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

VARGAS, D. F.; LARGHI, E. L.; KAUFMAN, T. S.

RSC Advances

Royal Society of Chemistry

Lugar: Londres; Año: 2019 vol. 9 p. 33096 - 33106

2046-2069

A straightforward and convenient approach toward the firsttotal synthesis of ampullosine, a structurally unique 3-methylisoquinoline alkaloid isolated from Sepedonium ampullosporum, is reported.Access to the related O-methylampullosine methyl ester from a common intermediate is also disclosed. Thesynthetic sequence toward the natural product comprised a Kolbe-typecarboxylation of 3,5-dihydroxybenzoic acid and further esterification of thediacid, followed by masking of one of the phenols through selective esterreduction and subsequent acetonide formation. Installation of the three-carbonatom required for the 3-methylpyridine ring was performed by triflation of theremaining free phenol and a Pd-catalyzed Suzuki-Miyaura reaction with potassiumE-propenyltrifluoroborate.Deprotection of the acetonide, followed by partial oxidation of the benzylicalcohol to the salicylaldehyde, O-methylation of the free phenol andhydrazonation of the resulting ortho-anisaldehyde derivative gave ahydrazone-based 1-azatriene. This was further subjected to 6p-azaelectrocyclization to afford permethylampullosine(11 steps, 14% overall yield), whereas exhaustive demethylation with AlI3generated in situ gave ampullosine (12 steps, 3.2% global yield).