Sparteine Subject

Sparteine (43) is oxidized to a mixture of isomers /J -didehydro-sparteine (44) and id -dehydrosparteine (45) (57). The other two stereoisomers of sparteine, a-isosparteine (46) (3S,j9) and S-isosparteine (sparta-lupine) (47) (58,60) have been subjected to mercuric acetate oxidation, each giving Zl -didehydrosparteine (44). 

The incidence of PMs of debrisoquine/sparteine has been investigated in many populations, in most of them with a fairly small number of subjects (16). Among 1011 Swedish Caucasians, we found 69 (6.3%) PMs of debriso-quine (Fig. 1) (17). This incidence is very similar to other European (16) and American (18) Caucasian populations. In collaboration with professor Lou and associates in Beijing, we showed that the incidence of PM among 695 Chinese was only 1.0% using the antimode MR = 12.6 established in Caucasian populations (Fig. 1) (17). A similar low incidence of PM has been shown in Japanese (18) and Koreans (19). 

An asymmetric synthesis of the aminocyclopentitol has been achieved from an acylated oxazolidinone (Scheme 38).110 Thus, the acylated oxazolidinone 295 was subjected to boron triflate-catalyzed condensation with 3-butenal to yield the syn aldol product 297 in 63% yield. Similarly, the A-acyloxazoI idineth ione 296 delivered the aldol adduct 298 in 75% yield when enolized with TiCl4-(—)-sparteine and then... 

Figure 4 Polymorphic drug oxidations by cytochrome P450. A, substrates subject to debrisoquine/sparteine polymorphism. R(+)-bufuralol is I -hydroxyl-ated by P450-IID6 the S(—)-enantiomer undergoes hydroxylation at the 2- and 4-positions debrisoquine is hydroxylated at the prochiral C4-atom to S(+)-hydroxy-debrisoquine sparteine metabolism by P450-IID6 consists of N-oxidation. B, substrates subject to hydantoin polymorphism (4 -hydroxylation). Extensive metabolizers convert S(+)-mephenytoin and -nirvanol to the 4 -hydroxy derivative (indicated by the arrow). Similarly, EMs metabolize the prochiral drug phenytoin to R(+)-4 -hydroxyphenytoin. = chiral center.

The effects of quinidine sulfate, 50 mg orally, an inhibitor of cytochrome CYP2D6, on the metabolism of dextromethorphan 50 mg have been studied in seven healthy volunteers in a randomized, double-blind, crossover, placebo-controlled study (24). Quinidine suppressed the conversion of dextromethorphan to dextrorphan in extensive metabolizers to the extent seen in poor metabolizers. The increased concentrations of dextromethorphan increased subjective and objective pain thresholds by 35 and 45 % respectively. This result suggests that debriso-quine/sparteine-type polymorphisms account for important differences in the effect of dextromethorphan and the balance between the analgesic effect of dextromethorphan and the hallucinogenic effect of dextrorphan. Concomitant use of quinidine or other inhibitors of CYP2D6 could... 

This alkaloid - CVIII), which is present in virtually all species of Genista (1) has lien the subject of many investigations. It had been long known that its nuclear structure was that of a hydroxy sparteine but location of the hydroxyl offered much difficulty. The hydroxyl is secondary (88). The following and other reactions are fully explicable on the structure (XCVIII) which is 12a-hydroxysparteine (84-86). 

These may be isolated by steam distillation. It is usual to make two such distillations, the first from acid solution, the second from alkaline. About 50-100 gm of tissue is homogenized, mixed with an equal quantity of water, acidified with tartaric acid and steam-distilled until a volume ecpial to the original sample taken has been collected. This distillate will contain neutral and acidic compounds such as hydrocyanic acid, phenol, and phosphorus. The tissue slurry is now made alkaline with sodium hydroxide solution and again subjected to steam distillation. This second distillate will contain basic compounds. The tip of the condenser should be immersed in dilute hydrochloric acid to trap the more volatile bases. The plant alkaloids most likely to be present are nicotine, coniine, arecoline, ephedrine, and sparteine, but a number of synthetic drugs, notably amjihetamine and other sympathomimetic bases, also occur in this fraction. Pethidine may also be isolated by steam distillation. The... 

Intramolecular enantiosituselectivity is exemplified by the biosynthetic formation of the mustard oil glucoside sinigrin (60) in horseradish, " the deprotonation of N-Boc-pyrrolidine (62) with sec-butyllithium (s-BuLi)/(-)-sparteine, followed by methylation, "" and, the oxidation of enol 64. Intermolecular enantiosituselective transformations are exemplified by the hydrolysis of racemic N-dodecanoylphenylalanine p-nitrophenyl esters (( )-67) in the presence of tripeptide catalyst (Z)-L-Phe-L-His-L-Leu (68) in each of the latter two cases, only one (externally) enantiotopic carbonyl reacts preferentially. It should be pointed out parenthetically, that as a result of the enantiosituselectivity in these transformations, one has, in effect, kinetic resolution of ( )-67. The electron-impact induced elimination in acetate 71, and the oxidation of 73 exemplify intramolecular diastereosituselective transformations. The epoxidation of the mixture 76/77 is an example of an intermolecular diastereosituselective process at the same time that each substrate is subject to enantiositunonselectivity of the carbonyl sub-sites. 

