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Totally Synthetic by Paul H. Docherty, 14 July 2009

Total Synthesis of Polyanthellin A


M. J. Campbell, J. S. Johnson, J. Am. Chem. Soc. 2009, 131, 10370-10371.

DOI: 10.1021/ja904136q

Deukjoon Kim - with his publication on (6Z)- and (6E)-Cladiellin Diterpenes - is an acknowledged master of this family of natural products. Lets look at how this fresh challenger Jeffrey Johnson deals with the target. The target is split into two components: The more complex cyclopropane-containing fragment was built using some really interesting chemistry. First up was an organocatalytic Michael addition of isovaleraldehyde into methyl vinyl ketone using a fairly standard proline based catalyst, aided with a bit of a catechol to increase reaction rate and yield. The remaining aldehyde was olefinated to yield a diene, which was ready for a cyclopropanation. Initial attempts were unsuccessful, so they used an interesting protocol based on research by Corey and Myers, which initially diazotises the 1,3-dicarbonyl, and then performs an insertion into the proximal alkene in the presence of a copper(II) salen complex.

The other fragment, an aldehyde, was built easily; asymmetry was introduced via a Sharpless epoxidation, and the resulting epoxide opened using an allyl cuprate. A few more steps including a 1-c homologation returned the desired aldehyde, ready for coupling. This Lewis acid (LA) mediated process is a formal [3+2] cycloaddition in the presence of a very exotic reagent, as more commonly used LAs resulted in aldol couplings of the aldehyde. This aluminium based catalyst, developed by Yamamoto, did the job nicely.

As any reader will see, we’re now perfectly set for a ring-closing metathesis to form the medium ring. This was done in high yield (70%) by using dilute conditions, and chlorinated solvents. However, metathesis catalysts often catalyse other chemistry too when attached to a terminal alkene. A common problem is demethylenation - loss of methylene units - from the starting material, generating a new, similar compound which can then react further. In Johnson’s case, this lead to a eight membered product. Additives to prevent this problem include acetic acid and titanium isopropoxide. In Johnson’s case, simply using DCM as solvent did the job…

The final intermediates are starting to look fairly similar to those generated by Kim. Looking back at that paper, Kim was able to perform an oxymercuration to form both the ethereal bridge and the tertiary alcohol. Johnson hoped, that a similar reaction worked, but achieved only a yield of 10%. He rescued the situation via a slightly more labourious route; iodolactonisation, followed by oxymercuration delivered the desired oxygenation, whilst a reduction with tin hydride removed both the extraneous heavy atoms. Only acetylation was required to finish the target, in a very interesting total synthesis that can compete with Kim's.