3'-叠氮D/L-核苷的合成（英文）

报道了两种正交保护的3'-叠氮-3'-脱氧-D/L-核糖关键中间体的合成,此二关键中间体与各种嘧啶、吡啶、嘌呤相关的杂环碱基进行糖苷化,得到了相应的3'-叠氮-3'-脱氧D核苷衍生物以及3'-叠氮-3'-脱氧L核苷衍生物.合成了药物相关的3'-叠氮-3'-脱氧-6-氮杂尿苷、4-脱氧尿苷、2-硫代尿苷、3-去氮尿苷、硝基吡啶核苷、异胞苷衍生物.31个最终产品中的14个是新化合物,其结构均得以确证.所有最终产品都是用本文描述的平行法从相应的新关键中间体合成而得.此二关键中间体可以用于合成含有任何不同碱基的新型核苷衍生物.     

碱退式辅酶B~1~2类似物的合成和光谱性质

本工作用改进的方法合成了一类新的辅酶B~1~2碱退式类似物-含2'-脱氧核苷钴啉醇酰胺。它们分别是2',5'-二脱氧尿苷钴啉醇酰胺(2'dUrdCbi), 2',5'-二脱氧腺苷钴啉醇酰胺(2'dAdoCbi), 2',5'-二脱氧胞苷钴啉醇酰胺(2'dCytCbi)以及5'-脱氧胸苷钴啉醇酰胺(ThyCbi)。研究了它们的UV-Vis和^1H NMR光谱性质。并且和相应钴胺素的有关性质作了比较。     

5'-脱氧-5'-氟-5-氟尿核苷的合成和性质

叙述了5'-脱氧-5'-氟尿核苷和5'-脱氧-5'-氟-5-氟尿核苷的合成, 并比较了它们以及尿核苷和5-氟尿核苷的一些性质。     

1,1'-螺二氢茚-7,7'-二酚(SPINOL)及类似物中螺环骨架的构建方法

1,1'-螺二氢茚骨架是在21世纪初发展起来的一类新型手性配体或催化剂的骨架,具有C2对称性,以及刚性强、稳定性高、易于修饰等特点.周其林等将手性1,1'-螺二氢茚-7,7'-二酚(SPINOL)发展为一系列螺环配体及催化剂,在催化不对称合成领域获得了巨大的成功.1,1'-螺二氢茚骨架的配体及催化剂被认为是为数不多的"优势手性配体和催化剂".尽管催化的不对称合成已经出现,目前方法得到的SPINOL及类似物多为外消旋体,需要进行费力的手性拆分.合成和拆分步骤繁琐的局限性对其大规模生产形成了阻碍.因此,如何从廉价易得的原料出发,发展相应手性螺环骨架配体的高效、不对称催化合成新方法,是非常迫切而且具有挑战性的课题.总结了最近20年SPINOL及螺环骨架类似化合物的合成方法,包括含杂原子的螺环骨架,希望能对配体或催化剂用途的螺环骨架的构建有所启发.     

E-5-(2-溴乙烯基)-2'-脱氧尿嘧啶的简便合成方法研究

以2'-脱氧尿嘧啶为原料, 在糖苷羟基未保护情况下, 经过羟甲基化、选择性氧化、Knoevenagel缩合和Hunsdiecker反应等4步反应, 简便地合成了抗病毒药物E-5-(2-溴乙烯基)-2'-脱氧尿嘧啶, 为工业化生产提供了可靠的依据.     

吡喃异黄酮Barbigerone及其类似物的简便合成

报道一种以间苯二酚为起始原料,通过傅-克酰基化、成吡喃环、羟醛缩合、氧化-重排-关环等五步反应,简洁、高效地合成天然吡喃异黄酮Barbigerone及其类似物的方法.该方法不仅原料易得、价格低廉、操作简单、条件温和,而且可得高达24%～30%的总收率.     

4-巯基-4-脱氧-4'-去甲表鬼臼毒素的立体控制合成

4-巯基-4-脱氧-4'-去甲表鬼臼毒素是合成4位硫取代的4'-去甲表鬼臼毒素的关键中间体,由4'-去甲表鬼臼毒素与硫化氢在BF~3·Et~2O存在下立体控制制备,也可通过以NH~3/CH~CN选择性 地水解4-乙酰硫基-4-脱氧-4'-去甲表鬼臼毒素而制备.     

合成卡培他滨的新方法

1',2',3'-0-三乙酰基核糖与硅醚化的5-氟胞嘧啶缩合制备了2',3'-0-二乙酰基-5'-脱氧-5-氟胞苷(2);2再与氯甲酸正戊酯反应得到2',3'-0-二乙酰基-5'-脱氧-5-氟-N4-[(戊氧基)羰基]胞苷(3);3经皂化合成了卡培他滨(总产率53%),其结构经1H NMR和元素分析表征.     

