Totally Synthetic by Paul H. Docherty, 25 February 2009
Total Synthesis of BE-43472B
Nicolaou
K. C. Nicolaou, Y. H. Lim, J. Becker, Angew. Chem. Int. Ed. 2009, 48, 3444-3448.
The total synthesis of BE-43472B begins with the synthesis of the
two coupling partners for a cycloaddition. The smaller, chiral fragment gains
its asymmetry from the chiral pool, in this case lactic acid. Unfortunately, it's the unnatural enantiomer that is required for this synthesis, but
Nicolaou didn’t
know this at the start, so actually he did the synthesis first with the cheaper
enantiomer. The synthesis
of the aromatic fragment is actually very interesting, but there’s nothing to get too
excited about. However, for the synthesis of an aryl stannane, they
used a fused cyclohexanone as starting material, performed a double α-bromination and then
elimination to give the ortho-bromophenol, which was stannylated in the end.
The highly controlled cycloaddition, which generated a single stereoisomer as
product, was performed in DCM at 85°C
in a sealed tube. Nicolaou suggests
that the control results from several parameters, including an intermolecular
hydrogen bond, and 1,3-allylic strain. The γ-hydroxy ketone is then perfectly
set to form the THF-hemiacetal, the initial terminus of this cascade sequence. ROESY
proofed that epimerisation of the α-keto
position occurs. This is probably inconsequential, as this stereocenter is
destroyed later in the synthesis. However, this position
could influence the synthesis later on.
Heating in toluene resulted in internal ketalisation. This process removes aromaticity from the system, so the expected resumption occurs via loss of methanol, and completion of the cascade in a very high yield.
Completion of the synthesis didn’t tax the group at all; first up was installation of the tertiary alcohol by epoxidation of the silyl enol ether. Desilylation gave them the desired hydroxyl group and an extraneous ketone was removed by dithiane formation and reduction. A second epoxidation was used to install a further hydroxyl group followed by rearranging this intermediate into the natural product using a mercury lamp - a reaction I’ve not seen in a very long time, and a rather nice way to end an impressive total synthesis.
