Catharanthine N-oxide

The extremely low yield of vincristine (2) from intact plants has made pursuit of its biosynthesis a very challenging problem, which at this point in time remains unsolved. Kutney et al. have used both anhydrovinblastine (8) (227) and catharanthine N-oxide (107) (233) as precursors to vincristine (2) in a cell-free preparation, but incorporation levels were extremely low. Therefore, the question of whether vinblastine (1) is an in vivo, as well as an in vitro, precursor remains to be answered. Several possibilities exist for the overall oxidation of vinblastine (1) to vincristine (2), including a direct oxidation of the A-methyl group or oxidative loss of the N-methyl group followed by N-formylation. 

While the coupling of vindoline to catharanthine N-oxide proceeds (particularly at low temperature) with high C-16 -C-14 PARF stereoselectivity, this result can be influenced by structural modifications which either increase the stability of the intermediate, cleavamine-derived cation... 

Coupling of other vindoline derivatives with ring D or E modified oxidation levels (92-96) to catharanthine N-oxide provided new binary products for biological evaluation 39, 95-97). The two diastereomeric C-16 -C-14 PARE anhydrovinblastines 42 and 97 were obtained in a 46 54 ratio (50% yield) from racemic catharanthine (98), and the corresponding 20 -desethyl compounds 98 and 99 were generated at - 20°C in a 1 1 ratio (16% yield each), and at -76°C in lower yields, together with the corre-... 

Details have been published of the synthesis of analogues of vinblastine by Polonovski coupling of catharanthine N-oxide and various transformation products of vindoline, and a synthesis of catharinine (vinamidine) has been... 

Catharanthine N-oxide [2] was treated with vindoline in methylene chloride-trifluoroacetic anhydride at -50 5 coupling occurred, to give the immonium ion [3] which w is educed with sodium borohydride to provide the -deoxyvinblastine (anhydrovinblastine)... 

It would thus appear that the presence of an a-acetoxy-group at C-15 severely inhibits the fission of the 16,21-bond in the coupling reaction, since the isovinblastine O-acetate (258) was obtained in yields of only 6 and 4%, respectively, from (257) and (260). The effect of a /3 -acetoxy-group is less well defined Honma and Ban " report the formation of anhydrovinblastine (255), but only as the minor product of the reaction, whereas Kutney and Worth report the formation of (253) and (254), but in unspecified yield. For the synthesis of vinblastine derivatives the absence of a C-15 substituent, as in catharanthine and dihydro-catharanthine, seems preferable for example, catharanthine N-oxide was... 

In another search for an alternative to Potier s modified Polonovski reaction of catharanthine A-oxide (45), it has now been found that anhy-drovinblastine (42) can be generated directly, in 77% yield, from a reaction of catharanthine and vindoline in 0.01 N acid, promoted by ionized ferric salts, followed by reduction with sodium borohydride (Scheme 30) (Wl). Remarkably, the cation radical 106 generated by Fe(III), in accord with other simple amine oxidations by Lindsay Smith and Mead (102), resulted in isoquinuclidine fragmentation and coupling to vindoline at 0°C, without the conformational inversion observed in the modified Polonovski reaction at that temperature (see Scheme 15). Other metal oxidants or ligand-bound Fe(lll) did not promote the coupling reaction. It will be of interest to see if the overwhelming competition of C-5-C-6 bond... 

The critical dependence of the stereochemical and regiochemical course of the modified Polonovski reaction on the oxygen functionality in the catharanthine derivative has been well exemplified in recent synthetic studies. Indeed, in the reaction that ultimately provided the first synthesis of anhydrovinblastine, a minor product proved to be the result of an alternative fragmentation of the catharanthine Nb-oxide derivative in which the 5,6-bond was cleaved [->(266)] and subsequent coupling of vindoline occurred at position 6, with formation of the dimeric species (267).159 When an attempt was made to couple the N-oxide of the lactone (238) with vindoline under Polonovski conditions, this type of coupling occurred exclusively, and the products were the lactone (268) (major product)163-165, the... 

Catharanthine [1] underwent oxidation with ro-chloro-perbenzoic acid to give the N-oxide. 

Polonovski reaction (3, 7 5, 3). French chemists have modified this reaction by use of trifluoroacetic anhydride rather than acetic anhydride and have applied this version to a useful synthesis of compounds related to antitumor alkaloids of Catharanthus roseus. Thus treatment of the N-oxide (1) of catharanthine, an iboganc alkaloid, with TFAA in CH2CI2 at -78" in the presence of vindoline (2) and then with NaBHi leads to three products, one of which is the desired (3),... 

In aqueous methanol, the oxidation of catharanthinic acid (236) with mercuric acetate gives a product (239), obtained by oxidative decarboxylation and rearrangement. A possible mechanism for this reaction is illustrated (Scheme 32). An alternative preparation of (239) involves the von Braun degradation of catharanthine (234), which severs the 21-Nb bond to give a cyanamide derivative (240). Saponification of (240) followed by bromodecarboxylation and removal of the N-cyano-group affords a tetracyclic amino-diene (241) which, on oxidation in methanol solution, gives the epimers (239)." ... 

Based on these electrochemical studies we developed a method for the quantitation of ajmalicine and catharanthine in cell cultures. These alkaloids were extracted from freeze-dried cells and purified by the solid-phase procedure described by Morris et al. (1985), except that ethanol was used as the extracting solvent instead of methanol. A dual-electrode coulometric cell was used in the screen mode. The potential of the first electode was set at +0.2 V (vs. Pd), which was at the base of catharanthine s voltammogram. The alkaloids were detected by the second electrode at +0.8 V, as this offered the best S/N ratio. Higher potentials led to lower S/N ratio, since the background current and noise started to increase exponentially above +0.85 V, due to the oxidation of water. The mobile phase was purified by a guard cell between the pump and injector. The guard cell operated at +0.8V. 

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