Synthesis Of Analogues Of Tasiamide And First Total Synthesis Of Tasiamide B

This master's dissertation described the preparation of eleven analogues of tasiamide and total synthesis and stereochemical reassignment of the marine anti-cancer peptide tasiamide B.Tasiamide, a novel linear heptapeptide isolated from the marine cyanobacterium Symploca sp. NIH304 by Moore et al in 2002 showed good cytotoxic activity against KB and LOVO cells. Now the total synthesis and structural reassignment of tasiamide was achieved by M.S Zhenhua Ma and Ni Song, and its preliminary structure-activity relationship study was slso obtained. In order to get a deeper understanding of the SAR, eleven analogues of tasiamide were synthesized using [4+1+2],[2+2] or stepwise enlongation as the strategy.Tasiamide B, a linear octapeptide, was also isolated from the lipophilic extract of marine cyanobacteria Symploca sp. NIH304 in 2003 by Moore et al, was found to be cytotoxic against KB cells with an IC50 value of 0.8μM. Considering the structure and bioactiviy similarity between tasiamide and tasiamide B, we decided to explore an efficient method for the total synthesis of tasiamide B.Tetrapeptide block1 was synthesized using stepwise elongation starting from several commercial amino acids. It was found that significant racemization occurred during the condensation of H-Val-OBn and L-lactic acid.In order to avoid the racemization benzylate was employed to protect the hydroxy group in L-lactic acid, and dipeptide block3(Bn) was obtained efficiently.The protected Ahppa was prepared with satisfactory yield and enantioselectivity in five steps according to the method reported by Hoffman in 1997,starting from commercially available phenylalanine. After Fmoc-N-Me-Gln-OH was obtained via reductive ring-opening of oxazolidinone intermediate, serious intramolecular cyclization occurred in following reaction if the side chain amide was unprotected.Several methods was employed to avoid the cyclization, but failed. Finally, Cbz-N-Me-Gln(Trt)-OH was synthesized successfully and nucleophilicity of the free amide group was eliminated by the protection of Trt group, making the bidirectional elongation from the C-terminus and the N-terminus possible, then the linear tetrapeptide block 2-3(tr) was obtained efficiently. Next, the coupling of block 2-3(tr) and block1 provided octapeptide tasiamide B(P), debenzylation under Pd/C catalyzed hydrogenolysis of which afforded synthetic tasiamide B.Analyzing the spectral data of the synthetic sample, it was found that the 13C NMR signals assigned to Nα-methyl-phenylalanine and alanine were most different from the reported data, and the optical rotation value of the synthetic sample was also much higher than that of the natural product. Three diastereomers of tasiamide B were designed and synthesized to confirm the real stereochemical structure of the natural product. Nα-methyl-L-phenylalanine of tasiamide B was replaced by Nα-methyl-D-phenylalanine to get the diastereomer tasiamide B-DPLA (1a), L-alanine was replaced by D-alanine to give the diastereomer tasiamide B-LPDA (1b), and both were replaced to obtain the diastereomer tasiamide B-DPDA (1c). After we got the NMR data based on the analysis of H-H COSY, HMQC and HMBC and the value of optical rotation, it was confirmed that the reported L-configuration of Nα-Me-phenylalanine residue in tasiamide B should be the D-configuration.