A life less ordinary

This month Albert Eschenmoser receives the RSC’s Barton gold medal. Cath O’Driscoll talks to him about a career spent chasing the mysteries of life.

’It’s like digging through geological layers. You start by thinking about what could have happened and develop certain ideas. Sometime later you recognise that your ideas are too na?ve, and you re-approach the problem. The view you develop is different from that on the first layer. And that doesn’t stop. It goes further and further, until you have gone through I don’t know how many layers, and you are still asking yourself whether you are approaching something that is actually real.’ Such, says Albert Eschenmoser, is the complexity of the question of how life began on Earth. Now officially retired as professor of organic chemistry at the Swiss Federal Institute of Technology (ETH) in Zurich, Eschenmoser has spent much of the latter part of his 50-year career in organic chemistry pursuing these fundamental questions of life’s origins. ’You keep asking yourself "what could molecule A do in the presence of molecule B?" It is the depth of that central problem of life’s origin that keeps you asking the question again and again. All that empirical knowledge accumulated in having done life-long synthesis seems a prerequisite, and so is the pleasure you must have experienced in doing synthesis all your career.’

Being retired doesn’t seem to be much of an obstacle. Eschenmoser continues to maintain a lab at ETH, as well as overseeing - together with Ram Krishnamurthy - the work of a group of postdoctoral collaborators at the Skaggs Research Institute for Chemical Biology (part of The Scripps Research Institute) in California. Ultimately though, Eschenmoser is resigned to the fact that the problem of life’s origin is ’by its very nature open ended’.

At ETH, Eschenmoser chose to specialise in chemistry part-way through his teaching diploma. Inspired by ’marvellous teachers, powerful personalities’, he went on in 1949 to study for a PhD in chemistry, officially under the supervision of Nobel laureate Leopold Ruzicka, the leading terpene chemist at that time.

At least for the first year and a half of his PhD, Eschenmoser saw nothing of Ruzicka, who was then more interested in his art collection, travelling frequently to London to buy cut-price artwork during post-wartime. Instead, Eschenmoser worked at ETH in the laboratory of Hans Schinz, a perfume chemist and former industrial collaborator of Ruzicka. From the outset, Eschenmoser had in mind a project of his own that he would like to turn his hand to: ’As still a student, I was lucky to recognise that one of the scientific papers of Ruzicka contained an error, a discovery that was of course to me as a beginner psychologically very important.’

This ’error’ concerned the structural assignment of the sesquiterpene zingiberene, a constituent of ginger oil. Eschenmoser had the experimental proof for correcting Ruzicka’s formula within a month of starting his research. After that, he was free to choose his own PhD problems. But Eschenmoser’s correction also had deeper implications, and cast doubt on the reliability of many other terpene formulae.

Until 1953 structural assignments of terpenes relied on the so-called isoprene rule, which dictated that the constitutional formulae of terpenes should be composed of ’isoprene units’. But there was no mechanism that might have explained this. Around the middle of the last century, however, a new way of thinking was emerging in organic chemistry, championed by chemists such as Christopher Ingold and Michael Dewar in the UK, or Paul Bartlett in the US. ’It was a way of qualitative mechanistic reasoning based on the so-called ’electronic theory’ of organic chemistry, gradually penetrating the thinking in natural products chemistry. As a young chemist you had the chance of absorbing such new thinking more easily than the members of the generation of your teachers so that you could gain a sort of advantage over them.’

Later expounded by Ruzicka at an IUPAC conference in 1953, this new view became known as the ’biogenetic’ isoprene rule, as opposed to the old ’empirical’ rule. Two years later, Eschenmoser and Arigoni succeeded in proposing - together with Ruzicka and Arigoni’s superviser Oskar Jeger - a complete and consistent stereochemical interpretation of the biogenetic isoprene rule for cyclic triterpenes, an achievement that J W Cornforth later referred to as ’the apotheosis of the isoprene rule’.

Ruzicka made sure that Eschenmoser’s contributions were rewarded. Only a year and a half into his PhD, Eschenmoser was ’ordered’ by Ruzicka to set up his own research group. Starting with two students, initial work was devoted to proving sesquiterpene formulae by synthesis. ’I was not really a good experimentalist, but there were a number of new formulae that were awaiting experimental proof,’ Eschenmoser reflects. Fortunately, his first student Jakob Schreiber was a superb experimentalist and stayed in Eschenmoser’s research group for the rest of his life, becoming one of his best friends. Less fortunately, Derek Barton, then at Birkbeck College in London, was also working in the field, and scooped Eschenmoser to the experimental structure proof for ?-caryophyllene in 1952.

