Canthines

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. 

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... 

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... 

Tetracyclic /3-carboline alkaloids, known as canthines, have a peri-fused indolo[3,2,Tnaphthyridine structure. Over 40 members of this class of compound have been isolated, and they are of interest on account of their broad range of pharmacological effects (antimicrobial, cytotoxic, antibacterial, anticancer). 

Canthin-6-one, which is a cytotoxic alkaloid, is synthesized in six steps from harmalane (Scheme 84) <1999TL7075>. The second step is a [4+2] cycloaddition with methyl 2-(dimethylamino)acrylate under singleelectron-transfer electrolysis. 

Differently substituted canthines can be prepared from the pyridoindoles 357 <2004EJ01286> and 358 <2004JHC531, 2005S28, 2005CPB653> (Scheme 85). A synthesis of this type has been used as a route to the natural product vincantril (Equation 126) <2005JOC5519>. 

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

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

To the best of my knowledge, canthin-4,5-diones are the only known representatives belonging to the class of bridgehead nitrogen containing quinones represented by 192. A literature search did not reveal any compounds containing fragment 193. 

Synthesis of 3alkyl-3H-5,6-dihydro-5,6-dioxoindolo[3,2,l-de][l, 5]naphthyridines (Canthin-5,6-diones)... 

Snyder and coworkers followed a completely different path to canthin-6-one (Fig. 23). Earlier they had shown that indole-substituted 1,24-triazine 66 could be heated in refluxing triisopropylbenzene (bp = 232 °C) to give /3-carboline 67 via an intramolecular cycloaddition/cycloreversion reaction [58]. Selective oxidation of 67 at C-6 was achieved through the use of triethylbenzylammonium permanganate [59]. Success of the reaction proved to be very sensitive to the solvent chosen. Heating 67 for 4 h at 70 °C in a 5 1 mixture of dichloromethane and acetic acid gave a 65% yield of 63, yet use of increasing amounts of dichloromethane slowed the reaction down (no reaction occurred in pure dichloromethane), while use of pure acetic acid led to an intractable mixture. 

As alluded to earlier, methoxy-substituted canthin-6-ones have also shown antitumor activity, so not surprisingly, there has been interest in the synthesis... 

A method was developed for preparation of the tetracyclic carboline alkaloids iso-canthine, isocanthin-6-one and l-methylisocanthin-3-one by an intramolecular hetero-Diels-Alder reaction. For example, oxime 317 in sulfolane at 285 °C afforded isocanthine 318 in 8% yield (equation 137) . 

Canthin-6-ones Ailanthus altissima Brucea javanica... 

The extraction of fetidine under various conditions has been reported (314-318). Isolation procedures for thalsimine (319), berbamine (320,321), oxya-canthine (321), and dauricine (322) have been described. An assay method for tubocurarine in cadaver liver by extraction with Bromothymol Blue/CHC13 has been reported (322a). 

The application of infrared circular dichroism (IRCD) in the determination of absolute configurations has been discussed, with particular reference to caly-canthine.109... 

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