Vinblastine synthesis vindoline

Tables 4.32 and 4.33 summarize the metrics for the synthesis plans for both products. The Fukuyama plans to both targets are very similar differing only in the very late stages of each plan. The Kuehne plan to vinblastine is considerably shorter than the Fukuyama one since it uses (—) -vindoline as an available starting material in stage 11. This explains why its overall kernel RME is 17 times larger than that of the Fukuyama plan. For a more fair comparison, if the upper two branches leading to (—)-vindoline are omitted from the Fukuyama plan, the number of stages remain the same at 27 but the number of reactions and inputs decreases to 29 and 47, respectively. These changes result in an increase in overall kernel RME from 0.3% to 0.5% but it is still an order of magnitude less than that determined for the Kuehne...

A total synthesis of (+ )-vinblastine widely used in cancer chemotherapy, has been reported. It includes the synthesis of (-)-vindoline. 1,3-Dipolar cycloaddition of a nitrile oxide has played an important role in the preparation of the indoloazacycloundecane moiety, whose coupling with (-)-vindoline occurs with the desired stereochemistry, leading to an intermediate readily transformed to the target (+ )-vinblastine (492). 

Salutaridinol 7-0-acetyltransferase catalyzes the conversion of the phenanthrene alkaloid salutaridinol to salutaridinol-7-Oacetate, the immediate precursor of thebaine along the morphine biosynthetic pathway in P. somniferum (Fig. 10.7).26 Acetyl CoA-dependent acetyltransferases have an important role in plant alkaloid metabolism. They are involved in the synthesis of monoterpenoid indole alkaloids in medicinal plant species such as Rauwolfia serpentina. In this plant, the enzyme vinorine synthase transfers an acetyl group from acetyl CoA to 16-epi-vellosimine to form vinorine. This acetyl transfer is accompanied by a concomitant skeletal rearrangement from the sarpagan- to the ajmalan-type (reviewed in2). An acetyl CoA-dependent acetyltransferase also participates in vindoline biosynthesis in Catharanthus roseus, the source of the chemotherapeutic dimeric indole alkaloid vinblastine (reviewed in2). Acetyl CoA deacetylvindoline 4-O-acetyltransferase catalyzes the last step in vindoline biosynthesis. A cDNA encoding acetyl CoA deacetylvindoline 4-0-acetyltransferase was recently successfully isolated.27... 

The real breakthrough toward synthesis of vinblastine and, in fact, the first significant laboratory preparation of binary indole-indoline alkaloids with the natural C-16 -C14 PARF configuration, was due to the work of the Potier-Langlois team at Gif (38,39 for reviews, see Refs. 40 and 41), buttressed by results obtained by the Kutney group in Vancouver (42,43,44), and the efforts of Atta-ur-Rahman and associates in Karachi. Their basic idea, which relied on the biogenetic consideration that binary indole-indoline alkaloids are formed in plants by the union of vindoline... 

Vincamine, vinblastine and vincristine are very important clinic alkaloids. They are produced naturally by plants vincamine by Vinca minor, and vinblascine and vincristine by Madagascar periwinkle Catharanthus roseus). The vindoline synthesis pathway starts with strictosidine and, via dehydrogeissoschizine, preakuammicine, stemmadenine and tabersonine, is converted to vindoline and vincristine (Figure 42). Conversion from vindoline to vinblastine is based on the NADH enzyme activity. Vinblastine and vincristine are very similar alkaloids. The difference is that vincristine has CHO connected to N, whereas vinblastine in the same situation has only CO3. This synthetic structural differences influence their activity. Vinblastine is used to treat Hodgkin s disease (a form of lymphoid cancer), while vincristine is used clinically in the treatment of children s leukaemia. Vincristine is more neurotoxic than vinblastine. 

The Polonovski reaction on catharanthine Nb-oxide (170) leads to fission of the 5,6-bond and re-cyclization with formation of (171) 106 in the presence of other nucleophiles (e.g. vindoline), this reaction forms the basis of the synthesis of the vinblastine group of alkaloids (q.v.). The formation of (171) is reversible in acid solution, and under appropriate conditions the methylene group (C-5) is lost as formaldehyde re-cyclization by the Mannich reaction then gives 5-norcatharan-thine (173) (Scheme 23).106"... 

