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Totally Synthetic by Paul H. Docherty, 25 February 2009

Total Synthesis of BE-43472B


K. C. Nicolaou, Y. H. Lim, J. Becker, Angew. Chem. Int. Ed. 2009, 48, 3444-3448.

DOI: 10.1002/anie.200900058

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 85C 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.