树脂上的固相合成——(一)多肽、低聚核苷酸、寡糖的固相合成

综述了典型的固相合成法,及其在多肽、低聚核苷酸和寡糖合成中的应用。比较了固相合成法与传统的液相合成法之优缺点。介绍了固相合成法中常用的高分子载体;氨基、羧基、羟基、磷酸基等功能基的化学保护方法。介绍了1984年诺贝尔奖金获得者,固相合成创始人R.B.Merrifield在此领域中的成就。引用了1963～1986年的60篇文献。     

E.coli O86 O-Antigen全保护五糖重复单元的化学简易合成

以5个单糖组分为原料, 经过7步, 以21%的总产率得到E.coli O86抗原全保护的五糖重复单元.在合成路线中, 充分利用糖基化反应的立体选择性原则, 结合HClO4-SiO2固体催化剂和“IP”策略, 大大提高了合成的效率. 整个合成路线设计操作简单, 选择性高, 消耗低, 产率高, 可以用于快速高效地合成其它一些具有生物活性的寡糖分子.     

糖肽合成的新进展

本文综述了近年来在糖肽合成方面的研究进展, 主要包括三氯乙酰亚胺酯法, 缩水内醚糖法, 酶合成法, 固相合成法及酶与固相结合法。分析了不同的离去基团和不同的保护基策略对糖肽合成的影响。     

与癌症相关的糖类抗原Globo-H六糖的全合成进展

Globo-H作为一种和乳腺癌、前列腺癌相关的复杂糖类抗原,其发现为糖类疫苗开发和癌症免疫治疗带来了机遇,但如何高效、高纯地获得合成糖类抗原,以供研究和临床应用,也向寡糖合成方法学提出了挑战.综述了1995年Danishefsky首次以糖烯组装策略全合成Globo-H以来的各种新方法,如:Schmidt的三氯乙酰亚胺酯法、Boons的双向糖苷化法、Wong的基于糖基给体活性差异的一锅煮策略、Seeberger的液相线性合成和固相自动组装法、Huang的多组份反复预活化一锅煮法和最新报道的酶法.就糖合成方法学而言,硫苷法依旧可称为"明星方法",糖烯、三氯乙酰亚胺酯和氟代糖也普遍采用,磷酸酯糖基给体在固相合成中的应用正显示出其新的活力.这些方法代表了当今糖化学的水平和发展趋势.     

糖苷化的亚氨基糖:分离、合成与生物活性

本文系统总结了糖苷化亚氨基糖的分离、合成方法与生物活性。天然存在的糖苷化的亚氨基糖根据其亚氨基糖部分的结构可以分为五类,大部分均具有重要的生物活性,尤其是糖苷酶抑制活性。此类化合物潜在的药理活性促进了相关合成方法的研究,根据糖苷键的构建方式大致可以分为酶催化的转糖基化反应和化学合成法,两者主要区别在于反应条件。酶催化的转糖基化反应条件温和,且能够减少保护基的使用,但在反应效率和选择性上仍需改进。化学合成法普适性高,有大量普通糖苷的合成经验可供借鉴,但存在反复上保护-脱保护的问题。通过以上两种合成方法,大量衍生物和类似物被设计和合成出来,大大丰富了糖苷化亚氨基糖的种类和生物活性。糖苷化亚氨基糖的生物活性往往与糖基结构和亚氨基糖环均有密切关系。作为传统糖化学与亚氨基糖的交叉领域,糖苷化亚氨基糖的结构多样性为发展高活性和选择性的先导化合物提供了优良的修饰骨架。因此,此类化合物有望在相关新药创制领域得到重要应用。     

