After a few (!) years of working with the 20-odd “naturally occurring” I have finally got around to doing something I should have done years ago: selective amine sidechain protection. This was prompted by a need for some Cbz-protected Orn, and one of the few commercial suppliers being far too slow.

The copper method is well known and has been used for years, but I have never been that keen on removing it with H2S. OK, you can also use EDTA, but I like the idea of the use of NaBH4 to reduce the Cu(II)  (Tetrahedron Lett. 2004, 45, 9297–9298 doi:10.1016/j.tetlet.2004.10.060).

Anyway, the initial coordination method with CuSO4 and Orn.HCl, and protection  with Cbz-Cl, I got from WO 2004/037174. Also I read the Boc protection method in J. Med. Chem 1986, 29, 655-660 10.1021/jm00155a012 (this uses amine base rather than carbonate). The protecting groups are going on at the moment…….

Both methods look good. The only problem is that while the Cbz-Orn can be filtered out of water, the Boc-version is water soluble and has to be extracted from aqueous solution using either EtOH/CHCl3 mixtures (the JMC paper) or acetone – a better option (the TL paper). This does at least explain the price difference between commerical Cbz and Boc O and K.

UPDATE on removing the copper: I have tried  reacting the complex with both NaBH4 (1eq. r.t. water) and Na2EDTA (1eq. 90degC, water), I have a clear winner yield-wise. It’s the EDTA. The borohydride route causes a lot of foaming and the black Cu product spreads everywhere.