Sparteine pathway

The empirical observation that (—)-sparteine 55 is necessary for catalysis implicates a base-promoted pathway in the mechanism. In the first step, a palladium alk-oxide is formed after alcohol binding, followed by p-hydride elimination of the alkoxide to yield a ketone product. On the basis of a kinetic study of the enantio-selective oxidation of 1-phenylethanol, it was revealed that (—)-sparteine plays a dual role in the oxidative kinetic resolution of alcohols, as a ligand on palladium and an exogeneous base " ... 

Dilithiation of Af-methyl-3-phenylpropaneamide (261) and subsequent addition of a slight excess of (—)-sparteine (11) form a mixture of epimeric ion pairs 262/epi-262, which is substituted by electrophiles to give the -substitution products 263 with good ee values (equation 63) . The intermediates are not configurationally stable, but at low temperature one epimer 262 or epi-262 dominates due to the higher thermodynamic stability. Consequently, Beak and coworkers propose on the basis of a detailed mechanistic investigation the pathway of dynamic thermodynamic resolution . 

The lupinine, lupanine, sparteine and cytisine synthesis pathway... 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

This pathway clearly proves that the first quinolizidine alkaloid to be synthesized is (—) lupinine (two cycling alkaloids) and subsequently both (+)-lupanine and (-)-sparteine. This is a new approach to the synthesis of this type of alkaloids because in the older literature just four cycling alkaloids (lupanine and sparteine) were mentioned as the first synthesized molecules . In the cadaverine conversion, the participation of diamine oxidase is more reliable than the oxosparteine synthase mentioned by some older studies °. 

Figure 51. Diagram of the lupinine, sparteine, lupanine and cytisine synthesis pathway. Abbreviations PLP = coenzyme pyridoxal phosphate C = cleavage of C4 unit.

This group of alkaloids has a pyridone nucleus and generally takes the tetracyclic or tricyclic form. The a for pyridone alkaloids is L-lysine, while the j8, q> and X the same as for other quinolizidine alkaloids. Quinolizidine alkaloids containing the pyridone nucleus are the P from the (—/-sparteine by cleavage of the C4 unit. The first quinolizidine alkaloid with the pyridone nucleus is tricyclic cytisine, which converts to four cyclic alkaloids. In this synthesis the anagyrine, the most poisonous quinolizidine alkaloid with a pyridone nucleus, has its own synthesis pathway. 

The pathway to sparteine and lupanine undoubtedly requires participation of another molecule of cadaverine or A piperideine. Experimental data are not clear-cut and Figure 6.25 merely indicates how incorporation of a further piperidine ring might be envisaged. Loss of one or other of the outermost rings and oxidation to a pyridone system offers a potential route to cytisine. 

Unfortunately, the presence of stereoisomers does not allow this class of compounds to proceed directly into clinical trials. There is hope that future synthesis using chiral bases like sparteine may allow enantioselective preparation of titanocene dichloride derivatives and not only ferrocenes [30]. Additionally, further reaction pathways leading to achiral titanocenes have to be explored. 

The most common group of alkaloids possessing a quinolizidine nucleus is that of the lupine alkaloids which can simply be classified as bicyclic (lupinine/epilupinine type), tricyclic (cytisine type) or tetracyclic, (sparteine/lupanine or matrine type). Fig. (23). This grouping is made according to structure complexity and without considering biosynthesis, as the detailed biosynthetic pathways are still not completely understood. 

Perpherazine and over-the-counter (OTC) ingredients codeine and dextromethorphan are made active by the debrisoquine-sparteine oxidative pathway. The percentage of an ethnic or racial population poorly metabolizing by this pathway varies greatly for example Switzerland 9-10%, Hungary 10%, United States 7%, Nigeria 3-8% and Japan 0.5% (Wood and Zhou, 1991), but if not will gain no pain relief. 

The lupin alkaloids sparteine (98) and lupanine (99) are both derived from lysine, and it is possible on the basis of past work that either one may be a precursor of the other.63 However, recent work suggests that they are derived by divergent pathways.64... 

