Synthesis of new representatives of 11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-b]pyridines - structural analogues of integrastatins A, B

The Claisen-Schmidt condensation reaction of 3,5-diacetyl-2,6-dimethylpyridine with salicylic aldehyde in the presence of an acid unexpectedly afforded 1-((5S,11S)-2,5-dimethyl-11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-b]pyridin-3-yl)ethan-1-one as the product of intramolecular cyclization instead of alpha,beta-unsaturated ketones (mono- or bis-azachalcones). The obtained 1-((5S,11S)-2,5-dimethyl-11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-b]pyridin-3-yl)ethan-1-one is a close nitrogen-containing structural analogue of natural inhibitors of HIV-1 integrase, namely integrastatins A and B, epicoccolide A and epicocconigrone A, containing a tetracyclic epoxybenzooxocine fragment. Substrate scope and mechanistic insights into the cyclization reaction were investigated. A possibility of selective oxidation of the methylene group of the oxocine ring with selenous acid to the carbonyl group was shown to prove structural similarity of the synthesized pyridine-containing analogs with the integrastatin scaffold.