Current Organic Chemistry

ISSN: 1385-2728

Current Organic Chemistry
Volume 11, Number 5, March 2007

Contents

Bioorganic Chemistry
Guest Editor: Harri Lönnberg


Editorial Pp. 407


Phosphopeptides - Chemical Synthesis, Analysis, Outlook and Limitations Pp. 409-426
G.K. Tóth, Z. Kele and G. Váradi
[Abstract]


Advances in the Synthesis of 7-Deazapurine - Pyrrolo[2,3 d]pyrimidine - 2’-Deoxyribonucleosides Including D- and L Enantiomers, Fluoro Derivatives and 2’,3’-Dideoxyribo nucleosides Pp. 427-462
Frank Seela, Xiaohua Peng and Simone Budow
[Abstract]


Artificial Restriction DNA Cutters (ARCUT) for Future Biotechnology Pp. 463-475
J. Sumaoka, Y. Yamamoto, Y. Kitamura and M. Komiyama
[Abstract]


General Articles


The Synthesis of Asymmetrical Tertiary Alkyl Ethers Catalyzed by Ionic Liquids with and without CO₂ Pp. 477-482
Xiumin Ma, Tao Jiang, Buxing Han, Jun Huang, Anlian Zhu and Jicheng Zhang
[Abstract]


Bestatin: Three Decades of Synthetic Strategies Pp. 483-496
Brent D. Feske
[Abstract]




Abstracts

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Editorial

This issue constitutes Part II of the first thematic issue of Bioorganic Chemistry published in Current Organic Chemistry. It contains three timely reviews that highlight three important subjects. Prof Toth with his co-workers describes the recent developments in synthetic chemistry of phosphopeptides. Proteomics of phosphoproteome is one of the most actively investigated fields of systems biology. Protein phosphorylation is a widely occurring post-translational modification that forms the chemical basis for intracellular signal transduction. Development of high throughput methods for analysis of phosphoproteome depends on availability of phosphopeptides and, hence, efficient and convenient methods of phosphopeptide synthesis are of utmost importance. Synthesis of structurally modified nucleosides is a field of equal importance. Nucleoside analogs have found applications as antiviral and anticancer drugs, as constituents structurally modified antisense oligonucleotides and as nucleoside triphosphate analogs in enzymatic sequencing of nucleic acids. In the second article, Prof Seela and his co-workers summarize in considerable depth the recent advances in the synthesis of nucleoside analogs derived from 7-deazapurine, i.e. pyrrolo[2,3-d]pyrimidine. In addition, the potential of 7-deazapurine nucleosides as antiviral or anticancer drugs, as well as the use of their triphosphates in Sanger´s dideoxynucleoside DNA-sequencing, are elucidated. Finally, the contribution of Prof Komiyama and his co-workers gives a fascinating example of the possibilities of man-made oligonucleotide conjugates as artificial nucleases. Systematic long-term research efforts have produced a methodology that enable in vitro tailoring of large DNA molecules in a pre-design manner. These studies are surveyed. I thank all the contributors for their thorough work that will benefit many organic chemists, not only those working on related subjects, but also a wider readership being interested in general progress of chemical biology.

Harri Lönnberg
Department of Chemistry
University of Turku
FIN-20014 Turku
Finland


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Phosphopeptides - Chemical Synthesis, Analysis, Outlook and Limitations
G.K. Tóth, Z. Kele and G. Váradi

Protein phosphorylation is one of the most important post-translational events in cell regulation and signal transduction. Since the isolation of phosphorylated peptides from biological sources is usually not feasible, there is a need for efficient chemical phosphorylation methods to allow the study of the role of phosphorylation/dephosphorylation in biological processes. The recent developments in phosphopeptide chemistry (special protecting groups for the phosphate moiety and new amidite reagents) have provided peptide chemists with a wide variety of different strategies applicable for work with the sensitive phosphoserine, phosphothreonine and phosphotyrosine-containing peptides. This has made possible the efficient chemical preparation of longer, multiply phosphorylated, possibly cell-permeable or fluorescent residue-bearing peptides.