若干具有复杂结构的寡糖及其缀合物的合成

通过化学合成手段得到一定量的具有特殊活性的寡糖或其缀合物,及其改变结构的类似物不但有助于阐明糖基在生命过程中的作用,同时亦对有机合成化学提出了挑战,对生命科学和有机化学的发展都有很大的意义。我们实验室运用己有的和发展了的合成方法学对若干具有重要活性的复杂寡糖和中药活性成分的皂甙进行了合成,在这里报导了三个目标分子的工作结果。     

用不保护或少保护的糖基受体合成寡糖*

用不保护或少保护的葡萄糖、甘露糖、鼠李糖作为糖基受体,经由糖原酸酯的中间体,能高区选和立体选地合成寡糖. α-(1→6)-连接的甘露寡糖、β-(1→6)-连接的葡萄寡糖、3,6-支化的甘露寡糖及葡萄寡糖用此方法能用很简单步骤合成,如具有重要生物活性的寡糖植保素激活剂葡萄六糖、具有抗肿瘤活性的香菇多糖的活性片段,以及一些具有重要生理功能的多糖的重复单元等.本文同时简述了用少保护的半乳糖和氨基葡萄糖为糖基受体合成寡糖的进展.     

6-甲氧基-1,2,3,9-四氢-4H-咔唑-4-酮肟的一锅合成

报道了6-甲氧幕-1,2,3,9-四氢-4H-咔唑-4-酮肟(3b)的一锅合成法,将Fischer吲哚合成与肟化两步反应并为一步,可简化操作,提高收率.反应可以在弱碱性且温度温和的条件下一锅合成,是由于肟化使Fischer吲哚环合变得容易,羰基与肟基在互变异构方向上的差别是影响环合反应的关键因素.     

以1-甲基-1-甲氧基乙基为保护基的一锅法合成5-芳香二酮-1H-四氮唑

报道了5-芳香二酮-1H-四氮唑(2)的一锅合成法,并且首次报道了1-甲基-1-甲氧基乙基作为四氮唑氮原子的保护基团,保护与脱保护反应条件温和,操作简便,收率高,为该类化合物的合成提供了一条捷径.采用该方法共合成6个未见文献报道的5-芳香二酮-1H-四氮唑类新化合物,以用于药理活性筛选.     

一种木葡聚糖类寡糖的化学合成及生物活性

天然木葡聚糖类寡糖是一类对植物生长具有调节作用的寡糖, 本文以3个单糖组分为原料, 经5步合成了一种木葡聚糖三糖(1)(总产率15%), 以及该三糖的糖苷缀合物1a及其异构体1b. 利用糖基化立体选择性原则, 一步偶联反应同时得到所需的α,β连接产物, 整个合成路线高效简捷. 活性测试结果表明, 3种目标寡糖在1 mg/L浓度下, 对烟草的生长均显示出一定的促进作用, 表明所合成的3种寡糖有望发展成为植物生长促进剂.     

Highly efficient syntheses of hyaluronic acid oligosaccharides

Highly efficient syntheses of hyaluronic acid oligosaccharides have been accomplished through the pre-activation based iterative one-pot strategy. A series of oligosaccharides ranging from di- to hexasaccharides were rapidly assembled using only near stoichiometric amounts of the building blocks without aglycon adjustment or purifications of intermediate oligosaccharides. Deprotection and oxidation protocols were developed for protective group removal and oxidation-state adjustment. The availability of such structurally well defined synthetic hyaluronic acid oligosaccharides will greatly facilitate the establishment of detailed structure-function relationships.     

Divergent heparin oligosaccharide synthesis with preinstalled sulfate esters

Traditional chemical synthesis of heparin oligosaccharides first involves assembly of the full length oligosaccharide backbone followed by sulfation. Herein, we report an alternative strategy in which the O-sulfate was introduced onto glycosyl building blocks as a trichloroethyl ester prior to assembly of the full length oligosaccharide. This allowed divergent preparation of both sulfated and non-sulfated building blocks from common advanced intermediates. The O-sulfate esters were found to be stable during glycosylation as well as typical synthetic manipulations encountered during heparin oligosaccharide synthesis. Furthermore, the presence of sulfate esters in both glycosyl donors and acceptors did not adversely affect the glycosylation yields, which enabled us to assemble multiple heparin oligosaccharides with preinstalled 6-O-sulfates.     

