Acylindole alkaloids

The use of (TMSlsSiH with acyl selenides can also yield new C-C bond formation, as shown with the a,/l-unsaturated lactam ester (Reaction 67). The resulting ketone can be envisaged as potentially useful for the synthesis of 2-acylindole alkaloids. Both the effects of H-donating ability and steric hindrance by the silicon hydride are evident. 

In 1971, Knox and Stobbe isolated, from T. orientalis (Ervatamia orientalis), ervatamine (44, C21H26N203, MP 98°C), 20-epi-ervatamine (45, C2IH26N203, MP 187°C, [a]D —22°), and 19,20-dehydroervatamine (50, C21H24N203, MP 200°C, [a]D +53°C), which were the first examples of a novel class of 2-acylindole alkaloids, lacking the most common indolylethylamine moiety (151). 

Gardnerine (106) has been converted into the 2-acylindole alkaloid ochropine (107) in nine conventional stages (Scheme 14).75... 

Mass spectrometry was also used to confirm the structure of burnamicine (222), which gives also fragments mainly by rupture of bonds in ring C,108 and another 2-acylindole alkaloid, picraphylline.109... 

A characteristic fragmentation pattern is reported for vobasine (226),114,115 a 2-acylindole alkaloid. The fission of the bond between C-5 and C-6 produces intermediate [227], which is decomposed by a McLafferty rearrangement,115 [227]->[228]. 

Oxosilicine (163), a new alkaloid of a Malagasy plant, Hazunta silicicola Pichon, has an a-acylindole structure related to 20-epiervatamine. Although details of the isolation are still not available, the synthesis of (163) has already been announced (Scheme 19) this constitutes the first total synthesis of an alkaloid of the dihydrovobasine-ervatamine group. The major feature of the route adopted is that the acylindole linkage is formed at the outset, and the bond to C-7 (indole jS -position) formed much later. This route may well be applicable to the synthesis of other 2-acylindole alkaloids. 

Mass spectrometry was also used to confirm the structure of burnamicine (222), which gives also fragments mainly by rupture of bonds in ring C, and another 2-acylindole alkaloid, picraphylline. Mass spectrometry aided also in the structure determination of apparicine (223), vallesamine (224), and o-acetylvallesamine. The spectrum of uleine (225) aided in the identification of naturally occurring derivatives thereof. ... 

The 2-acylindole alkaloids and the synthesis of bisindole alkaloids and their derivatives have been reviewed. 

The absolute configurations of several 2-acylindole alkaloids (86a—g) have been confirmed as being all in the same series by c.d. measurements. ... 

Sodium borohydride reduction of 4-substituted isoquinolinium salts led to vinylogous cyanamides, ureas, and urethanes, as well as the corresponding tetrahydroquinolines (640). Hydrogenation of /8-acylpyridinium salts (641) to vinylogous ureas was exploited in syntheses of alkaloids (642), leading, for instance, to lupinine, epilupinine, and corynantheidine (643, 644). Similarly, syntheses of dasycarpidone and epidasycarpidone were achieved (645) through isomerization of an a,/0-unsaturated 2-acylindole and cyclization of the resultant enamine. 

Among the alkaloids of Hunteria ebumea Pichon (Table I) were four interrelated ones (11). Two of them, eburnamine and isoeburnamine, were diastereoisomeric pentacyclic indoles (XVII) convertible by acids into eburnamenine, an A-vinylindole (XVIII), on the one hand, and by chromic acid into eburnamonine, an V-acylindole (XIX), on the other. Reduction of eburnamonine with lithium aluminum hydride regenerated the alcohols, XVII (7,11). When eburnamonine was heated with selenium... 

The alkaloids ochropamine (CCCLVII-C) and ochropine (CCCLVII-D) from Ochrosia poweri are the only representatives of the growing 2-acylindole class so far encountered in the genera under study (192d). The nature of the chromophore (A 243 and 315 m/x, e 18,900, 17,700) present in CCCLVII-C was determined both by alkaline degradation to 2-acetyl-1,3-dimethylindole and by comparison with the known 1-keto-1,2,3,4-tetrahydrocarbazole. The presence of carbomethoxyl (5.78 fi,... 

Melinonine B is formulated as C2oH2 N20+ on the basis of analyses of the chloride, iodide, and perchlorate the chloride, mp 311° (dec.), has [a]D —14.8° (methanol-water) (54). The alkaloid has one A-methyl group but no methoxyl or (7-methyl groups. Its UV-spectrum is that of a 2,3-disubstituted indole and its IR-spectrum exhibits both hydroxyl (3.05 /x) and N—H (3.20 /x) absorption. Acetylation of melinonine B gives a crystalline 0,A-diacetyl derivative which results from attack at the indolic Na, since the UV-spectrum of this derivative is that of an A-acylindole and its IR-spectrum has both ester and amide bands. 