5’-脱氧肌苷的合成

以肌苷为原料,经丙酮叉保护得到2',3'-O-异亚丙基肌苷(3);3经溴化得到5'-脱氧-5'-溴代-2',3'-O-异亚丙基肌苷(4);4经Pd/C催化氢化得到5'-脱氧-2',3'-O-异亚丙基肌苷(5);5在甲酸存在下水解制得5'-脱氧肌苷,总收率25.1%.其结构经1H NMR和MS确证.     

异脱落酸的合成及植物生长调节活性

通过空间位阻影响的选择性亲核加成、碳碳叁键的选择性还原以及Dess-Martin氧化和Lindgren氧化等反应合成了异脱落酸(11),同时还得到了2',3'-二氢异脱落酸(12)、异炔酸(13)和异脱落酸内酯(14),经手性制备液相色谱分离得到了异脱落酸的两个对映异构体(+)-11和(-)-11.以脱落酸(ABA)为对照,对异脱落酸类似物进行了植物生长调节活性测试,结果表明:异脱落酸(+)-11的活性略低于天然脱落酸,而(-)-11只具有很弱的活性;2',3'-二氢异脱落酸(12)具有较低的活性,说明六元环上的双键是保持脱落酸活性的必需结构.对比四种生测模式,异脱落酸类似物对莴苣种子萌发的效果最好.     

Cyclopentene carbocyclic nucleosides related to the antitumor nucleoside clitocine and their conversion to 8-Aza-neplanocin analogues. Synthesis and antiviral activity

Synthesis of the cyclopentene carbocyclic analogue of the naturally occurring nucleoside clitocine ( 1 ) is reported. Starting with racemic cyclopentenylamine ( 10 ), the heterocyclic moieties of the clitocine analogue 4 and related 1,6-dihydro-6-oxo, 5 , and 2-amino-1,6-dihydro-6-oxo, 6 , analogues were constructed. These compounds were respectively converted to 8-aza-neplanocin A (7) , 8-aza-neplanocin D ( 8 , the inosine analogue), and the corresponding 8-aza-guanosine analogue 9 after reduction of the nitro group followed by nitrous acid cyclization. Extensive antiviral evaluation revealed that only 8-aza-neplanocin A ( 7 ) had enough antiviral activity to warrant further studies. This compound showed weak antiviral activity against HSV-1, HSV-20 and the thymidine kinase deficient (TK-) HSV-1. However, it displayed good antiviral activity against human cytomegalovirus (HCMV) at a concentration of 0.40–2.50 μg/ml, well below the cytotoxicity threshold. This activity profile is consistent with a mechanism of action involving the inhibition of the enzyme adenosylhomo-cysteine hydrolase.     

The self-assembly and lyotropic mesomorphism of riboguanylic acids (GMP)

The three isomeric guanylic acids (5'-GMP, 3'-GMP and 2'-GMP) and the 3':5'-cyclic derivative (cGMP) form, in water solution, left-handed columnar aggregates which, at higher concentration, pack to give left-handed cholesteric mesophases. The self-assembly process and liquid crystal formation are discussed in relation to the behaviour of the 2'-deoxy analogues.     

Hydrolysis of substrate analogues catalysed by beta-D-glucosidase from Aspergillus niger. Part II: Deoxy and deoxyhalo derivatives of cellobiose.

The hydrolysis of sixteen mainly deoxy and deoxyhalo derivatives of celloboise catalysed by beta-D-glucosidase from Aspergillus niger has been studied by means of 1H NMR spectroscopy and progress-curve enzyme kinetics in both single-substrate and competition experiments. In the non-reducing ring of cellobiose it was found that the hydroxy groups at positions 2', 3', and 4' are essential for the enzymatic hydrolysis. The primary hydroxy group on 6' in this ring is, although important for the hydrolysis, not essential. The analogues modified at positions 3' and 4' and the 6'-bromo-6'-deoxy derivative were not inhibitors, whereas the 2'-deoxy derivative inhibited the enzymatic hydrolysis of methyl beta-cellobioside to some extent. Of the analogues modified in the reducing ring, some were hydrolysed faster (e.g. the deoxy compounds) and some slower than methyl beta-cellobioside in single-substrate experiments, but all derivatives were hydrolysed at a lower rate than this reference substrate in direct competition and displayed relatively weak inhibitory effects. The results are interpreted qualitatively with respect to changes in the free binding energies of the substrates and catalytic transition states based on the Michaelis-Menten mechanism, and some mechanistic implications of these findings are discussed.     

