The long and winding road to a published paper (and lovely crystal structures)

Dedicated to Professor Allan White 1938 – 2016



Xray crystal structure of the diene-dione (1)

This years theme #ChemTogether is all about our chemistry community.  I’ve chosen this year to talk about our recent paper and how it came to be, and the people involved. This paper covers some work that was done over the course of 25 years. That’s a heck off a long time you say. The second thing you’re likely to say is “how can this work that is so old still be relevant?” And that’s a fair question.  So buckle up, settle in and let me tell you a tale. Also depending on your timezone and inclination, you may want to make yourself a cup of tea or coffee, or maybe a beer. Or you might want to snag a copy of the paper here.

“Stereoelectronic effects on dienophile separation influence the Diels-Alder synthesis of molecular clefts” Martin J. Stoermer, Wasantha A. Wickramasinghe, Karl A. Byriel, David C. R. Hockless, Brian W. Skelton, Alexandre N. Sobolev, Alan H. White, Jeffrey Y. W. Mak, David P. Fairlie, European Journal of Organic Chemistry, 2017, in press.

Some history.

This project was only ever supported by one grant, at the very beginning. The grant application was submitted in 1990 while we were employed by Bond University on the Gold Coast, and with an overseas collaborator who was visiting on sabbatical. At the time Bond was Australia’s only private university, but by the time that the grant was successful, Bond was in trouble financially, and by Christmas the science department had been shut, the academics sacked, and the postgraduate students cast adrift.

By the time the 3D Centre had found a new home at the University of Queensland which eventually, after waiting for the political  fallout to subside took over administration of the grant, I began working on other, more medchem-based projects. This was to be the core focus of the new 3D Centre. And so, while working on our long running HIV protease program, this project was marginalised. Nevertheless I was still tinkering with the system in my spare time.

This pattern continued for a number of years, with the research not getting any more government funding including for me personally several postdoctoral fellowship applications. Occasionally we’d get spurred into action and do a little bit of work and have a minor success or two, but then we’d hit the wall and I’d go back to doing what I was paid to do. Some of this earlier work got published in 2003 and we thought we’d be able to wrap up the newer results up quickly. We did, but the paper got rejected several times in one form or another. Mostly the reviewers thought there wasn’t a complete package.

From the outset we knew that this project would need X-ray crystallography to help guide us in our chemistry, and also to see if we’d accomplished our goals. In this we grew our own crystals and sent them to the team at UWA to get the structures solved. Alan White and his team were a delight to work with in those early days, and we are all the poorer for his passing last year. I can still remember when the fax machine would spring into life when Alan sent through the structures. Yes, by fax. On more than one occasion I had the joyful job of re-typing in XYZ coordinate data by hand as it we couldn’t seem to get the data electronically. Times have certainly changed. As is often the case when projects are not officially funded, but manage to move along in fits and starts, some of the crystal structures were done a little closer to home, by Karl Byriel at UQ’s own chemistry department.

The chemistry.

And so to the chemistry. Fundamentally we wanted to build a new class of rigid hydrophobic molecules, which we grandly defined in the original grant application as “enzyme mimics”. In phase one of the work we wanted to build simple systems based on Diels-Alder reactions of templates such as (1) above to create U-shaped structures, capable of binding very small hosts. One such molecular cleft (below) was shown to bind chloroform inside it’s narrow “binding site”. Others bound units of pyridine, cyclohexane, dichloromethane and water.


A rigid synthetic molecular receptor which binds small molecules

Sadly, the lack of granting support in later years meant we couldn’t move along to more complex systems which we had envisaged as catalysts and artificial enzymes.

One of the more interesting aspects of chemistry in this series of molecules, was the relative lack of reactivity at the carbonyl carbon of templates like (2). Whilst we could relatively easily reduce them to the corresponding diols, they were completely inert to reductive amination, which we wanted to  use to make better diamine chelators. In addition, instead of reacting with Grignard reactions or alkyllithiums in the expected manner, the diene-dione instead gets alkylated four times with, in this case methyl groups.


Novel tetra alpha-alkylation of the diene dione

The steric constraint of this tetra methylation pushes the two alkene moieties even closer together. I won’t go into more details here, but pushing those two alkenes back and forth by changing the central ring has interesting effects on reaction rates.


The last hurdle is always to get the work published. And as I’ve said above, without funding, it’s particularly hard to get time and money to do that one last experiment that get’s it over the line. I’ve lost count of the number of rejections we’ve had on this over the years, both on this paper and a bunch or related work that still hasn’t found a home. But over the years, the negative and positive comments of reviewers have helped us along, so a big shout out to the often maligned reviewers, who are after all our peers and part of the chemistry community. As many of you know my ill health has enforced my early retirement from the lab, so it has been additionally hard to get this work published. And the final push in this case came when a colleague Jeff Mak came on board with new ideas, perspectives, and importantly, a pair of lab hands. And with the support of my longtime boss Professor David Fairlie, we finally got this one done. There’s more to do, but for now I can look happily at those 5 beautiful crystal structures, and say yes! They’ve been set free.




About martin

almost on holidays
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