Title
New Synthetic Routes towards 1,4-Naphthoquinone Annulated Aza-Heterocyclic Compounds
Datum en locatie: 15/03/2010, 16h00 in room D0.03
Abstract
Over the last decades numerous metabolites composed of a 1,4-naphthoquinone core annulated with
an aza-heterocyclic ring have been isolated from natural sources. Compounds belonging to this rare
class of natural occurring alkaloids often exhibit interesting antibiotic properties against a wide range
of fungal and bacterial pathogens and are even scrutinized for their cytotoxic effects on human cancer
cell lines. New synthetic routes towards quinones annulated to a pyridine, indole or an oxazole ring
were successfully investigated. For the construction of the 2-aza-anthraquinones core a strategy was
developed involving a Sonogashira coupling of an alkyne with a suitably functionalized 1,4-dimethoxy2-bromonaphthalene as the key step. This reaction was followed either by a thermal cyclization in
aqueous ammonia and a Ce(IV)-mediated oxidation leading to 3-substituted 2-aza-anthraquinones or
by a protonucleophile induced ring closure followed by a PIFA oxidation to obtain 1,2,3-trisubstituted1,2-dihydrobenzo[g]isoquinolines. A C-1 activation of the intermediary formed 3-substituted 5,10dimethoxybenzo[g]isoquinoline-5,10-diones and a subsequent oxidative demethylation yielded 1,3disubstituted 2-aza-anthraquinones. In the framework of an Structure Activity Relationship (SAR study
for antibiotic activity against Mycobacterium tuberculosis) study, a synthetic route towards the lower
ring homologues of the 2-aza-anthraquinones i.e. the benzo[f]isoindole-4,9-diones developed. For this
a desymmetrization strategy starting from 2,3-bis(bromomethyl)-1,4-dimethoxynaphthalene, consisting
of an intramolecular reductive amination, was developed. In a last topic a one pot annulation strategy
delivered a series of oxazole annulated α-naphthols and 1,4-naphthoquinones, revealing a new
synthetic route towards an interesting class of alkaloids bearing a benzoxazole motive.