Synthesis of Amino Acids from Chiral NiII Schiff Base Complexes for Novel Stapled Peptides
thesisposted on 14.02.2019, 11:37 by Emad K. M. Zangana
Protein–protein interactions (PPIs) are key elements of several important biological processes. Several types of stapled peptides have been reported to increase the binding affinity and the stability of the peptides in the biological area. Work on a new generation of hydrocarbon staple, that avoids the weaknesses of olefins stapled peptides, has involved asymmetric synthesis of alkyne functionalised amino acids for novel 1,3-diyne bridged peptides will be described by C-alkylation of a series of NiII Schiff base complexes using ligand (S) or (R)-N-(2-benzoylphenyl)-1-(2-fluorobenzyl)-pyrrolidine-2-carboxamide (2-FBPB) from L-proline. This thesis describes, in chapter two, the design, synthesis and characterisation of a series of NiII Schiff base 2-FBPB complexes with glycine, alanine, valine, leucine or phenylalanine: (S,S) 55 and (S,R) 97; (S,S) 101 and (S,R) 102; (S,S) 56 and (S,R) 98 complexes with high yields and with excellent diastereoselectivities. In chapter three, new NiII Schiff base complexes 134-142 have been synthesised by alkylation reactions. The methodology for alkylation has been modified. Decomposition of these complexes has led to novel amino acids in good yields and high diastereoselectivities 137, 143-148. Fmoc protection of these amino acids have been achieved successfully 149-152. In chapter four, the same strategies have been adopted to generate a number of novel fluorinated amino acids via either alkylation or aldol reactions. Amino acids 202-207 have been generated in good yields and high diastereoselectivities (>99 % de). Chapter five describes the design, synthesis and evaluation of stapled peptides. Four model peptide pairs (linear and 1,3-diyne bridged) have been prepared and their helicity established by CD spectroscopy. The greatest helicity was shown for a 1,3-diyne bridge peptide incorporating a C7-alkynyl-alanine amino acid. This was then applied to a new model of the Bim peptide and the helicity of the resulting 1,3-diyne bridged peptide compared to the linear (unbridged) peptide: 67 % for ring closure and 51 % for ring opening. Chapter six outlines the experimental work and characterisation data for the products prepared in this work. Complexes 95-97, 99-101, 134, 136, 137, 140, 141, 190, 192 and 198 have been structurally characterised by single crystal X-ray diffraction.