The rise of translational research and the death of organic synthesis (again)?

The journal ACS Neuroscience has an editorial lamenting the shortage of qualified synthetic organic chemists and pharmacologists in the pharmaceutical and biotech industries. The editorial lays much of the blame at the feet of flagging support for these disciplines at the expense of the fad of 'translational research'. It makes the cogent point that historically, accomplished synthetic organic chemists and pharmacologists have been the backbone of the industry; whatever medicinal chemistry and drug design they learnt was picked up on the job. The background and rigor that these scientists brought to their work was invaluable in discovering some of the most important drugs of our time, including ones against cancer, AIDS and heart disease.

The current fascination of applied basic science, i.e., translational science, to funding agencies, due in large part to the perception of a more immediate impact on human health, is a harbinger of its own doom. Strong words? It is clear in the last 10 years that research funding for basic organic chemistry and/or molecular pharmacology is in rapid decline. However, the quality of translational science is only as strong as the basic science training and acumen of its practitioners—this truth is lost in the translational and applied science furor. A training program that instills and trains the “basics” while offering additional research in applied science can be a powerful combination; yet, funding mechanisms for the critical first steps are lacking. 

Historically, the pharmaceutical industry hired the best classically trained synthetic chemists and pharmacologists, and then medicinal chemistry/drug discovery was taught “on the job”. These highly trained and knowledge experts could tackle any problem, and it is this basic training that enabled success against HIV in the 1990s. When the next pandemic arises in the future, we will have lost the in-depth know-how to be effective. Moreover, innovation will diminish.

I have a problem pushing translational research at the expense of basic research myself. As I wrote in a piece for the Lindau Nobel Laureate meeting a few years ago, at least two problems riddle this approach:

The first problem is that history is not really on the side of translational research. Most inventions and practical applications of science and technology which we take for granted have come not from people sitting in a room trying to invent new things but as fortuitous offshoots of curiosity-driven research...For instance, as Nobel Laureates Joseph Goldstein and Michael Brown describe in a Science opinion piece, NIH scientists in the 60s focused on basic questions involving receptors and cancer cells, but this work had an immense impact on drug discovery; as just one glowing example, heart disease-preventing statins which are the world’s best-selling drugs derive directly from Goldstein and Brown’s pioneering work on cholesterol metabolism. Examples also proliferate other disciplines; the Charged-Coupled Device (CCD), lasers, microwaves, computers and the World Wide Web are all fruits of basic and not targeted research. If the history of science teaches us anything, it is that curiosity-driven basic research has paid the highest dividends in terms of practical inventions and advances. 

The second more practical but equally important problem with translational research is that it puts the cart before the horse. First come the ideas; then come the applications. There is nothing fundamentally wrong with trying to build a focused institute to discover a drug, say, for schizophrenia. But doing this when most of the basic neuropharmacology, biochemistry and genetics of schizophrenia are unknown is a great diversion of focus and funds. Before we can apply basic knowledge, let's first make sure that the knowledge exists. Efforts based on incomplete knowledge would only result in a great squandering of manpower, intellectual and financial resources. Such misapplication of resources seems to be the major problem for instance with a new center for drug discovery that the NIH plans to establish. The NIH seeks to channel the newfound data on the human genome to discover new drugs for personalized medicine. This is a laudable goal, but the problem is that we still have miles to go before we truly understand the basic implications of genomic data.

It is only recently that we have started to become aware of the "post-genomic" universe of epigenetics and signal transduction. We have barely started to scratch the surface of the myriad ways in which genomic sequences are massaged and manipulated to produce the complex set of physiological events involved in disease and health. And all this does not even consider the actual workings of proteins and small molecules in mediating key biological events, something which is underlined by genetics but which constitutes a whole new level of emergent complexity. In the absence of all this basic knowledge which is just emerging, how pertinent is it to launch a concerted effort to discover new drugs based on this vastly incomplete knowledge? It would be like trying to construct a skyscraper without fully understanding the properties of bricks and cement.

As an aside, that piece also mentions NIH's NCATS translational research center that has been the brainchild of Francis Collins. It's been five years since that center was set up, and while I know that there are some outstanding scientists working there, I wonder if someone has done a quantitative analysis of how much the work done there has, well, translated into therapeutic developments.

