Oral Presentation 6th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2017

Challenging olefin metathesis with peptidomimetic synthesis (#1)

Andrea Robinson 1 , Alessia Belgi 1 , William Jackson 1
  1. Monash University, Clayton, VIC, Australia

For over a decade we have explored the use of metathesis to generate peptides with enhanced potency, selectivity, plasma and physical stability. We have centred our attention on the replacement of native disulfide bridges due to their inherent in vivo instability and often problematic handling during solid phase synthesis. This led to the development of regioselective strategies for the formation of multiple dicarba bridges, the adoption of pseudoproline residues to promote RCM, and new strategies for overcoming deleterious aggregation during catalysis.[1] The generation of dicarba analogues of cystine-rich peptides can also be used to elucidate the unknown mechanism of action of a target peptide. Two notable examples from our laboratory investigating human insulin and a-conotoxins will be discussed. RCM on recombinant peptides, however, remains an undeveloped area. Genetic incorporation of non-proteinogenic allyl and crotyl glycine residues, inter alia, has been reported[2] however the chemistry required to deal with the resultant highly polar, unprotected substrates has yet to be fully met. Oxytocin, a mammalian hormone responsible for the prevention of post-partum haemorrhage following birth, was used as a test substrate to develop methodology to facilitate protecting-group free olefin metathesis and our progress to date will be discussed.[3]


  1. J. Burnley, W. R. Jackson, and A. J. Robinson, J. Org. Chem. 2015, 80, 9057−9063; A. J. Robinson, J. Elaridi, J. Patel, W. R. Jackson, Chem. Commun. 2005, 5544.
  2. J. C. M. van Hest, K. L. Kiick and D. A. Tirrell, J. Am. Chem. Soc., 2000, 122, 1282-1288.
  3. E. C. Gleeson, W. R. Jackson and A. J. Robinson, Chem. Commun. 2017 Aug 17. doi: 10.1039/c7cc04100d.