B.R.S.M. Yield isn't everything

19Apr/1213

Woodward Wednesday 4: And All That Could Have Been

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given him to lecture on the work that actually won him the prize, instead choosing to speak on his entirely new and unpublished work on cephalosporin C. I think Woodward entirely deserved his Nobel prize, which he gained through an unbelievable pertinacity where chemical problems and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.

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29Sep/1110

Woodward Wednesdays 2: Erythromycin A

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.[1] 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.[2] 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.[3]

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3Sep/115

Woodward Wednesdays 1.5: A Brief History Of Boc

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.[1]

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25Aug/1111

Woodward Wednesdays 1: (+)-cephalosporin C (1966)

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.[1] 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.[2] 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.

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17Aug/114

Announcing: Woodward Wednesdays

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!

 

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