Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 13, Issue 7, Pages 1929-1945Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.200601639
Keywords
alkaloids; DNA cleavage; heterocycles; natural products; palladium; pyrroles
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Conflicting reports are found in the literature on whether the orthopyrrolophane derivative 6, which has been named bwutylcycloheptylprodigiosin even though it is a cyclononane derivative, is a natural product or merely a mis-assigned structure. This dispute has now been resolved by an unambiguous total synthesis of this complex alkaloid which confirms the initial structure assignment. The chosen approach is largely catalysis-based, featuring the first application of a Narasaka-Heck reaction in natural product chemistry. This palladium-catalyzed transformation allows the unsaturated oxime ester 26 to be converted into the bicyclic dihydropyrrole 27. Other notable reactions of the reported approach to 6 are a regioselective Tsuji-Trost reaction of the doubly allylic acetate 21 with methyl acetoacetate, a base-induced aromatization of 27 to the corresponding pyrrole 28, a chemoselective oxidation of the benzylic methyl group in 33 with cerium ammonium nitrate in a biphasic reaction medium that does not affect the labile pyrrole nucleus, and a Suzuki cross-coupling for the completion of the heterocyclic domain. Diversification in the latter step leads to a set of analogues that differ from the natural product in the terminal (hetero)arene ring. This structural modification results in complete loss of the very pronounced ability of the parent compound 6 to induce oxidative cleavage in double stranded DNA in the presence of Cu-II. Several cyclononane-, cyclononene- and cyclononadiene derivatives prepared en route to 6 have been characterized by crystal structure analysis, allowing the conformational behavior of nine-membered carbocycles to be studied.
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