Recent developments in oligosaccharide synthesis: tactics,solid-phase synthesis and library synthesis

Oligosaccharides, commonly found on the cell surfaces, are deeply involved in a variety of important biological functions, yet demanding difficulties synthesizing such structures limit the investigation of their functions. Technologies to chemically synthesize these oligosaccharides have dramatically advanced during the last two decades mainly due to the introduction of good anomeric leaving groups. In addition, tactical analyses have been addressed to enhance the overall efficiency of oligosaccharide synthesis. Based on the advancement of solution-phase chemistry, solid-phase technologies are being investigated in connection with the current trend of combinatorial chemistry and high throughput screening. This review summarizes the necessary solution-phase methodologies, the status of solid-phase synthesis of oligosaccharides, and combinatorial synthesis of oligosaccharide libraries.     

Benzothiazines in synthesis. Toward the synthesis of pseudopteroxazole

[reaction: see text] The tricyclic benzothiazine 15 was prepared in a straightforward fashion via a completely stereoselective intramolecular Friedel-Crafts alkylation. This compound represents a potential precursor to the antitubercular agent, pseudopteroxazole. Its synthesis proceeded via a completely selective, intramolecular addition of a sulfoximine-stabilized carbanion to an alpha,beta-unsaturated ester, followed by functional group manipulations.     

Biology-oriented synthesis

Which compound classes are best suited as probes and tools for chemical biology research and as inspiration for medicinal chemistry programs? Chemical space is enormously large and cannot be exploited conclusively by means of synthesis efforts. Methods are required that allow one to identify and map the biologically relevant subspaces of vast chemical space, and serve as hypothesis‐generating tools for inspiring synthesis programs. Biology‐oriented synthesis builds on structural conservatism in the evolution of proteins and natural products. It employs a hierarchical classification of bioactive compounds according to structural relationships and type of bioactivity, and selects the scaffolds of bioactive molecule classes as starting points for the synthesis of compound collections with focused diversity. Navigation in chemical space is facilitated by Scaffold Hunter, an intuitively accessible and highly interactive software. Small molecules synthesized according to BIOS are enriched in bioactivity. They facilitate the analysis of complex biological phenomena by means of acute perturbation and may serve as novel starting points to inspire drug discovery programs.     

Total synthesis of apoptolidin: completion of the synthesis and analogue synthesis and evaluation

The total synthesis of apoptolidin (1) is reported together with the design, synthesis, and biological evaluation of a number of analogues. The assembly of key fragments 6 and 7 to vinyl iodide 3 via dithiane coupling technology was supplemented by a second generation route to this advanced intermediate involving a Horner-Wadsworth-Emmons coupling of fragments 22 and 25. The final stages of the synthesis featured a Stille coupling between vinyl iodide 3 and vinylstannane 2, a Yamaguchi lactonization, a number of glycosidations, and final deprotection. The developed synthetic technology was applied to the construction of several analogues including 74, 75, and 77 which exhibit significant bioactivity against tumor cells.     

Heterodiene synthesis

Both 1,4,-cycloaddition with the formation of a 1,4-dihydro-1,2,4-triazene derivative and electrophilic addition of acetyldicarboxylic acid ester to the secondary nitrogen atom occur during the reaction of acetylenedicarboxylic acid ester with 1,5-diphenyl-3-methyl-3-methylformazan. In the case of l,5.diphenylformazan, the reaction proceeds only in the second direction.See [3] for Communication II.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1704–1705, December, 1970.     

Anion-templated synthesis

In contrast to the well-studied templating properties of cationic and neutral species there are relatively few examples of anion-templated syntheses. This is attributed to some of the intrinsic properties of anions such as their diffuse nature, pH sensitivity, and their relative high solvation free energies. However, the increasing number of anion-templated assemblies reported over the past few years demonstrates that these limitations are not as critical as first thought. This review summarizes the most important results on the use of anions as directing agents for the syntheses of a wide range of inorganic and organic assemblies (such as macrocycles, cages, helicates, rotaxanes, and extended structures). It is hoped that this will stimulate a closer look into this emerging area of supramolecular chemistry.     

