Cinchona alkaloids formation

Interestingly, certain chiral tertiary bases, viz., the Cinchona alkaloids, result in an asymmetric 1,3-elimination to give enantiomerically enriched azirine esters 29 (Scheme 15). The best results were obtained with quinidine in toluene as the solvent at a rather high dilution (2 mg mL ) at 0 °C. In an alcoholic solvent no asymmetric conversion was observed. It is of importance to note that the pseudoenantiomers of the alkaloid bases gave opposite antipodes of the azirine ester, whereby quinidine leads to the predominant formation of the (k)-enan-tiomer (ee = -80%). To explain this asymmetric Neber reaction, it is suggested... 

The first attempt to effect the asymmetric cw-dihydroxylation of olefins with osmium tetroxide was reported in 1980 by Hentges and Sharpless.54 Taking into consideration that the rate of osmium(VI) ester formation can be accelerated by nucleophilic ligands such as pyridine, Hentges and Sharpless used 1-2-(2-menthyl)-pyridine as a chiral ligand. However, the diols obtained in this way were of low enantiomeric excess (3-18% ee only). The low ee was attributed to the instability of the osmium tetroxide chiral pyridine complexes. As a result, the naturally occurring cinchona alkaloids quinine and quinidine were derived to dihydroquinine and dihydroquinidine acetate and were selected as chiral... 

The separation mechanism is based on stereoselective ion-pair formation of oppositely charged cationic selector and anionic solutes, which leads to a difference of net migration velocities of the both enantiomers in the electric field. Thus, the basic cinchona alkaloid derivative is added as chiral counterion to the BGE. Under the chosen acidic conditions of the BGE, the positively charged counterion associates with the acidic chiral analytes usually with 1 1 stoichiometry to form electrically neutral ion-pairs, which do not show self-electrophoretic mobility but... 

Asymmetric ring opening of achiral monocyclic, bicyclic and tricyclic anhydrides under formation of the corresponding chiral monoesters can be accomplished in high yield with modest enantioselectivity with methanol in the presence of less than stoichiometric amounts of cinchona alkaloids in toluene or diethyl ether (Table 9)91 94. As expected the use of cinchonine A or quinidine C, and of cinchonidine B or quinine D gives opposite enantiomers. Recrystallization of the monoesters and lactones affords material of considerably higher enantiomeric purity (Table 9, entries 15, 16, 21, and 23). 

Bis-hydroxylation. Molecular oxygen or air was used as the terminal oxidant in the osmium-catalyzed oxidation of alkenes to form cis-diols with high conversions at low catalyst amount.1298 In a triple catalytic system using H2O2 as the terminal oxidant, a cinchona alkaloid ligand has a dual function—it provides stereocontrol and acts as reoxidant via its IV-oxide. The formation of the latter is catalyzed by a biomimetic flavin component.1299... 

Recent developments in the understanding of the mechanisms of catalytic and asymmetric dihydroxylation reactions are discussed in Section V,E,l,b. An important aspect of this work is the kinetics and thermodynamics of the formation of adducts with N heterocycles, which have an important role in promoting many reactions. The crystal structure of the [0s04] adduct with the cinchona alkaloid ligand (dimethyl-... 

Most remarkably, catalytic aminohydroxylation of cinnamate amides with sulfonamides in the absence of cinchona alkaloid ligands showed a remarkable chemoselectivity in favor of amino alcohol formation [75]. 

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

Polymer-supported organocatalysts have been used for cycloaddition of ketene, 127, to chloral, 128 [141]. Use of homo-acrylate polymers of cinchona alkaloids led to formation of the desired /Mactone (S)-130 with enantioselectivity up to... 

Extension of the approach described resulted in a short synthesis of (+)-mero-quinene (Fig. 13). Formation of this alkaloid also synthetically connects the indole with the quinoline alkaloids, a link which has been suggested from the biosynthetic point of view for multiple decades quinine alkaloids are expected to be enzymatically formed from the indole framework. Meroquinene is a simple piperidine derivative which can be obtained by degradation of cinchonine and other Cinchona alkaloids under acidic conditions. It also plays a key role in the chemical synthesis... 

Very good enantioselectivities were recently reported by Hatakeyama and coworkers [33]. The reaction of a variety of aldehydes 28 with the highly reactive 1,1,1,3,3,3-hexafluoro iso-propylacrylate 27 using modified Cinchona-alkaloids as the catalyst resulted, at a temperature of-55 °C, in formation of the Baylis-Hillman-products 30 in 31-58% yields with 91-99% ee (Scheme 6). The use of the tricyclic derivative 29, which was prepared from quinidine in one step [34], proved crucial in order to obtain high enantioselectivities. The success of catalyst 29 can be explained by the (compared with quinidine) increased nucleophilicity, by the... 

Scheme 2.26 Catalytic formation of a chiral nucleophile by an optically active cinchona alkaloid.

A frequently observed side reaction in the AA process is the formation of the diol instead of the aminoalcohol. Generally, the Cinchona alkaloid ligands have a beneficial effect on the chemoselectivity of the AA. However, some examples of AAs producing a considerable amount of diol have been reported in the literature [40,54,55]. 

Azomethine ylides are very important 1,3-dipoles, and they are usually used to react with alkenes leading to the formation of the highly substituted pyrrolidine derivatives [17]. A novel and practical process for the 1,3-dipolar cycloaddition of azomethine ylides with alkenes had been reported by j0rgensen and coworkers [18]. They proposed that a dipol-chiral base ion pair would be generated between a-imino ester-metal complex and a cinchona alkaloid, and subsequent cycloaddition with dipolarophile would take place in a stereoselective manner (Scheme 10.13). 

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