Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 9 March 2009

Total Synthesis of Omaezakianol


Y. Morimoto, T. Okita, Angew. Chem. Int. Ed. 2009, 48, 2538-2541.

DOI: 10.1002/anie.200805857

Omaezakianol is the most complex natural product bearing tetrahydrofuran (THF) cores described here (see sylvaticin back in 2006 for the other example). To the casual eye, the molecule looks deceptively symmetrical, but it isn’t. In fact, only the two rightmost THFs are alike, with the others differing in substitution, making the synthesis considerably more complex. And to be frank, that’s the only reason we’re looking at it, as there doesn’t appear to be any biological activity. More about the isolation of the compound and this family of laurencia targets can be seen in a paper in Helvetica Chimica Acta.

A look in that publication in HCA indicates its relation to squalene, and a hint towards the synthesis. However, rather than simply perepoxidising squalene and letting the compound zip-up (which is probably what nature does), we chemists have to be more careful. Morimoto’s retrosynthesis suggests that the three rightmost THFs can be formed in a cascade, whilst the leftmost could be derived from Hoye’s cyclisation. This in turn results from more epoxidation, meaning a lot of titanium isopropoxide and fructose are required.

We start with Sharpless' asymmetric epoxidation of the allylic alcohol, then Shi’s fructose-catalyzed epoxidation of the internal alkene in the presence of DMDO. Unfortunately, the Shi catalyst used is derived from L-fructose - the unnatural variety. However, Shi has published a rather nice prepration of this catalyst from natural L-sorbose. The lower d.r. in the Shi epoxidation is maybe a result of a conflict between substrate and reagent control… Anyway, addition of a base then induced the cyclisation.

The reaction returned the first THF with high stereospecificity. Oxidation of the primary alcohol and methylenation gave a terminal olefin ready for a cross metathesis with the other half of the molecule with three epoxides in place. Both fragments of this reaction are rather sensitive, and are not affected by the metathesis reaction, returning an 87% yield. The freshly installed olefin was then reduced with another smart reaction: a diimide reduction. This reagent reduces olefins very selectively

Addition of diimide with acetic acid in methanol resulted in reduction, but apparently the protons from the acetic acid did not promote the cylisation. Camphersulfonic Acid (CSA) was strong enough, causing three consecutive 5-exo-tet cyclisations, and formation of the three remaining THFs in one cascade. Nice, even if the yield is only moderate.

Removal of the acetonide then gave a diol, elimination of which would give the prenyl sidechain. However, the paper describes an oxidative cleavage to give a lactol, and then olefination of the lactol. Perhaps a Corey-Winter olefination was intended, but didn’t work?