Time for an asymmetric hydrogenation

      God, I am really slowing down on this blog.  Sorry, folks.  I am currently working on the sister website, my own personal website, PHARMNBIOFUEL.COM and got quite involved with that one.  Hopefully, it will roll out soon.  You are welcome to stop by.  Anyhow, I always take a look at the ASAP articles on Organic Process Research & Development, to see what articles are coming out so I can get a preview.   I will only refer to this one by its DOI because it is not published yet.  I thought this would be an interesting article, because everyone has had the need to do an asymmetric hydrogenation.   I remember working on a hydrogenation and it was decided that we would hydrogenate our substrate, resulting in two enantiomers, carry the racemate forward and separate the diastereomers at the end of the synthesis by SMB chromatography.  I think there was some work done to screen for catalysts to do an asymmetric hydrogenation but we were unsuccessful.  Anyways, on with the show !! 

“Rapid Identification of a Scalable Catalyst for the Asymmetric Hydrogenation of a Sterically Demanding Aryl Enamide” by Laurent Lafort et al, doi:0.1021/op100011y

 

Colleagues at DSM were working on this project for Merck.  Merck scientists had previously found that the following asymmetric catalyst was working for them [(S,S)-Me-BPE-Rh(COD)]BF4  providing them with 87-90 % ee and 100 % conversion.  When the article mentioned that they had used the Endeavor™ for their screening initially, I could appreciate the value of that instrument as I had used one as well in my past.  But then they mentioned the following reactor that was made by Premex, found at www.premex-reactorag.ch/index.php?page=464, I was in awe.  96 hydrogenation reactions at once, an Endeavor on steroids.  I, personally, like new technologies and new screening instruments and this is one of them.  Wow.  Anyways, the instrument is one thing but for an asymmetric hydrogenation screen, the ligands are another.  DSM undertook the development of a rhodium catalyst based on a monodentate phosphoramidite ligand, which was many magnitudes cheaper than a chiral phosphate ligand.  Through several screens, they were able to zero-in a chiral catalyst that held some promise and were able to scale up to kilogram scale.

They were able to find a phosphoramidate that worked and this was the structure:

DSM formed the desired catalyst by using 1/2 equivalent of Rh(COD)2BF4 to form Rh(COD)L2BF4 as the desired catalyst.  0.35 mol % catalyst, 9 wt% substrate, 7.5 L i-PrOH, 6 bar H2 and 32 °C to get conversion in 20 hrs and 98.9 % e.e.  The rhodium count was high, so a recrystallization was done to give 99.9 % e.e. and a rhodium count of 3 ppm.  Pretty nice.  In fact, I like how they set up their data tables, it was easy to see what conditions were optimal.  Thumbs up. 

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