Alkaloids vindoline

The skeleton of the indole alkaloid ( )-vindoline was prepared in a similar way [27]. 

Scheme 4.29. Synthesis of analogues of the indole alkaloid vindoline.

Having an efficient total synthesis of the indole alkaloid vindoline in mind, the Boger group [47] developed a facile entry to its core structure using a domino [4+2]/[3+2] cycloaddition. Reaction of the 1,3,4-oxadiazoles 4-139 led to 4-140 in high yield and excellent stereoselectivity via the intermediates 4-141 and 4-142 (Scheme 4.29). 

Extensive biotransformation studies have been conducted with the As-pidosperma alkaloid vindoline, but much less work has been done with monomeric Iboga and dimeric alkaloids from this plant. The long-standing interest in this group of compounds stems from the clinical importance of the dimeric alkaloids vincristine and vinblastine, both of which have been used for more than 2 decades in the treatment of cancer. Few mammalian metabolites of dimeric Catharanthus alkaloids have been characterized. Thus the potential role of alkaloid metabolism in mechanism of action or dose-limiting toxicities remains unknown. The fact that little information existed about the metabolic fate of representative Aspidosperma and Iboga alkaloids and Vinca dimers prompted detailed microbial, mammalian enzymatic, and chemical studies with such compounds as vindoline, cleavamine, catharanthine, and their derivatives. Patterns of metabolism observed with the monomeric alkaloids would be expected to occur with the dimeric compounds. 

D. Vindoline and related alkaloids Vindoline (38) Streptomyces sp. A17000... 

Quaternary ammonium compounds are important as osmoprotectants in times of water deficiency and cold stress, as well as being constituents of membrane phospholipids, p-Alanine and phosphoethanolamine are each methylated three times on their nitrogens to produce the products P-alanine betaine and phosphocholine, respectively (Fig. ll.l).24"27 An example of O-methylation and N-methylation occurring on the same molecule can be found in the indole alkaloid vindoline from Catharanthus roseus (Fig. 11.1) 28,29... 

It would be a limitation of any of these methods if they could not be used with heterocyclic nitrogen compounds. This is a serious matter because amines are easily converted into N-oxides as we saw in the last chapter. The synthesis of the alkaloid vindoline 237 by Langlois raised this question. 

An important landmark in the elucidation of the structure of vinblastine (169), C46H58O9N4, was the discovery that the i.r. spectrum was largely super-imposable on the addition spectrum of two monomeric Vinca alkaloids, namely vindoline (171) and catharanthine (172). The structures of these two alkaloids, vindoline with a 6-methoxyindoline chromophore, catharanthine with an indole chromophore unsubstituted on nitrogen, were at that time unknown. 

Quebracho (cortex). The bark of the quebracho tree, Aspidosperma quebracho-bianco (Apocynaceae), a large tree (up to 20 m high), indigenous to the west of South America. The bark contains ca. 1% monoter-penoid indole alkaloids such as yohimbine, aspido-spermine, quebrachamine. The Aspidosperma alkaloids are structurally related to the Catharanthus alkaloid vindoline. Quebracho bark contains over 25 different alkaloids of widely differing types. ... 

These alkaloids are considered to be formed by the coupling of the iboga alkaloid catharanthine and the Aspidosperma alkaloid vindoline, both of them derived from tryptophan. The other parts of both alkaloids are derived from a secoiridoid (Cjo) unit, and strictosidine is the primary precursor of both alkaloid units (Section 2.9) [8]. Mangeney et al. [9] succeeded in the syntheses ofVLB andVCR by the coupling of catharanthine and vindoline. VLB can be oxidized under controlled conditions to VCR. 

Fig. 20.6. Biosynthesis of secologanin and die indole alkaloid vindoline (modified from Inouye and Uesato, 1986 used with permission of the copyright owner, Springer-Verlag, Vienna).

Vinblastine, vincaleucoblastine a dimeric indole-indoline alkaloid, m.p. 211-216°C (d.), [a]])-l-42° (CHClj). Structurally, V. is equivalent to a combination of the alkaloids vindoline and catharidine (see Vinca alkaloids). Very low concentrations of V, accompanied by vindoline and catharidine are present in Vinca rosea. V. is one of the most effective naturally occurring antitumor agents, and is used primarily in the treatment of Hodgkin s disease. 

Catharan-thus roseus 71D12 Taberosine 16-hydroxylase Terpene indole alkaloids Vindoline [207]... 

Ionic liquid-based ultrasound-assisted extraction (ILUAE) was successfully applied to the extraction of three alkaloids, vindoline, catharanthine, and vinblastine from Catharanthus roseus. Twelve ionic liquids, with different cations and anions were investigated in this work. In addition, ultrasound extraction parameters, including soak time, solid-liquid ratio, ultrasound power and time, and the number of extraction cycles, were optimized. ILUAE offered short extraction times (from 0.5 to 4 h) and remarkable efficiency. Therefore, the use of ionic hquids in the ultrasound-assisted extraction of key chemicals from medicinal plants shows great potential [12]. 

Yang L, Wang H, Zu Y, Zhao C, Zhang L, Chen X, Zhang Z (2011) Ultrasound-assisted extraction of the three terpenoid indole alkaloids vindoline, catharanthine and vinblastine from Catharanthus roseus using ionic liquid aqueous solutions. Chem Eng J 172 705-712... 

Geraniol 10-hydroxylase (CYP76B6) from Catharanthus roseus is a key regulatory enzyme in the synthesis of the terpene indole alkaloid vindoline [51]. Alkaloids such as vincristine and vinblastine (derived from vindoline) are used in modem medicine as anti-neoplastic agents (Fig. 3). 

Denteriam Labelling.—Kmdb/me (57). Biosynthetic mapping by direct mass spectrometry was successfully achieved with the indole alkaloid vindoline (57 R = R = H). A deuteriovindoline was prepared by the administration of... 

Biichi disclosed a sequence of cyclizations involving an indole that rapidly leads to structural complexity (Scheme 11.22) [121]. Exposure of 137 to BF2 OEt2 enabled the conjugate addition of the indole to the unsaturated ketone to produce iminium ion 138. This was in turn subject to attack by the enol of the methyl ketone to form 139 in 89 % yield. This process constituted a key transformation in the construction of the targeted polycyclic skeleton of the alkaloid vindoline (140). 

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