Rapid Fire & Poster Presentation 7th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2019

Synthesis of naturally occurring N-methylated cyclic tetrapeptides   (#21)

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

 

The mechanistic insights gained during our synthetic studies will likely prove valuable in improving the synthetic accessibility of further naturally occurring or biologically active CTPs.

  1. Rodriguez, L. M. D. L.; J. Weidkamp, A.; A. Brimble, M. An Update on New Methods to Synthesize Cyclotetrapeptides. Org. Biomol. Chem. 2015, 13 (25), 6906–6921. https://doi.org/10.1039/C5OB00880H.
  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. Pseudoxylallemycins A–F, Cyclic Tetrapeptides with Rare Allenyl Modifications Isolated from Pseudoxylaria Sp. X802: A Competitor of Fungus-Growing Termite Cultivars. Org. Lett. 2016, 18 (14), 3338–3341. https://doi.org/10.1021/acs.orglett.6b01437.
  3. Almeida, C.; Maddah, F. E.; Kehraus, S.; Schnakenburg, G.; König, G. M. Endolides A and B, Vasopressin and Serotonin-Receptor Interacting N-Methylated Peptides from the Sponge-Derived Fungus Stachylidium Sp. Org. Lett. 2016, 18 (3), 528–531. https://doi.org/10.1021/acs.orglett.5b03553.
  4. Cameron, A. J.; Squire, C. J.; Gerenton, A.; Stubbing, L. A.; Harris, P. W. R.; Brimble, M. A. Total Synthesis and Crystallographic Studies of Pseudoxylallemycin A; a Naturally-Occurring Cyclic Tetrapeptide. Org. Biomol. Chem., 2019, 17 (16), 3902-3913. https://doi.org/10.1039/C9OB00227H
  5. K. Davison, E.; J. Cameron, A.; R. Harris, P. W.; A. Brimble, M. Synthesis of Endolides A and B: Naturally Occurring N -Methylated Cyclic Tetrapeptides. MedChemComm 2019. https://doi.org/10.1039/C9MD00050J.