The alkaloid sparteine was isolated only from the plant Chelidonium majus. It differs in its constitution from the already mentioned groups of alkaloids which were derived from 1-benzylisoquinoline precursors. Schiitte (443) studied the biosynthesis of sparteine in Chelidonium majus by means of radioactive cadaverine. He arrived at the conclusion that in this plant the biosynthesis takes the same pathway as in Lupinus luteus L. 

We propose the biosynthetic pathway of the carbon framework of matrine as shown in Fig. 4. This scheme also indicates the pathway for the formation of sparteine and lupanine. The former part of this scheme was proposed by Wink et al. [63], with minor modification by Leete [64], from the in vitro experiments using isolated chloroplasts of leaves of Lupinus. They postulated the presence of 17-oxosparteine as the first key intermediate for the formation of lupanine and sparteine [63]. However, this hypothesis involving 17-oxosparteine synthase was not confirmed by the tracer experiments using and independently conducted by the groups of Spenser [65, 66] and Robins [67]. They, in turn, hypothesized the pathway involving the diiminium cation (73) as the tetracyclic intermediate [68, 69]. The postulation of the presence of this reactive intermediate is consistent with the results of isotope incorporation into lupanine and sparteine. The biosynthetic scheme of matrine can be also drawn by involving the electronically equivalent diiminium cation (76) preceded by additional 1,3-hydride shift or imine-enamine isomerization (74 75). All these reactions take... 

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... 

Fig. 3. The difTerent oxidative metabolic pathways of antipyrine. hydroxymephenytoin was not affected by either treatment, nor was the metabohc ratio of sparteine/dehydrosparteine in 8 hour urine [6, 27], The results of this study have clearly illustrated that the cocktail allows the assessment of the differential effects of dmg treatment on oxidative enzyme activity. This approach could also be usefiil in new dmg development in order to assess whether or not a new compoimd will give rise to potential risks of dmg-drag interactions through induction or inhibition of dmg metabolism. Rather than performing several different studies with different (probe) dmgs, the cocktail approach should allow sufficient pertinent information to be obtained in the context of one experimental protocol.

Schlosser [80] andVoyer [81] reported that N-Boc-N-methylbenzylamine 106 can be deprotonated with 5ec-BuLi in the presence of (-)-sparteine. The resulting organolithium can be trapped with electrophiles to provide a-substituted benzylamines 107 with high enantioselectivities (Scheme 31). Schlosser and coworkers showed that the reaction pathway of N-methyl-hl-Boc benzylamines 107 is an asymmetric deprotonation followed by racemization and asymmetric substitution, and provided rationalization of solvent effects in terms of ion paired species [80]. The enantioselectivity of this reaction sequence is highly dependent on the solvent, electrophile, and reaction time. 

Since benzyUithium compounds having no adjacent heteroatom are configurationally labile [93], their enantioselective reactions may proceed through an asymmetric substitution pathway. In 1971, Nozaki and coworkers commented in the first enantioselective reaction of benzyllithiiun compounds that the enantiomeric ratio of organolithium compounds might be influenced by a chiral additive [94]. Deprotonation of ethylbenzene was performed with n-BuLi-(-)-sparteine at 70°C, followed by carboxylation at -65°C [Eq. (39)]. 

This reaction showed high enantioselectivity even when (-)-sparteine was added after hthiation of the carboxamide. Also, the racemic lithium carbanion derived from the racemic tin precursor via metal exchange reaction, gave products with high enantioselectivity [Eq. (41)], whereas when the carbanion prepared from the corresponding chiral tin compound was reacted with an electrophile such as TMSCl without (-)-sparteine it yielded racemic product. These results indicate that the reaction of the lithiated 3-phenylpropionamide proceeds through an asymmetric substitution pathway. Furthermore, a warm-cool procedure and then reaction with a substoichiometric amount of an electrophile confirmed a dynamic thermodynamic resolution pathway for this reaction. 

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