Vindoline fragmentation

Pseudovinblastinediol (21) (formerly named pseudovincaleukoblas-tinediol) has been isolated from C. rose us as a minor constituent (44). The high-resolution mass spectrum of 21 established a molecular formula of C44H5ftN40g. The characteristic vindoline fragments of miz 469 and 282 were shifted 58 mass units to miz 411 and 224, respectively, indicating the... 

As shown in Scheme 13.57, consummation of the synthesis of (+)-vinblastine required activation of the catharanthine fragment (from Scheme 13.56) and reaction of that activated piece with the (-)-vindoline fragment from Scheme 13.53. Then, once the two fragments had been cojoined, the final protecting groups were removed, and the last ring was put in place. 

Vincovalinine (29), C44H56N4O7, has been isolated from C. ovalis as an amorphous material (62). The mass spectrum of 29 suggested the presence of a vindoline moiety showing the characteristic fragments at mfz 282, 135, 122, and 121, which was supported by the H-NMR spectrum. Comparison of the H-NMR spectrum of 29 with that of leurosine (11) indicated the absence of a methoxycarbonyl resonance, and a new signal was observed at 8 6.10 that could be attributed to 18 -H, establishing the 18 -demethoxycarbonylleurosine structure for 29. 

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... 

In trifluoroacetic acid, 15-oxo-15,20-dihydrocatharanthine (275a + b) fragments, presumably via the enol of the C-7-protonated species, to give the epimeric tetracyclic keto-esters (326). Hydrogenation of the (165)-epimer of (326), followed by reaction with jV-chlorobenzotriazole and condensation with vindoline in acid solution, gives a bisindole species (327) unfortunately, this has the undesired 16 R configuration (Scheme 43).140... 

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]. 

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). ... 

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). 

In face of the structural similarities unraveled during the 1960s of vindoline and catharanthine with the dimeric alkaloids, and due to their great abundance in the plant, these two compounds were immediately considered the most likely monomeric precursors of the Vinca alkaloids, although the cleavamine moiety of vinblastine presented some differences from catharanthine, namely a fragmentation of the C5-C18 bond, Fig. (2). 

In the fragmentation of the monohydrazide particularly informative was the ion m/e 592 which corresponded to the loss of C3H6N2O3, a combination that must contain the hydrazido group (H2N NH CO—) plus two oxygens and two carbons. This piece of evidence localized the hydrazido group on the vindoline moiety, i.e., in the C-16, C-17 bridge. It also showed that the methoxycarbonyl which was lost came from the velbanamine portion and that the dimeric link could not have been at... 

Scheme lb) with trifluoroacetic anhydride (TFAA) to form intermediate 5, intramolecular fragmentation through the indicated mechanistic pathway afforded iminium system 6a, an intermediate suitably activated for nucleophilic interception at C-16 by vindo-line (2). Indeed, when this sequence was performed at low temperature (—50°C) in the presence of vindoline (2), anhydrovinblastine (7) was formed in approximately 50 % yield following the addition of NaBH4 (to reduce the C21 —N4 iminium species originally formed within 6a). This new product (7) could then be converted into 1 through a short sequence of reactions. 

It was first shown, using C-labelled mevalonate, that ajmalicine [162], catharanthine [162] and vindoline [162-165] in Catharanthus roseus as well as other alkaloids in Catharanthus roseus [162], Rauwolfia serpentina [166] and Rhazia stricta [162] gave the appropriate specific incorporation consistent with a monoterpenoid origin for the C q (or Cg) fragment additional to the trypt-amine-derived [167, 168] moiety. This work was rapidly followed by independent demonstrations [169-172] that [2- C]geraniol and its pyrophosphate, which is to be regarded as the prototype monoterpenoid in Nature, are incor-... 

Scheme 13.47. A cartoon representation of the potential coupling of fragments resembling (-)-vindoline and (modified) (+)-catharanthine to produce vinblastine.

The first synthesis of vinblastine was reported by Potier and coworkers more than a decade later and three more, again, after about another decade had passed. The syntheses all used a naturally occurring fragment (viz. vindoline) to complete the work. These works are worthy of study. However, a recent synthesis by Fukuyama and coworkers has captured the imagination and is reported below. 

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-... 

Scheme 13.48. The fragments (vindoline) and catharanthine-hke needed to produce (+)-vin-blastine. See Yokoshima, S. Ueda, T. Kobayashi, S. Sato, A. Kuboyama, T Tokuyama, H. Fukuyama,T. PureAppl. Chem., 2003, 75,29.

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. 

ESI-MS" in positive-ion mode. The protonated molecule ions of [M + H]" and major fragment ions were observed in the full scan MS and MS spectra in positive-ion mode. We choose the protmiated molecular ions and the highest intensity of product ions as the quantification ions. Thus, vinblastine, vindoline, ajmalicine, catharanthine, and vinleurosine were miz 825 807, 457 397, 353 144, 337 —> 144 and 809 748 were chosen by LC-IT-MS, respectively. 

The most important, indeed crucial, idea put forward on the biosynthesis of these alkaloids was that they are formed by fragmentation of a cyclopentane monoterpene [as (6.237)]. The pathway outlined in Scheme 6.43 indicates how the major skeletal types represented by ajmalicine (6.243) and akuammicine (6.242), catharan-thine (6.239), and vindoline (6.244) may be formed where one of... 

---