Chloroindolenine

The mechanism of the rearrangement is explained as shown in Scheme 19. Protonation of the 9-hydroxy group followed by its elimination and subsequent chloride attack at the 4a-carbon generates a chloroindolenine 126. Addition of water to the 9a-imine carbon atom of 126 gives 127. Concerted elimination of the chloride with rearrangement of the alkyl side chain attached to the 9a carbon atom results in 3,3-disubstituted oxindole structure 120a. 

Zinnes and Shavel found that chloroindolenines, derived from various yohimbine alkaloids, gave directly the corresponding oxindoles by being refluxed in aqueous methanol at pH 6 (267, 268). This procedure can be applied for both D/E-cis and D/E-trans yohimbine alkaloids (267-269). 

Treatment of chloroindolenine 7Vb-oxide (552), derived from yohimbine (74), with ethanolic potassium hydroxide gave 3-hydroxyyohimbine Nb-oxide (553). The same type of reaction occured, when 552 was treated either with methanolic sodium methoxide or with methanolic potassium cyanide, the products being 3-methoxyyohimbine iVb-oxide (554) and 3-cyanoyohimbine Nb-oxide (555), respectively (275). 

A related approach, developed almost simultaneously by Neuss and co-workers at Eli Lilly (25) and by Kutney et al. in Vancouver (26), utilized as coupling substrate the chloroindoline alkene 17, which, through equilibrium with the corresponding chloroindolenine, was readily prepared by chlorination of dihydrocleavamine 18. Condensation with the 17-deacetyl-16-carboxyhydrazide derivative of vindoline (19) gave a binary indole-indoline product (20) (Scheme 4). The undesired C-16 con-... 

That only the wrong C-16 diastereomer seemed to be produced in this reaction was then demonstrated by the Kutney group, who prepared a series of binary indole-indoline alkaloids using the chloroindolenine approach. The apparent simplicity of this coupling reaction and the rapidity in assembling such binary alkaloids prompted an extensive study of reaction conditions (28), with the desire to find a procedure suitable for generation of the C-16 (S) isomer, required for anticancer activity. Despite the intensive effort involved in this in-depth study, no success could be realized, and it was therefore widely accepted that .. . it is very unlikely that any natural dimer could be obtained in this way (7). At this point it may be noted, however, that we were able to show subsequently that the desired C-16 -C-14 PARF relative stereochemistry can be obtained as a preferential result, albeit only in very low yield [3.6% PARF versus 2.1% PREF (priority reflective)], when the chloroindolenine reaction with vindoline is initiated with silver tetrafluoroborate (13). 

Fig. 2. Various conformations of cationic intermediates in the chloroindolenine approach to vinblastine-type alkaloids.

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... 

The a-face of 104 is considerably more hindered than the (3-face, a supposition that was supported by the difficulties encountered in the reduction of 101 and 107. Increasing the steric bulk of the chlorinating agent should favor attack on the (3-face of 104, thus providing a greater relative amount of chloroindolenine 108. When 104 was treated with t-BuOCl in pyridine instead of triethylamine, the desired chloroindolenine... 

On the basis of their 13C n.m.r. spectra, and in particular on the similarity of the C-5 and C-6 resonances, the 7-chloroindolenine derivatives of the cleavamines and quebrachamines have been concluded to have the same stereochemistry at C-7 as voaphylline hydroxyindolenine, whose configuration is known 14,15-dehydroquebrachamine 7-chloroindolenine thus has the stereochemistry shown in (125).88... 

Reference has been made above to the determination of the stereochemistry at C-7 of cleavamine 7-chloroindolenine.88... 

Earlier investigations had shown that the coupling of 7-chloroindolenine derivatives of velbanamine, cleavamine, and their relatives invariably gives products having the undesired (16 R) configuration, presumably because the intermediate ion, e.g. (219), is attacked by nucleophile at its less hindered face. 

