Total Synthesis Of Marine Cyclopeptide Thalassospiramide B

Thalassospiramides A and B, two novel cyclopeptide isolated from a new member of the marineα-proteobacterium Thalassospira (strain CNJ-328), show immunosuppressive activity in an interleukin-5 production inhibition assay. They showed IC50 values of 10μM and 5μM with no observable cytotoxicity at concentrations of 10μM.This thesis describes the total synthesis of thalassospiramide B.First of all, twoγ-amino-β-hydroxyl acids were synthesized. (3S, 4S)-Bn2- Ahppa-OtBu 10a was obtained from L-Phe via methyl ester protection, N-dibenzyl protection, cleavge of methyl ester, Claisen ester condensation and stereoselective reduction (de=86.3%). The overall yield was 31.1% for 5 steps. (3S, 4S)-Adpa was racemized via the same synthetic route. The original method was improved. C-tert-butyl ester protection replaced the methyl ester, and milder Mg-enolate was used in Claisen ester condensation. (3S, 4S)-Bn2-Adpa(TBS)-OMe 20a was obtained from L-Ser in 16.3% overall yield for 7 steps (de=81.0%).A [4+4] strategy was applied to the total synthesize of thalassospiramide B.Remove of the dibenzyl protection in (3S, 4S)-Bn2-Ahppa-OtBu 10a and coupling with unsaturated acid 25 gave dipeptide fragment 26. The tripeptide fragment 27 was obtained from remove of tert-butyl ester in 26 and coupling with Val-OtBu. Remove of tert-butyl ester in 27 and then coupling with remove of dibenzyl protection of (3S, 4S)-Adpa 21a yielded tetrapeptide M2.Finally, it turned to the synthesis of cyclopeptide fragment. It was a 12-membered ring, which had big tension and was hard to cyclize. Cyclization was studied from three sites, the ester bond between side-chain hydroxyl in Ahpea and Tyr, the peptide bond between Ahpea and Val and the peptide bond between Val and Tyr. Two tripeptides 34 and 49 and a tetrapeptide 41 were obtained. But it was unsuccessful. More flexible C-C single bone could decrease the tension of the ring, so change the route to eliminate the 18-hydroxyl into a double bond after cyclization. It was proved that the protected hydroxyl was more conducive to cyclization. The cyclopeptide was obtained in 25.0% yield. Under the process of elimination the hydroxyl into a double bond in kinds of conditions, the ring opened before the double bond formed, and the cyclopeptide of natural products had not been finally obtained.