Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 14 May 2007

Total Synthesis of Salinosporamide A (NPI-0052)


T. Ling, V. R. Macherla, R. R. Manam, K. A. McArthur, B. C. M. Potts, Org. Lett. 2007, 9, 2289-2292.

DOI: 10.1021/ol0706051

This target has certainly seen it’s share of interest, and you certainly know it’s an interesting target if industry decide to make it! Indeed, this paper is by some folks at Nereus Pharmaceuticals, San Diego, who were clearly interested in its 20S proteasome inhibition activity. Although there have been several syntheses of Salinosporamide A, the group state that they needed a route suitable for analogue generation - apparently that β-lactone is very attractive compound.

The reactions of interest to me kick-off very early, with an interesting auxiliary directed aldol reaction, closing the β-keto oxazolidinone to give a lactam. The mechanism for this aldol reaction is thought to be through the “self-regeneration of stereocenters (SRS) principle” developed by Seebach, seen in this paper. This paper’s worth a thorough read!

Interestingly, the only chromatography in the entire synthesis is purification of that starting material. The allyl substituent was then oxidised with Upjohn conditions, and the diol cleaved to generate the lactol - nice work to make a complex 5,5,5 unit so quickly. At this point, the route to the target is relatively transparent, and is nicely achieved; however, they state the route is amenable to scale up. However, a major issue is the multitude of oxidation and reduction steps…

Also worth a mention: chlorination of a primary alcohol using Ph3PCl2. How stable is that reagent?

Selected Comments

22 May, 2007 at 0:26, Lurker says:
If I remember correctly, Ph3PCl2 and Ph3PBr2 are both easily prepared from triphenylphosphine and the corresponding halogen. I think it’s a pretty stable substance. I’ve never used it myself, but I don’t think it’s unstable or particularly hard to make…
22 May, 2007 at 0:46, Tot. Syn. says:
Fair enough, always worth learning something new. I guess it’s not really that different to converting an alcohol to a bromide with PPh3 and Br2.
22 May, 2007 at 4:42, milkshake says:
I worked with massive amounts of Ph3PBr2 (PPh3, Br2, acetonitrile, add Br2 with cooling on ice until orange, then evaporate). If you melt BINOL with the neat reagent, you get 2,2′-di-Br-binaphtyl. You add Celite, let solidify, break the flask with hammer, peal off the glass, break the formed ball into chunks of smoky corrosive hygroscopic asphalt, extract this tar it in Soxhlet, column, re-crystallize. …