Synthesis of Some Halogen- and Nitro-substituted Nicotinic Acids and Their Fragmentation Under Electron Impact

Features of electrophilic and nucleophilic substitution under chlorination and nitration reactions conditions have been investigated for 6-hydroxy- and 6-methyl-substituted derivatives of 3-cyano-4-methyl-2(1H)-pyridones. The polychloro- and nitro-substituted 3-cyano-4-methylpyridines obtained were used as synthons in the synthesis of some polyhalo- and nitro-substituted nicotinic acids and their amides. The fragmentation pathways of the synthesized compounds under electron impact have been studied.     

Solid-phase chemical synthesis of phosphonoacetate and thiophosphonoacetate oligodeoxynucleotides

Phosphonoacetate and thiophosphonoacetate oligodeoxynucleotides were prepared via a solid-phase synthesis strategy. Under Reformatsky reaction conditions, novel esterified acetic acid phosphinodiamidites were synthesized and condensed with appropriately protected 5'-O-(4, 4'-dimethoxytrityl)-2'-deoxynucleosides to yield 3'-O-phosphinoamidite reactive monomers. These synthons when activated with tetrazole were used with an automated DNA synthesizer to prepare phosphonoacetic acid modified internucleotide linkages on controlled pore glass. The phosphinoacetate coupling products were quantitatively oxidized at each step with (1S)-(+)-(10-camphorsulfonyl)oxaziridine or 3H-1,2-benzodithiol-3-one-1,1-dioxide to produce mixed sequence phosphonoacetate and thiophosphonoacetate oligodeoxynucleotides with an average per cycle coupling efficiency of greater than 97%. Completely deprotected, modified oligodeoxynucleotides were purified by reverse-phase HPLC and characterized by ion exchange HPLC, (31)P NMR, and MALDI/TOF mass spectroscopy. Both analogues were stable toward hydrolysis with snake venom phosphodiesterase and stimulated RNase H1 activity.     

Conversion of bis(o‐nitrophenyl)diselenides to heterocycles containing selenium and nitrogen with the aid of samarium diiodide

Treatment of bis(o‐nitrophenyl)diselenides with SmI₂ led to simultaneous reduction of nitro groups and reductive cleavage of Se Se bonds as well as to the formation of the intermediates 2 . The intermediates 2 were “living” double‐anions formed in situ, and reacted readily with ω‐bromoketones and α‐bromocarboxylic acid derivatives to afford the desired 2H‐1,4‐benzoselenazines and 2H‐1,4‐benzoselenazin‐3(4H)‐ones, respectively, in moderate to high yields and under mild conditions. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:302–306, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10034     

A new route to α-alkyl-α-fluoromethylenebisphosphonates

A new route to α-alkyl-α-fluoromethylenebisphosphonates, 2 has been developed starting from commercially available tetraethyl fluoromethylenebisphosphonate (1), and alkyl halides using either caesium carbonate in DMF or sodium dimsyl. De-esterification of 2 provided biologically important α-alkyl-α-fluoromethylenebisphosphonic acid, 3, while alkoxide-induced carbon-phosphorus bond cleavage of 2 gave α-fluorophosphonates, 4, which are useful synthons in organic synthesis.     

FTIR监测7-氟-2H-1,4-苯并噁嗪-3(4H)-酮的固相合成

我们已经合成了一系列具有生物活性的杂环取代苯并噁嗪酮类化合物, 为了构建一个苯并噁嗪酮类化合物的组合物库, 我们又探索出了一种固相合成7-氟-2H-1,4-苯并噁嗪-3(4H)-酮的方法, 并用FTIR技术成功地监测、优化了整个反应过程, 并根据得到的红外光谱图对反应动力学进行了探讨.     