The editorial also has testimonials from leading organic chemists like Phil Baran, E J Corey and Stephen Buchwald who attest to the power of basic science that they discovered in their academic labs, power that they see almost disappearing from today's labs and funding agencies. This basic science which they have pioneered unexpectedly found use in industry. Buchwald's emphasis on C-N cross-coupling reactions is especially noteworthy since it was these kinds of reactions which really transformed drug synthesis and which led to Nobel Prizes for their inventors.

Baran's words are worth noting:

“It is ironic that a field with such an incredible track record for tangible contributions to the betterment of society is under continual attack. Fundamental organic synthesis has been defending its existence since I was a graduate student. If the NIH continues to disproportionally cut funding to this area, progress in the development of medicines will slow down and a vital domestic talent pool will evaporate leaving our population reliant on other countries for the invention of life saving medicines, agrochemicals, and materials.”

Baran is right that fundamental organic synthesis has been defending its existence for the last twenty years or so, but as has been discussed on this blog and in other sources, it's probably because it worked so well that it became a victim of its own success. The NIH is simply not interested in funding more total synthesis for its own sake. To some extent this is a mistake since the training that even a non-novel total synthesis imparts is valuable, but it's also hard to completely blame them. The number of truly novel reactions that have been invented in the last thirty years or so can be counted on one hand, and while chemists like Baran continue to perform incredibly creative feats in the synthesis of complex organic molecules, what they are doing is mostly applying known chemistry in highly imaginative new ways. I have no doubt that they will also invent some new chemistry in the next few years, but how much of it will compare to the fundamental explosion of new reactions and syntheses in the 1960s and 70s? I don't think this blog as well as others have denied the kind of training that synthetic organic chemistry provides, but I have certainly questioned the aura that sometimes continues to surround it (although it has declined in the last few decades) as well as the degree to which the pharmaceutical industry truly needs it.

To some extent the argument is simply about degree. The biggest challenge in most of the pharmaceutical company's postwar history was figuring out the synthesis of important drugs like penicillin, niacin and avermectin. In the era of massive screening of natural products, design wasn't really a major consideration. Contrast this period to today. The general problem of synthesis is now solved, and the major challenge facing today's drug discovery scientists is design. The big question today is not "How do I make this molecule?" but rather "How do I design this molecule within multiple constraints (potency, stability, toxicity etc.) all at the same time?" Multiparameter optimization has replaced synthesis as the holy grail of drug discovery. There are still undoubtedly tough synthetic puzzles that would benefit from creative problem-solving, but nobody thinks these puzzles won't yield to enough manpower or resources or would necessitate the discovery of fundamental new chemical principles. We of course still need top-notch synthetic organic chemists trained by top-notch academic chemists like Corey and Baran, but we equally (or even more) need chemists who are trained in solving such multiparameter design problems. Importantly, the solution to these problems is not going to come only from synthesis but also from other fields like pharmacokinetics, statistics and computer-aided design.

Another major point which I think the editorial does not touch on is the massive layoffs and outsourcing in industry which have bled it dry of deep and hard-won institutional knowledge. Drug discovery is not theoretical physics, and you cannot replenish lost talent and discover new drugs simply by staffing your organization with smart twenty-five year old wunderkinds from Berkeley or Harvard. Twenty or thirty years' experience counts for a hell of a lot in this industry; far from being a fever chill, age is a unique asset in this world. To me, this loss of institutional knowledge is a tragedy that is gargantuan compared to the lack of support for training synthetic organic chemists, and one that may have likely hobbled pharmaceutical chemistry for decades to come, if not longer.

Other than that the editorial gets it right. Too much emphasis on translational research can detract from the kind of rigorous, character-building experience that organic synthesis and classical pharmacology provide. As with many other things we need a bit of both, and some moderation seems to be in order here.

Phil Baran keeps the dream of classical organic chemists alive

I am very happy to note that organic chemist Phil Baran from Scripps is one of this year's recipients of the MacArthur "Genius" Award. It's rare for a chemist and especially a "pure" organic chemist to receive this recognition. 

The first reason why chemists should be happy of course is that Baran is a phenomenal chemist. Ever since he was a graduate student he has been churning out innovative molecules and methods to make them. It's probably safe to say that he is the most promising young organic chemist in the world right now.

