Credit: © 2008 NPG

Two of the most recent concepts that have been introduced in the quest to achieve ideal synthesis are atom economy and chemoselective synthesis. Atom economy describes how many of the reactant atoms end up in the desired product, and accounts not only for reaction yield, but also stereoselectivity and the use of any stoichiometric reagents. Chemoselective synthesis is used in attempts to create new reactions with high selectivity between several functional moieties that might otherwise require the use of protecting groups. There is no tougher testing ground for these concepts than in the total synthesis of complex natural products.

Now, Barry Trost and Guangbin Dong from Stanford University, have achieved1 an asymmetric total synthesis of bryostatin 16 — one of a family of compounds that have anticancer activity — using a combination of these approaches. Bryostatin 16 is an ideal target because it has the potential to be converted to many other members of the bryostatin family, and earlier reported syntheses serve as a useful benchmark for the improved method. A simple synthesis of this parent structure may also allow access to analogous structures, which will be useful for an investigation of biological activity.

Transition-metal-catalysed reactions are often key components of atom economical and chemoselective synthesis, and this example is no exception. In a total of 39 steps (26 steps being the longest linear sequence), Trost and Dong make use of ruthenium-catalysed alkene–alkyne coupling in forming the B-ring, a palladium-catalysed alkyne–alkyne coupling — previously achieved with a problematic macrolactonization — to form the macrocycle, and a gold-catalysed cyclization to form an acid-sensitive C-ring towards the end of the synthesis.