Benzothiazines in synthesis. A total synthesis of pseudopteroxazole

An enantioselective total synthesis of the naturally occurring antitubercular agent pseudopteroxazole is described. The synthesis is organized around the use of a stereoselective, intramolecular addition of a sulfoximine carbanion to an alpha,beta-unsaturated ester to form an enantiomerically pure benzothiazine. Other important processes include a completely stereoselective intramolecular Friedel-Crafts alkylation and a stereoselective and regioselective hydrogenation. [structure: see text]     

Computer-aided organic synthesis

It is tempting for those in the field of organic synthesis to liken the process of retrosynthesis to a game of chess. That the world chess champion was recently defeated by a computer leads us to think that perhaps new and powerful computing methods could be applied to synthetic problems. Here the analogy between synthesis and chess is outlined. Achievements in the 35-year history of computer-aided synthetic design are described, followed by some more recent developments.     

Heterodiene synthesis

2-Phenyl-4,6-diaryl-1,2-dihydro-sym-triazines react with hexafluoro-2-butyne as a dienophile to give 4,5-bis(trifluoromethyl)-2,6-diarylpyrimidines.See [1] for communication V.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 122–123, January, 1977.     

New synthesis of vaulted biaryl ligands via the Snieckus phenol synthesis

[reaction: see text] In an effort to develop a synthesis of the VAPOL ligand that avoids the use of a chromium carbene complex, a route was examined that involved the annulation of a naphthalene carboxamide via the method of Snieckus. The latter derivatives could be converted in a two-step sequence to 2-phenyl-4-phenanthrols in 60-72% overall yields. The utility of this method for the synthesis of VAPOL derivatives is demonstrated in the synthesis of (S)-7,7'-dimethyl-VAPOL.     

Application of an automated synthesis suite to parallel solution-phase peptide synthesis

An in-house developed automated synthesis suite was used to prepare a library of 72 tetrapeptide derivatives, the starting materials for pharmaceutically attractive pentapeptides, employing a convergent strategy. An initial set of 18 dipeptides were synthesized on a large-scale (100-1000 g) using automated synthesis workstations, and then 72 tetrapeptides were synthesized on a medium scale (5-10 g) using an automated system. Each di- or tetrapeptide was prepared in a single operating cycle using a modified methanesulfonic acid method, then a sub-library of 56 pentapeptides were synthesized in parallel, on a small-scale (100 mg-1 g) using a robotic workstation.     

RNA-catalyzed thioester synthesis

A series of efficient ribozymes with thioester synthetase activities have been isolated from CoA-linked RNA libraries containing four different lengths (30N, 60N, 100N, and 140N) of random nucleotide regions. Competitive evolution of these size-heterogeneous CoA-RNA libraries resulted in an RNA size population in the order of 30N > 60N > 100N > 140N. From isolated clones in the 30N and 60N size groups, two predominant RNA sequences, TES1 (30N) and TES33 (60N), have been shown to catalyze the synthesis of different thioesters using various acyl adenylates as the substrates. Together with our previous findings, the current results demonstrate a CoA thioester synthetic pathway catalyzed by individual metabolic ribozymes, and suggest a likely mechanism for thioester synthesis and utilization in an RNA world.     

Automated oligosaccharide synthesis

Peptides and oligonucleotides are prepared by automated synthesizers that can be operated by non-specialists. Carbohydrates have been hard to assemble, but the increasing awareness of the biological importance of this class of complex repeating biopolymers has prompted efforts to accelerate their synthesis. This tutorial review defines the state of the art of automated solid phase oligosaccharide synthesis and identifies areas in need of further innovation. Application of the automated synthesis method to prepare a malaria vaccine candidate is briefly highlighted.     