But the more important reason why this recognition is almost heart-warming is because it reaffirms faith in the soul of "pure" organic chemistry and synthesis. Baran's style of synthesis reminds one of the golden age of the discipline in the 50s and 60s, when legendary practitioners like Woodward, Corey and Stork used to make molecules for the sake of making them, for exploring the beauty and difficulty of their architectures and for appreciating the simple tricks and reagents that could turn a complex synthesis into a simple one. Phil Baran produces the same wistful nostalgia in a young aspiring organic chemist that a Detroit car manufacturer from the 50s would produce in a young automobile engineer standing on the empty grounds of a once-thriving factory. He reminds us of the time when synthesis was king.

Throughout his career Baran has continued to achieve all the goals savored by the giants of synthesis. He has followed his mentor E J Corey in synthesizing some very complex compounds as well as in developing new methods. When I read about his work I think of the young Woodward making reserpine or of the young Corey discovering new protecting groups for alcohols. 

The last few years have seen some cynicism - much of it well-directed - about total synthesis, about the tendency to treat molecule-making as a marathon rather than a sprint. And yet young Baran has proven that there are still gems to be unearthed from the dross of hammer and tong chemistry, and that there is still hope for the next generation of purely synthetic chemists who are looking for truly innovative molecules and methods.

This seems to me to be a more than adequate reason to toast Baran and his accomplishments. Congratulations Phil!

Woodward, and the importance of being born at the right time

Woodward as a freshman at MIT (Image: CHC)

On his blog Derek has a contemplative post on the conditions necessary for seeing titans in particular fields, and whether these conditions can be replicated again. I completely concur with his viewpoint that it’s possible to discover the structure of DNA, or formulate general relativity, or revolutionize organic synthesis, just once.

Putting it another way, the question to ask is whether the general problem has been solved. Woodward is certainly a case in point...

Read the rest of the post on my Scientific American Blog

Gilbert Stork on steaks, synthesis and more

Few chemists in the twentieth century have contributed as many important ideas to the science and art of organic synthesis as Gilbert Stork. Stork has made any number of groundbreaking and elegant contributions to the discipline, from the enamine reaction to radical chemistry to pathbreaking total syntheses like his synthesis of quinine. And from his perch at Columbia University where he has been for almost fifty years, he has emerged as one of his generation's most productive trainers of leading chemists in academia and industry. Here's a nice presentation listing his achievements.

Stork is now being celebrated on occasion of his 90th birthday by chemist and historian Jeff Seeman in Angewandte Chemie. Jeff brings us a wonderful collection of anecdotes, quotes and stories, both by Stork himself and by his friends and colleagues which include some of the twentieth century's leading organic chemists. There are also dozens of memorable photos. Unlike some of his contemporaries, Story is a rather unassuming man who has shunned the limelight, so it's a treat to hear these stories. There's lots of amusing stuff in there, from Stork's literally explosive relationship with cars to his being thrust into the unenviable situation of having to give a talk right after a stellar lecture by R. B. Woodward. For me two stories stood out.

First, a tale of steak disposal that momentarily triggered a panic attack and illustrated a nice lesson about kinetics (notwithstanding the fact that aqua regia contains hydrochloric, not sulfuric acid):

“There was this one really idiotic time. I remember I was really scared that I was going to blow up the entire Chemistry Department at the University of Wisconsin. I had a steak on the window ledge of my office. It was the winter, and I used the window ledge as a refrigerator. You obviously were not supposed to be cooking steaks in the lab, but I had a small lab where I was usually alone in there, and so I had a steak. But I also was not aware that biodegradable material is biodegradable, and this steak was clearly degraded on the window ledge. And the question was, what to do with it? And I decided to toss the steak in a hot acid bath which we used to clean up glassware. So, it's fuming nitric and sulfuric acid. It's really aqua regia in that bath, in that heavy lead dish, and the steak.

“And then, as I just had thrown it in there, and it fumed furiously and red fumes of who knows what, nitrous oxide of various kinds were being produced there. I became frantically concerned because fat is glycerides. So, I am hydrolyzing the fat to glycerin. You make nitroglycerine by taking glycerin and nitric acid and sulfuric acid, and obviously, I am going to produce a pile of nitroglycerine and blow up the entire building with my steak.

