R. B. Woodward et al., J. Am. Chem. Soc., 1952, 74, 4223 [PDF] (Full paper)
Hundreds, if not thousands, of steroids have been characterised to date, isolated from a bewildering variety of organisms from across the animal, plant and fungal kingdoms. Their roles as hormones, drugs, and in cell membranes make them crucial to life as we know it, and are the reason that they’re one of the best studied classes of natural products. People have been interested in making steroids since the earliest days of total synthesis in the 1930s and 40s, and the field of steroid synthesis has made the careers of legendary chemists such as Russell Marker, George Rosenkranz, Arthur Birch and Carl Djerassi, as well as ensnaring and captivating many others. Indeed, some five Nobel Prizes have been awarded for steroid research, and the fruits of these labours have included many important drugs and much useful chemistry.
R. B. Woodward was also heavily involved in steroid chemistry during his early career, perhaps inspired by his PhD studies on ‘A Synthetic Attack on the Oestrone Problem’. As I wrote about in an earlier post, he also famously collaborated with Konrad Bloch to elucidate the details of steroid biosynthesis, work for which Bloch would receive the Nobel Prize in medicine the year before Woodward received his in chemistry. Woodward’s synthetic contributions to the field came in the form of a groundbreaking synthesis of methyl 3-keto-Δ4,9(11),16-etiocholatrienate, which he resolved and converted into a number of known compounds, achieving the formal total synthesis of some of the best known steroids.
This flexible intermediate contained enough latent functionality (largely in the form of unsaturation in the carbon skeleton) to enable the interception of previously reported compounds that could be converted into cortisone, testosterone, progesterone and cholesterol, the archetypal members of four of the most important steroid families.
Okay, this second post is a lot later and a fair bit shorter than I had hoped it would be, but it's been a crazy and not entirely pleasant month. Enjoy!
In the previous Woodward Wednesday post I showed you guys the first half of Woodward's epic total synthesis of the popular bioactive natural product reserpine. If you didn't catch that when it came out, go and check it out, because I'm just going to carry straight on where it left off. Here goes!
I'm going to do this one in two parts, in the hope that posting the first half now will force me to find time to write the second part at the weekend. Also, it'll hopefully make for shorter and more readable posts. Enjoy!
Reserpine is an indole alkaloid isolated in 1952 from the extract of Rauwolfia sepentina or ‘Indian snake root’, a popular plant in traditional Indian medicine used as a sedative and antipyretic, and reportedly taken by Mahatma Gandhi himself. It's also enjoyed some attention from Western doctors as an antihypertensive and antipsychotic, notably being the first ever drug to successfully demonstrate antidepressant properties in a randomized placebo-controlled trial (although it’s rarely used nowadays because of its numerous side effects, which are as varied as they are unpleasant). Its structure was solved in just 3 years (a remarkably short period for the pre-NMR era) and, when it was finally reported in the summer of 1955, Woodward immediately set to work. By the end of 1956, just a year later, he was able to report a detailed series of studies culminating in the landmark first total synthesis of the natural product, again pushing forward the complexity limit at which synthetic chemists could operate. In the years that followed, reserpine became a classic target, worked on by some of the greatest chemists of the past 50 years. In fact, it remains a popular molecule to this day, as indicated by a new total synthesis reported just a month or so ago by Jacobsen and co-workers, (Org. Lett., 2013, 3, 706).
Although Woodward’s synthesis of this target, supposedly his personal favourite of all those he masterminded, has been discussed in just about every book to be written on the history of total synthesis, I can’t resist the temptation of writing my own summary of it any longer, so here goes.
Although it's been a while I do intend to do at least one full size Woodward Wednesday post this month. In the mean time here's a short (but important) synthesis that you may not know about.
Who do you think was the first person to publish the preparation of tert-Butyllithium? Some big shot organometallic or inorganic chemist? Not so much. As far as I can tell it was none other than legendary organic chemist R. B. Woodward (J. Am. Chem. Soc., 1941, 63, 3229)! Many before tried and failed, and indeed Woodward noted that the the reaction between lithium and tert-butyl chloride was quite slow, although he discovered that it was efficiently catalysed by a few mole percent of magnesium. Eventually, the reaction could be performed using just lithium, providing it was finely enough divided. This so-called 'lithium sand' was prepared using a classic piece of kit invented by a fellow Harvard chemist: the Hershberg Wire Stirrer. This allowed molten lithium (in mineral oil at 250 degrees) to be whipped up into fine pieces. The mixture could then be cooled, the oil washed off and the lithium quickly used before it had a chance to react with the nitrogen atmosphere used to exclude air. You might ask why Woodward spent time fiddling around with such a dangerous reagent that appeared to defy all attempts to force it into existence. As best as I can tell, the answer was sheer curiosity; not so much regarding the substance itself, but to see if it could be used to prepare the elusive tri-tert-butyl carbinol. Alas, the only reaction observed with hexamethylacetone was reduction. Still, despite recent bad press, tert-BuLi remains a very useful reagent, and has helped me out of a tight synthetic spot on a few occasions.
