A cool new reduction of amides

Beller and co-workers recently published a superb new method for reducing tertiary amides into amines. The reaction is tolerant of a wide range of functionalities including ester, thiomethyl, nitrile, secondary amide, and hydroxyl groups. This post is timely from my perspective because we just had a group meeting discussion about what is new and what is old in the area of reduction technologies. My point at that meeting was that, while there are some incredibly innovative and functional group tolerant methods in contemporary literature, it is important to keep in mind some of the more obscure and less known processes. But old and obscure will be the subject of another post (when we reduce some of our ideas to practice – no pun intended).

Back to Beller’s innovative new chemistry: the most useful aspect here is that no air-sensitive reagents are involved. The reaction uses readily accessible phenylsilane and a rhodium(dppp) catalyst. A fairly extended portion of the paper is dedicated to just one experiment that describes selective reduction of one of cyclosporine A’s tertiary amides (the O-acetylated version of the molecule was used in this process). I am really curious who was brave enough to use 6.5 g of cyclosporine A in this reaction (Sigma Aldrich charges $180 per 25 mg). This has to be connected to the fact that one of the co-authors of this paper is from Novartis (in Basel). Given the continuing interest in cyclosporine A and related compounds, it would be interesting to find out the cellular permeability of the partially reduced version.

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http://onlinelibrary.wiley.com/doi/10.1002/anie.201503584/abstract

 

4 thoughts on “A cool new reduction of amides

  1. Recently I tried to downscale a reductive amination protocol for NaIO4-oxidized RNA to tens of nanomols scale. The problem was that original paper did it at tens of micromols scale in a 250 mL round-bottom flask with pH meter. Recalculated price of starting material for them would be over 1 million $ and they got ~50% yield with no recovery of the starting material.

  2. cyclosporine A can be sourced from Asia for a very low cost. something like ~$2.50/gram. we have had kilos of the stuff sitting around in our facility. a 6.5-gram reaction on this substrate is not a big deal. Interesting regioselectivity though.

    • Well – I did not know that! This is pretty interesting. Reminds me how expensive BINOL ligand used to be (and then became dirt cheap once a really simple route was developed). But BINOL ain’t a natural product… Wow.

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