Vincamine Apovincamine

The study of the chromatographic behavior of natural indole alkaloids on cyclodextrin polymers was different, and unexpectedly high retentions were observed in mildly acidic buffer solutions at room temperature, which permitted their separation by inclusion chromatography (25) (Table IV). Figure 7 shows the separation of two Vinca-alkaloids of very similar structure, the (+)-vincamine and (+)-apovincamine. 

Figure 7. Separation of (+)-vincamine (2 mg) and (+)-apovincamine (3 mg) on 6-cyclodextrin polymer (1.6x90 cm, pH 5 citrate buffer, flow rate 80 ml/h, 20 °C).

The hydroxyl group in XXXV could not be acetylated instead, the iV-vinyl indole, the apo compound, XXXVIII was obtained. In fact, simple heating or solution of the alkaloid in strong acid was all that was necessary. The latter experiment, which finds an analogy in eburnamine itself, required the intermediacy of the iminium form (see Chart II). This iminium form was apparently stable in strong acid, since vincamine in 11 N hydrochloric acid had a UV-spectrum with a long wavelength maximum at 360 mp (log e = 3.85) compatible with XXXIX which reverted irreversibly into apovincamine (XXXVIII R = H) upon dilution (18). 

Vincamine showed peaks from M, M-l, M-CH3, M-C2H5, M-COOMe, M-H2O, and M-HCOOCH3. Since the last two peaks were equivalent to apovincamine and eburnamonine, it was not surprising to observe their characteristic fragmentation peaks in the line-rich spectrum. 11-Methoxyvincamine behaved similarly to vincamine, except that the aromatic peaks were displaced by + 30 mass units (18). 

Vincamine is an alkaloid extracted from the plant Vinca minor. Ethyl apovincaminate is a related synthetic ethyl ester of vincaminic acid. These drugs have spasmolytic effects similar to those of reserpine, but also have metabolic effects, including, in high doses, inhibition of phosphodiesterase. Although increased cerebral blood flow has been reported after the intravenous administration of vincamine, there have been no reliable studies of blood flow after oral medication. Improvement in scores on some psychometric tests have been obtained in some patients with cerebrovascular disease, but no clear-cut practical benefit has been demonstrated. 

In the laboratory of A.G. Schultz during the asymmetric total synthesis of two vincane type alkaloids, (+)-apovincamine and (+)-vincamine, it was necessary to construct a crucial c/s-fused pentacyclic diene intermediate. The synthesis began by the Birch reduction-alkylation of a chiral benzamide to give 6-ethyl-1-methoxy-4-methyl-1,4-cyclohexadiene in a >100 1 diastereomeric purity. This cyclohexadiene was first converted to an enantiopure butyrolactone which after several steps was converted to (+)-apovincamine. 

Schultz, A. G., Malachowski, W. P., Pan, Y. Asymmetric Total Synthesis of (+)-Apovincamine and a Formal Synthesis of (+)-Vincamine. Demonstration of a Practical "Asymmetric Linkage" between Aromatic Carboxylic Acids and Chiral Acyclic Substrates. J. Org. Chem. 1997, 62, 1223-1229. 

Chrom Q column by Gazdag et al.. Derivatization (silylation with N,0-bis(trimethylsilyl) trifluoroacetamide) was needed for those alkaloids containing free hydroxy groups and/or a carboxylic acid group (vincaminic and apovincaminic acids). In Table 17.6 the retention times and elution temperatures of the vinca alkaloids investigated - as such and as derivatives -are given. 

Column pBondapak C18 (300x3.9 mm ID), mobile phase acetonitrile - 0.01 H ammonium carbonate (6 4), flow rate 1 ml/min, detection UV 280 nm. Peaks 1, (+)-cis-apovincamine 2, (+)-cis--dehydroepivincamine 3, (+)-cis-dehydrovincamine 4, (+)-trans-vincaminic acid ethyl ester 5, (+)-cis-epivincamine 6, (-)-cis-epivincamine 7, (+)-cis-vincamine 8, (-)-cis-vincamine 9, (+)-cis-epivincaminic acid ethyl ester 10, (+)-trans-epivincaminic acid ethyl ester 11, (+)-cis-vincamone 12, (+)-cis-vincanole 13, (+)-cis-vincaminic acid ethyl ester 14, (+)--cis-isovincanole 15, (+)-cis-apovincamine 16, (+)-trans-apovincaminic acid ethyl ester ... 

Seven alkaloids have been isolated/ including tabersonine, voaphylline, A " -vincamine, 16-epi-A -vincamine, 12-methoxy-A -vincamine, and A -apovincamine, which have previously been isolated from the root bark. The seventh alkaloid criocerine, is new, and has been assigned the structure and absolute configuration (159), on the basis of its spectroscopic properties and its partial synthesis by a Polonovski reaction on the N-oxide of A -vincamine. ... 

C-21) by hydrogenation of a Bischler cyclization product [formation of (191)]. The unexpectedly resistant enol ether function in (191) required vigorous hydrolytic conditions, hence the resulting apovincamine, presumably obtained via dehydration of vincamine, had to be reconverted into vincamine, a stage not previously realized. 

Reaction of (-)-vincadifformine (2) with lead tetraacetate in benzene gave the acetoxy indolenine 298 in about 50% yield. This compound, when treated with trifluoroacetic acid in chloroform at 0° followed by reaction with sodium acetate in aqueous acetic acid, gave a mixture of (+)-vincamine (277), (-)-16-epivincamine (299), and (+)-apovincamine (300)... 

Vincamine, an alkaloid first isolated from Vinca minor has gained wide application in recent years as a specific cerebral vasodilator. Another alkaloid from the same species, (-)-ebur-namonine is marketed with a similar indication. A semisynthetic derivative of vincamine, the (+)-apovincaminic acid ethyl ester is produced under the trade name CAVINTON by the Hungarian Pharmaceutical Company Gedeon Richter. The latter compound has the trade name CALAN in Japan with a substantial share of the market. 

Vincamine is extracted from the leaves of Vinca minor belonging to Apocynaceae family, known as lesser periwinkle native to central and southern Europe. A closely related semisynthetic derivative of vincamine most widely used as medicine is known as ethyl-apovincaminate or vinpocetine [16-19] (Fig. 20.5f). 

The strained S-lactam was opened smoothly to yield fS-ketoester 324, which on treatment with sodium methylate provided lactam 323. A highly selective Borch reduction finally led to (+)-eburnamonine. Olefination of both enantiomers followed by allylic bromination and oxidation eventlessly afforded apovincamine, which had been converted into vincamine already. 

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