Pyrroloquinazolinoquinoline Alkaloids 3.5.1

Luotonins A, B, and E

Luotonin A (26), a novel pyrroloquinazolinoquinoline alkaloid isolated from the aerial parts of Peganum nigellastrum Bunge by Nomura et al. [99,100], showed a cytotoxic activity against mouse leukemia cells (P-388) and an inhibitory activity against topoisomerase I and II [101]. The biological activity of luotonin A coupled with the structural similarity with the topoi-somerase inhibitor camptothecin (111 in Scheme 27) [102] have triggered a number of synthetic approaches to this alkaloid and of course also analogues thereof. Very comprehensive review on luotonin A by Ma et al. has appeared recently [29], and here, only selected examples of total synthesis will be discussed focusing on synthetic routes. A number of total syntheses of luotonin A reported heretofore are classified into three main routes by ring-construction strategies. Route I constructs B (or B, C) ring by Friedländer quinoline synthesis [270,271], and or by intramolecular Povarov reaction [272] (Scheme 27). Route II constructs ring C by Heck coupling [273275], and or by Mitsunobu cyclization [276] (Scheme 28), and route III constructs C, D (or D) rings by cycloadditions including Kametani quinazolinone synthesis by amide condensation [227] (Scheme 29).

Friedländer condensation of pyrrolo[2,1-fr]quinazoline-3,9-dione (112) with anthranylaldehyde 114 gave luotonin A 26 in 36% yield (Scheme 27) [277279].

Dione 112 was obtained from 10 (Jones oxidation, 56%), 11 (SeO2 oxidation, 42%), and 113 (ozonolysis, 63%). One-pot synthesis of 26 from 10 is devised also [277]. Intramolecular hetero Diels-Alder (Povarov) approach has been developed by Twin and Batey [280]. Intramolecular Povarov reaction between aldehyde precursor 116 prepared from acetate 115 with aniline under the shown conditions afforded 26 in 51% yield presumably after in situ oxidation of the initially formed 1,2-dihydroquinoline (Scheme 27).

The route II approaches are summarized in Scheme 28. The very concise synthesis of luotonin A 26 as well as rutaecarpine 16 (see Sect. 3.2.1)

Ri R2

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