Formation of Vincamine and Its Derivatives

Of all the rearrangement reactions of vincadifformine, the one that has been the subject of the most intensive investigations is the rearrangement to vincamine. The earliest studies were summarized in Volume 17 (1). These include the oxidation of vincadifformine (76) by means of p-nitroperbenzoic acid, followed by treatment of the intermediate 16-hydroxyindoIenine Aft-oxide (284) so formed with triphenylphosphine and acetic acid. The N-oxide function in 284 was thereby reduced, and the resulting hydroxyindo-lenine 285 rearranged to a mixture of vincamine (286) and 16-epivincamine 

In recent years some alternative, more refined, and higher yielding processes have been developed. One method that employs milder conditions than the earlier ones and avoids the formation of the N, -oxide involves ozonization of vincadifformine (76) in 0.43 M sulfuric acid in methanol at 60°C, which gives a 74% yield of a 7 3 mixture of vincamine (286) and 16-epivincamine in a one-pot reaction (276). Here again the 16-hydroxyindoienine derivative 285 is an intermediate, since it can be isolated if the ozonization reaction is conducted at 20°C. The stereochemistry of 285 follows from its reaction with potassium cyanate in dii clohexyl-lS-crown-6 and methylene chloride, which affords the hexai cUc urethane 294. Similarly, the ozonization of tabersonine (78) at 65°C affords a 71% yield of a mixture of 14,15-didehydrovincamine (287) and its 16-epimer (276). 

16-Hydroxy vincadifformine indolenine (285) can also be rearranged to a mixture of vincamine (286) and 16-epivincamine by pyrolysis or flow thermolysis at 580°C (795). 

The same group of workers have also investigated the dye-sensitized photo-oxygenation of vincadifformine. After reduction of the reaction mixture with sodium thiosulfate, the related 16-hydroxyindolenine derivative 285 was obtained, which (without isolation) was rearranged in acetic acid to vincamine in 46% yield. Tabersonine behaved similarly (277). These results are broadly in agreement with those obtained by L6vy and his collaborators in an independent study of the photochemical oxidative rearrangement of vincadifformine (218). 

An independent method (279) involves passing oxygen through a solution of vincadifformine (76) in the presence of metal salts (e.g., copper sulfate, ferric chloride, or cobalt stearate) in aqueous hydrochloric acid at 50°C for 8 days vincamine (286) is thus obtained in 20% yield and 16-epivincamine in 15% yield. Again, tabersonine gave similar results. 

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