The Synthesis Of Tasiamide B Analogues And The Study On Synthesis Of Thalassospiramide B

This dissertation describes the synthesis of tasiamide B analogues and the study on synthesis of thalassospiramide B.Tasiamide B, an 8-residue acyclic peptide isolated from the marine cyanobacteria Symploca sp. was found cytotoxic against KB cells. Twelve analogues were designed and synthesized in the first part. Analogues sxmA1, sxmA2 and sxmA3 were designed as truncating C-terminal residues of tasiamide B; Analogues sxmB1-sxmB6 were designed as changing N-terminal residues; sxmC is an analogue containing residues without N-Me and sxmD1 and sxmD2 are analogues designed as decreaseing molecular weight of tasiamide B.Based on the total synthesis of tasiamide B, the analogues were prepared successfully through fragments coupuling strategy. Starting from commercially available amino acids, all the fragments were prepared in presence of condensing agents EDC or HATU and HOAt. Afterwards, the protective groups were removed, and the objective analogues were prepared by coupling these fragments using standard solution-phase techniques.Based on the previous work, Thalassospiramide B were prepared by coupuling the liner portion (M2) with the ring portion (M1). M1 is a 12-membered-ring in which the inherent ring strain makes the synthesis of this portion very difficult. In our studies, we tried to induct removable turn inducers to valine,a residue in the"middle site"of linear peptides precursor, to promote cis amide conformations and facilitate ring contraction. P-methoxyphenyl (PMB) and 2-nitrophenyl (ONB) were introduced to Val-Oallyl respectively through reductive amination procedure. But the coupling of the N-substituted Val-OAllyl to block2* are failed completely. It is possibly due to the bulky groups of PMB or ONB. we modified this strategy and introduced substituents to the N of amide. PMB and allyl were chosen as the substituents, but only allyl was inrtoduced to the amide successfully in presence of NaH and gave the N-substituted fragment sxmG2.In the synthesis of M3, N-protected (R)-4-amino-5-hydroxypentanoic acid was obtained from commercial available D-pyroglutamic acid in four steps. The linear peptides precursor sxm-â…¢-23 was synthesised efficiently through [1+1+1] strategy. The final cyclization was conducted at room temperature for two days and gave the desired cyclic product sxm-â…¢-26 in 4.5 % isolated yield.