“Now, what is an interesting point there, why didn't it? And of course, the reason is kinetics. That is, the kinetics of oxidation of the glycerol at that temperature is much, much, much, I mean, infinitely faster than the cold temperature nitration of glycerin. And so the place was safe.”

And second, some reflections on the real value and utility of chemical synthesis:

“The toughest question to ask in synthetic organic chemistry after the work is done is: what have you learned? And you can have extraordinarily complex things. They look complex as hell. Maybe they have 80 asymmetric centers and maybe the answer is, [you've learned] nothing. I mean, you could have learned that humans are capable of enormous focused efforts and are capable of sticking with a problem which is extraordinarily complicated.

On the other hand, if somebody makes polyethylene, as somebody obvi- ously did, then you learn a lot, even though it will not thrill most synthetic chemists because this would be comparable to building a highway for an architect. I mean, it's important, but it's fairly dull compared to [building] the Guggenheim Museum, for instance... ”

“So something could be not terribly glamorous but extremely important, or vice versa. I think that B12 was vice versa. It's enormously complicated.”

That's a really important point he makes, and one that should define the choice of a research problem especially for a young investigator. There's not much point in attempting that 80 step synthesis using "hammer-and-tong" chemistry if it's not going to teach you much; that's also one of the reasons that people like Woodward get so much credit for synthesizing something first, since they really demonstrated that such complex synthesis was possible. On the other hand, throwing in two simple chemicals and watching them form an astonishingly intricate infinite lattice can really teach you something new. So can synthesizing a boringly repetitive polymer with novel properties.

The real deal in chemistry as in any other science is understanding, and the nature of experiments that impart real understanding changes with the evolution of chemical science. Stork's message for new researchers is clear; pick a problem that may not be glamorous, but whose solution would teach you something new. Stamina is not quite as important as creativity and discovery, and although perseverance is admirable, you don't make an important contribution just by proving that you can stick with a problem for ten years. Even though it may appear that way, science is not a marathon; it's scuba diving.

Image source

Note on the cultish status of organic synthesis: Part 2

In 1828, Friedrich Wöhler synthesized urea - a substance hitherto thought to be produced only by living organisms - from simple inorganic substances. The discovery was a watershed in the history of science. In one fell swoop it shattered the widespread doctrine of vitalism which held that there is something fundamentally different between the animate and inanimate worlds. Wöhler was the triumphant messenger, heralding great expectations for the new adventurers while shattering the dreams of keepers of the faith.

Only ten years before in 1818, a different kind of vitalism was being conceived. That was the year when Mary Shelley published "Frankenstein; or, The Modern Prometheus". "Frankenstein" did for the science fiction genre what Wöhler did for chemistry. It infused the vivid imaginations of generations of writers, thinkers and movie-makers with notions of reanimating dead matter.

Now fast-forward to 1960. Woodward synthesizes chlorophyll. Chlorophyll. The substance which more than any other fuels life on this planet. There are telling similarities between Wöhler's synthesis of urea, Shelley's creation of "Frankenstein" and Woodward's synthesis of chlorophyll. All three speak to man's mastery over Nature. All three embody a conscious or unconscious sense of hubris. And all of them tell us that the allure of vitalism is still alive, albeit in a very different sense. The chemists of Wöhler's generation strove to annihilate the distinction between living and non-living. But the synthetic chemists of Woodward's generation want to do one better and are closer to the brilliant, troubled protagonist of Shelley's novel; they want to not only starkly state the difference between life and death but they want to become the creators of both.

Wöhler's urea and Woodward's chlorophyll demonstrate the second reason for the cultish status of organic synthesis. The first was the cult of personality, but the second is the all-powerful cult of elemental ambition. There is a truly seductive feeling of power in being able to synthesize a substance like chlorophyll whose constitution and very identity seemed for years to be among Nature's most closely guarded secrets. A creature who could unravel the workings of this most fundamental of nature's engines would announce himself to be a true master of creation. What better way to make this announcement than to not only tease apart the strands of this secret but to create it from scratch? In fact it's worth noting the other landmark Nobel Prize winning discovery related to photosynthesis: the unraveling of the structure of the photosynthetic reaction center protein by Harmut Michel, Johann Diesenhofer and Robert Huber. As important as it was, the psychological impact of even this discovery cannot compare to the creation of chlorophyll through human ingenuity.