The intramolecular photoaddition of an alkene to an N-acylindole has been used for the formal synthesis of the alkaloid vindorosine (113). Ultra-violet light irradiation of (114) yielded (115), which is presumed to arise from spontaneous opening of the adduct (116). The product was accompanied by a minor stereoisomer, presumably possessing structure (117). The stereoselectivity of the reaction was improved by using compound (118) the adduct obtained was converted to a previously reported vindorosine precursor. ... 

Although little has previously been known of the photochemistry of indoles, five reports of cycloadditions to indole have appeared this year (Giesler et al., inter alia). Intramolecular photoaddition of an alkene to an N-acylindole has been used in synthesis of the alkaloid vindorosine (36) (Winkler et al.). Irradiation of mesitylene... 

Acylation of 3-substituted indoles is more difficult, however 2-acetylation can be effected with the aid of boron trifluoride catalysis." " Indoles, with a carboxyl-containing side-chain acid at C-3, undergo intramolecular acylation forming cyclic 2-acylindoles." Intramolecular Vilsmeier processes, using tryptamine amides, have been used extensively for the synthesis of 3,4-dihydro-p-carbolines, a sub-structure found in many indole alkaloids (P-carboline is the widely used, trivial name for pyrido[3,4-fc]indole). Note that it is the imine, rather than a ketone, that is the final product the cyclic nature of the imine favours its retention rather than hydrolysis to amine plus ketone as in the standard Vilsmeier sequence " this ring closure is analogous to the Bischler-Napieralski synthesis of 3,4-dihydro-isoquinolines (9.15.1.7). 

Although the correct structural formula had been intuitively proposed earlier, the structure of strychnine was founded on a firm basis only when Woodward 6t al.8 discovered that strychnone obtained from the oxidation of IP-strychnine gave ultra-violet absorption maxima resembling those of N-acylindoles. Strychnine, oh the other hand, gives bands similar to N-acyldihydroindoles. Woodward and McLamore recently established the structure of another alkaloid, semperivinine, on the basis of its ultra-violet absorption spectrum. (For absorption data of alkaloids. see references 94 and 95.)... 

An intramolecular addition-elimination reaction of 3-chloro-2-acylindole substrate provided the central tropinone ring in a total synthesis of marine alkaloid caulersin 191 <04T2I47>. 

Ban s general entry to the Strychnos and Aspidospema alkaloids makes ingenious use of a novel photoisomerization of 1-acylindole derivatives to 3-acylindolenines. When applied to the tryptamine derivative (132), the derived indolenine (133) spontaneously rearranged, with formation of the indole-amide (134) in 80% yield (Scheme 22). Obvious stages then led to (135), which... 

The photo-Fries reaction of AT-acylindoles has been applied to the synthesis of alkaloids possessing the Strychnos, Aspidosperma, Schizo-zygane, and Eburnamine skeletons [37]. The key intermediate in these syntheses was the nine-membered lactam 12, which is prepared in 90% yield from photolysis of the AT-acylindole 13. It was demonstrated that this reaction proceeds via the unstable indolenine intermediate 14, which is intercepted by the amine side chain, as shown in Scheme 5. The high yield of this reaction is in part due to the fact that the acyl group in 13 is tethered so that it cannot rearrange to the indole 4 and 6 positions. 

In Scheme 21, the regioselective (and stereoselective) intramolecular addition of a 1,2-unsymmetrically disubstituted alkene to an Al-acylindole is used to achieve a formal synthesis of the alkaloid vindorosine 59 [53]. The key step is formation of cycloadduct 60, which undergoes in situ retro-aldol opening to 61. The face selectivity of attack of the alkene on the indole is governed by the size of the R2 substituent. 

A formal total synthesis of ajmaline has been accomplished. Most of the alkaloids can be interconverted with the exception of a general method for preparing 2-acylindoles from their ring-closed equivalents. Some progress has been made toward this goal (3), dihydroburnamicine being the synthetic closest to a natural product. 

Bumamicine. This natural constituent isolated in trace quantities from Hmteria eburnea is included here because of its obvious relationship to corynantheol and because it represents a good example of the use of mass spectrometry in structure deduction. Bumamicine had an ultraviolet absorption maximum typical of a 2-acylindole which changed to that of a typical indole upon either sodium borohydride reduction or solution in acid. After the latter experiment the original chromophore was regenerated in basic solution. From the nuclear magnetic resonance spectrum the four aromatic protons, the ethylidene and the N-methyl were identifiable. The recovered alkaloid upon acetylation had an ultraviolet and nuclear magnetic resonance spectrum consistent for an ind N,0-diacetate (probably primary). 

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