Several simple derivatives of vindoline have been prepared117 as intermediates in the synthesis of model vinblastine derivatives. 

Further use of the modified Polonovski reaction has been made166 in the synthesis of four model vinblastine derivatives (271)—(274) from the vindoline relatives mentioned earlier 117 all four products have the natural stereochemistry at C-16. ... 

For the synthesis of pandoline (284) and 20-epi-pandoline (285), the epoxy-aldehyde (286) was condensed with the indolo-azepine (278) (Scheme 40) the result was an equimolecular mixture of the two alkaloids, in total yield of 64%, based on (278). In accordance with earlier observations, pandoline and 20-epi-pandoline can be reduced to the velbanamine derivatives (287) and (288), which can be isomerized to the C-16 epimers (289) and (290). These compounds contain, respectively, the complete structure and stereochemistry of the non-vindoline component of the oncolytic alkaloids leurosidine and vinblastine. 

The partial synthesis of vinblastine itself makes use of 20-acetoxycatharanthine (223), prepared from catharanthine as described earlier. The modified Polonovski reaction in the presence of vindoline gave an intermediate immonium ion, which was reduced to 20 -acetylvinblastine (Scheme 37). Mild alkaline hydrolysis afforded deacetylvinblastine, the secondary hydroxy-group of which could be re-acetylated preferentially, with formation of vinblastine (271). ... 

In view of the importance of vindoline (44) as a constituent of the oncolytic bisindole alkaloid vinblastine, methods for the synthesis of both vindorosine (43) and vindoline from members of the quebrachamine and vincadifformine groups have been extensively investigated. The first results... 

Buchi has presented an interim report " on progress towards the total synthesis of vinblastine. The general strategy involves the condensation of vindoline (174)... 

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]. 

Kutney s work on the manipulation of the functional groups of vindoline, as a preliminary to the partial synthesis of vinblastine analogues, and the synthesis, in... 

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. 

Ishikawa H, Colby DA, Boger DL (2008) Direct coupling of catharanthine and vindoline to provide vinblastine total synthesis of (+)- and enr-(-)vinblastine. J Am Chem Soc 130 420 21... 

Since vinblastine is a dimeric alkaloid, consists of vindoline moiety and carbomethoxyvelbanamine part, schemes for the total synthesis of both are required followed by joining the two monomeric units to produce the dimeric alkaloid. 

A highly efficient and commercially important synthesis of vinblastine from catharanthine and vindoline has recently been described (48). 

Polonoeski reaction (2, 7 5, 3). The first synthesis of the dimeric indole alkaloid vinblastine (4), used in the treatment of lymphomas, involved coupling of two indole units using a Polonovski reaction. Thus reaction of the N-oxide (1) and vindoline (2) with trichloroacetic anhydride afforded the quaternary im-monium compound (3), which was converted into (4) by standard methods (reduction with NaBH, rcacclylalion). ... 

C21H24N2O2, Mr 336.43, mp. 196 C (as hydrochloride), (aJi) +310° (CHjOH). T. is a member of the Aspido-sperma alkaloids and occurs in numerous genera and species of the Apocynaceae. For biosynthesis, see monoterpenoid indole alkaloids. T. is a precursor of vindoline a building block of the dimeric alkaloids " vinblastine and " vincristine. T. is also formed in plant cell cultures but under these conditions cannot be completely transformed to vindoline. The biosynthesis of the dimeric alkaloids is not possible in cell cultures. For synthesis, see Lit.. ... 

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 13.57, 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. 

Initially, vincristine and vinblastine were isolated from leaves of the Madagaskar periwinkle, however, the yield was very low. The plant tissue contains only 0.0002% vinblastine (Noble, 1990), and the vincristine content is even lower. Therefore, a partial synthesis for the dimeric indole alkaloids was developed starting from the monomers vindoline and catharanthine (Dewick, 2002). 

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