That is why, among all the chemical sciences, organic synthesis still enjoys a unique status. It harkens back to one of man's deepest and most primitive desires, to remake the world in his image; to first closely study, then mimic, and finally improve over nature. There can be no higher accolade for a species than to be congratulated for being able to trump it's very creator. This accolade is manifest in the Nobel committee's tribute to Woodward as well as to organic synthesis when it noted that "It is sometimes said that organic synthesis is at the same time an exact science and a fine art. Here Nature is the uncontested master, but I dare say that the prize-winner of this year, Professor Woodward, is a good second." In addition organic synthesis not only creates the molecules of life but it saves life, and the production of novel drugs further drives the image of synthesis as an instrument of human triumph.

The new science of synthetic biology promises to satisfy the same craving. The deliberate synthesis and rearrangement of genes to create new organisms from scratch promises the same kind of psychological benefits that the total synthesis of complex substances afforded to both organic chemists and lay audiences. No wonder that discoveries by Craig Venter and others are heralded in the press as the dawn of a new age, and they undoubtedly are. But in terms of their goals, these spectacular advances simply constitute the extensions of an age that began in 1828. And the psychological need goes back even further, when man was living in caves and creating innovative tools, agricultural implements and clothing from animal hides.

It's just vitalism and Frankenstein writ large all over again.

Note on the cultish status of organic synthesis: Part 1

When I was in graduate school, a friend and I used to joke that the most egotistical elitists are to be predominantly found in two fields: particle physics and the total synthesis of complex organic molecules. As with most jokes and exaggerations, this one had a shred of truth in it. We had read about the hubris arising from a belief in strict reductionism to be found among particle physicists, and we had heard of similar hubris arising from a sense of mastery over nature found among synthetic organic chemists. What physicist has not heard Paul Dirac's quote that quantum mechanics would explain "all of chemistry", and what organic chemist does not like to gossip about slave-driving synthetic chemists who think they are doing other chemists a favor by contributing to what they have proclaimed to be the highest calling in their field? There is little doubt that more than many other branches of chemistry, organic chemistry and synthesis in particular enjoy (or is it suffer from?) a cultish status.

More recently, a few comments on the "greatest chemists" post at The Skeptical Chymist again struck a chord. The writers of the post wondered whether "organic chemists are just a little insular and think that their bit of the chemistry kingdom is the only one that matters?". Another commenter reaffirmed this sentiment by saying that more than other fields of chemistry, "organic chemists have a culture of legend-making".

I agree with both these statements and I think there are three main reasons why organic synthesis has lent itself to cult-making. A major reason is the personalities, their exquisite language and metaphors, their harnessing of armies of graduate students and postdocs and the stories they loved to weave around their science. The second reason is simply the great practical utility of organic chemistry in improving the quality of life. The last and perhaps the most important reason is the continued perception of organic synthesis as the ultimate chemical science which has lifted the great veil of nature and allowed man to wrest Nature's deepest secrets from her; there is something stupendous in having a mere mortal synthesize chlorophyll from scratch. The three reasons are connected, but each brings a distinct flavor to the argument. In this post I will dwell on the perceived cult of personality in organic synthesis, and will leave the rest of the discussion for another post.

So let's talk about the personalities. At the outset let's make it clear that not all organic chemists revel in showmanship, and such generalizations can be flawed. There are of course dozens of brilliant chemists who are extremely unassuming, letting their colleagues put on the shows in papers and in lectures. Yet as we all know, belief depends as much on perception as on reality, and there is a very distinct feeling in the chemical community that synthetic organic chemists love to perform more than others.

Is this true? Well, more than most other chemists, organic chemists have surrounded themselves with stories reminiscent of tales of great human adventures, exploits, triumphs and follies. Myth-making has contributed somewhat uniquely to organic chemistry. Part of the myth-making and legend-building was engendered by a happy accident of history that inadvertently did some harm to the perception of the field- the name of this happy accident was Robert Burns Woodward. So much has been said about him that it's not worth repeating. But there was no comparable chemist in any field during his time, and as long as he lived, Woodward achieved feats that almost defied belief. It's hard to see how organic synthesis would have turned into a mythical endeavor had it not been for this singular man. Others like Corey, Djerassi, Danishefsky, Nicolaou etc. simply carried on the tradition. Harvard became the mecca of organic synthesis, and Woodward and Corey's laboratories turned into Plato's academies through which every budding intellectual in the field had to pass in order to get a stamp of respect. Even today it's remarkable how many top synthetic organic chemists in the world have trained with one of these masters. The students in turn have carried forward the legend-making and perpetuated the reputation of the field, like Homer's portraits of Hector, Achilles and the great wars they fought in.

