Nucleophilic substitution approach to 4′-substituted thymidines by employing 4′-benzenesulfonyl leaving group

Synthesis of 4′-substituted thymidines was investigated based on nucleophilic substitution using organosilicon and organoaluminum reagents. Two substrates having a benzenesulfonyl leaving group at the 4′-position were prepared for this purpose: 1-[4-benzenesulfonyl-3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-α-l-threo-pentofuranosyl]thymine (8α) and the 4′-(benzenesulfonyl)thymidine derivative (8β). The reaction of 8α with organosilicon reagents (Me₃SiCH₂CHCH₂ and Me₃SiN₃) in combination with SnCl₄ gave preferentially the 4′-substituted β-d-isomer: the 4′-allyl (12β) and 4′-azido (15β) derivatives, respectively. The reaction of 8α with AlMe₃, however, gave the 4′-methyl-α-l-isomer (16α) as the major product, presumably through an ion pair mechanism. By employing the substrate 8β in this reaction, the 4′-methylthymidine derivative (16β) was obtained exclusively in high yield. The 4′-ethyl (20β) and 4′-cyano (24β) derivatives were also synthesized by reacting 8β with the respective organoaluminum reagent.     

Synthesis of 2'-substituted 4-bromo-2,4'-bithiazoles by regioselective cross-coupling reactions

The synthesis of the title compounds (1) was achieved in two steps starting from readily available 2,4-dibromothiazole (2). In a regioselective Pd(0)-catalyzed cross-coupling step, compound 2 was converted into a variety of 2-substituted 4-bromothiazoles 3 (10 examples, 65-85% yield). Alkyl and aryl zinc halides were employed as nucleophiles to introduce an alkyl or aryl substituent. The Sonogashira protocol was followed to achieve an alkynyl-debromination. Bromo-lithium exchange at carbon atom C-4 and subsequent transmetalation to zinc or tin converted the 4-bromothiazoles 3 into carbon nucleophiles which underwent a second regioselective cross-coupling with another equivalent of 2,4-dibromothiazole (2). The Negishi cross-coupling gave high yields of the 2'-alkyl-4-bromo-2,4'-bithiazoles 1a-g (88-97%). The synthesis of the 2'-phenyl- and 2'-alkynyl-4-bromo-2,4'-bithiazoles 1h-j required a Stille cross-coupling that did not proceed as smoothly as the Negishi cross-coupling (58-62% yield). The title compounds which were accessible in total yields of 38-82% are versatile building blocks for the synthesis of 2,4'-bithiazoles.     

Synthesis and mesomorphic properties of 4-alkylamino-4'-substituted diphenyldiacetylenes

Various substituted aminodiphenyldiacetylenes of the type with X = C₃H₇, C₅H₁₁, F or NO₂ and R, R' = H, CH₃-C₆H₁₃ were synthesized and their mesomorphic properties determined. Semi-empirical and ab initio quantum chemical calculations using AM1, 421G and 631G* suggested that the amino group would increase the dielectric anisotropy and optical birefringence as compared to the alkyl chain. Mesomorphic properties were found to be poor with the maximum nematic phase range being 44.8°C and many of the compounds having no nematic phase. Both melting temperatures and enthalpies for those having nematic phases were too high to form good eutectic mixtures.     

Synthesis and mesomorphic properties of 4-alkylamino-4'-substituted diphenyldiacetylenes

Various substituted aminodiphenyldiacetylenes of the type with X = C₃H₇, C₅H₁₁, F or NO₂ and R, R' = H, CH₃-C₆H₁₃ were synthesized and their mesomorphic properties determined. Semi-empirical and ab initio quantum chemical calculations using AM1, 421G and 631G* suggested that the amino group would increase the dielectric anisotropy and optical birefringence as compared to the alkyl chain. Mesomorphic properties were found to be poor with the maximum nematic phase range being 44.8°C and many of the compounds having no nematic phase. Both melting temperatures and enthalpies for those having nematic phases were too high to form good eutectic mixtures.     

