Thursday, January 29, 2015

Oxidase Toolkit: C-H Azidation

Do you ever stare at your late-stage molecules, thinking "They're almost perfect, but I really wish I could add an amine right over there." Thanks to a new reaction, you might soon be able to.

Reporting in NatureJohn Hartwig and coworkers have cracked the case: a mixture of iron (II), a tridentate nitrogen ligand, and a modified Togni reagent Zhdankin reagent reliably functionalize tertiary C-H bonds with an azide(N3 group). The selectivity, yield, and mild conditions match pretty well with White's C-H oxidation, which utilized a similar catalytic manifold.


Hartwig's initial targets for this new reaction include two modified steroids and a gibberellic acid derivative. Sadly, precious few heteroatoms exist in these molecules to gum up the ironworks, but I'm certain they'll address that in the full paper. I'd especially like to point readers to Figure 3, in which the group shows subsequent transformations: heterocycle formation, amine reduction, chemical ligation, and capping with fluorescent tags.

These two reactions together, along with a variety of C-H halogenations and sulfidations, seem to support the growing "oxidase phase" approach to total synthesis. One could imagine that, in a few years, a naked carbon scaffold could be suitably decorated with O, N, S, or X at positions of the scientists' choosing. Wow.

11 comments:

  1. this is a really impressive piece of work. Unlike White catalyst, the preparation of which is painful on multigram scale (photochemical oxidation in the presence of mercury, and also the subsequent purifications), making the iPr-PyBox ligand is trivial, and they use only 11mol% loading of it. With enough substrate-specific re-optimization on large scale, you can probably bring it down to something like 5 mol%. I also like how they get selectivity between different tertiary CH groups. And their azide reduction with NaBH4 + CuSO4 is also lovely.

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  2. The initial disclosure of the azidoiodinane in the JACS (1996) by Zhdankin is quite a fascinating read. They report oxidation of cyclohexene by heating the azide reagent to reflux in chlorobenzene (bp 132 C) in the presence of benzoyl peroxide. Brave.

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  3. Both catalysts for the White and Hartwig reactions are chiral, but are not used per se for asymmetric reactions. I suppose this fact could result in weird matched and mis-matched cases or even kinetic resolutions if working with racemic substrates. Anybody have experience in this regard?

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    1. L-valinol used to make iPr-Pybox is considerably cheaper than racemic valinol...

      Aso, free radicals do not have much enantiospecificity

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  4. White's catalyst is about as good at enantioselectivity as it is at... any sort of selectivity. Poor.

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    1. Christina White started working on these Fe+H2O2 systems as a postdoc in hope of finding a catalyst for asymmetric epoxidation of terminal (monosubstituted) olefins. It was a messy going, because you have a competing Fenton radical chemistry to complicate things. But to her defense, she was always dogged in the pursuit of misery, and some historically productive catalyst systems (salen - ligand based, for example) also looked very discouraging at first

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    2. Are we still in the 'at first' stage here?

      She's certainly determined. Although there are other words I think of first tbh...

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    3. not to put words in your mouth - was it by chance "nasty, brutish and short" ?

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    4. If you want to put it politely, sure.

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  5. Why do you call it Togni reagent? Wasn't it first prepared by Zhdankin?

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