Synthesis of naturally occurring <em>N</em>-methylated cyclic tetrapeptides — ASN Events
  1. Schedule
  2. Poster Session 1 and Drinks
  3. Synthesis of naturally occurring N-methylated cyclic tetrapeptides

Synthesis of naturally occurring N-methylated cyclic tetrapeptides (#131)

Emma K Davison 1 2 3 , Alan J Cameron 1 2 3 , Christopher J Squire 3 , Paul WR Harris 1 2 3 , Margaret A Brimble 1 2 3
  1. School of Chemical Sciences, University of Auckland, Auckland, New Zealand
  2. The Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
  3. School of Biological Sciences, University of Auckland, Auckland, New Zealand

Cyclic tetrapeptides (CTPs), in particular those bearing N-methylated residues, provide attractive pharmaceutical leads due to their conformational rigidity and compliance with Lipinski's rules.1 As such, our research group has sought to develop reliable methods of synthesising these notoriously challenging targets. Both the pseudoxylallemycin and endolide families of CTPs bear N-methylation in the i and i+2 positions of their backbone. The pseudoxylallemycin family represents a number of compounds bearing allenyl modifications of aromatic residues, while the endolide family possess a rare 3-(3-furyl)alanine residue and display outstanding biological profiles.2,3 The first chemical syntheses of pseudoxylallemycin A and endolides A and B will be discussed.

 

The linear precursors for both families of CTPs were synthesised using Fmoc-SPPS, employing on-resin N-methylation of the appropriate residues. The linear precursor of pseudoxylallemycin A adopted an all-trans (ttt) extended linear conformation as revealed by X-ray crystallography.4 This linear tetrapeptide was cyclised using 1-propanephosphonic anhydride (T3P) to provide a sample of the natural product with the native trans,cis,trans,cis (tctc) conformation.4 During cyclisation, two kinetically favoured unstable cyclic conformers initially formed, with subsequent conversion to the thermodynamically stable tctc macrocycle taking place slowly. Insight into this unprecedented reaction mechanism will be discussed. A similar phenomenon was observed during the synthesis of endolides A and B, whereby T3P was again used to mediate a solution-phase cyclisation of the linear tetrapeptides.5 Interestingly, the stereoselectivity during cyclisation of the endolides was found to be reagent-controlled, and was independent of the linear precursors C-terminal configuration.

 

This novel methodology could prove extremely valuable in improving the synthetic accessibility of further naturally occurring or biologically active CTPs.

  1. De Leon Rodriguez, L. M.; Weidkamp, A. J.; Brimble, M. A. Org. Biomol. Chem. 2015, 13, 6906–6921.
  2. Guo, H.; Kreuzenbeck, N. B.; Otani, S.; Garcia-Altares, M.; Dahse, H.-M.; Weigel, C.; Aanen, D. K.; Hertweck, C.; Poulsen, M.; Beemelmanns, C. Org. Lett. 2016, 18, 3338–3341.
  3. Almeida, C.; Maddah, F. E.; Kehraus, S.; Schnakenburg, G.; König, G. M. Org. Lett. 2016, 18, 528–531.
  4. Cameron, A. J.; Squire, C. J.; Gerenton, A.; Stubbing, L. A.; Harris, P. W. R.; Brimble, M. A. Org. Biomol. Chem. 2019, 17, 3902-3913.
  5. Davison, E. K.; Cameron, A. J.; Harris, P. W. R.; Brimble, M. A. Med. Chem. Commun. 2019, 10, 693- 698.