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


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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BIBS, the newest silicon protecting group

Note: I'm currently on holiday. I do have internet access, but drawing chemical structures on the netbook I've borrowed may just be too painful. I'll try and get some updates out ASAP.

Di-t-butylisobutylsilyl, Another Useful Protecting Group

Corey et al., Org. Lett., 2011, ASAP; [PDF] [SI] [GROUP]



I suspect that anybody who’s been engaged in synthetic chemistry for more than a year or two has probably used a silicon protecting group. I’ve used plenty, and they’re generally very useful, easy to put on and take off, and pretty robust under a lot of different conditions. One of the great things about these groups is the huge range available; from the labile TMS and TES, to the more robust (and useful) TBS and TBDPS, to the hardy TIPS.[1] At the extreme end of the scale an even tougher group is the tri-t-butylsilyl group, but that’s very hard to put on or take off, and the silylating reagent itself is a pain to make. This week Corey published an attempt to fill the niche for a group tougher than TIPS, but more useful than tri-t-butylsilyl, with the disclosure of the di-t-butylisobutylsilyl (BIBS) group.

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