Improvement of Peptide Yield and Solvent Reuse Via Membrane Enhanced Peptide Synthesis

There have been many fascinating advances in peptide coupling and green solvent methods in recent years.[1-4] In order to achieve successful translation of this research to industry, more innovation is required in flow chemistry.[3-7] One promising technology which can achieve lower solvent use and be scaled up industrially is membrane enhanced liquid phase peptide synthesis.[6, 8] Two common issues noted in liquid phase synthesis, is peptide and solvent recovery. Peptide recovery can be improved by increasing the size of the growing peptide by using star structures and implementing multiple membrane filtration stages. [8-11] To keep building on this research momentum, this proposal first intends to extend star size to larger systems such as 6-arm and 8-arm species. Secondly, a secondary membrane nanofiltration system will be developed and optimized to recycle solvent back into the reactor. The overall goal is to increase reaction sustainability by decreasing fresh solvent use via recycling and increasing peptide yield via star size modification. References: 1. Al Musaimi, O., B.G. de la Torre, and F. Albericio, Greening Fmoc/tBu solid-phase peptide synthesis. Green Chemistry, 2020. 22(4): p. 996-1018. 2. Behrendt, R., P. White, and J. Offer, Advances in Fmoc solid-phase peptide synthesis. J Pept Sci, 2016. 22(1): p. 4-27. 3. Bogdan, A.R. and A.W. Dombrowski, Emerging Trends in Flow Chemistry and Applications to the Pharmaceutical Industry. J Med Chem, 2019. 62(14): p. 6422-6468. 4. Gordon, C.P., The renascence of continuous-flow peptide synthesis - an abridged account of solid and solution-based approaches. Org Biomol Chem, 2018. 16(2): p. 180-196. 5. Farkas, V., et al., Cost-Effective Flow Peptide Synthesis: Metamorphosis of HPLC. Organic Process Research & Development, 2021. 25(2): p. 182-191. 6. Peeva, L., et al., Continuous purification of active pharmaceutical ingredients using multistage organic solvent nanofiltration membrane cascade. Chemical Engineering Science, 2014. 116: p. 183-194. 7. Weeranoppanant, N. and A. Adamo, In-Line Purification: A Key Component to Facilitate Drug Synthesis and Process Development in Medicinal Chemistry. ACS Med Chem Lett, 2020. 11(1): p. 9-15. 8. So, S., et al., Membrane enhanced peptide synthesis. Chem Commun (Camb), 2010. 46(16): p. 2808-10. 9. Castro, V., et al., Novel Globular Polymeric Supports for Membrane-Enhanced Peptide Synthesis. Macromolecules, 2017. 50(4): p. 1626-1634. 10. Li, H., et al., Resin-free peptide synthesis mediated by tri(4-benzoylphenyl) phosphate (TBP) derivatives as small-molecule supports. Organic Chemistry Frontiers, 2020. 7(4): p. 689-696. 11. Yeo, J., et al., Liquid Phase Peptide Synthesis via One-Pot Nanostar Sieving (PEPSTAR). Angew Chem Int Ed Engl, 2021. 60(14): p. 7786-7795.