A Novel Approach to the Pyridoacridine Ring System: Synthesis of the Topoisomerase Inhibitor 13‐Deazaascididemin

Abstract

A novel approach to the pyridoacridine ring system of the ascididemin-type marine alkaloids is presented. This approach allows for the introduction of the ring A of the alkaloids by using a simple aromatic aldehyde building block. The viability of this approach is demonstrated with the synthesis of AK37, a bioactive deaza analogue of the alkaloid ascididemin. Starting from 3-cyano-4-methylquinoline, a sequence of regioselective homolytic benzoylation, annulation of a bromopyridine ring, and radical cyclization leads to the pentacyclic ring system.

Synthesis of the Azaoxoaporphine Alkaloid Sampangine and Ascididemin‐Type Pyridoacridines through TMPMgCl·LiCl‐Mediated Ring Closure

“…[17,19,23] The synthesis of deazaascididemin (3) started with the Suzuki cross-coupling [24] of 4-bromobenzo[c] [2,7]naphthyridine (5) and commercially available 2-methoxycarbonylphenylboronic acid to give biaryl carboxylate 6a in 90 % yield (Scheme 1). [17,19,23] The synthesis of deazaascididemin (3) started with the Suzuki cross-coupling [24] of 4-bromobenzo[c] [2,7]naphthyridine (5) and commercially available 2-methoxycarbonylphenylboronic acid to give biaryl carboxylate 6a in 90 % yield (Scheme 1).…”

“…For the development of this new route to ascidideminand sampangine-type scaffolds, we chose deazaascididemin (3) and sampangine (4) as the first target molecules, since we had authentic samples of these compounds in hand from previous investigations. [17,19,23] The synthesis of deazaascididemin (3) started with the Suzuki cross-coupling [24] of 4-bromobenzo[c] [2,7]naphthyridine (5) and commercially available 2-methoxycarbonylphenylboronic acid to give biaryl carboxylate 6a in 90 % yield (Scheme 1). Analogously to our recently published synthesis of demethyldeoxyamphimedine, [22] we supposed that direct metallation with Knochel's TMPMgCl·LiCl [25] should take place regioselectively at the peri position (C-5) of the benzo[c] [2,7]naphthyridine scaffold without affecting the ester group, and avoiding undesired nucleophilic addition reactions to the naphthyridine ring system ( Figure 3).…”

“…The appropriate 4-arylbenzo[c] [2,7] naphthyridine (6a-6d, 10a, 10b) or 1-aryl-2,7naphthyridine (13a, 13b) was dissolved in dry THF (7 mL), and then this solution was added dropwise to the reaction mixture over 2 min. [23] m.p. aqueous NH 4 Cl solution (10 mL), and extracted with dichloromethane (3 ϫ 30 mL).…”

Pyridoacridines in the 21st Century

“…Using the Minisci reaction, 4‐methyl‐3‐cyanoquinoline was converted into the ketone 119 . Functionalisation of the methyl group produced a 2‐pyridone unit and conversion into halide 120 allowed a radical, but low yielding, substitution to complete the pentacycle (Scheme ) …”

“…Synthesis of 4-deaza-ascididemine 89 via a radical aromatic substitution. [71] Scheme 38. Synthesis of 4-deaza-ascididemine 89 and structures of analogues 123 and 124.…”