Canthine skeleton

Scheme 31 Microwave-assisted cyclocondensation-cycloaddition-N2 expulsion for the synthesis of the canthine skeleton...

Canthine skeleton 52 Cardiotonic agent, heart failiu-e 3 Caspase-3 inhibitors, non-peptide 269 Catch and release , 2,4,5-trisubstituted pyrimidines 98 Chloro dehydroxylation 17 Click chemistry, 1,4-disubstituted triazoles 45... 

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]. 

The canthines are a tetracyclic subclass of j8-carboline alkaloids bearing an additional D-ring. Members of the canthine family have been shown to have pharmacological activity, including antifungal, antiviral, and antitumor properties. In 2003 Lindsley and coworkers described a microwave-mediated procedure for one-pot synthesis of the basic canthine skeleton [122]. The key step is an inverse-electron demand Diels-Alder reaction and subsequent chelotropic expulsion of N2, a reaction that can be achieved after a three-component condensation of an acyl hydrazide-tethered indole with a 1,2-diketone and excess ammonium acetate to form a triazine (Scheme 10.61). 

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. 

Snyder has conducted similar chemistry but with the goal of generating carbon skeletons for the total synthesis of alkaloids. Using indole 84 as a dienophile, the canthine alkaloid skeleton 85 was produced. Access to aspidosperma alkaloids was obtained when 86 was transformed into 87. 

Scheme 6.269 One-pot preparation of the tetracyclic canthine alkaloid skeleton.

C16H12N2O, was confirmed mass spectrometrically. Tuboflavine is reduced by lithium aluminum hydride to a mixture of two compounds, both of which have the UV-absorption of indolic-V-methylharman, indicating substitution of Na. By the successive action of dilute alkali and methanolic hydrochloric acid, tuboflavine was cleaved to 1-carbo-methoxy-/J-carboline (CCCXLVIII-A), a result which would exclude a true canthine-type structure based on the skeleton (CCCXLVIII-B). 

UV spectra of canthin-5,6-dione alkaloids 3 and 33, which were isolated by Ohmoto and Koike (3,48) from Picrasma quassioides, showed a characteristic absorption between 400 and 500 nm. This absorption was hypochromically shifted under acidic conditions. The UV spectrum of 3 in acidic solvents resembles that of 5-hydroxycanthin-6-one (16) (Fig. 3). This fact, that is, that 3 undergoes chemical shift in acidic solvents, indicates that the carbonyl at position 5 of the canthin-5,6-dione skeleton in 16 is protonated, producing 42a. On the basis of the above observations, Ohmoto and Koike refluxed 16 and 33 with dimethyl sulfate in acetone and synthesized 3 and 28 (Scheme 3). 

Under this heading the recent chemistry of those alkaloids having the canthine, eburnamine, and schizozygia skeletons are considered,... 

The molecular skeleton of infractopicrin resembles that of vincamine, a representative alkaloid which lowers blood pressure, isolated from plants of the genus Catharanthus (Vinca). There is, however, no evidence of a biogenetic relationship of these alkaloids, and the absence of an angular ethyl group in infractopicrin and in the accompanying metabolites suggests rather different biosynthetic pathways in both cases (177). Studies on the canthin-6-one alkaloids of various natural origins were recently reviewed by Ohmoto and Koike in Volume 36 of this treatise (179). 

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. 

The biosynthetic route of l-methoxycanthin-6-one was studied [6], and it was clarified that the methoxyl moiety of this alkaloid was introduced after the canthin-6-one skeleton was formed. 

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