First total synthesis of ampullosine, a unique isoquinoline alkaloid isolated from Sepedonium ampullosporum , and of the related permethylampullosine.

A straightforward and convenient approach toward the first total synthesis of ampullosine, a structurally unique 3-methylisoquinoline alkaloid isolated from Sepedonium ampullosporum , is reported. Access to the related O -methyl ampullosine methyl ester from a common intermediate is also disclosed. The synthetic sequence toward the natural product comprised a Kolbe-type carboxylation of 3,5-dihydroxybenzoic acid and further esterification of the diacid, followed by masking of one of the phenols through selective ester reduction and subsequent acetonide formation. Installation of the three-carbon atom required for the 3-methylpyridine ring was performed by triflation of the remaining free phenol and a Pd-catalyzed Suzuki-Miyaura reaction with potassium E -propenyltrifluoroborate. Deprotection of the acetonide, followed by partial oxidation of the benzylic alcohol to the salicylaldehyde, O -methylation of the free phenol and hydrazonation of the resulting ortho -anisaldehyde derivative gave a hydrazone-based 1-azatriene. This was further subjected to 6π-azaelectrocyclization to afford permethylampullosine (11 steps, 14% overall yield), whereas exhaustive demethylation with AlI 3 generated in situ gave ampullosine (12 steps, 3.2% global yield).