Quinidine formation

In the ease of the dextrorotatory pair, einchonine and quinidine, these hydroxydihydro-bases may lose a molecule of water between the two. CHOH. groups at positions 9 and 10 with the formation of ether oxides, represented by formula (C) of which there should be a pair of stereoiso-merides for eaeh alkaloid. This type of compound has not been obtained from the laevorotatory bases, einchonidine and quinine. 

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... 

Further evidence for the formation of intermediate compounds in catalytic reactions is afforded by the observation (a) that optically active camphor is formed from optically inactive (racemic) camphor carboxylic acid in the presence of the d- or /-forms of quinine, quinidine or nicotine and (6) that optically active bases, e.g., quinidine, catalyze the synthesis of optically active mandelonitrile from benzaldehyde and hydrocyanic acid.10 These results hardly admit of any other interpretation than the intermittent production of a catalyst-reactant compound. 

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). 

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... 

One of the complicating factors with chemical inhibitors is that a chemical that inhibits one CYP enzyme may activate another enzyme. If both enzymes contribute to metabolite formation, the inhibitory effect of the chemical on one enzyme may be offset by its activating effect on the other enzyme. a-Naphthoflavone is an inhibitor of CYP1A2 but an activator of CYP3A4, whereas quinidine is an inhibitor of CYP2D6 but, in certain cases, an activator of CYP3 A4 (184-186). a-Naphthoflavone and quinidine both appear on the list of FDA preferred and acceptable chemical inhibitors, so their ability to inhibit one enzyme but activate another are relevant to reaction phenotyping. 

Ngui JS, Chen Q, Shou M, et al. In vitro stimulation of warfarin metabolism by quinidine increases in the formation of 4 - and 10-hydroxywarfarin. Drug Metab Dispos 2001 29 877-886. 

The use of a heteroatom a to the ester carbonyl group allows for the formation of a chelate with the metal counterion hence, the geometry of the ester enolate can be assured.336-338358359 This approach was used in the rearrangement of the glycine allylic esters 13 to y,8-unsaturated amino acids in good yields and excellent diastereoselectivity (Scheme 26.13).358 The enantioselectivity could be reversed by using quinidine instead of quinine. 

A linear model also was used to relate bio phase quinidine concentrations to the time course of electrocardiographic QT interval changes after intravenous and oral dosing of this drug (12). As shown in Figure 19.3/ the slope was greater after oral doses and that was attributed to the formation of active metabolites of quinidine during first-pass metabolism of the oral dose (13). 

Alkalosi.s tend.s to hyperpolarixc the cell membrane and. thereby, reduces the cfi ect of antiarrhythmic drugs. Because of this, alkalosis promotes the formation of mure of the free-base antiarrhythmic agent, increasing the rate of recovery from the block. Alkalo.sis-inducing salts such as. sodium lactate have been used to counteract toxicity caused by the antiarrhythmic quinidine. 

Another catalytic application of chiral ketene enolates to [4 + 2]-type cydizations was the discovery of their use in the diastereoselective and enantioselective syntheses of disubstituted thiazinone. Nelson and coworkers described the cyclocondensations of acid chlorides and a-amido sulfones as effective surrogates for asymmetric Mannich addition reactions in the presence of catalytic system composed of O-TM S quinine lc or O-TMS quinidine Id (20mol%), LiC104, and DIPEA. These reactions provided chiral Mannich adducts masked as cis-4,5 -disubstituted thiazinone heterocycles S. It was noteworthy that the in situ formation of enolizable N-thioacyl imine electrophiles, which could be trapped by the nucleophilic ketene enolates, was crucial to the success of this reaction. As summarized in Table 10.2, the cinchona-catalyzed ketene-N-thioacyl-imine cycloadditions were generally effective for a variety of alkyl-substituted ketenes and aliphatic imine electrophiles (>95%ee, >95%cis trans) [12]. 

Scheme 12.5 En route to quincoridine. Proposed mechanism of QCD formation from quinidine.

Recent developments extend the asymmetric P-lactone formation to dichloroaldehydes 183 with formation of the ketene 163 by elimination on acetyl chloride rather than from a ketene generator. A mixture of the aldehyde 183, Hunig s base and 2 mol % quinidine 169 is treated with acetyl chloride to give the p-lactones 184 in good yield (40-85%) and excellent ee. Reduction with DIBAL gives the diol 185 with the two chlorine atoms intact.42... 

---