Addition of difluorocarbene to 4',5'-unsaturated nucleosides: synthesis and deoxygenation reactions of difluorospirocyclopropane nucleosides

Synthetic routes to 4'-(2,2-difluorospirocyclopropane) analogues of adenosine, cytidine, and uridine are described. Treatment of 2',3'-O-isopropylidene-4',5'-unsaturated compounds derived from adenosine and uridine with difluorocarbene (generated from PhHgCF3 and NaI) gave diastereomeric mixtures of the 2,2-difluorospirocyclopropane adducts. Stereoselectivity resulting from hindrance by the isopropylidene group favored addition at the beta face. Removal of base and sugar protecting groups gave new difluorospirocyclopropane nucleoside analogues. The protected uridine analogue was converted into its cytidine counterpart via a 4-(1,2,4-triazol-1-yl) intermediate. Stannyl radical-mediated deoxygenation of the 3'-O-TBS-2'-thionocarbamate derivatives gave the 2'-deoxy products of direct hydrogen transfer. In contrast, identical treatment of the 2'-O-TBS-3'-thionocarbamate isomers resulted in opening of the vicinal difluorocyclopropane ring upon generation of a C3' radical followed by homoallylic hydrogen transfer to give 4'-(1,1-difluoroethyl)-3',4'-unsaturated nucleoside derivatives. Structural aspects and biological effect considerations are discussed.     

Synthesis and biological properties of C-2 triazolylinosine derivatives

O(6)-(Benzotriazol-1H-yl)guanosine and its 2'-deoxy analogue are readily converted to the O(6)-allyl derivatives that upon diazotization with t-BuONO and TMS-N(3) yield the C-2 azido derivatives. We have previously analyzed the solvent-dependent azide·tetrazole equilibrium of C-6 azidopurine nucleosides, and in contrast to these, the O(6)-allyl C-2 azido nucleosides appear to exist predominantly in the azido form, relatively independent of solvent polarity. In the presently described cases, the tetrazole appears to be very minor. Consistent with the presence of the azido functionality, each neat C-2 azide displayed a prominent IR band at 2126-2130 cm(-1). A screen of conditions for the ligation of the azido nucleosides with alkynes showed that CuCl in t-BuOH/H(2)O is optimal, yielding C-2 1,2,3-triazolyl nucleosides in 70-82% yields. Removal of the silyl groups with Et(3)N·3HF followed by deallylation with PhSO(2)Na/Pd(PPh(3))(4) gave the C-2 triazolylinosine nucleosides. In a continued demonstration of the versatility of O(6)-(benzotriazol-1H-yl)purine nucleosides, one C-2 triazolylinosine derivative was converted to two adenosine analogues via these intermediates, under mild conditions. Products were desilylated for biological assays. The two C-2 triazolyl adenosine analogues demonstrated pronounced antiproliferative activity in human ovarian and colorectal carcinoma cell cultures. When evaluated for antiviral activity against a broad spectrum of DNA and RNA viruses, some of the C-2 triazolylinosine derivatives showed modest inhibitory activity against cytomegalovirus.     

Metal ion complexes of antivirally active nucleotide analogues. Conclusions regarding their biological action

Acyclic nucleoside phosphonates (ANPs), i.e., analogues of (2'-deoxy)nucleoside 5'-monophosphates, have been studied during the past 15 years for their potential as antiviral drugs. One of these compounds, 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; Adefovir) was recently approved in the form of its bis(pivaloyloxymethyl)ester (Adefovir dipivoxil) for use in hepatitis B therapy, a disease evoked by a DNA virus. Diphosphorylated PMEA(2-), i.e., PMEApp(4-), is initially recognized by nucleic acid polymerases as an excellent substrate, but after insertion in the growing nucleic acid chain, this is terminated due to the lack of a 3'-hydroxy group. Based on the metal ion-binding properties of PMEApp(4-) it can be explained why the ether oxygen in the aliphatic chain, R-CH(2)-O-CH(2)-PO(3)pp(4-), is compulsory for a useful biological activity. Consequently, this critical review presents an overview on the coordination chemistry of various ANPs and correlates this to their biological properties.     

Synthesis of 3'-deoxynucleosides with 2-oxabicyclo[3.1.0]hexane sugar moieties: addition of difluorocarbene to a 3',4'-unsaturated uridine derivative and 1,2-dihydrofurans derived from D- and L-xylose1