A corollary to the legend-making is the language and the metaphors. Look up some of the most famous total synthesis papers and the authors make them sound less like synthesis and more like a combination of Tenzing and Hillary's conquest of Everest and Michelangelo's painting of the Sistine Chapel. For instance, a review on the synthesis of the CP molecules begins with stories and portraits of Thesus's pursuit of the fearsome Minotaur. Organic synthesis is portrayed as the ultimate art and adventure and organic chemists are intrepid explorers venturing into the unknown. There is no doubt that synthesis is an art and that synthetic chemists are explorers, but so are other scientists. In fact, protein crystallography probably lends itself to the mountain-climbing metaphor even more since crystallographers sometimes stake their entire careers on the relentless chase of a single structure. Yet it's organic synthesis and not other branches of chemistry which claims to be the epitome of art, science, adventure and determination. I suspect that is partly because unlike synthesis, crystallography is a more interdisciplinary activity that cannot be easily labeled as chemical.

Again, one has to inevitably partly blame Woodward. For instance, consider this masterpiece from his colchicine synthesis which makes us feel like we are reading not Woodward but Tolkien:

"Our investigation now entered a phase which was tinged with melancholy. Our isothiazole ring had served admirably in every anticipated capacity and some others as well...it had mobilised its special directive and reactive capacities dutifully, and had not once obtruded a willful and diverting reactivity of its own. Now it must discharge but one more responsibility- to permit itself gracefully to be dismantled, not to be used again until someone might see another opportunity to adopt so useful a companion on another synthetic adventure. And perform this final act of grace it did."

A more exquisite paean to a five-membered ring containing carbon, nitrogen and sulfur was never penned. No wonder synthesis acquired the status of a highly-refined art form. One wonders how the field would have been perceived had it not been for the flourishing phrases, the allusions to mountain-climbing and Greek classics and the romantic metaphors. Not everyone does this of course, but it seems to be widely prevalent among top synthetic chemists.

The power of personality also extends to power over other human beings, and this has always been a sensitive topic that has contributed to the field's reputation. In the latter half of the twentieth century, the ability to synthesize increasingly complex molecules translated to the need to amass armies of students and postdocs. Woodward's collaboration with Swiss master Albert Eschenmoser on the stunning synthesis of Vitamin-B12 is a telling example; the synthesis involved dozens of graduate students and postdocs in a kind of trans-Atlantic relay that spanned 12 years and almost a hundred steps. Who would not be swayed by such overarching ability to attract personnel, resources, time and funding? Other total synthesis chemists also typically command such a glut of labor. For a long time, organic synthesis was regarded as the ultimate character-building experience. Hard work is of course essential to success in any science, but organic synthesis seemed to require a particularly intense combination of the ability to constantly bounce back from failure and the cheerful stamina of a marathon runner. This is perhaps one of the reasons why total synthesis students in my department appeared darker and more self preoccupied than others, and it could also contribute to the perceived sense of hubris among synthetic chemists. But that is also one of the reasons why total synthesis students are highly sought-after in both academia and industry, not just for their technical abilities but for their doggedness.

Nonetheless, while synthetic activity continues to be regarded as a character-building experience, the reputation of synthetic chemists has suffered in recent years because of their reliance on cheap labor and the unusually harsh working hours that synthesis students have to endure. Synthetic chemists have been held up as slave-drivers who care little about their students' education and simply need them to serve as automatons who plug one step's intermediate into the next. There have even been rumors of students forced to compete against each other for the quickest route to the product, with the "loser" not making it to the authors' list on the paper. New students are being advised not to spend five years working in a high-profile total synthesis group if they want to have a life outside graduate school. Stories of student suicides have done nothing to improve the situation, although one wonders if such stories are also not to be found in other disciplines and are simply being highlighted because of the high-profile nature of the groups. Is this reputation deserved? I don't know, but it certainly seems to contribute to an unfavorable view of total synthesis.

