Ulapualides are macrocyclic natural products whose complexity has made them an attractive target for synthetic chemists. In this article, Gerald Pattenden at the University of Nottingham, UK, and colleagues report the total synthesis of (-)-ulapualide A. Pattenden explains more about the work below: 

Ulapualide A was isolated in 1986 from the striking red eggmasses (which resemble rosebuds) layed down by a brilliantly coloured nudibranch (also called a sea slug) which lives off the coast of Hawaii. It derives its name from the two Hawaiian words "ula" (meaning red) and "pua" (meaning flower). 

Ulapualide A was the very first natural product to be isolated containing more than one, continuously linked, oxazole. Several others are now known. It shows antileukemic, antifungal and ichthyotoxic properties. 

We were attracted to ulapualide A because of its new and novel structure, but also because its macrocyclic system containing various O- and N- centres suggested that its biological properties could be associated with its capacity to sequester and transport metal ions. 

Motivated by these thoughts, in 1993, we carried out a molecular mechanics study of a hypothetical metal-chelated ulapualide A, which gave us a predicted stereochemistry for the natural product. Hitherto, no stereochemical detail whatsoever was available, and a crystalline derivative of ulapualide A, suitable for X-ray analysis had not been forthcoming. 

In 1998 we achieved the first synthesis of a "ulapualide" having the stereochemistry generated via the aforementioned molecular mechanics study. The synthetic compound showed superimposable proton NMR spectroscopic and optical rotation data, together with chromatographic behaviour, with natural ulapualide A. 

However, there were small, but discernible differences in some carbon NMR shift data, which led us to be cautious in announcing we had synthesised the full stereochemistry for natural ulapualide A. 

In 2004, Rayment et al established the absolute stereochemistry of ulapualide A by X-ray crystal analysis of its complex with the protein G-actin. The X-ray structure showed that our earlier synthesised ulapualide A was in fact nearly the mirror image of the natural product along the C1 to C26 portion of the structure. 

Driven by instinct and a desire for completeness, we simply had to synthesise ulapualide A with the correct absolute stereochemistry. However we decided to simultaneously develop a conceptually new total synthesis which we felt followed more closely a biosynthetic pathway to the tris-oxazole unit in the natural product. 

The total synthesis was completed by PhD student Gary Walker, in September 2006. We were gratified to find that all the carbon NMR spectroscopic data obtained for the synthetic material were now completely superimposable on those of the natural product, recorded simultaneously under the same conditions. Phew! 

The clear messages were: 

i) total synthesis remains vital in establishing structure and stereochemistry of natural products. 

ii) Proton NMR spectroscopy cannot always be relied on when comparing the structures of natural and synthetic compounds, particularly those containing several stereocentres. 

iii) Where possible, proof of structure and stereochemistry of natural and synthetic compounds should be ascertained by recording 'mixed' proton and carbon NMR spectra, c.f. mixed melting point measurements used for decades by our synthetic chemistry ancestors!