B.R.S.M. When all you have is a hammer everything looks like a nail


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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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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