Combinatorial synthesis of linearly condensed polycyclic compounds, including anthracyclinones, through tandem Diels-Alder additions
Double exocyclic 1,3-dienes such as 2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptane and its 1-substituted derivatives undergo two successive Diels-Alder additions with large reactivity difference between the addition of the first equivalent (k(1)) and the second equivalent (k(2)) of dienophile. This allows one to prepare, through parallel synthesis, a large number of linearly condensed polycyclic systems containing three annulated six-membered rings, including naphthacenyl systems and anthracyclinones. The large k(1)/k(2) rate constant ratio is a consequence of the Dimroth principle, the first cycloaddition being significantly more exothermic then the second one. Control of regio- and stereo selectivity of the two successive cycloadditions is possible by 1-substitution of the 2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptane, for instance by a 1-(dimethoxymethyl) group, or by stereoselective disubstitution of the double diene by arenesulfenyl substituents. Enantiomerically pure anthracyclinones and analogues are obtained using enantiomerically pure dienophiles such as 3-oxo-but-2-en-2-yl esters. The chemistry so-developed has allowed the preparation of enantiomerically pure 6-((aminoalkoxy)oxy)methyl-6,7-dideoxyidarubicinones that are DNA intercalators and inhibitors of topoisomerase II-induced DNA strained religation.
Keywords: anthracyclines ; desymmetrization ; Diels-Alder reactions ; DNA strand religation ; furans ; 2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptane ; topoisomerase inhibitors ; Regiospecific Total-Synthesis ; Intermolecular Orbital Theory ; Non-Conjugated Chromophores ; Anti-Tumor Agents ; Antitumor-Activity ; Organic-Synthesis ; Regioselective Synthesis ; Asymmetric-Synthesis ; Efficient Synthesis ; Adriamycin Analogs
Record created on 2010-11-30, modified on 2016-08-09