Synthesis of Cell-cycle Inhibitory Peptides and Their Development for Medicinal Use

本课题合成了从链霉菌菌株中分离得到的新型19元环六肽类抗生素GE3和聚氧多肽(A、B)，以及从海洋海绵海绵属Theonellaa中分离得到的具有抗HIV活性的新型环肽类化合物和具有细胞毒活性的新型环肽类化合物。用夏普莱斯的不对称双羟基化和立体选择性的Evan和Paterson的Aldol方法实现了GE3的酰基侧链链段的立体选择性合成。通过手性2，3-环氧醇的区域选择性开环，立体选择性地合成了聚氧肽的酰基侧链链段。利用RuC_2(BINAP)催化的氢化反应，从相应的β-keto-α-氨基酸酯出发，通过动态动力学拆分，高效地合成了环多肽组分(2R，3R)-和(2S，3S)-羟亮氨酸及其非对映异构体，并以SnI_2为关键步骤，通过非对映选择性环化反应实现了(2S，3R)-3-羟基-3-乙基丙氨酸(2)的立体选择性合成。以(S)-焦谷氨酸为原料，立体选择性地合成了(3S，4R)-3，4-二甲基-(S)-谷氨酰胺。通过合成的3，4-二甲基焦谷氨酸与天然产物的水解物的光谱比较，明确地证实了天然二甲基谷氨酰胺的立体结构为(2S，3S，4R)-立体化学。Β-甲氧基酪氨酸(β-OMeTyr)是木瓜酰胺类化合物的立体结构成分。β-(MeTyr)的所有立体异构体都是从(S)-丝氨酸和(R)-丝氨酸分别立体选择性地合成的，用于木瓜酰胺的结构测定和全合成。这三个环去脂肽的最终结构研究正在实验室进行中。

In this project, GE3 and Polyoxypeptins (A and B), novel 19-membered cyclic hexadepsipeptide antibiotics from Streptcmyces strains and Papuamides (A and B), novel cyclodepsipeptides with anti HIV and cytotoxic activies from the marine sponge genus Theonellawere synthetically studied. Stereoselective synthesis of the acyl side chain segment of GE3 has been achieved by using Sharpless's asymmetric dihydroxylation and stereoselective Evan's and Paterson's aldol methodologies. Stereoselective synthesis of the acyl side chain segment of Polyoxypeptins has been carried out through regioselective opening of chiral 2,3-epoxyalcohol. (2R,3R)-and (2S, 3S)-Hydroxyleucines, components of the cyclodepsipeptides, were efficiently synthesized along with their diastereomers from the corresponding β-keto-α-amino acid ester through dynamic kinetic resolution using RuC_2(binap) catalyzed hydrogenation, Stereoselective synthesis of (2S,3R)-3-hydroxy-3-raethylproline (2), a component of polyoxypeptins, has been achieved by use of diastereoselective cyclization reaction using SmI_2 as a key step. (3S,4R)-3,4-Dimethy1-(S)-glutamine,a component Papuamides, was stereoselectively prepared from (S)-pyroglutamic acid. The stereostructure of natural dimethylglutamine was unambiguously confirmed to be (2S,3S,4R)-stereochemistry by comparisons of their spectra of the synthetic 3,4-dimethylpyroglutamic acid with the hydrolysate from the natural product. Β-Methoxytyrosine (β-OMeTyr) is a stereoundefined component of papuamides. For structural determination and total synthesis of papuamides, all stereoisomers of β-(MeTyr were stereoselectively prepared from (S)-and (R )-serine, respectively.Further studies on final construction of the three cyclodepsipeptides are under investigation in this laboratory.