Conversion of bis(o‐nitrophenyl)disulfides to heterocycles containing sulfur and nitrogen by the action of samarium diiodide

Treatment of bis(o‐nitrophenyl)disulfides 1 with SmI₂ led to simultaneous reduction of nitro groups and reductive cleavage of S–S bonds as well as the formation of the active intermediates 2 . The intermediates 2 reacted smoothly with aldehydes or ketones, acid chlorides or anhydrides, α‐bromoketones, and α,β‐unsaturated ketones at room temperature to afford the desired benzothiazolines 3 , benzothiazoles 4 , 2H‐1,4‐benzothiazines 5 , and 2,3‐dihydro‐1,5‐benzothiazepines 6 , respectively, in moderate to high yields under mild and neutral conditions. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:156–160, 2001     

Efficient synthesis of methyl 3,5-di-O-benzyl-alpha-D-ribofuranoside and application to the synthesis of 2'-C-beta-alkoxymethyluridines

Methyl 3,5-di-O-arylmethyl-alpha-D-ribofuranosides have been used extensively as synthons to construct 2'-C-branched ribonucleosides. Herein, we describe efficient access to methyl 3,5-di-O-arylmethyl-alpha-D-ribofuranosides (aryl: 2-ClC(6)H(4), 3-ClC(6)H(4), 4-ClC(6)H(4), 4-BrC(6)H(4), 2,4-Cl(2)C(6)H(3), Ph) in 72-82% yields from methyl D-ribofuranoside. We also demonstrate efficient access to the versatile precursor methyl 3,5-di-O-benzyl-alpha-D-ribofuranoside (3f) and the synthesis of 2'-C-beta-methoxymethyl- and 2'-C-beta-ethoxymethyluridine in six steps from 3f with overall yields of 18% and 32%, respectively.     

Total synthesis of (S)-(+)-curcudiol, and (S)-(+)- and (R)-(-)-curcuphenol.

A highly enantioselective synthesis of the versatile chiral synthons possessing one stereogenic center, (S)- and (R)-4-aryl-5-hydroxy-(2E)-pentenoate (3) was achieved based on the enzymatic reaction of (+/-)-3 with commercially available lipases MY-30 or OF-360 from Candida rugosa. Application of (S)-3 and (R)-3 to the total syntheses of(S)-curcuphenol (1), (S)-curcudiol (2), and (R)-curcuphenol (1), respectively, is described.     

Mono- and dimethylbenzyls as new protecting groups for no-carrier-added nucleophilic aromatic radiofluorination

In this work, we tested the applicability of several methyl substituted benzyl groups as an alternative to the methyl group for the protection of the hydroxyl groups in the nucleophilic aromatic radiofluorination. As a model synthesis, the no-carrier-added (n.c.a.) preparation of 2-[¹⁸F]fluoro-3-hydroxy-6-methylpyridine from O-protected 3-hydroxy-6-methyl-2-nitropyridine was chosen. Conditions for acidolytic and hydrogenolytic cleavage of heteroaryl esters were studied. Among various protecting groups tested, 4-methylbenzyl and 2,4-dimethylbenzyl groups proved to be the best by resulting in about 70% yields of [¹⁸F]-labelled product after hydrolysis with 32% HCl at 120 °C for 10 min. Furthermore, 4-methylbenzyl ester cleaved readily under catalytic transfer hydrogenation condition using ammonium formate and 10% Pd/C in boiling methanol to give 2-[¹⁸F]fluoro-3-hydroxy-6-methylpyridine in radiochemical yield of 75% within a reaction time of 10 min. Conditions for the cleavage of both 4-methylbenzyl and 2,4-dimethylbenzyl esters are well suited for the implementation into an automated synthesis module.     

Facile solid-phase synthesis of sulfated tyrosine-containing peptides: total synthesis of human big gastrin-II and cholecystokinin (CCK)-39.

