioselectivities up to 92% ee were obtained with tetralones trimethylsilyl enol ethers Sa-d using 10 mol% of organocatalyst 6 (Table 7.1, entries 1-4). Indanone silyl enol ethers Se-g afforded the corresponding ketones 7e-g with lower selectivities (64—74% ee, Table 7.1, entries 5-7) while the 2,2,6-trimethyl-cyclohexanone was obtained with only 58% ee, the reaction being conducted at — 10 °C (data not shown in Table 7.1). 

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. 

The first cinchona rearrangement is also feasible without Ag +, provided stringent stereochemical and experimental conditions are fulfilled. In the preferred conformation of epi-la-OMs, the C9-OMs leaving group and migrating C7-C8 0-bond are antiperiplanar (Scheme 12.41). Under optimized conditions with NaOBz as a buffer (for the liberated methanesulfonic acid), a-amino ether 107-OMe was formed in 81%... 

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