Yet this view has not generally colored the status of the field. Total synthesis still commands the attention of first-rate blogs, synthesis papers still make it to highly-cited lists, and total syntheses are still enthusiastically lauded as the works of art which they undoubtedly are. While the reputation of synthesis may have suffered because of myriad factors, the power of personality and the artistic metaphors have guaranteed it a special place in the minds and souls of chemists. The ghost of Robert Burns Woodward lives on in more than one way.

Stimulating quasi-erotic excitement through organic structure determination

Thanks to the graces of the intertubes I came across this rare and fascinating video of R B Woodward put up by some kind soul a couple of months ago. The novelty of the quintessential Bostonian accent, the cigarette and glass of scotch adorning the lectern and the man in blue are only eclipsed by his achievements and what he has to say. He especially saves the coup de grace for the end.

Woodward essentially sheds light on the remarkable developments in organic chemistry until then by providing contrasting examples from his own research. He emphasizes how times had changed between his own work and the state of the art in 1979. One can make similar comparisons right now. Woodward basically attributes the astonishing progress in organic chemistry in the last forty years to two factors- an intense infusion of theoretical concepts in their most general form (MO theory, quantum chemistry etc.), and the path-breaking developments in physical methods, including IR, UV and NMR spectroscopy and x-ray crystallography. He then provides famous examples from his own work to starkly emphasize the contrast.

The first example is from his synthesis of quinine. In this synthesis, one of the steps involved the elimination of a quaternary ammonium ion to form a double bond. The question was whether the double bond formed was a vinyl double bond or an ethylidene double bond; it was the vinyl that was desired.



Nowadays, and even in 1979, a graduate student could settle this question in literally a matter of minutes, but at that point (circa 1945), Harvard did not even have the experimental facilities necessary to chemically investigate this fact. Woodward had to send the sample to the famous chemist Max Tischler at Merck. Tischler got back saying it was an ethylidene. This threw the chemists into a state of despondency for a few days, until Tischler called back to inform them that Merck had made a mistake and it was in fact the vinyl double bond. The tense drama during this situation seems almost comical in the light of modern structure determination methods.

The second example concerned Woodward’s astonishing decade-long synthesis of Vitamin B12. He expressed wonder how an NMR spectrometer had been able to obtain the natural abundance C13 spectrum of 1 mg of the synthetic finished product using 995,000 transient scans. This incredulity would sound almost laughable today. Capillary NMR and 1 GHZ machines have pushed the science and art of structure determination to limits, and doing a million scans on 1 mg of material is almost old hat.

The third example was a nice little anecdote. Woodward had a wager with Linus Pauling in the 1950s whether he could chemically determine the structure of the antibiotic terramycin faster than Pauling could do it with x-ray crystallography. Woodward won the wager, but also admitted that he would probably lose it today because x-ray crystallography had gotten so powerful. Today x-ray crystallography is already at the top of its game, and who knows what breakthroughs in structure determination would be possible with AFM and STM.

The last example cracked everyone up. Woodward talked about the structure determination of cantharidin, the active principle of the Spanish fly. Chemists had isolated up to 500 grams of cantharidin to find out its structure. “Just think of it, 500 grams of cantharidin”, says Woodward. “There are many people who would think it’s an absolute tragedy. Realize that that would be enough to keep the entire population of Spain in a state of quasi-erotic excitement for a period of a full year!”

What would be Woodward’s reaction if he were to suddenly materialize today in a poof of chemical pixie dust and survey the synthesis landscape? My humble guess is that he would not be too impressed. He would undoubtedly be excited by the development of the Sharpless and Grubbs methods and the great success of the palladium-catalyzed reactions (not to mention the general development of organometallic chemistry, in the founding of which he himself played a role). But beyond that, I doubt if he would notice any fundamental change in the science of organic synthesis compared to what he witnessed and orchestrated during his own lifetime. Sure, things have become more efficient, streamlined and automated, but those details, as impressive as they are, are really operational details.

My personal guess is that Woodward would be much more impressed by the application of organic synthesis to biology and materials science. But as for the science itself, it probably still stands very close to where Woodward left it thirty years ago, and the whiz-kid from Quincy would have little trouble bringing himself up to speed on it in no time at all.