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Advances in the Synthesis of 7-Deazapurine - Pyrrolo[2,3 d]pyrimidine - 2’-Deoxyribonucleosides Including D- and L Enantiomers, Fluoro Derivatives and 2’,3’-Dideoxyribo nucleosides
Frank Seela, Xiaohua Peng and Simone Budow

This review reports on the synthesis of 7-deazapurine 2’-deoxyribonucleosides, including β-D- and β-L-enantiomers, fluoro derivatives, and 2’,3’-dideoxyribonucleosides. It covers the various aspects of convergent nucleoside synthesis. Stereochemically defined α-D- and α-L-2-deoxy-3,5-di-O-(p-toluoyl)-erythro-pentofuranosyl chlorides as well as 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide were employed in nucleobase anion glycosylation. This glycosylation reaction is regioselective for the pyrrole nitrogen and stereoselective for β-nucleoside formation. 7-Deazapurine 2’,3’-dideoxyribonucleosides were synthesized by the same protocol as 2’-deoxyribonucleosides using 2,3-dideoxy-5-O-[(1,1-dimethylethyl)dimethylsilyl]-D-glycero-pentofuranosyl chloride. 7-Deazapurine 2’,3’-dideoxyribonucleosides were also obtained from 2’-deoxy- or 3’-deoxyribonucleosides by Barton deoxygenation or by elimination of sugar hydroxyl groups. The review discusses the scope and limitations of the glycosylation reaction performed with pyrrolo[2,3-d]pyrimidines as well as on the regioselective halogenation reactions followed by the Sonogashira cross coupling. It reports on the use of 7-deazapurine nucleoside triphosphates in the Sanger dideoxy DNA-sequencing and the application of 7-deazapurine nucleosides as antiviral or anticancer agents.


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Artificial Restriction DNA Cutters (ARCUT) for Future Biotechnology
J. Sumaoka, Y. Yamamoto, Y. Kitamura and M. Komiyama

Recent chemical approaches towards artificial restriction DNA cutters (ARCUT) are reviewed. New tools to cut either single-stranded DNA or double-stranded DNA at predetermined sites have been prepared. As molecular scissors, these cutters employ Ce(IV)/EDTA complex that preferentially hydrolyzes single-stranded DNA over double-stranded DNA. Hot-spots for site-selective scission are prepared at predetermined site with the use of appropriate DNA or peptide nucleic acid (PNA) additives. Thus, gap-structures are formed in single-stranded DNA using two oligonucleotide additives, whereas invasion of a pair of PNAs is used for the scission of double-stranded DNA. These single-stranded portions are hydrolyzed by Ce(IV)/EDTA, resulting in the site-selective scission. The DNA scission proceeds totally via hydrolysis of phosphodiester linkages. Both linear DNA and supercoiled DNA are selectively cut at the target site by these restriction DNA cutters, and the fragments are efficiently combined with foreign DNA by using ligase. The recombinant DNA is successfully expressed in cells and produces the target protein (e.g., green fluorescent protein and other fusion proteins). No undesired side-reactions concurrently take place during the DNA manipulation. The length and the sequence of the recognition sites of these man-made DNA cutters are freely chosen, and thus, in principle, even huge DNA of higher animals and higher plants can be selectively cut and manipulated.


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The Synthesis of Asymmetrical Tertiary Alkyl Ethers Catalyzed by Ionic Liquids with and without CO₂
Xiumin Ma, Tao Jiang, Buxing Han, Jun Huang, Anlian Zhu and Jicheng Zhang

The synthesis of a series of asymmetrical tertiary alkyl ethers from the etherification of tertiary alkyl alcohols with corresponding alcohols was investigated. Ionic liquids (ILs) with Brønsted acidity, [BsMIm][HSO₄] (1-(4-sulfonic acid) butyl-3-methylimidazolium hydrogen sulfate) and [BMIm][HSO₄] (1-butyl-3-methylimidazolium hydrogen sulfate), were found to be suitable catalysts for the reactions. Tertiary alkyl ethers including MTBE (methyl tert-butyl ether), ETBE (ethyl tert-butyl ether), IPTBE (isopropyl tert-butyl ether), TAME (tert-amyl methyl ether), and TAEE (tert-amyl ethyl ether) could be produced. Effects of reaction temperature, reaction time, and amount of the catalyst used on the synthesis of the MTBE were investigated. The conversion of TBA (tert-butyl alcohol) and the selectivity of MTBE could reach 69.9 % and 77.4 %, respectively at 393 K as the molar ratio of TBA: Methanol: [BMIm][HSO₄] was 20:20:1. The reaction mixture splited into two phases after reaction, and the IL could be separated from the products simply by decantation and could be reused. CO₂ could enhance the conversion of TBA and the selectivity of MTBE significantly at suitable pressures.


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Bestatin: Three Decades of Synthetic Strategies
Brent D. Feske

Bestatin (ubenimex) is a dipeptide that can treat a variety of diseases. Over the last thirty years synthetic chemists have developed an assortment of routes to optically pure (-)-Bestatin. Many strategies include the use of pure starting materials like sugars and amino acids. In addition, the utilization of chiral auxiliary groups have been implemented to achieve an increase in stereoselectivity and to simplify the purification process. Lastly, asymmetric catalysis using enzymes or inorganic catalysts has also been used to afford the desired stereochemistry. This review will cover 23 synthetic strategies to (-)-Bestatin through the year 2005.