Syntheses of 3'-deoxy analogues of adenosine, cytidine, and uridine with a 2,2-difluorocyclopropane ring fused at C3'-C4' are described. Treatment of a 2',5'-protected-3',4'-unsaturated derivative of uridine with difluorocarbene [generated from (CF3)2Hg and NaI] gave a diastereomeric mixture of the 3',4'-difluoromethylene compounds (alpha-L-arabino/beta-D-ribo, approximately 5:4). The limited stereoselectivity for addition at the beta face results from competitive steric hindrance by an allylic 4-methoxybenzyloxy group at C2' on the alpha face and a homoallylic nucleobase at C1' on the beta face. Protected uracil derivatives were converted into their cytosine counterparts via 4-(1,2,4-triazol-1-yl) intermediates. Treatment of 1,2-dihydrofurans derived from D- and L-xylose with difluorocarbene resulted in stereospecific addition at the beta face (anti to the 1,2-O-isopropylidene group on the alpha face). Glycosylations with activated enantiomeric sugar derivatives with the fused difluorocyclopropane ring on the beta face gave protected adenine nucleosides, whereas attempted glycosylation with an alpha-fused derivative gave multiple products. Removal of base- and sugar-protecting groups gave new difluoromethylene-bridged nucleoside analogues.     

Substrate 2'-hydroxyl groups required for ribozyme-catalyzed polymerization

A polymerase ribozyme has been generated that uses nucleoside triphosphates to elongate an RNA primer by the successive addition of nucleotides complementary to an RNA template. Its polymerization is accurate, with an average error rate less than 3%, and it is general in terms of the sequence and the length of the primer and template RNAs. To begin to understand how the substrate contacts contribute to this accurate and general activity, we investigated which primer and template 2'-hydroxyl groups are involved in substrate recognition. We identified eight positions where 2'-deoxy substitutions can influence polymerization kinetics. All eight are within five nucleotides of the primer 3' terminus. Some, but not all, of the 2'-deoxy effects appear to be sequence dependent. These results begin to build a picture of how the polymerase ribozyme recognizes its substrates.     

Visualization of Host–Guest Interactions Between a Modified Nucleoside and Organic Moieties. Crystal Structures of 2'-Deoxy 5'-O-trityluridine and 2'-Deoxy 5'-O-tritylthymidine with Benzene, Toluene, Xylene, Trimethylbenzene, Cyclohexane and Water

This paper describes the crystal structures of 2'-deoxy 5'-O-trityluridine(5'-TU) and 2'-deoxy 5'-O-tritylthymidine (5'-TT) containing different organic moieties. There are two crystallographically independent nucleoside molecules present in the asymmetric units of all the structures. Uracil and thymine bases of the 2'-deoxy 5'-trityl uridine(5'-TU) and all the 2'-deoxy 5'-tritylthymidine structures are in an anti conformation with respect to their furanose rings. Thymine bases of molecules A and B form symmetric self pairs through N(3)-–O(2) hydrogen bonds, whereas uracil bases are not engaged in hydrogen bonding between themselves. Ribose moieties of both molecules of 2'-deoxy 5'-trityithymidine with benzene and toluene are in the C(2')-endo conformations while molecules A and B of 2'-deoxy 5'-tritylthymidine containing xylene, trimethylbenzene, cyclohexane and water are in the C(3')-endo and C(1')-exoconformations, respectively. Both ribose moieties of 5'-TU show C(3')-endo puckering. The conformation about the C(4')-–C(5') bond for all the 2'-deoxy 5'-tritylthymidine structures is g⁺, contrasting with the g^- for the 5'-TU structure. Benzene and toluene molecules stack between TT base pairs, while xylene, trimethylbenzene and cyclohexane are oriented obliquely to the base pairs. 2'-Deoxy 5'-tritylthymidine containing toluene shows a type V C-–H interaction between the methyl group of toluene and the thymine base. Remarkably, the 2'-deoxy 5'-tritylthymidine-containing xylene, trimethylbenzene, cyclohexane and water structures demonstrate a strong type I O-–H interaction between the ribose O(3') and the thymine base seen only in 1.25% of the structures. Molecular packing and hydrogen bonding are discussed.     

A conformationally preorganized universal solid support for efficient oligonucleotide synthesis

A novel, conformationally preorganized nonnucleosidic universal solid support for oligonucleotide synthesis was developed. The solid support featured two chemically equivalent hydroxy groups locked in syn-periplanar orientation and orthogonally protected with 4,4'-dimethoxytrityl and acetyl groups. The solid support was extensively tested in the preparation of oligonucleotides and their phosphorothioate analogues containing 2'-deoxy, 2'-O-methyl, and 2'-O-methoxyethylnucleoside residues at the 3'-terminus. Upon completion of oligonucleotide chain assembly, the support-bound oligonucleotide material was treated with concentrated ammonium hydroxide, which removed the O-acetyl protection. The deprotected hydroxy group then effected the transesterification of a phosphate linkage between the solid support and the 3'-terminal nucleoside residue to result in a facile release of the oligonucleotide to solution. The kinetics of the release process was studied in a continuous flow of concentrated aqueous ammonium hydroxide at a temperature of 300.15 K. Optimal conditions for the release of oligonucleotides depending on the chemistry of the backbone and 3'-terminal nucleoside residue were formulated.