Consequently, a substrate such as secopandoline (220), with opposite configuration at C-14, should lead to bisindole bases having the desired (16 S) configuration, and since this configuration appears to be vital for pharmacological activity, such a reaction may well afford a route to new compounds of potential clinical use. The condensation of the chloroindolenine from (220) with vindoline gave, as expected, the vinblastine isomer (221) as shown in Scheme 27 it is of interest to note that this base is also isomeric with vincovaline (vide supra), but is not identical with it 124 if the stereochemistry deduced for these bases is correct, vincovaline (199) is epimeric with the new base (221) at C-16 and possibly also at C-20. ... 

In view of these results, attention was turned to amine 124, whose derivatives could be hoped to react with electrophiles from the opposite face. Indeed, formamide 127 gave (+)-fischerindole I (117) in 47% overall yield after treatment with ferf-butyl hypochlorite and triethylamine followed by addition of silica gel deactivated with triethylamine and subsequent exposure to the Burgess reagent. This transformation presumably takes place by generation of chloroindolenine 128, anti elimination to give 129, tautomerism to 130 and final dehydration (Scheme 30). 

The hydrogen atoms at C-15 and C-20 in rhynchophylline are thus oriented trans with respect to each other, a conclusion which is amply confirmed by the partial synthesis of rhynchophylline from dihydro-corynantheine (XXXII) (66). Reaction of XXXII with tertiary butyl hypochlorite gave the chloroindolenine derivative XXXIII, which on methanolysis was converted into the imidoether XXXIV. Hydrolysis of XXXIV with refluxing aqueous acetic acid then gave rhynchophylline. 

Prenylboration of generated in situ 3-chloroindolenine derivatives was used in synthesis of gypsetin and triptostatin B6. 

Chlorination of indole alkaloids.2 Indole alkaloids of the type (1) on reaction with a 5-10% molar excess of 1-chlorobenzotriazole in dry methylene chloride or benzene are converted in high yield into chloroindolenines (2). /-Butyl hypochlorite has been used previously for such conversions. Reported yields are not so high as those obtained... 

Alkaloid synthesis. BUchi and Manning transformed ibogaine (5) into the naturally occurring ester alkaloid voacaagine (9) by the four-step process formulated. Treatment of ibogaine with r-butyl hypochlorite afforded the chloroindolenine (6),... 

The base 358 is only one of four products obtained when vincadifformine chloroindolenine (295) is allowed to stand with aqueous acetic acid 243). The other products are the corresponding hydroxyindolenine 285 the pen-tacyclic base (362), identical with that obtained earlier by solvolysis of 295 with hot aqueous tetrahydrofuran 244) and a new tetracyclic base, formulated as 3. When heated in acetic anhydride, the chloroindolenine... 

In an attempt to convert the tetracyclic lactam 456 into vincadine (7), Ban and his collaborators (285) found that reaction of 456 with t-butyl hypochlorite, followed by potassium cyanide, did not give the expected 16-cyano derivative but instead the 7-cyano derivative 457. However, reaction of the 7-chloroindolenine derivative 458 with dimethylamine followed by methyl iodide gave the quaternary salt 459, which then gave the desired 16-cyano derivative 460 on prolonged reaction with potassium cyanide. An unexpected product, obtained in comparable yield, was the pentacyclic lactam 461, whose structure was established by X-ray crystallography (Scheme 45). 

In the alcoholic treatments5 8d of the 16-chloroindolenine (65) from tabersonine (Scheme 24), the ring-opened vincadine system (66) is formed by trapping with alcohol addition after N(l)-prdonation and C(7)—C(21) reverse Mannich cleavage of the usual type the unnatural system (67) is believed to arise by a further rearrangement of the initial product as shown. 

Venenatine is thus a 9-methoxyyohimbine and may be formulated as X (stereochemistry so far not defined). The stereochemistry of venenatine was unequivocally deduced as follows. Reaction of venenatine with tert-butyl hypochlorite gave the corresponding 7-chloroindolenine derivative, which was converted by methanolic hydrogen chloride into Zl -dehydro-venenatine. Reduction of the latter with sodium borohydride yielded... 

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. 

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