Anhydrovinblastine oxidation

The isolation of Catharine (10), C45H54N40,o, mp 271-275°C, an on-colytically inactive alkaloid, has been reported from several Catharan-thus species C. roseus (29-31), C. ovalis (32), and C. longifolius (33). The structure of Catharine (10) has been elucidated by X-ray crystallography (89-91) of its acetone solvate. Catharine (10) can be obtained by mild oxidation of either leurosine (11) (30) or anhydrovinblastine (8) (92-93). In view of the ease of this oxidation, Catharine (10) may be considered as an artifact of the isolation process. 

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... 

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. 

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-... 

The relatively facile formation of anhydrovinblastine (42) by the modified Polonovski reaction, and the poor yields experienced on coupling of other catharanthine derivatives, made anhydrovinblastine an attractive precursor for the preparation of additional binary alkaloids, including vinblastine itself (50,57). Hydrogenation to 20 -deoxyleurosidine (61a), formation of its Af -oxide (78), and reaction with trifluoroacetic anhydride led to the enamine 59 (Scheme 23). Oxidation of this enamine with thal-... 

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 chemical reactivity of N-6 (or N ), directed entirely by the basicity of this atom, is controlled by the nature and stereochemistry of the substituents at C-4 (vide supra). Oxidation of N-6 occurs under mild conditions in several naturally occurring bisindole alkaloids. Thus, treatment of a dichloromethane solution of leurosine (4) with m-chloroperben-zoic acid at -20°C for 4 hr gives the N -oxide (15) in greater than 90% yield after preparative reversed-phase chromatography (46). Leurosine A/ -oxide has also been isolated from Catharanthus roseus and should therefore be considered a naturally occurring bisindole (50). The analogous conversion of vinblastine (1) to its A/ -oxide (16) proceeds under similar conditions but requires longer exposure to the peraeid (24 hr) (5/) 3, 4 -anhydrovinblastine is converted to its N -oxide (17) in 10 min at 0°C... 

The product from the reaction of anhydrovinblastine Nfc-oxide 1 with trifluoroacetic anhydride in methylene chloride was treated, after evaporation of the excess of the reagent, with a mixture of water and THF. This gave a mixture of products, only one of which could be obtained pure (27%), namely 5 -noranhydrovinblastine 2. 

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... 

Further information is available on the biosynthesis of vinblastine-type alkaloids (cf. Vol. 11, p. 19 Vol. 10, p. 19). Anhydrovinblastine (61) was found to be metabolized to leurosine (63) and Catharine (64) in cultures of a C. roseus cell-line that do not normally produce these alkaloids.55 Ring-opening in the conversion of the skeleton of anhydrovinblastine (61) into that of Catharine (64) has been suggested to occur by Baeyer-Villiger-type oxidation of an imine las (62). The alternative 21 -imine could give catharinine.56... 

Oxo-15,205 -dihydrocatharanthine (275a), prepared as described above, has been employed in a new synthesis of anhydrovinblastine (323). Stereospecific reduction of (275a), followed by acetylation and formation of the A -oxide, gave an... 

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]. 

If the C-15, C-16 bond is oxidatively cleaved, the secodine skeleton results (the proposed progenitor of the Aspidosperma and the iboga systems) through alternative Diels-Alder type cyclizations to afford tabersonine and catharanthine. The bisindole alkaloids of Catharanthus roseus reflect the union of vindoline and catharanthine to afford anhydrovinblastine modification affords the clinically significant alkaloids, vinblastine (VLB) and vincristine (VCR Fig. 39). The alkaloids, particularly VCR, are important as anticancer agents and have led to the development of the semisynthetic derivatives vindesine and vinorelbine (Fig. 40). Synthetic approaches are available to join the monomeric precursors. The enzymatically controlled sequence of reactions from tabersonine to vindoline has been elucidated. 

In a special case of tertiary amine oxidations, the electrogenerated diiminium ion obtained from the indole alkaloid cantharanthine couples in the 16-position with the electron-rich aromatic subunit of vindoline in the 10-position to give the highly cytostatic anhydrovinblastine. In the presence of methanol, the methoxy group is introduced in the 16-position, yielding, after a follow-up reduction, 16-methoxyclea-vamine [18]. 

The vinblastine alkaloids are important chemotherapeutic materials, and are well known for their antitumor properties. A two-electron electrooxidation of alkaloid cantharanthine (74), followed by nucleophilic capture of the resulting imminium ion 75 by Cjo of vindoline (76), affords 77 and provides access to this important class of materials [21], Oxidation of cantharanthine (74) was carried out in the presence of vindoline (76) at a potential that allowed the selective oxidation of the former. Oxidation was shown to occur in a stepwise manner with vindoline (76) serving to intercept the putative dication 75, and leading to the production of 77. Reduction of the latter with sodium borohydride afforded anhydrovinblastine (78) in a 52% yield accompanied by 12% of the material epimeric at C]. ... 

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]. 

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). 

Sundberg, R. J., Gadamasetti, K. G., Hunt, P. J. Mechanistic aspects of the formation of anhydrovinblastine by Potier-Polonovski oxidative coupling of catharanthine and vindoline. Spectroscopic observation and chemical reactions of intermediates. Tetrahedron 1992,48, 277-296. 

The Canadian group have also followed their synthesis of anhydrovinblastine (266) by studying the introduction of oxygen substituents to positions 15 and/or 20. Oxidation of anhydrovinblastine with t-butyl hydroperoxide afforded a moderate yield of leurosine following experience with other substrates in this reaction Kutney etal. formulate leurosine as the -epoxide, rather than the a-epoxide (258) favoured " by other workers. However, both formulations are at present tentative, and it will be intesting to note which one ultimately proves to be correct. 

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