金属蒸气合成在金属有机合成中的应用

本文简要地介绍了金属蒸气合成法的基本原理、仪器和实验技术, 并按金属原子分别与炔、单烯、多烯、环烯、芳烃体系、卤代烃、有机混和物的反应及有机金属硼化合物的合成, 对金属蒸气合成法在金属有机合成中的应用进行了讨论。     

Formal synthesis of dictyostatin and synthesis of two dictyostatin analogues

A formal convergent synthesis of dictyostatin from (R)-Roche ester is described. Synthetic highlights include a Ni-catalyzed Nozaki-Hiyama-Kishi coupling between an aldehyde and a Z vinyl iodide to assemble the two main fragments, a diastereoselective Myers alkylation, a stereoselective Evans aldolization, two asymmetric Duthaler crotyltitanations, and a stereoselective Pd-catalyzed Marshall allenylindium addition to install the stereogenic centers of dictyostatin. The synthesis of (9R)-epi-dictyostatin and a new ring-contracted dictyostatin isomer were also achieved.     

Trimethylsilylcellulose synthesis revisited

A simplification of the overall method of producing trimethylsilylcellulose solutions in common organic volatile solvents is reported. Microcrystalline cellulose was derivatized aiming its solubilization in tetrahydrofuran and toluene to obtain ultra-thin films of cellulose by spin-coating. The main simplifications are: 1) elimination of a swelling step before dissolution in the binary solvent N,N-dimethylacetamide/LiCl by using microcrystalline cellulose; 2) derivatization of cellulose –OH groups with –Si(CH₃)₃ groups was successful with no additional catalyst, like trimethylsilyl chloride, the degree of substitution (DS) being 2.2 ± 0.1. The DS at the extreme surface of the films was computed from the X-ray Photoelectron Spectroscopy data: using solely C 1s fitted component areas and, alternatively, from both C 1s and Si 2p areas. The DS estimated with a technique specific of the surface is close to the bulky one obtained from gravimetric measurements reported in the literature for materials synthesized with catalyst. The topographic uniformity is shown by Atomic Force Microscopy.     

离子热法合成沸石咪唑骨架材料及其溶解-结晶机理研究

基于沸石咪唑骨架材料在离子液体和低共熔溶剂中冷却结晶的析出方式,开发了一种离子热法合成沸石咪唑骨架材料的新途径,采用X射线衍射、扫描电镜、核磁共振光谱、红外光谱以及热重分析等方法对制备的产物进行了表征,研究了合成条件对产物结晶度、尺寸和形貌的影响,探讨了沸石咪唑骨架材料在离子热合成体系中的溶解-结晶析出机理.研究发现,冷却速率能够影响产物形貌,急速冷却时,sod(RCSR代码)型产物的形貌为球形,zni(RCSR代码)型产物为棒状或平板状;程序控制冷却时,sod型产物的形貌为多面体,zni型产物呈团簇状.     

Organosilanes in synthesis: application to an enantioselective synthesis of methyl-l-callipeltose

[reaction: see text] Methyl-l-callipeltose, the carbohydrate associated with callipeltoside A, has been synthesized in eight steps and 23% overall yield from enantioenriched allylsilane 6 and acetaldehyde. The key steps are a highly diastereoselective formal [4 + 2] annulation and a Cr(VI)-catalyzed oxidative C-C bond cleavage to produce lactone 11.     

Toward the synthesis of thapsigargin: enantioselective synthesis of 7,11-dihydroxyguaianolides

[reaction: see text] The enantioselective synthesis of a 7,11-dihydroxyguaianolide bearing the stereochemistry present in thapsigargin, a potent and selective inhibitor of the Ca(2+) SERCA-ATPase pumps, is described. Starting from (+)-dihydrocarvone, the synthesis presents two key steps. The first one involves the photochemical rearrangement of a gamma,delta-unsaturated ketone eudesmane into the corresponding guaiane. The second step consists of the regioselective oxidation of an unprotected tetrahydroxylated ketone to provide a dihydroxylactone with the required stereochemistry.     

a novel furan synthesis

γ-ray induced addition of acetaldehyde to perfluoro-3,4-dimethyl-3-hexene gives a product which, in two novel steps, may be converted to a fluorinated furan.