N-(5'-溴-4'-取代嘧啶-2'-基)苯磺酰脲化合物的合成和生物活性

乙酰羟基酸合成酶(Acetohydroxyacid synthase,AHAS,EC 4.1.3.18)是植物和微生物中亮氨酸、异亮氨酸和缬氨酸合成途径的一个关键酶,以AHAS为靶标的磺酰脲类除草剂具有高效、高选择性和对环境友好的特点.通过2-氨基-4-甲基嘧啶溴代反应以及进一步的衍生、磺酰基异氰酸酯的胺解,合成了一系列含有5-溴嘧啶基的新磺酰脲.其结构经1H NMR、质谱和元素分析确定.生物活性测试表明目标化合物在离体水平对大肠杆菌乙酰羟基酸合成酶同工酶AHASⅡ表现出了与市售除草剂苯磺隆相当甚至更优的抑制活性,而盆栽除草活性低于苯磺隆.     

Phenylsulfanylation of 3',4'-unsaturated adenosine employing thiophenol-N-iodosuccinimide leads to 4'-phenylsulfanylcordycepin: synthesis of 4'-substituted cordycepins on the basis of substitution of the phenylsulfanyl leaving group

Upon reaction of the 3',4'-unsaturated adenosine derivative 2 with N-iodosuccinimide (NIS) and thiophenol, an unexpected electrophilic hydrophenylsulfanylation proceeded to provide 4'-phenylsulfanylcordycepin 7 in 79% yield with the ratio 7a/7b = 6.6/1. A study of the reaction mechanism revealed that hydrogen iodide (HI) generated from NIS and PhSH acted as an active species. On the basis of a deuterium experiment using PhSD, initial protonation occurred at the β face of the double bond to furnish the β-π complex III, which underwent anti addition of PhSH as a major pathway. Nucleophilic substitution of N(6)-pivaloylated 9 with various alcohols in the presence of N-bromosuccinimide (NBS) gave the respective 4'-α-alkoxycordycepins 15a-21a as the major stereoisomers. Use of DAST in place of an alcohol gave the 4'-α-fluoro analogue 23a stereoselectively. Radical-mediated carbon-carbon bond construction was also applicable to 7, giving 4'-α-allylcordycepin (24a) and 4'-α-cyanoethylcordycepin (25) derivatives.     

Preparation of 4-heteroaryl-4-cyanopiperidines via SNAr substitution reactions

The scope and limitations of S_NAr substitution reactions of metalated 4-cyanopiperidines with heterocyclic halides were explored. These facile reactions provide rapid access to a wide range of 4-heteroaryl-4-cyanopiperidines and have resulted in improved yields, faster reaction times, and lower temperatures than previously published synthetic methods.     

Preparation of novel selenopenams by intramolecular homolytic substitution

Photolyses of the thiohydroximate ester derivatives 13 and 21 of the 4- (benzyl-seleno)-2-azetidinoines 7 and 20, afford the 1-aza-7-oxo-4-selenabicyclo- [3.2.0]heptane ring systems 14 and 21 in good to moderate yield in processes that presumably involve intramolecular homolytic substitution at selenium with expulsion of benzyl radical. Extension of this methodology to the preparation of derivatives 24 of 12,2a-dihydro-1H,8H-azeto[2,1-b][1,3]benzoselenazin-1-one (22) is also described.     

Investigations on the electronic effects of the peripheral 4'-group on 5-(4'-substituted)phenylazo-8-hydroxyquinoline ligands: zinc and aluminium complexes

A new series of 5-(4'-substituted)phenylazo-8-hydroxyquinolines (H[L-R]; R = N(CH(3))(2), C(2)H(5), n-C(4)H(9), C(CH(3))(3), H, and F, ) has been prepared and the corresponding Zn[L-R](2) (1a-6a) and Al[L-R](3) (1b-6b) complexes successfully synthesized. These compounds have been studied in order to design new molecular materials with enhanced electron transport properties. The obtained species have been extensively characterized by absorption and emission spectra and by cyclic voltammetric measurements. Experimental and computational results show that the Zn[L-N(CH(3))(2)].2H(2)O (1a) and Al[L-N(CH(3))(2)](1b) complexes only feature luminescence (at 620 and 600 nm), respectively. The unique effects, which are induced by the N=N-C(6)H(4)-N(CH(3))(2) group, are further proved by a reversible electron transfer process detected by cyclic voltammetry. These outcomes, discussed on the basis of theoretical calculations performed on the (H[L-N(CH3)2])-, H[L-N(CH3)2] and (H[L-N(CH3)(2)])+ species, suggest that metal complexes formed by 5-(4'-N,N-dimethylamino)phenylazo-8-hydroxyquinoline should be considered as electron transport materials suitable for applications in photonic devices.     

