Synthesis of constrained α-cyclic peptides, cages and their complexes

• Main Authors: Subrata Chakraborty, 傑卡巴舒巴
• Other Authors: Dar-Fu Tai
• Format: Others
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/3a6zgg

博士 === 國立東華大學 === 化學系 === 102 === Synthesis of a naturally occurring cyclic tetrapeptide cyclo(Gly-L-Ser-L-Pro-L-Glu) [cyclo(GSPE)] was performed and crystal structure of it was obtained. X-ray crystal structure of cyclo(GSPE) showed a cis-trans-cis-trans (two transoid amide bonds between Gly-Ser, Pro-Glu and two cisoid amide bonds between Ser-Pro, Glu-Gly) peptide bond sequence. The conformation of synthesized cyclo(GSPE) fixes the coordination to lead ion in a 1:1 ratio. This cyclo(GSPE)-Pb complex was constructed as an asymmetric 3D network in the crystalline state. The polymerization of a rigid asymmetric cyclic tetrapeptide in the presence of a heavy metal ion represents the first example of a new class of macrocyclic complexes. Cyclo(GHPE), an analogue of the natural product, was also synthesized. A few unprotected α-cyclic tripeptides (CtPs) have been previously reported. Four new CtPs, cyclo(L-Ser-L-Ser-L-Ser)OBn, cyclo(L-Glu-L-Glu-L-Glu), cyclo(L-Ser-L-Pro-L-Glu), cyclo(L-Ser-L-Pro-L-Ser), cyclo(L-Ser-L-Pro-Gly) that consist of either protected glutamate (E(OBn)), protected serine (S(Bn)), or proline (P) were prepared from corresponding linear tripeptides. We were able to synthesize cyclo(E-E-E) and cyclo(S-P-E) by regioselective enzymatic hydrolysis of α-methyl or benzyl ester on glutamate of corresponding linear precursors Boc-E(OBn)-E(OBn)-E(OBn)(OMe) and Boc-S(Bn)-P-E(OBn)2. An attempt was also made to synthesize CtPs that contained unprotected glycine (G). Although cyclo(S-P-G) was obtained, all the attempts to synthesize the reported natural product cyclo(G-P-E) failed. Since NMR patterns of the natural product are similar to that of synthesized cyclic hexapeptide cyclo(G-P-E)2, we propose that the reported natural product may be a cyclic hexapeptide. Four water-soluble C3-symmetric cages containing α-cyclic tripeptide were efficiently synthesized. Two of the cages are 1,2,3-triazole containing big cages. The key steps include a click reaction to incorporate L-glutamic or L-aspartic acids to a tripodal linker and a unique one-pot cyclotrimerization. Other two cages were amide linked small cages. Glutamyl small cage showed intense blue color, which changes with pH. Aspartyl small cage was able to encapsulate three molecules of D2O or water. It also showed five times selectivity towards D2O molecule.