Total synthesis, molecular editing and evaluation of a tripyrrolic natural product: the case of "butylcycloheptylprodigiosin".
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 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.
Fürstner
Alois
A
Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
Radkowski
Karin
K
Peters
Hartwig
H
Seidel
Günter
G
Wirtz
Conny
C
Mynott
Richard
R
Lehmann
Christian W
CW
D001671:Biochemistry / Q000379:methods*; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects; D015394:Molecular Structure; D011353:Prodigiosin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C513603:butylcycloheptylprodigiosin; D004247:DNA; D011353:Prodigiosin