Site-selective protein modification poses a Catch-22. If the chemistry you want to use can modify natural amino acids, you have to worry about the selectivity of your desired site of modification vs. other sites. If the chemistry you’re using doesn’t react with the natural amino acids, you have to figure out a way to incorporate an unnatural amino acid site-selectively.
Ben Davis addresses this and other issues related to the use of olefin metathesis in site-selective protein modification in his 2009 minireview. It’s been more than a decade since Dave Tirrell’s group first reported the genetic incorporation of homoallylglycine into proteins, but the use of the metathesis reaction in this context has been slow to catch on for a number of reasons. Davis (who has pioneered the use of S-allyl cysteine as a metathesis substrate) describes the challenges and solutions on the way to developing methodology for site-selective protein modification using olefin metathesis, a goal which is now within reach.