1. I'll probably do reserpine next, but I'm not too sure what to do after that. Please leave suggestions in the comments!
2. Although, by Woodward's own admission, a couple of papers by the father of organometallic chemistry Henry Gilman from the previous year do imply that tert-BuLi was successfully prepared and used.
Woodward was a member of the highly elite few; organic chemists who won Nobel prizes not for a specific reaction, discovery, or work with a particular element but for simple mastery of organic chemistry - theory, synthesis, methodology, structural determination, biochemistry - the list goes on. The elegant citation for his prize summed this up nicely:
"Professor Woodward's research work covers vast and various fields in Organic Chemistry. A leading feature is that the problems have been extremely difficult and that they have been solved with brilliant mastery. He has attacked them with a maximum of theoretical knowledge, a never-failing practical judgement and, not least, a genial intuition. He has, in a conspicuous way, widened the limits for what is practically possible."
I'd be very surprised if we see a Nobel Prize award to a synthetic organic chemist any time soon. The total synthesis/general organic crowd never seem very high up Paul's lists. As we saw in the very first post in this series, Woodward interestingly didn't use the opportunity given him to lecture on the work that actually won him the prize, instead choosing to speak on his entirely new and unpublished work on cephalosporin C. I think Woodward entirely deserved his Nobel prize, which he gained through an unbelievable pertinacity where chemical problems and puzzles were concerned, as well as the willingness to take on daunting challenges. Woodward's chemical legacy was enviable and it's telling that no conversation or book on classic synthesis can fail to cover such masterpieces as his work on reserpine, strychnine, chlorophyll and B12. That aside, I've heard numerous chemists talk about his contributions to other Nobel Prize winning work, so I thought it might be interesting to write a post on this.
Okay, so it's not Wednesday, but I've just finished this and I'm not going to sit on it for another 4 days. Merry Christmas!
The Total Synthesis of Chlorophyll a
Full Paper: R. B. Woodward et al., Tetrahedron, 1990, 46, 7599-7659 [PDF]
Communication: R. B. Woodward et al., J. Am. Chem. Soc., 1960, 82, 3800 [PDF]
Lecture: R. B. Woodward, Pure Appl. Chem., 1961, 2, 383 [PDF] FREE!
One thing I enjoy most about reading Woodward’s work is the variety of targets and natural product classes he worked on. He conquered steroids, alkaloids, polyketides and amino acid derivatives with equal aplomb, pushing the limits of complexity in each field, and always looking for the highest peak to climb. Woodward’s synthesis of chlorophyll a has been somewhat overshadowed by his truly epic collaborative synthesis of vitamin B-12 (some years later), but for its time was an outstanding accomplishment, unmatched in the field of porphyrin chemistry. Unfortunately, most books on classic or collected total syntheses only cover B-12, but plenty of interesting chemistry (as well as breathtaking experimental skill) was brought to bear in this earlier, simpler campaign. I’m not going to write anything here about the importance of chlorophyll as it's a bit obvious, so on to the chemistry.
Update 01/10/11 - It seems that I never actually gave the references for the original papers. The synthesis was actually published in three back-to-back JACS papers - the first is J. Am. Chem. Soc., 1981, 103, 3210, and you can read on from there. I also found the relevant synarchive page to be helpful when writing this.
I hadn't planned to cover this synthesis, Woodward's last, so early in this series, but as a review on the use of thiopyrans as templates in polypropionate syntheses was recently published in Chem. Commun. it seems timely to mention it now. Woodward once said in a talk at CIBA in India that
"Much of the art of directed synthesis involves the design of ways to place constraints on molecular motion, with the aim of bringing about desired changes and suppressing others"
A popular way of doing this, as has been said before, is through the use of cyclic templates, a tactic used extensively by chemists of the Woodward and Corey eras. The ease with which desulfurisation can be accomplished using Raney Nickel makes thianes and thiopyans uniquely suitable as temporary rings which can be cleaved mildly and selectively later on. This property made them the cornerstone of Woodward's approach to erythromycin A where they were used to set 8 of the 10 stereocentres found on the macrocyclic ring.
It hasn't escaped my notice that today is not Wednesday, but this is just a follow up post, and you know what they say about gift horses and looking...
