Total Synthesis, Molecular Editing and Evaluation of a Tripyrrolic Natural Product: The Case of "Butylcycloheptylprodigiosin"

• Published in: Chemistry : a European journal Vol. 13; no. 7; pp. 1929 - 1945
• Main Authors: Fürstner, Alois, Radkowski, Karin, Peters, Hartwig, Seidel, Günter, Wirtz, Conny, Mynott, Richard, Lehmann, Christian W.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.01.2007; WILEY‐VCH Verlag; Wiley
• Subjects: alkaloids; Biochemistry - methods; Chemistry; Chemistry, Multidisciplinary; Crystallography, X-Ray; DNA - drug effects; DNA cleavage; heterocycles; Molecular Structure; natural products; palladium; Physical Sciences; Prodigiosin - analogs & derivatives; Prodigiosin - chemical synthesis; Prodigiosin - chemistry; Prodigiosin - pharmacology; pyrroles; Science & Technology; KETONE O-PENTAFLUOROBENZOYLOXIMES; DIVERTED TOTAL-SYNTHESIS; alkaloids; PALLADIUM-CATALYZED CYCLIZATION; CANCER-CELL-LINES; pyrroles; DNA-CLEAVING PROPERTIES; BOND-CLEAVAGE; PRODIGIOSIN DERIVATIVES; natural products; CROSS-COUPLING REACTIONS; STREPTOMYCES-COELICOLOR A3; heterocycles; DNA cleavage; palladium; CERIC AMMONIUM-NITRATE
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200601639

Conflicting reports are found in the literature on whether the ortho‐pyrrolophane derivative 6, which has been named “butylcycloheptylprodigiosin” 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 CuII. 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. The dispute as to whether “butylcycloheptylprodigiosin” is a natural product or solely a mis‐assigned structure has lasted for more than a decade. This question has now been resolved by the first total synthesis of this tripyrrole alkaloid and a set of analogues (see scheme), which is largely catalysis‐based and features the first application of a “Narasaka–Heck” reaction to natural product synthesis. The capacity of such compounds to damage DNA under oxidative conditions has also been investigated.