Oligosaccharide assembly by one-pot multi-step strategy

Saccharide synthesis is a formidable task for synthetic chemists. Although in recent years many advances have been made in this area, development of more convenient and efficient strategies for oligosaccharide synthesis is still in great demand. This review focuses on one of these new strategies--the one-pot sequential glycosylation approach as a potent tool for oligosaccharide assembly.     

Oligosaccharide synthesis and library assembly by one-pot sequential glycosylation strategy

The oligosaccharide residue in glycoconjugates located in cell membranes is responsible for intercellular recognition and interaction: it acts as a receptor for proteins, hormones, and microorganisms and governs immune reactions. These significant activities have stimulated great interest in the field of oligosaccharides and glycoconjugates. Although many advances have been made in the synthesis of oligosaccharides, more convenient and efficient methods are still needed. This review describes one of these new methods-the one-pot sequential glycosylation approach as a potent tool for oligosaccharide assembly. The oligosaccharide library construction in a one-pot fashion is also summarized.     

Pre-activation-based one-pot synthesis of an alpha-(2,3)-sialylated core-fucosylated complex type bi-antennary N-glycan dodecasaccharide

Synthesis of N-glycans is of high current interests due to their important biological properties. A highly efficient convergent strategy based on the pre-activation method for assembly of the complex type core fucosylated bi-antennary N-glycan dodecasaccharide has been developed. Retrosynthetically, this extremely challenging target is broken down to three modules: a sialyl disaccharide, a glucosamine building block and a hexasaccharide diol acceptor. The sialyl disaccharide was easily obtained by selective activation of a new 5-N-trichloroacetyl protected sialyl donor in the presence of a thiogalactoside acceptor. The hexasaccharide diol module was produced by double mannosylation of a fucosylated tetrasaccharide acceptor, which in turn was generated by glycosylation of a alpha-fucosylated disaccharide with a beta-mannose containing disaccharide donor. The union of the three modules was performed in one-pot giving the fully protected dodecasaccharide in high yield. This synthesis is characterized by minimum protective group and aglycon adjustment on oligosaccharide intermediates, thus greatly enhancing the overall synthetic efficiency. The modular feature of this strategy suggests that this method can be readily adapted to the synthesis of a wide variety of N-glycan structures.     

Multi-component one-pot synthesis of the tumor-associated carbohydrate antigen Globo-H based on preactivation of thioglycosyl donors

Two efficient routes for the rapid assembly of the tumor-associated carbohydrate antigen Globo-H hexasaccharide 2 by a preactivation based iterative one-pot strategy are reported. The first method involves the sequential coupling of four glycosyl building blocks, leading to the desired hexasaccharide in 47% overall yield in one-pot synthesis. Although model studies on constructing the challenging Gal-alpha-(1-4)-Gal linkage in Gb3 trisaccharide yielded the desired alpha linkage almost exclusively, a similar approach to assemble the hexasaccharide led to the formation of a significant amount of beta anomer. As an alternative, the second synthesis utilized three components in one pot with the Gal-alpha-(1-4)-Gal linkage preformed, producing the desired hexasaccharide in a similar overall yield as the four component approach. Both methods demonstrate that oligosaccharides containing alpha and beta linkages within the same molecule can be constructed in one pot via a preactivation based approach with higher glyco-assembly efficiencies than the automated solid-phase synthesis strategy. Furthermore, because glycosylations can be carried out independent of anomeric reactivities of donors, it is not necessary to differentiate anomeric reactivities of building blocks through extensive protective group adjustment for chemoselective glycosylation. This confers great flexibilities in the building block design, allowing matching of the donor with the acceptor, leading to improved overall yield.     