As we saw in the inaugural Woodward Wednesday post last week, the second step in Woodward's 1965 synthesis of cephalosporin C was the Boc protection of an amino acid derivative. Having chosen cysteine as the starting material, and performed the known reaction with acetone, the next transformation that the group needed to carry out was this was this:
What I wasn't aware of when I wrote that post was that one of the authors on the Woodward paper, Helmut Vorbrüggen, actually went on to publish a paper on the difficulties of this step and the group's eventual solution more than 40 years later (Synthesis, 2008, 3739-3740). It turns out that the nearby gem-dimethyl group made this protection unexpectedly challenging, and Vorbrüggen provides a good insight into the difficulties Boc protection used to entail, as well as the thought processes that lead to the final choice of reagents.
Normally, when I want to make a carbamate, I reach for the corresponding chloroformate (ROCOCl) or maybe the carbonate, but it turns out that neither is very useful for the introduction of Boc groups. BocCl is woefully unstable and decomposes rapidly if you handle it roughly, by, say, storing it in the fridge or showing it traces of air or water. Conversely, (t-BuO)2CO isn't so much unreactive as inert, remaining unchanged even under quite vigorous conditions such as heating to 150 ºC in concentrated sodium hydroxide solution, which greatly limits its synthetic usefulness. A few papers describing the use of the relatively stable yet reactive BocF also exist, but the main drawback of this reagent is the difficulty associated with its production.
This inaugural Woodward Wednesdays post will discuss the subject of Woodward's 1965 chemistry Nobel Prize lecture - work culminating in the synthesis of (+)-cephalosporin C. It was difficult to choose a synthesis to open the series with, as a lot of Woodward's papers are, quite rightly, considered classics and have been dissected elsewhere. Woodward's synthesis of strychnine, for example, crops up in a number of reviews, has a wikipedia page and is discussed at length in Nicolaou's Classics in Total Synthesis (Chapter 2) as well as T. Hud's Way of Synthesis (pages 803-808) and probably many other places besides; I'm not sure I can add much there that hasn't already been said! Woodward's reserpine synthesis, one of my top five syntheses of all time, is (unfortunately?) also covered in a similarly comprehensive fashion. Strangely, the cephalosporin synthesis remains much less well known, despite containing some excellent chemistry and a few 'Woodwardian' steps.
"Having here this morning the responsibility of delivering a lecture on a topic related to the work - for which the Prize was awarded, I have chosen to present an account of an entirely new and hitherto unreported investigation which, I hope, will illuminate many facets of the spirit of contemporary work in chemical synthesis" - R. B. Woodward, Nobel Prize Lecture, 11 December 1965
So began Woodward's Nobel lecture - in a departure from tradition, for he spoke for the entirety of his lecture solely on his thus far undisclosed work on the synthesis of (+)-cephalosporin C, unpublished until the following year (J. Am. Chem. Soc., 1966, 88, 852), in his characteristically intelligent and articulate manner.
It's been suggested that I need a few more (semi-) regular features, and a number of people seem to have enjoyed some of the work from the older literature I've highlighted (my posts on Eaton's synthesis of cubane and Hoffmann's use of TNT are among the most popular I've written). I considered a few possible ways of combining these two and, after chatting to a wise coworker, I have decided to launch Woodward Wednesdays. Basically, I'll post something about work done by R. B. Woodward on roughly one Wednesday a month until you or I get bored. I'm not going to write a long justification of this - the man was a genius and hopefully we can learn something from him.
The inspiration for this series was probably the recent appearance of Woodward's notes on organic superconductors being published in the current issue of tetrahedron (Tet., 2011, 67, 6771-6797) with a wonderful accompanying article in C&En, which just reminded me what a remarkable individual he was, with an enviable breadth of research interests far beyond organic synthesis. Bits of the tetrahedron article are way over my head, but the C&En article is a very enjoyable read. The latter contains a number of recollections from Woodward's son, including this one from his teenage years:
“My father arrived punctually at home at 6:25 every night for dinner. One night we sat down and he said, ‘I’ve had an inspiration. I think I can make a room-temperature superconductor.’ He described how that would be a material that loses no energy as it conducts electricity over large distances and how that would change the world,” Eric remembers. “He rarely would say anything about chemistry, but this day he was particularly inspired.”
Wow, nothing like setting your sights high! From talking to a few physicists I know, I get the impression we're still nowhere near this goal 40 years later. But Woodward gave it serious thought, producing 699 pages (or around 8") of notes on everything from scraps of paper to hotel stationary and napkins, all bearing his characteristic beautiful hand drawn structures.
Another piece on Woodward's involvement with the Woodward Research Institute in Basel, Switzerland and the work done there appeared in Helvetica Chemica Acta back in June, further illustrating the continued interest in the life and work of this amazing chemist (HCA, 2011, 94, 923-946). So, I'm getting on the Woodward bandwagon. First post next Wednesday. Look forward to it!