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.
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?