Catharanthine A -oxide

More recently, Kutney and co-workers (220) have investigated whether the same dihydropyridinium intermediate 109 is involved in the enzymatic conversion of catharanthine (4) and vindoline (3) to anhydrovinblastine (8) as is involved in the chemical conversion. Use of a cell-free preparation from a 5-day culture of the AC3 cell line gave 18% of the bisindole alkaloids leurosine (11), Catharine (10), vinamidine (25), and hydroxy-vinamidine (110), with 10 predominating. When the incubations were carried out for only 5-10 min, the dihydropyridinium intermediate was detected followed by conversion to the other bisindole alkaloids, with FAD and MnClj required as cofactors. Clearly a multienzyme complex is present in the supernatant, but further purification led to substantial loss of enzymatic activity. The chemical formation of anhydrovinblastine (3) is carried out with catharanthine A-oxide (107), but when this compound was used in the enzyme preparation described, no condensation with vindoline (3) occurred to give bisindole alkaloids. This has led Kutney and co-workers to suggest (220) that the A-oxide 108 is not an intermediate in the biosynthetic pathway, but rather that a 7-hydroperoxyindolenine... 

A coupling of vindoline (3) with catharanthine A-oxide (45), mediated by trifluoroacetic anhydride, and subsequent reduction with sodium boro-hydride delivered anhydrovinblastine (42) in up to 40% yield, accompanied by minor amounts of the undesired C-16 (R) isomer 24 as well as some 17-deacetylanhydrovinblastine (46) (Scheme 13) (38-41). The struc-... 

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 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. 

Atta-ur-Rahman et al. reported the oxidation of catharanthine by a modified Prevost reaction to result in formation of the 20-a-acetoxy derivative. Coupling of its A-oxide (77) to vindoline, using trichloroacetic anhydride (rather than the usual trifluoro compound), and subsequent re-... 

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-... 

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... 

This reaction has been extensively studied in the case of the chlopromazine radical (R -mediated aminopyrine (S) oxidation [41], a typical reaction for xenobiotics, as well as in the case of the vindoline radical (R -mediated catharanthine (S) oxidation [42], a key reaction in the biosynthesis of the anticancer drugs, vinblastine and vincristine, which are obtained from Catharanthus roseus. 

Treatment of catharanthine V-oxide (194 Scheme 69) with TFAA in CH2CI2 at -78 C in the presence of vindoline, and then with NaBlL in a one-pot reaction leads to anhydrovinblastine (197), in the natural (5)-configuration at C-16, in 50% yield. The reaction proceeds via the intermediate (195), its fragmentation to (196), and immediate attack of vindoline at the a-face of (196). 

At slightly elevated temperatures (40—60 °C) catharanthine. b-oxide (219) undergoes a facile [2,3]-sigmatropic rearrangement with quantitative conversion into the isoxazolidine derivative (220), whose structure was established by the X-ray method. Oxidation at to C-3, followed by Mannich ring-closure, affords an... 

In spite of the importance of vindoline (101), the chemistry of this alkaloid had been little investigated until recently, and was stimulated by a desire to vary the nature of the unit coupling with catharanthine IV-oxide... 

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... 

The long series of experiments involving the synthesis of vinblastine analogues by the Polonovski coupling of catharanthine Nb-oxide derivatives with vindoline has culminated in the synthesis of vinblastine (290) itself, and this forms a fitting climax to any report on the past year s progress in indole alkaloid chemistry. 

The Polonovski reaction of demethoxycarbonylcatharanthine -oxide with trifluoroacetic anhydride in the presence of vindoline leads to a coupling reaction in which 16 -demethoxycarbonylanhydrovinblastine and its C-16 epimer are produced a third product was formulated as demethoxycarbonyl-catharan-thine with a 10-vindolinyl unit attached to position 3. A re-examination of this last product has shown that it is entirely analogous to that produced in the similar coupling of catharanthine iV-oxide with vindoline, and has the structure (251). 

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... 

Several natural products and pharmaceuticals have been made in which a TRAP-catalysed oxidation of a primary alcohol to aldehyde step occnrs, and these are listed in 2.1.3 abscisic acid, altohyrtin A, (+)-arisngacin A, 14-[2H]-arteether (Fig. 2.4), astrogorgin, avermectin-Bla (Fig. 2.6), (H-)-batzelladine A (Fig. 1.13), brevetoxin B, (+)-catharanthin, ( )-epibatidine, 2-epibotcinolide, (-)-7-epicylin-drospermopsin, ( )-epimaritidine, epothilone C, irisqninone (Fig. 2.3), gambieric... 

Ferric ion-induced coupling of catharanthine (135) and vindoline (140) in aqueous acidic media to produce 3,4 -anhydrovinblastine has been proposed to occur via the formation of a cation radical (136) of the tertiary amine of catharanthine (Scheme 30). Rearrangement and subsequent fragmentation between C16 and C21 leads to ring opening. A second oxidation followed by nucleophilic attack of the diiminium (137) by vindolene (140) results in the formation of iminium (139), which on borohydride reduction yields 3,4 -anhydrovinblastine (77 %) [238]. 

The alkaloid anhydrovinblastine has been prepared in an elegant way by anodic fragmentation of the radical cation of catharanthine to a distonic radical cation, which after oxidation to the dication undergoes an electrophilic aromatic substitution at vindo-line to afford the complex target alkaloid [110b]. 

Alkaloids (e.g. vindoline, catharanthine and ajmalicine) deserve a special mention as potential substrates for the enzyme. On the one hand, these compounds are not usually regarded as good substrates of peroxidases, since they are oxidized with a kinetic constant one thousandfold less than that of phenolics (Table 1). However, alkaloids are accumulated in vacuoles through a cation-trap mechanism, and a certain... 

Details have been published of the total syntheses of velbanamine, isovel-banamine, cleavamine, 18/3-carbomethoxycleavamine, and catharanthine. Rosen-mund s route to the iboga alkaloids has now been appropriately modified to yield ibogamine and ibogaine, in addition to epi-ibogamine, and details of this work are also available. Hydroboration-oxidation of (227), presumably obtained by a thio-Claisen rearrangement [cf. (200)- (201)] affords the alcohol (228) which is a key intermediate in a Kutney-type synthesis of cleavamine however, details of the synthesis are not yet available. ... 

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