Guest post by Dr. Elisa Meschini

Anyone who has ever worked in a chemistry lab will be all too familiar with the “trials and tribulations” that Unsworth and Taylor so vividly describe in this review article, in which they recount their journey towards the total synthesis of the natural product ‘upenamide.

‘Upenamide is a fascinating molecule with many challenging structural features, which has raised considerable interest from the synthetic organic chemistry community. It contains a 20-membered macrocyclic ring and 8 stereogenic centres (including two unusual N,O-acetals). Biosynthetically, ‘upenamide is thought to derive from a similar synthetic pathway to that of another marine alkaloid, manzamine. ‘Upenamide is a promising anticancer target, although biological studies against cancer cell lines necessitate the total synthesis of the natural product.

At the start of my PhD in anticancer drug discovery, I found myself expressing my frustration to one of my advisors, Prof. Bernard Golding, about a reaction that was not proceeding according to plan. Prof. Golding assured me that if I kept working and stuck to my methods, the reaction would come through in the end. His career a shining example of this healthy and positive philosophy, he was of course right.

The field of total synthesis was officially inaugurated by Friedrich Wöhler’s synthesis of urea in 1828, which demonstrated that organic molecules can be produced from inorganic precursors (thereby disproving the existence of a so-called “vital force” in organic compounds. Since then, total synthesis has been engaging generation after generation of chemists in alternating bouts of frustration and elation. A marriage of rigorous science and sophisticated art, total synthesis has provided massive contributions to the development of science for the benefit of humanity.

In a notable example, after the cancer chemotherapy drug paclitaxel was first discovered in 1967 and its therapeutic properties were evaluated, the National Cancer Institute (NCI) in the United States was driving the pacific yew (from whose bark the natural product was initially sourced) to extinction in order to acquire enough material for clinical trials. It was organic synthesis that saved the day, when R.A. Holton first devised a semisynthetic route to paclitaxel in 1992. K.C. Nicolaou later reported the first total synthesis of taxol in 1994. Holton’s semisynthesis was the primary route for the sourcing of paclitaxel until an industrial process based on the fermentation of Taxus cell lines was developed in 2003.

From strychnine, quoted by R.B. Woodward as being ‘for its molecular size, (…) the most complex substance known’, to vitamin B12, to penicillin, the milestones set by dedicated synthetic organic chemists over the past two centuries have been many and breathtaking. It is impossible to overstate the difficulties faced, and the creativity and genius required to overcome them. By its very nature, as stated by Taylor and Unsworth in their review, this is a field where the frustrations are inevitable but the journey, however rich with obstacles, is as important as the destination.

When reading Unsworth and Taylor’s remarks in the Conclusions section of their review, one can feel the exasperation.

‘Unfortunately, the spectroscopic data for neither synthetic compound match those of the natural product, meaning that the true structure of the natural material remains uncertain. Given that a huge amount of effort by several research groups has gone into the synthesis of ‘upenamide, it is disappointing that we were not able to elucidate its structure through total synthesis, and its true structure remains a mystery.’

One can almost hear the sheet of paper bearing the latest spectrum being ripped from the printing machine in trepidation, then the exasperated sigh of anticlimax and perhaps a fist colliding with the desktop, causing the beaker containing the NMR tubes to be upended. We have all been there.

The history of the association between the Taylor group at York and ‘upenamide (a word deriving from the Hawaiian for fishing net or trap, a reference to both the natural product’s marine origins and unusual shape) goes back to 2004, when the synthesis of a model of ‘upenamide’s ABC ring system was first described. At the same time, a separate research group in France was working on a model DE ring system for the same molecule.

It wasn’t until 2007 that the ABC and DE ring systems were successfully coupled by a group in Pennsylvania. Still the total synthesis of the natural product was not complete, although the efforts towards ‘upenamide had by then resulted in the development of an array of excellent synthetic techniques, as the many synthetic challenges posed by ‘upenamide at each step of the synthesis had been met with several creative solutions. Finally, in 2012, the Taylor group managed to build upon these international pioneering studies and complete the synthesis of what had, by then, been accepted as the most likely proposed structure for the natural two diastereoisomers.

Unfortunately, (cue fist on desktop) as these two diastereoisomers were being investigated spectroscopically, it became clear that neither of them corresponded to the true structure of ‘upenamide. The two products were insoluble in the solvents that had been used to characterise ‘upenamide. Furthermore, the NMR data were considerably different from those of ‘upenamide.

There are many possible explanations for these discrepancies. Errors may have been committed either by the chemists who isolated the natural product, or by those attempting its synthesis. Some of the spectroscopic data along the way may have been misassigned. Unfortunately, ‘upenamide eludes as of yet all efforts to obtain an X-ray crystal structure and future studies will have to wait until the now-depleted stocks of the original natural product are replenished by further extraction from the Indonesian sponge Echinocalina sp.

Taylor and Unsworth have succeeded in conveying their enthusiasm at being part of such important endeavours, and this should serve as inspiration for the next generations of chemists that the discipline is both attractive and important, and when pursued with optimism it never fails to bring immeasurable benefits to society.


Elisa is a Publishing Editor at the Royal Society of Chemistry, where she works on synthetic organic and medicinal journals such as OBC and MedChemComm. She previously completed a PhD in anticancer drug development at the Newcastle Cancer Centre. Elisa is a keen follower of the latest developments in synthetic organic and medicinal chemistry and the Woodward paper on strychnine was one of her first undergraduate assignments.

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