Antitumor alkaloids

Azaspirocyclic ketoaziridines 304 (X = Cl or OTBS), potential intermediates for the total synthesis of antitumor alkaloid cephalotaxine 305, have been prepared in 26% (X = Cl) and 76% (X = OTBS) yields, respectively, via an lAOC reaction of azide 303 (Eq. 34) [80]. 

As will be discussed later, the novel pentacyclic antitumor alkaloid roseophilin continues to attract much synthetic effort and several approaches relied on the venerable Paal-Knorr condensation for construction of the pyrrole moiety. For instance, Trost utilized this reaction upon diketone 1 to afford the tricyclic core 2 of roseophilin in a strategy featuring an enyne metathesis as a key step <00JA3801>, while another formal synthesis of this alkaloid utilized a radical macrocyclization to produce the ketopyrrole core <00JCS(P1)3389>. 

The antitumor alkaloid ellipticine (5,1 l-dimethyl-6//-pyrido[4,3-b]carbazole) has been isolated from many species of Ochrosia and Aspidosperma. Ellipticine and its derivatives are highly active versus several experimental neoplasms, and the compound has been widely subjected to studies devoted to its total synthesis, the preparation of derivatives, and metabolism. Metabolic transformation studies with ellipticines have been conducted, using microorganisms, in vivo and in vitro... 

Leurosine (75) (Scheme 20) is the most abundant of the dimeric antitumor alkaloids isolated from Catharanthus roseus G. Don. Several species of Strep-tomyces produced a common metabolite of the alkaloid, and S. griseus (UI1158) was incubated with 400 mg of leurosine sulfate to obtain 28 mg of pure metabolite (180). The metabolite was identified as 76 primarily on the basis of its H-NMR spectrum. The mass spectrum indicated that the metabolite contained one oxygen atom more than 75. The H-NMR spectrum contained all of the aromatic proton signals of the vindoline portion of the molecule, and aromatic proton signals for the Iboga portion of the compound occurred as a doublet of doublets... 

This treatise is a companion work to Volume 25 of this series entitled Antitumor Alkaloids, which covers all classes except the bisindole alkaloids presented here. 

This is the latest volume in the series "The Alkaloids Chemistry and Biology and covers a group of alkaloids comprising the carbazole nucleus. Single-topic volumes in this series have been rare, and the last one discussed antitumor alkaloids and was published as Volume 25 in 1985. This is the first volume dedicated to a single alkaloid structure type since Volume 8, which dealt with the monoterpene indole alkaloids over 40 years ago. 

SCHEME 8. Hale and Domostoj s use of die Hough-Richardson aziridine in their 2004 enantiospecific total synthesis of die antitumor alkaloid (—)-agelastatin A. 

Ciufolini et al. (61) reported a facile assembly of the benzazocenone 307 as a part of the total synthesis of the antitumor alkaloids mitomycin C (309) and FR 900482 (310) based on intramolecular 1,3-dipolar cycloadditions of aryl azides with electron-rich alkenes (Scheme 9.61). Azide 305 was heated in refluxing toluene with a catalytic amount of K2CO3 to give the triazoline 306 in 55% yield. Irradiation of a solution of the triazoline 306 in wet THF with a sun lamp gave an 84% yield of the required benzazocene 308, which was converted to the target molecules 309 and 310. 

Pyridines and their N- oxides undergo attack by enamines under acylating conditions (Scheme 168), and the results for reactions of N- oxides have been surveyed (B-71MI20500). A modification of this heteroarylation reaction has been employed in the first step of a new synthesis of the antitumor alkaloid olivacine (241 Scheme 169) (81CC44). Electron-withdrawing groups attached at C-4 in the pyridine nucleus appear to facilitate this reaction. 

The provision of the pyridine lactone 585, through the agency of the oxazoline DMG, was used in the construction of the antitumor alkaloid ellipticine (Scheme 175) [79JCR(M)4801]. Thus, metalation of 411 fol-... 

Only the antitumor alkaloids of Camptotheca have been reported. Davidia involucrata, as tested here, was positive (1/3) (it is sometimes placed in a family of its own, Davidiaceae) three species of Nyssa were negative N. biflora, N. ogeche, N. sylvatica. 

Domostoj MM, Irving E, Scheinmann F, Hale KJ (2004) New Total Syntheses of the Marine Antitumor Alkaloid (-)-Agelastatin A. Org Lett 6 2615... 

Unique total synthesis of antitumor alkaloid, pancratistatin (97), which was isolated from the roots of the Hawaiian Pancratium littorale Jacq., by / -azido-nation reaction of triisopropylsilylenol ether (183) with Phl=0-TMSN3 as the key reaction has been accomplished by Magnus and Sebhat [138] (Scheme 47). 

In a very recent examination of C. manii Hook., a new antitumor alkaloid was isolated but found to be structurally unrelated to the usual Cephalotaxus alkaloids. In view of the chemical results the botanical classification of the plant is being reexamined (96). 

Fused carbazoles related to pyrido[4,3-6]carbazole alkaloids were prepared by a Diels-Alder route, and a 3-aza bioisostere of the antitumor alkaloid olivacine was synthesized <02CPB1479>. Indoloid [3.3]cyclophane 40a gave the pentacyclic indoloid 41a upon heating <02OL127>. This led to a concise formal total synthesis of ( )-strychnine in 12 facile steps from tryptamine when a similar transannular inverse-electron-demand Diels-Alder reaction of indoloid [3.3]cyclophane 40b gave 41b <02AG(E)3261>. 

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