Vincadifformine reactions

Reaction of vindoline (3) with the chloroindolenines derived from vin-cadifformine (127a), iJ -vincadifformine (133), -tabersonine (133a), or synthetic pandoline (34) (7/5, 116), followed by reduction of the resulting imines 145 and 145a (Scheme 40) with potassium borohydride, had given... 

Assembly of the indolazepine intermediate for synthesis of vincadifformine [92] encompasses a 1,2-rearrangement-retro Mannich-Mannich reaction sequence. Need-... 

An analogous strategy was applied for annelation of ring D in Kuehne s syntheses of 20-epi- ((/-vincadifformine (96) and yz-vincadifformine (97). Upon slow addition of n-BujSnH and AIBN via syringe pump to the phenylselenyl ether 94,20-epi- vincadifformine (96) and vincadifformine (97) were formed in a 1 2 ratio. The separated products did not epimerize under the reaction conditions, indicating a facial preference in the hydrogen transfer to the pentacyclic radical intermediate 95. The ethyl substituent blocked 5-exo-trig cyclization. 

Reaction of the N-oxide (44) with acetic anhydride-pyridine provides a direct means for the in situ generation of the highly reactive dehydrosecodine intermediate (45). This species undergoes spontaneous cyclization to give vincadifformine (46 12%) via an intramolecular Michael reaction followed by B/c ring closure (Scheme 8). i((-Vincadifformine (48) is also produced in this reaction via the enamine... 

Although not strictly a rearrangement reaction, the behavior of (-)-vincadifformine (76) when heated in a sealed tube in a microwave oven is of interest. Almost quantitative racemization occurs, presumably via reversible Diels-Alder fission of ring C and the related achiral secodine intermediate (211). 

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). 

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). 

In all the preceding reactions the rearrangement of the vincadifformine skeleton to the eburnane skeleton was achieved via a 16-hydroxyindolenine derivative, such as 285 the analogous rearrangement of the 16-chloro deriv-... 

The synthesis of ( )-pseudovincadifformine (666) by Szantay and collaborators (270) accompanied the same workers synthesis of vincadifformine, discussed previously (Scheme 33). Thus, application of the Polonovski reaction to the N-oxide of tetrahydrosecodinol (417) gave the precursor 418b of vincadifformine, and also an isomeric secodine 696, which spontaneously cyclized to pseudovincadifformine (666) (Scheme 101). 

The stereochemistry of eburine was established by correlation with (—)-vincadifformine (2) (40). Reduction of (—)-vincadifformine (2) with zinc in acetic acid gave the 2,16-dihydro derivative 74, identical with eburine except for optical rotation. Epimerization of eburine with sodium methoxide gave 16-epieburine, which could be oxidized with lead tetraacetate to (+)-vincadifformine (75). This reaction could not be carrie d out on eburine itself consequently, eburine has the structure 76 in which the carbomethoxyl group is /3 (40). 

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)... 

The 16-hydroxyindolenine 301, which is probably an intermediate in the first reaction, could also be produced by reaction of (-)-vincadifformine with p-nitroperbenzoic acid to give 302. Treatment with tri-phenylphosphine in aqueous acetic acid gave the hydroxyindolenine 301 as an intermediate which subsequently underwent rearrangement to (+)-vincamine (277) in 66% yield and to (—)-16-epivincamine (299) in 21%... 

The same sequence of reactions was also conducted on (+)-vincadifformine (75) to give (—)-vincamine (303), (+)-16-epivincamine... 

Le Men and co-workers have performed several studies of the chemistry of the chloroindolenine of tabersonine (320) (174,178). This compound is produced in high yield when tabersonine (28) is treated with a slight excess of tert-butyl hypochlorite in anhydrous methylene chloride at —16° in the presence of triethylamine (178). In order to demonstrate that no skeletal changes had occurred, they carried out reconversion to tabersonine with potassium ferf-butoxide in benzene under reflux. Similarly prepared was the chloroindolenine of vincadifformine. Subsequent reactions demonstrated that these chloroindolenines were highly reactive. 

Zsadon and Horvath-Otta have investigated some of the simple reactions of tabersonine (28) and vincadifformine (2) (185,186). Zinc and hydrochloric acid in methanol gave the 2,16-dihydro derivatives 274 and 74, which could be hydrolyzed to the corresponding carboxylic acids. Reduction of the dihydro esters with lithium aluminum hydride gave the carbinols 345 and 78. 

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