Vindoline coupling with catharanthine

Boger et al. have reported a single-step biomimetic coupling of catharanthine (124) with vindoline (123) to yield vinblastine (117) efficiently. Thus, the FeCls (5 equiv)-mediated coupHng of vindoline (123) and catharanthine (124) in 0.1 N FICl—CF3CH2OH is followed by the addition of the reaction mixture to a Fc2(ox)3 (iron(III) oxalate hexahydrate, 10 equiv) solution cooling to 0 °C and saturation with air. The subsequent addition of NaBFl4 (20 equiv) initiates both the reduction of the intermediate imi-... 

Two new analogues of catharanthine, 753 and 754, differing from catharanthine in the fusion of the indole ring to the non-aromatic portion of the iboga skeleton have been synthesized in racemic form and their reactivity toward coupling with vindoline examined. The [2,1] fused analogues (e.g., 753) were found to give low... 

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-... 

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... 

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... 

Within the natural products field, the investigation of complete biosynthetic pathways at the enzyme level has been especially successful for plant alkaloids of the monoterpenoid indole alkaloid family generated from the monoterpene gluco-side secologanin and decarboxylation product of tryptophan, tryptamine [3-5]. The most comprehensive enzymatic data are now available for the alkaloids ajmalicine (raubasine) from Catharanthus roseus, and for ajmaline from Indian Rauvolfia serpentina [6] the latter alkaloid with a six-membered ring system bearing nine chiral carbon atoms. Entymatic data exsist also for vindoline, the vincaleucoblastin (VLB) precursor for which some studies on enzymatic coupling of vindoline and catharanthine exist in order to get the so-called dimeric Catharanthus indole-alkaloids VLB or vincristine [7-9] with pronounced anti-cancer activity [10, 11]. 

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... 

The most interesting and important bases are the dimers represented by vincaleukoblastine (V). By very careful classical analyses, coupled with the full use of UV-, IR-, and NMR-spectroscopy, it was concluded that vincaleukoblastine, as well as leurosine, were indole-indoline dimers, most probably catharanthine linked to vindoline (12). Leurocristine... 

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... 

Terpenoid indole alkaloid biosynthesis actually starts with the coupling of tryptamine and secologanin (Fig. 12). In the next step, a glucosidase splits off the sugar moiety and the reactive dialdehyde formed is further converted through different pathways to a cascade of products, including ajmalicine, catharanthine, tabersonine, and vindoline. 

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. 

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)... 

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). 

There have been several recent syntheses of anhydrovinblastine, stimulated in part by its role as a key intermediate in the synthesis of the anticancer drug, Navelbine (vinorelbine). Anhydrovinblastine has been prepared via an electrochem-ically mediated coupling of catharanthine (667) and vindoline (668). The oxidation of catharanthine on a platinum anode in MeCN-Et4NC104 at controlled potential (0.6 V vs. SCE) in the presence of vindoUne, gave, after in situ reduction with NaBH4, (16 5)- and (16. R)-anhydrovinblastine, in yields of 52 and 12%, respectively (Scheme 46) (459,460). 

Of course, the final step in the discussion of the biosynthesis and in the production of vinblastine in C. roseus requires an oxidative coupling of vindoline and catharanthine (or their respective equivalents) as shown earlier in Scheme 13.47. At this writing, it appears that the coupling of the fragments is accomplished with the help of a nonspecific peroxidase. 

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-... 

Although there are many examples of bisindole derivatives that are prepared by reaction of a naturally occurring alkaloid with various reagents, there are few examples of compounds that result from chemistry that alters the skeletal features of these compounds. Much interest has been directed at the synthesis of the dimeric compounds by the coupling of the monomer units vindoline (21) and catharanthine (38), in part because of the necessity of using this strategy to prepare bisindoles by total synthesis. 

Although the precise mechanism of the coupling reaction is not thoroughly established, one can visualize the formation of (71) as arising from initial fragmentation of the C(16)—C(21) bond of (69), followed by condensation of vindoline with the more accessible a face of the iminium ion (73). The impact of the Polonovski approach in this area is emphasized by the fact that all other attempts to couple vindoline with 16,21-seco derivatives of catharanthine lead invariably to formation of the unnatural dimer. A Polonovski reaction was also a key step in the subsequent elaboration of anhydrovinblastine (71) to (68). ... 

In 1975, Potier and collaborators proposed that, in planta, the dimeric vinblastine type alkaloids resulted from the coupling of catharanthine and vindoline and, in light of this hypothesis, they reported for the first time the chemical synthesis of a dimer with the natural configuration through a modified Polonovski reaction [18, 19]. This reaction resulted in the formation of an iminium dimer which, after reduction with NaBH4, yielded a-3 ,4 -anhydrovinblastine, Fig. (2), later proved to be the first dimeric biosynthetic precursor of vinblastine in the plant. The group of Potier investigated possible modifications of anhydrovinblastine and produced vinorelbine, Fig. (1), which was the first active derivative with an altered cleavamine (catharanthine) moiety [20, 21]. 

The chemical coupling of catharanthine and vindoline to yield anhydrovinblastine led to the obvious hypothesis that this compound might also be the first product of dimerization in the plant, and the dimeric precursor of vinblastine and vincristine. For three years it was not possible to find anhydrovinblastine in the plant, until Scott et al. in 1978 [115], by modifying the established methods for extraction and purification of alkaloids, isolated anhydrovinblastine from C. roseus plants, with incorporation of radiolabelled catharanthine and vindoline, thus proving that anhydrovinblastine was actually a natural product. 

As shown in Scheme 13.47, and in concert with the syntheses that had preceded this one, it was recognized that vinblastine could be looked at as derived from a coupling between species related to the simpler fragments vindoline and (a modified) catharanthine. For the latter, it is clear that the modification (were the alka-... 

Terpenoid indole alkaloid biosynthetic enzymes are associated with at least three different cell types in C. roseus TDC and STR are localized to the epidermis of aerial organs and the apical meristem of roots, D4H and DAT are restricted to the laticifers and idio-blasts of leaves and stems, and GlOH is found in internal parenchyma of aerial organs (St-Pierre et al. 1999 Buriat et al. 2004) thus, vindoline pathway intermediates must be translocated between cell types. Moreover, enzymes involved in terpenoid indole alkaloid biosynthesis in C. roseus are also localized to at least five subcellular compartments TDC, D4H and DAT are in the cytosol, STR and the peroxidase that couples catharanthine to vinblastine are localized to the vacuole indicating transport of tryptamine across the tono-plast, SGD is a soluble enzyme associated with the cytoplasmic face of the endoplasmic reticulum, the P450-dependent monooxygenases are integral endomembrane proteins, and the N-methyltransferase involved in vindoline biosynthesis is localized to thylakoid membranes (De Luca and St-Pierre 2000). 

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