Chemical synthesis of tyrosine O-sulfated peptides is still a laborious task for peptide chemists because of the intrinsic acid-lability of the sulfate moiety. An efficient cleavage/deprotection procedure without loss of the sulfate is the critical difficulty remaining to be solved for fluoren-9-ylmethoxycarbonyl (Fmoc)-based solid-phase synthesis of sulfated peptides. To overcome the difficulty, TFA-mediated solvolysis rates of a tyrosine O-sulfate [Tyr(SO3H)] residue and two protecting groups, tBu for the hydroxyl group of Ser and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) for the guanidino group of Arg, were examined in detail. The desulfation obeyed first-order kinetics with a large entropy (59.6 J.K-1.mol-1) and enthalpy (110.5 kJ.mol-1) of activation. These values substantiated that the desulfation rate of the rigidly solvated Tyr(SO3H) residue was strongly temperature-dependent. By contrast, the SN1-type deprotections were less temperature-dependent and proceeded smoothly in TFA of a high ionizing power. Based on the large rate difference between the desulfation and the SN1-type deprotections in cold TFA, an efficient deprotection protocol for the sulfated peptides was developed. Our synthetic strategy for Tyr(SO3H)-containing peptides with this effective deprotection protocol is as follows: (i) a sulfated peptide chain is directly constructed on 2-chlorotrityl resin with Fmoc-based solid-phase chemistry using Fmoc-Tyr(SO3Na)-OH as a building block; (ii) the protected peptide-resin is treated with 90% aqueous TFA at 0 degree C for an appropriate period of time for the cleavage and deprotection. Human cholecystokinin (CCK)-12, mini gastrin-II (14 residues), and little gastrin-II (17 residues) were synthesized with this method in 26-38% yields without any difficulties. This method was further applied to the stepwise synthesis of human big gastrin-II (34 residues), CCK-33 and -39. Despite the prolonged acid treatment (15-18 h at 0 degree C), the ratios of the desulfated peptides were less than 15%, and the pure sulfated peptides were obtained in around 10% yields.     

Asymmetric aldol addition of α-azido ketones to ethyl pyruvate mediated by a cinchona-based bifunctional urea catalyst

The first asymmetric synthesis of ethyl 4-aryl-3-azido-2-hydroxy-2-methyl-4-oxobutanoates via a cinchona organocatalyst induced aldol addition of α-azido ketones to ethyl pyruvate has been developed. The coupling reaction under optimized conditions was carried out to furnish tetrafunctionalized synthons with enantioselectivities of up to 91:9 and enriched diastereoselectivities of up to 95:5 (syn:anti).     

Asymmetric synthesis of alpha-branched primary amines on solid support via novel hydrazine resins

[reaction: see text]. Two novel chiral hydrazine resins for asymmetric solid-phase synthesis have been developed. The enantiopure beta-methoxyamino auxiliaries, derived from trans-4-hydroxy-(S)-proline and (R)-leucine, were attached to Merrifield resin and transformed into their corresponding hydrazines. Immobilization of various aldehydes, followed by 1,2-addition of organolithium reagents to the resulting enantiopure hydrazones and reductive cleavage from the solid support, furnished alpha-branched amines, which were isolated as their corresponding amides in good overall yields and enantiomeric excesses of up to 86%.     

Synthesis of methionine- and norleucine-derived phosphinopeptides

We present herein a straightforward synthesis of N-Fmoc-protected synthons derived from a phosphinic analogue of methionine. These precursors were used successfully for the solid-phase synthesis of methionine-mimic phosphinopeptides using BOP-catalyzed coupling without protection of the phosphoryl moiety. We also prepared a new type of pseudopeptide derived from a phosphinic analogue of norleucine with a -PO(OH)-CH₂-COOR moiety.     

METAL CHELATES OF NEW LIGANDS: 1,2-BENZOTHIAZINE-1,1-DIOXIDE DERIVATIVES

Abstract

The novel chelates ML₂ (M = Co, Ni, Cu, Zn) were obtained by the interaction of 3-benzoyl-4-hydroxy-1,2-benzothiazine-4(3H)-on-1,1-dioxide and 2-methyl-3-benzoyl-4-hydroxy-1,2-benzo-thiazine-4(3H)-on-1,1-dioxide with elemental metals (direct electrochemical synthesis) or their acetates (chemical synthesis) in methanol. The tetrahedral or polymeric-octahedral structures with a β-diketonate fragment are assigned based on IR and ¹H NMR spectra. The studied ligands and their complexes are model compounds of molecules used as anti-inflammatory drugs.     