Synthesis of 4-acylcoumarins by NHC-catalyzed nucleophilic substitution

Coumarins are bioactive; consequently their syntheses are of importance to medicinal chemists. We describe the one-step organocatalytic syntheses of 4-acylcoumarins from 4-chlorocoumarin. The leaving group at the 4-position of the coumarin was replaced by aroyl groups that originate from aromatic aldehydes by NHC-catalyzed umpolung. 4-Acylthiocoumarins and 2-acylquinolin-2-ones were also prepared using this method. These are the first examples of nucleophilic substitutions at the β-carbons of enones to afford γ-ketoenones.     

Preparation of SF5 aromatics by vicarious nucleophilic substitution reactions of nitro(pentafluorosulfanyl)benzenes with carbanions

Vicarious nucleophilic substitutions (VNS) of hydrogen in 1-nitro-4-(pentafluorosulfanyl)benzene with carbanions provide 2-substituted 1-nitro-4-(pentafluorosulfanyl)benzenes in good to high yields. VNS of 1-nitro-3-(pentafluorosulfanyl)benzene gives a mixture of 6- and 4-substituted 1-nitro-3-(pentafluorosulfanyl)benzenes in 85:15 to >98:2 ratio and good to high yields. In basic media, the VNS reactions lead to the formation of carbanions that can be alkylated by alkyl halides affording the corresponding alkylated products in moderate yields. Transformation of primary products to substituted (pentafluorosulfanyl)anilines and 3- or 4-substituted (pentafluorosulfanyl)benzenes is also described.     

Preparation of a sorbent for metal ions based on N-(5-methylimidazol-4-ylmethyl) chitosan with medium degree of substitution

A procedure was developed for preparing a heterocycle-containing chelating amino polymer, N-(5-methylimidazol-4-ylmethyl) chitosan, by polymer-analogous transformations of chitosan in reaction with 4-chloromethyl-5-methylimidazole. The procedure allows synthesis of the polymer with the degree of substitution of up to 0.8, with simultaneous formation of the cross-linked structure. The structure of the polymers prepared was proved by IR and ¹³C NMR spectroscopy. The ability of N-(5-methylimidazol-4-ylmethyl) chitosan with the degree of substitution of 0.54 to sorb Cu²⁺ and Ni²⁺ ions was evaluated. According to the sorption isotherms, the sorption capacity of this derivative exceeds that of the unmodifi ed polymer by a factor of 5.     

Efficient synthesis of DNA containing the guanine oxidation-nitration product 5-guanidino-4-nitroimidazole: generation by a postsynthetic substitution reaction

[reaction: see text] A convertible nucleoside was synthesized and used to prepare the 2'-deoxynucleoside of 5-guanidino-4-nitroimidazole, a putative in vivo product of the reaction of peroxynitrite with guanine. The convertible nucleoside was incorporated into an oligodeoxynucleotide by the phosphoramidite method and converted postsynthetically to yield an oligodeoxynucleotide containing 5-guanidino-4-nitroimidazole at a specific site. The oligodeoxynucleotide was inserted into a viral genome. Melting temperature analysis revealed that duplexes containing 5-guanidino-4-nitroimidazole were greatly destabilized relative to unmodified duplexes.     

Defective transport of thymidine by cultured cells resistant to 5-bromodeoxyuridine.

A line of HeLa cells resistant to 5-bromo-2'-deoxyuridine (BUdR) was established by continuous culture in growth medium containing BUdR; during the selection period, BUdR concentrations, initially 15 micrometer, were gradually increased to 100 micrometer. Cells of a clone (HeLa/B5) established from this line were also resistant to 5-fluoro-2'-deoxyuridine (FUdR), but not to the free base, 5-fluorouracil. Although extracts of HeLa/B5 cells exhibited levels of thymidine kinase activity comparable to those of parental cells, rates of uptake of BUdR, FUdR, and thymidine into intact cells were much reduced. The kinetics of uptake of uridine and adenosine, nucleosides which appear to be transported independently of thymidine in HeLa cells, were similar for HeLa/B5 and the parental line (HeLa/O). Relative to thymidine uptake by HeLa/O cells, that by HeLa/B5 cells was distinctly less sensitive to nitrobenzylthioinosine (NBMPR), a specific inhibitor of nucleoside transport in various types of animal cells. Despite this difference in NBMPR sensitivity, both cell lines possessed the same number of high affinity NBMPR binding sites per mg cell protein. The altered kinetics of thymidine uptake and the NBMPR insensitivity of that function in HeLA/B5 cells suggest that resistance to BUdR is due to an altered thymidine transport mechanism.     

