Credit: © 2010 NPG

Complanadine A is an alkaloid natural product isolated from the club moss Lycopodium complanatum. It may be useful in the treatment of diseases of the central nervous system. As with many natural products, its synthesis is important to provide sufficient quantities of material for further biological testing. Two recently developed1,2 total syntheses of (+)-complanadine A highlight different approaches to this interesting and complex structure.

Although it is immediately evident that complanadine A is a dimeric structure, efforts towards its synthesis are complicated because the molecule is only pseudosymmetric — the dimer is formed by a bond between the 2-position of one pyridine ring and the 3-position of the second. Daniel Fischer and Richmond Sarpong from the University of California, Berkeley, nevertheless aimed1 to prepare the molecule by formation of this bipyridyl (C2–C3′) bond. They rapidly prepared a key pyridyl triflate intermediate ready for a cross-coupling reaction. The same pyridyl triflate was reduced to the pyridine and, using an iridium-catalysed C–H functionalization, the second cross-coupling partner — a boronic ester — was produced. A Suzuki-type cross-coupling and deprotection then gave the natural product.

At the same time, Dionicio Siegel and co-workers, from the University of Texas at Austin, prepared2 the same target by a sequence of two cobalt-catalysed [2+2+2]-cycloaddition reactions to form each of the pyridine rings. They were unable to find conditions under which the two cycloadditions would occur in one pot, but succeeded in a stepwise formation of one pyridine ring followed by the other. In the process, however, they observed that the addition of a phosphine ligand to the reaction mixture resulted in an interesting switch between the undesired symmetrical product — linked by a bond between the 2 and 2′ positions of the pyridines — and the desired asymmetric natural product.