Murrastifoline-F: first total synthesis, atropo-enantiomer resolution, and stereoanalysis of an axially chiral N,C-coupled biaryl alkaloid

Abstract

The first total synthesis of the Murraya alkaloid murrastifoline-F (3), an unsymmetric, N,C-bonded heterobiarylic biscarbazole, is described. Starting from the likewise naturally occurring-but here synthetically prepared-"monomer" murrayafoline-A (6), lead tetraacetate-mediated oxidative non-phenolic biaryl coupling gives 3 as the main regioisomer. The existence of this natural product as a pair of stable atropo-enantiomers was demonstrated analytically through LC-CD investigations. Preparatively, the racemate resolution succeeded by O-demethylation, derivatization with Mosher's reagent, and chromatographic separation of the resulting diastereomers. The absolute configurations of the atropisomers were assigned by CD spectroscopy in combination with quantum chemical CD calculations at the stage of the alkaloid 3 and by ROESY experiments of the diastereomeric Mosher derivatives. In the root extract of the curry leaf plant Murraya koenigii (Rutaceae), murrastifoline-F (3) was found to exist as a 56:44 mixture in favor of the M-enantiomer, by LC-CD coupling.