A five-component one-pot synthesis of phosphatidylinositol pentamannoside (PIM5)

A practical and efficient synthesis of phosphatidylinositol pentam annoside (PIM₅) was achieved based on a five-component one-pot sequential glycosylation protocol with exclusive regio- and stereo-selectivity.     

Simplifying oligosaccharide synthesis: efficient synthesis of lactosamine and siaylated lactosamine oligosaccharide donors

A practical sequence is described for converting d-glucosamine into peracetylated Gal(beta-1,4)GlcNTroc(beta1-S)Ph and Neu5Ac(alpha-2,3)Gal(beta-1,4)GlcNTroc(beta1-S)Ph building blocks using a synthetic strategy based on chemoenzymatic oligosaccharide synthesis. The known trichloroethoxycarbonyl, N-Troc, protecting group was selected as a suitable protecting group for both enzymatic and chemical reaction conditions. These oligosaccharide building blocks proved effective donors for the beta-selective glycosylation of the unreactive OH-3 of a polymeric PEG-bound acceptor and for the axial OH-2 of a mannose acceptor in good yields. The resulting complex oligosaccharides are useful for vaccine and pharmaceutical applications.     

Convergent Synthesis of Oligosaccharide Fragments Corresponding to the Cell Wall O‐Polysaccharide of Salmonella enterica O53

Conventional glycoconjugate vaccines are prepared with polysaccharides isolated from bacterial fermentation, an approach with some significant drawbacks such as handling of live bacterial strains, the presence of biological impurities, and inter‐batch variations in oligosaccharide epitope structure. However, it has been shown in many cases that a synthetic fragment of appropriate structure conjugated to a protein can be an effective vaccine that circumvents the shortcomings of using full‐length oligosaccharides. The development of synthetic strategies to prepare glycoconjugate derivatives against pathogenic bacterial strains is therefore of great interest. Oligosaccharide fragments corresponding to the repeat unit of the cell wall O‐antigen of Salmonella enterica strain O53 were synthesized in good yield. Sequential and block glycosylation strategies were used for the synthesis of the target compounds. A number of recently developed reaction conditions were used in the synthetic strategy. A one‐pot reaction scheme was also developed for the multiple glycosylation steps. The stereoselective outcomes of all glycosylation reactions were very good.     

Oligosaccharide synthesis with glycosyl phosphate and dithiophosphate triesters as glycosylating agents

Described is an efficient one-pot synthesis of alpha- and beta-glycosyl phosphate and dithiophosphate triesters from glycals via 1,2-anhydrosugars. Glycosyl phosphates function as versatile glycosylating agents for the synthesis of beta-glucosidic, beta-galactosidic, alpha-fucosidic, alpha-mannosidic, beta-glucuronic acid, and beta-glucosamine linkages upon activation with trimethylsilyl trifluoromethanesulfonate (TMSOTf). In addition to serving as efficient donors for O-glycosylations, glycosyl phosphates are effective in the preparation of S-glycosides and C-glycosides. Furthermore, the acid-catalyzed coupling of glycosyl phosphates with silylated acceptors is also discussed. Glycosyl dithiophosphates are synthesized and are also used as glycosyl donors. This alternate method offers compatibility with acceptors containing glycals to form beta-glycosides. To minimize protecting group manipulations, orthogonal and regioselective glycosylation strategies with glycosyl phosphates are reported. An orthogonal glycosylation method involving the activation of a glycosyl phosphate donor in the presence of a thioglycoside acceptor is described, as is an acceptor-mediated regioselective glycosylation strategy. Additionally, a unique glycosylation strategy exploiting the difference in reactivity of alpha- and beta-glycosyl phosphates is disclosed. The procedures outlined here provide the basis for the assembly of complex oligosaccharides in solution and by automated solid-phase synthesis with glycosyl phosphate building blocks exclusively or in concert with other donors.