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Totally Synthetic by Paul H. Docherty, 26 February 2008

Total Synthesis of Okilactomycin


A. B. Smith, III, K. Basu, T. Bosanac, J. Am. Chem. Soc. 2007, 129, 14872-14874.

DOI: 10.1021/ja077569l

The total synthesis of okilactomycin is an awesome piece of work… The compound offers cytotoxicity against the human cell lines P388 and lymphoid leukemia with fairly small numbers: IC50 0.09 and 0.037 µg/mL. However, if we’re fair - the amazing 11,6,6,5- ring system is much more interesting! Time for retroanalysis:

So the larger ring was to be completed by ring closing metathesis, introduction of the extraneous unsaturation, and production of the smallest ring by an enolate-type addition into a carbonate. This is followed by the construction of the complex pair of linked six-member rings using a relatively simple acetal formation, followed by Petasis-Ferrier rearrangement… ambitious! The linear fragment is a standard polyketide, and the heavily substituted cyclohexane resulted from a Diels-Alder reaction modified by Rawal… lets start from there:

After the Diels Alder reaction, and a few functional group transformations, they were set for a short series of very interesting reactions: first, a catalytic carbonylation, and then diastereoselective allylation. They then transformed the enol ether  into a dimethyl acetal by treatment with mCPBA in methanol, delivering the oxidant diastereoselectively, and providing the required tertiary alcohol. After a few more functional group transformations, which were required for optimal results in the next few steps, they were set for the unification of the two fragments.

Formation of the acetal/lactone (apparently a “dioxanone”) was followed by methylenation of the carbonyl group and then by that very interesting rearrangement. The result is really nice! Then carbonyl chemistry: deprotonation of the free alcohol and enolate formation is followed by addition of methyl chloroformate to yield a pair of carbonates. This biscarbonate was subjected to chemoselective methanolysis to form an intermediate sodium enolate, derived from the enol carbonate, which in turn undergoes cyclization with the tertiary carbonate to furnish the lactone. A very nice synthetic step! With the 1,3-dicarbonyl in place, methylation was easy, and also stereoselective.

Ring closing metathesis and reduction of the alkene furnished the macrocycle, leaving them with only a few functional group transformations to complete the molecule. However, these steps seemed to trouble the group: the planed selenoxide eliminations were tricky, as they couldn’t form both the enolates required to trap PhSeCl. They overcame this by performing one elimination as usual, and the other by first completing a Grieco-Nishizawa elimination, and then oxidising the product (over a few steps) to the desired unsaturated acid.

Again, this total synthesis is an awesome read, and full of interesting chemistry.