After the sesquiterpenes, Eschenmoser was already hooked by the power of organic synthesis. ’I was caught by the challenge of synthesising complex molecules. This was the time when research in organic natural product synthesis moved from target to target, from one level of complexity to the next. R B Woodward at Harvard was the field’s hero.’ Eschenmoser’s group joined the race for colchicine, the poisonous principle of the autumn crocus, used for the treatment of gout since antiquity. The alkaloid itself had been known for over 100 years, but its constitution, a highly unusual one for that time, had just been elucidated.

The biggest synthetic challenge was yet to come, however. Dorothy Hodgkin had published the X-ray structure of vitamin B ₁₂ in 1956. ’It was clear to us that this had to be the next target. Essentially no chemistry of that novel molecular structure was known, quite different from the case of colchicine, where much of its chemistry had been in the literature. That was a major reason, besides the extraordinary challenge as such, for synthesising vitamin B ₁₂. In attempting to do so, we would be forced to develop new synthetic chemistry.’

But where to begin? ’The corrin nucleus of the molecule was structurally brand new and it had a cobalt atom in the centre. The central question for us was: how does one synthesise a corrin complex?’ We attacked this problem toward the end of 1959 and reached a solution after four years’ work.’ At Harvard, Woodward had also begun work on vitamin B ₁₂ in 1961, ’by jumping directly on the whole thing’. Eschenmoser reflects that ’I can’t really remember who first proposed joining forces, but around 1965 the two groups decided to collaborate. It seemed sensible enough; Harvard had tackled the difficult stereochemical problem at the left side of the molecule, and we had shown how to build a corrin and had been working on the chromophore part on the right side’.

Eschenmoser remembers thinking that synthesising the natural product would be ’though more complex, a repetition in a way of what had been done already’. In this, he was ’seriously wrong’: the chemistry needed to construct the natural molecule turned out to be quite different. It took the two groups another seven years to reach the final goal of their joint vitamin B ₁₂ synthesis in 1972.

’Then a whole family of dark versions of this ring closure were found, not just one or two. That ended in a drastic change in the way how we looked at vitamin B ₁₂ concluding that its structural complexity is in fact just an apparent complexity. You simply must look at it, and approach it from, the right direction.’ But if the structure of the complex vitamin B ₁₂ molecule is intrinsically simple, are the structures of all fundamental biomolecules simple? And how old are these molecules? This was the connection, Eschenmoser says, to ask ’and where did these molecules come from? Can we as chemists do something about this question and, if so, where would we end up? Well, in thinking about the origin of life as a whole’.

This train of thinking has preoccupied Eschenmoser for the rest of his career - and led him to his current work on nucleic acids, RNA and DNA, the central molecules of life. More than a decade ago Eschenmoser hit upon a finding that would change forever the way that we think about these fundamental structures. A model study in the laboratory led to the synthesis of ’homo DNA’, which differs from conventional DNA by possessing just one extra methylene (CH ₂) group in the sugar ring. Especially significant was the observation that homo DNA forms even stronger base pairs [between A and G, C and T] than DNA itself - a fact that threw into turmoil previous assumptions about DNA and the uniqueness of its base-pairing capability. Eschenmoser recalls the disbelief of one biochemist after he first presented his results at a conference in 1989: ’the person simply refused to believe that nature had not made the best molecule - the one that has the strongest base pairing’.

RNA and, even more so, DNA, are themselves chemically too complex to have been the first self-replicating molecules to have emerged on primitive Earth, Eschenmoser believes. ’The same may be true for the threofuranosyl nucleic acid system (TNA), a potentially natural nucleic acid alternative we have studied, one that speaks the same ’base-pairing language’ as RNA, but is structurally simpler than RNA.’ ’To doubt that RNA was the first replicator means considering that it originated in an environment that contained life already, a life that would have had to be more primitive. To conceive, make and study potentially natural informational oligomers that are as simple as possible is one of the present challenges.’

The final challenge for chemists, Eschenmoser says, will be to create artificial chemical life in the laboratory - to prove, by producing artificial model systems, that life can arise by organising organic matter. Such an achievement will emerge gradually, much as natural life itself emerged gradually from a geochemical environment. And it will teach us, ’and this is the major point’, Eschenmoser reflects, what life is at its most elementary level.

Acknowledgements

Cath O’Driscoll 

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