Nuclcophilic substitution reactions of 5-acetoxymethyl-and 5-p-nitrophenoxymethyluraeils

The synthesis of a number of 5-acetoxymethyl- and 5-p-nitrophenoxymethyluracils and their nucleophilic substitution reactions with sodium methoxide and sodium borohydride are reported. These reactions all appear to involve intermediates with carbonium ion character, the formation of which are dependent upon structural features of the heterocycle. Most facile reactions occur when the 1-position of the heterocycle can accommodate a negative charge to assist in the formation of highly reactive 5-methenyluracil (VII) intermediates. Where ionization is precluded, as with 1-methyl derivatives (IVb, VIb) displacements are retarded but may be assisted by addition of a nucleophilc to the 6-position of the heterocycle. Analogous 1,3-dialkylpyrimidines may react with nucleophiles at the 4-carbonyl group to give anomalous products. Biological connotations of these reactions are discussed.     

Preparation and evaluation of capillary columns with phases with 5–33% phenyl substitution

Summary A polysiloxane with 33% phenyl substitution, OV-61, and mixtures of this phase and SE-54 were coated on deactivated fused silica or borosilicate glass capillaries, using diphenyltetramethyldisilazane (DPTMDS) for high temperature silylation. Film stability was achieved also without crosslinking agents such as azo-tert-butane, thus avoiding the activity introduced by such treatment. Columns were stable up to 350°C. Presented at the 15th International Symposium on Chromatography, Nürnberg, October 1984     

Acylation is rate-limiting in glycosylasparaginase-catalyzed hydrolysis of N4-(4'-substituted phenyl)-L-asparagines

Glycosylasparaginase catalyzes the hydrolysis of the N-glycosylic bond between N-acetyl-D-glucosamine and L-asparagine in the catabolism of glycoproteins. The mechanism has been proposed to resemble that of serine proteases involving an acylation step where a nucleophilic attack by a catalytic Thr residue on the carbonyl carbon of the N-glycosylic bond gives rise to a covalent beta-aspartyl-enzyme intermediate, and a deacylation step to give the final products. The question posed in this study was: Is the acylation step the rate-limiting step in the hydrolysis reaction as in serine proteases? To answer this question a series of mostly new substituted anilides was synthesized and characterized, and their hydrolysis reactions catalyzed by glycosylasparaginase from human amniotic fluid were studied. Five N4-(4'-substituted phenyl)-L-asparagine compounds were synthesized and characterized: 4'-hydrogen, 4'-ethyl, 4'-bromo, 4'-nitro, and 4'-methoxy. Each of these anilides was a substrate for the enzyme. Hammett plots of the kinetic parameters showed that acylation is the rate-limiting step in the reaction and that upon binding the electron distribution of the substrate is perturbed toward the transition state. This is the first direct evidence that acylation is the rate-limiting step in the enzyme-catalyzed reaction. A Br?nsted plot indicates a small, negative charge (-0.25) on the nitrogen atom of the leaving group anilines containing electron-withdrawing groups, and a small, positive charge (0.43) on the nitrogen atom of the leaving group anilines containing electron-donating groups. The free energy (incremental) change of binding (delta deltaGb) in the enzyme-substrate transition state complexes shows that substitution of a substituted phenyl group for the pyranosyl group in the natural substrate results in an overall loss of binding energy equivalent to a weak hydrogen bond, the magnitude of which is dependent on the substituent group. The data are consistent with a mechanism for glycosylasparaginase involving rapid formation of a tetrahedral structure upon substrate binding, and a rate-limiting breakdown of the tetrahedral structure to a covalent beta-aspartyl-enzyme intermediate that is dependent on the electronic properties of the substituent group and on the degree of protonation of the leaving group in the transition state by a general acid.