To assess in a single session the incidence of the poor-metabolizer phenotypes for sparteine and mephenytoin, and the variability in nifedipine metabolism, in a Dutch population of 172 subjects [20]. A 7.4% incidence of poor metabolizers of sparteine was detected, which is quite similar to that found in other Caucasian populations. For mephenytoin 2.3% of this population was found to poorly metabolize it to para-hydroxymephenytoin. In a similar study in 130 healthy subjects a cocktail of phenytoin, sparteine and nifedipine was administered [22], The results of this study for nifedipine have been presented in Fig. 1, whereas a similar extent of variability in the plasma kinetic (AUC) for phenytoin was observed. Correlations between relevant kinetic and metabolic parameters of the three probe drags were all low and non-significant. None of the data of nifedipine and phenytoin were different between extensive and poor metabolizers of sparteine. Thus the major oxidative metabolic pathways of nifedipine, sparteine and phenytoin are not related to each other. The three compounds can in principle be used... 

To assess selectivity in the inducing and inhibiting effects of environmental factors (for example, dmg treatment) on the activity of the different P-450 enzymes. In one of such smdies, nifedipine, sparteine, mephenytoin and antipyrine were administered simultaneously to 15 healthy subjects, including four poor metabohzers of sparteine and four poor metabolizers of mephenytoin [6], They received the cocktail on three different occasions without pretreatment, after pentobarbital pretreatment and together with cimetidine. Concentrations of nifedipine, its pyridine metabolite, and of sparteine and its dehydro metabolite were measured in the plasma nifedipine metabohtes, sparteine, dehydrosparteine, 4-hydroxymephenytoin, antipyrine and its three major metabohtes were all measured in urine. The kinetic parameters obtained clearly indicated that nifedipine metabolism is very sensitive to pentobarbital induction (Fig. 4), whereas antipyrine metabolism is sensitive only to a moderate degree and sparteine metabolism is unaffected. Cimetidine inhibited the metabohc clearance of all three compounds to a similar extent and also inhibited renal clearance of sparteine, most likely at the level of tubular secretion. Urinary excretion of 4-... 

The pharmacokinetic patterns of the enantiomers following oral administration in humans appear to be essentially parallel. The plasma R/S ratio seems to range from 0.67-1.44 in different patient populations 3,56,59. stereoselective elimination has been suggested in healthy subjects, which have been classified as poor metabolizers of the sparteine debrisoquine type R-flecainide is predominant in plasma after oral administration of the racemate. The oral AUCs of the enantiomers as well as the elimination half-lives were slightly, but significantly, different. This has been interpreted as being the result of stereoselective hepatic metabolism17. 

The q clopropylalaninol derivative rac-184 was subjected to a deprotonation by s-BuLi/(-)-sparteine (ether, 7 to 10 h at -78°C) and the intermediate sparteine-Hthium compounds 185/187 were quenched by CO2 or acid chlorides to yield mixtures of diastereomers 186/188 in a ratio of approx. 90 10 with greater than 95% ee in an average yield of 37%. (S)-184,42%, 80-85% ee, was reisolated. As expected, the pro-S proton in (i )-184 was abstracted preferentially, since it leads to the matched pair. 

A kinetic resolution of lower efficiency could also be achieved when the racemic stannane rac-198 was subjected to MeLi/(-)-sparteine [Eq. (52)] [120]. 

After taking phenobarbital 100 mg daily for 2 weeks the clearance of a single 20-mg dose of nifedipine in a cocktail also containing sparteine, mephenytoin and antipyrine was increased almost threefold in 15 healthy subjects. The nifedipine AUC was reduced by about 60%. ... 

In vitro studies have indicated that Scotch broom has a stimulating effect on the uterus (Seel 1949 Wolfes et al. 1936). The compound sparteine was the subject of human clinical trials as a labor inducer and was found to be as potent as oxytocin (Casarett et al. 2001). 

Deprotonation of t-Bu-BisP (BH3)2 with 1.2 equivalents of s-BuLi/( )-sparteine formed a mixture of mono- and dilithiated t-Bu-BisP (BH3)2 whose - intermolecular oxidative coupling with Cu(II) afforded a mixture of tetraphosphine borane 86 and hexaphosphine borane 87. The use of ( )-sparteine may surprise the reader, as the reaction does not involve any enantioselective deprotonation. However, it was found that its presence was beneficial to activate the -BuLi, showing that ( )-sp is not only a chiral inductor, but also modifies the reactivity of the organolithium reagents. After separation by column chromatography, 86 and 87 were obtained in 26% and 14% isolated yields respectively. Tetraphosphine borane 86 was subjected to similar reactions, affording compounds 88 (29% yield) and 90 (8% yield), which contain 8... 

Owing to the use of lupin seeds for feeding animals, much attention has been given to the selection of species free from the more toxic alkaloids of the group, particularly sparteine, to methods of removing alkaloids from the seeds, a subject on which there is an extensive literature and to methods of estimating alkaloids in lupins on which a critical review has been published by Brahm and Andresen. ... 

Regulatory Status. Regulated in the United States as a dietary supplement. Subject of a German therapeutic monograph, with preparations not to contain more than 1 mg/mL of sparteine for treatment of functional heart and circulatory disorders (blumenthal 1 wichtl). 

Currently, the enantioselective lithiation ofN-Boc-carbamates using sec-butyllithium in the presence of sparteine or sparteinelike diamines and the following interaction with the silanes are under very intensive experimental and theoretical studies (see, for example (142—145)) and the results should be a subject of a special review. 

Several other control experiments provided further insight into these transformations (Figure 13.3) [60], When optically active stannane 83 was subjected to lithiation at -78 °C in the presence or absence of TMEDA, followed by quenching with TMSCl, the racemic product ( )-82 was obtained. Lithiation of 83 at -78 °C in the presence of (-)-sparteine followed by addition of TMSCl furnished (S)-82 in 62 % ee. Remarkably, treatment of 83 with sec-BuLi and (-)-sparteine at -78 °C, followed by warming to -25 °C for 2h prior to recooling to -78 °C before addition of TMSCl, led to the formation of enantiomeric (R)-82 in 85 % ee. These results constituted a useful protocol for the generation of enantiomeric products in the presence of... 

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