Canthine derivatives

A ruthenium-catalyzed metathesis of the allyl- and alkynyl-substituted pyridoindole 364 gives the canthine derivative 365 (Equation 131) <2005TL7267>. 

Non-isoprenoid Tryptamines. The stems of Picrasma ailanthoides, from which plant canthine derivatives had previously been obtained, has now yielded 1-methoxycarbonyl- and l-hydroxymethyl-j5-carboline. The molecular shape of eserine (= physostigmine) in the crystal has been determined. The new evidence fits in well with information, summarized previously, from n.m.r. NOE measurements. More alkylations at the C-1 methyl of harmaline have been reported.The A -methyl derivative of 1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine has been isolated from cranberries. 

Intermediate 50 was subsequently heated under reflux in triisopropylbenzene (232 °C) for 1.5 to 20 h to provide the basic canthine skeleton 51. Recently, Lindsley et al. reported a rapid MW-mediated procedure for synthesis of 51 [95]. This reaction, performed in a monomode MW reactor at 180 °C, required a reaction time of only 5 min. Even more interesting, treatment of the acryl hydrazide-tethered indole input, with benzil in the presence of 10 equiv. NH4OAC delivered not only the expected triazine 50 but also, directly, the 1,2-diphenyl canthine derivative 51 (Scheme 17.37, reaction path b). The products were formed in a 9 1 ratio of 50 and 51, respectively. In the one-pot reaction, the indole underwent a three-component condensation to generate 50 followed by an intramolecular inverse-electron-demand Diels-Alder reaction and subsequent chelotropic expulsion of N2 to generate the 1,2-diphenyl canthine 51. 

Roxb., the root bark of which contains several antileukaemic simaroubolides, together with four canthine derivatives canthin-6-one (15a), 1-methoxycanthin-6-one (15b), 5-methoxycanthin-6-one (15c), and 8-hydroxycanthin-6-one (15d). Of these, the first three were already known, but the fourth is new. 

Ailanthus altissima is a tall deciduous tree of Chinese origin. A study of the wood extractives has revealed the presence of three alkaloids canthin-6-one, can-thin-6-one-3-oxide, and l-methoxycanthin-6-one (118). Another member of the same family, Simarouba amara, contains 5-hydroxycanthine-6-one (93). The root bark of Ailanthus excelsa contains four canthine derivatives canthin-6-one, 1 -methoxycanthin-6-one, 5-methoxycanthin-6-one, and 8-hydroxanthin-6-one (27). 

Similarly, permanganate oxidation of a number of naturally occurring canthin-6-one derivatives (295) leads to j8-carboline-l-carboxylic acid or its methyl ester.A j8-carboline-l-carboxylic acid... 

Further recent work on cycloaddition chemistry of nitrogen heterocycles deals with 1,2,4-triazines. These cyclic dienes undergo a cycloaddition-cycloreversion series as well in this case, nitrogen is evolved and thus a pyridine derivative is generated as final product. Snyder et al. efficiently constructed the canthine skeleton by heating the indolyl-tethered 1,2,4-triazine 3-85 which yielded the tetracyclic product 3-86 (Fig. 3-25) [325,326]. 

A synthesis of XIV was accomplished as follows (9) /J-carboline-1-carboxylic acid chloride was condensed with the magnesium ethoxy derivative of malonic ester to yield, after acid hydrolysis, 4-hydroxy-canthin-6-one (XV). This compound, with phosphorous oxychloride followed by heating in a sealed tube with potassium methyl mercaptide, gave the alkaloid XIV. If 4-hydroxycanthin-6-one is condensed with phosphorous oxychloride-phosphorous pentachloride, 4,5-dichlorocan-thin-6-one and 4-hydroxy-5-chlorocanthin-6-one are formed. 

Several kinds of j8-carboline derivatives have been isolated from fungi since the first isolation of canthin-6-one alkaloids from this toadstool. 

Similarly, Matus and Fischer (100) heated l-alkyl-/3-carboline with an excess of dialkyl oxalate and synthesized canthin-5,6-dione derivatives in 20-65% yield (Scheme 4). Catalytic hydrogenation of TV -benzylcanthin-... 

The antiherpes activity of four kinds of canthin-6-one alkaloids was assayed biologically together with 10 /3-carboline derivatives. Among these compounds, 8 and 28 had activity on a level with that of acyclovir, the control. It was noticed, however, that the therapeutic ratio was small 106). 

With the inhibitory activity against cyclic adenosine monophosphate phosphodiesterase as an index, in vitro bioassay of the activity of 21 canthin-6-one alkaloids was carried out. The strongest inhibitory activities were detected with 4, 17, and 27 among the compounds tested. The activities shown by 10, 28, and 34 were the same, twice as strong, and 15 times as strong, respectively, as the activity of papaverine, the control. Acetylation and methylation of the hydroxy derivatives of canthin-6-one decreased activity (108,109). 

Table I is a compilation of plant species which contain the simple indole alkaloid types of Fig. 1. As mentioned earlier, the main requirement for the inclusion of a certain simple indole alkaloid into Table I is that it contain a tryptamine unit as a readily distinguishable feature in its structure. That tryptamine is a precursor in the biosynthesis of many of the b, c, d, and e type simple indole bases is yet to be shown although it is felt that future work will prove the correctness of such a view. Gramine, the simplest indole alkaloid, has been included in the tryptamine classification a because it is biosynthetically related to tryptophan cryptole-pine has been likewise included therein although its structural relationship to tryptophan appears more obscure (Volume VIII, Chapter 1, pp. 4, 19). The calycanthine type does not possess a tryptamine structure but it is included in the simple indole alkaloid b classification since most of its congeners are tryptamine derivatives and since it exhibits a close biogenetic relationship to this latter (chimonanthine) type (Volume VIII, Chapter 16). Type d is represented by the small number of the so-called canthin-6-one alkaloids (Volume VIII, pp. 260-252, 497-498). The most recent variation of the simple indole alkaloids is found in the Anacardiaceae family. Its indoloquinolizidine nucleus suggests inclusion with type d on the basis of structural and biogenetic similarity. Finally, simple indole alkaloid type e is composed of the well-defined evodiamine (rutaecarpine) structural form (Volume VIII, Chapter 4).

For convenience, those alkaloids related to the canthin-6-one group are considered here although their chemistry is different from the cooccurring hydroaromatic bases. Whether they are derived in a simple manner or are degradation products of the more complex bases is not known. 

It is considered that the P-carboline skeleton is formed by adding a C2 unit derived firom the polyketide biosynthetic route to tryptamine. On the other hand, the canthin-6-one skeleton is formed by adding a C4 unit, such as acetoacetate, derived from the polyketide biosynthetic route. 

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