Total synthesis of aaptamine of potent α-blocking activity via thermal cyclization of 1-azahexatriene systems

Abstract

The total synthesis of the marine alkaloid aaptamine (1), 1H-benzo[de][1,6]naphthyridine, has been completed, based on the thermal cyclization of the 1-azahexatriene system, the key intermediate for the construction of the isoquinoline moiety. 5-Nitroveratraldehyde (7) is converted, via a Wittig reaction, into the nitrostyrene (8). Reduction of (8) to the aniline (9) and subsequent treatment of (9) with ethyl 2-formylacetate gives the enamino ester (10). Preparation of the quinolone nucleus is achieved by heating compound (10) in diphenyl ether, which affords the N-benzylquinolone (12) along with the quinoline (13). Treatment of an inseparable mixture of (12) and (13) with hydroxylamine gives the debenzylated quinolone oxime (11), methylation of which affords a separable mixture of the N,O-dimethyl quinolones (14) and (15). The methyloxime (14)(the 1-azahexatriene system) when heated in o-dichlorobenzene gives the unnatural 1 -methylaaptamine (3). In a similar way, benzylation of (15) affords the N,O-dibenzyl quinolone derivatives (16) and (17). The benzyloxime (16) when heated in o-dichlorobenzene affords N-benzylaaptamine (18). Subsequent cleavage of the N-benzyl protecting group with concentrated hydrochloric acid gives aaptamine hydrochloride (1).