Short Total Synthesis of the Marine Alkaloid Subarine

Abstract

The marine benzo [c] [2,7]naphthyridine alkaloid subarine is prepared in 4 steps, starting from commercially available 1,10-phenanthroline, via oxidative cleavage to the bipyridine-dicarboxylate, conversion to the mono(2-iodoanilide), and radical cyclization. The alkaloid does not show any significant antimicrobial or cytotoxic activity.

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

“…The desired product 13‐deazaascididemin (AK37; 5 ) was obtained in poor yield (5%), and the yield could not be increased by modifications of the reaction conditions. This parallels our previous experiences in the total synthesis of subarine, a formal seco analogue of pyridoacridines utilizing a comparable cyclization step 37. The spectroscopic data of 5 were in full accordance with the values published before for this compound 10.…”

Pyridoacridines in the 21st Century

“…A second and somewhat shorter synthesis of subarine also began with an oxidative cleavage, leading to dimethyl [2,2′‐bipyridine]‐3,3′‐dicarboxylate 148 (Scheme ) . Amide formation with 2‐iodoaniline to 149 and a final carbon–carbon bond‐forming radical step gave the alkaloid, though only in 7 % yield for the last step …”

New Perspectives in the Chemistry of Marine Pyridoacridine Alkaloids

“…Subarine ( 212 ), a marine pyridyl benzo[ c ][2,7]naphthyridine alkaloid, is closely related to the pyridoacridine family, as it is formally a seco analogue of ascididemin-type alkaloids. This alkaloid was prepared following two different approaches by the Delfourne [ 56 ] and Bracher [ 57 ] groups.…”

“…A significantly shorter synthetic route towards the alkaloid subarine ( 212 ) was reported by Lotter and Bracher in 2009 [ 57 ]. This four-step approach starts with the oxidation of 1,10-phenanthroline ( 213 ) using potassium permanganate.…”

“…Amidation of 215 with 2-haloanilines under Weinreb conditions (trimethylaluminum, heptane) furnished the mono-2-haloanilides 216 and 217 in moderate yields, accompanied by the corresponding dianilides. The final cyclization step was accomplished by treating 2-iodoanilide 216 with tributyltin hydride and a catalytic amount of azobis(isobutyronitrile) in benzene to afford subarine ( 212 ) in very poor yield [ 57 ]. Significant amounts of deiodination product 218 were obtained in this reaction.…”