Conformationally constrained 2'-N,4'-C-ethylene-bridged thymidine (aza-ENA-T): synthesis, structure, physical, and biochemical studies of aza-ENA-T-modified oligonucleotides

The 2'-deoxy-2'-N,4'-C-ethylene-bridged thymidine (aza-ENA-T) has been synthesized using a key cyclization step involving 2'-ara-trifluoromethylsufonyl-4'-cyanomethylene 11 to give a pair of 3',5'-bis-OBn-protected diastereomerically pure aza-ENA-Ts (12a and 12b) with the fused piperidino skeleton in the chair conformation, whereas the pentofuranosyl moiety is locked in the North-type conformation (7 degrees < P < 27 degrees, 44 degrees < phi m < 52 degrees). The origin of the chirality of two diastereomerically pure aza-ENA-Ts was found to be due to the endocyclic chiral 2'-nitrogen, which has axial N-H in 12b and equatorial N-H in 12a. The latter is thermodynamically preferred, while the former is kinetically preferred with Ea = 25.4 kcal mol-1, which is thus far the highest observed inversion barrier at pyramidal N-H in the bicyclic amines. The 5'-O-DMTr-aza-ENA-T-3'-phosphoramidite was employed for solid-phase synthesis to give four different singly modified 15-mer antisense oligonucleotides (AONs). Their AON/RNA duplexes showed a Tm increase of 2.5-4 degrees C per modification, depending upon the modification site in the AON. The relative rates of the RNase H1 cleavage of the aza-ENA-T-modified AON/RNA heteroduplexes were very comparable to that of the native counterpart, but the RNA cleavage sites of the modified AON/RNA were found to be very different. The aza-ENA-T modifications also made the AONs very resistant to 3' degradation (stable over 48 h) in the blood serum compared to the unmodified AON (fully degraded in 4 h). Thus, the aza-ENA-T modification in the AON fulfilled three important antisense criteria, compared to the native: (i) improved RNA target affinity, (ii) comparable RNase H cleavage rate, and (iii) higher blood serum stability.     

An efficient solid-phase synthesis of 2-alkyl-4,6-diaminopyrimidines and 2,4,6-triaminopyrimidines

An efficient and simple approach for the solid-phase synthesis of 2,4,6-triaminopyrimidines and 2-alkyl-4,6-diaminopyrimidines is described. Primary amines were immobilized on 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene resin via reductive amination. Attachment of two different 4,6-dichloropyrimidines led to the corresponding 4-chloro-6-aminopyrimidine intermediates. Aromatic nucleophilic substitution with various aliphatic amines or the corresponding lithium amides afforded the desired aminopyrimidines in high yield and excellent purity after acidic cleavage from the resin. The products were characterized by LC-MS, ¹H and ¹³C NMR spectroscopy. Deuterium exchange experiments revealed that the investigated aminopyrimidines have a general tendency toward C-5 protonation.     

Solid phase library synthesis of cyclic depsipeptides: aurilide and aurilide analogues

A solid-phase combinatorial synthesis approach toward the cyclic depsipeptide aurilide (1) and related analogues is described. The peptide moiety 2 was assembled on trityl linker-functionalized SynPhase Crowns using an Fmoc strategy. Optimization of the tetrapeptide assembly 5 was carried out using parallel multiple synthesis and LC/MS analysis. The aliphatic moiety 3a was coupled with the solid-supported 2 using DIC/HOBt. Following deprotection and cleavage of linear precursor 26, macrocyclization was achieved under high dilution conditions. Removal of the methylthiomethyl protecting group provided aurilide (1) in 11% overall yield. Synthesis of a combinatorial library of aurilide derivatives 4 was accomplished with a similar protocol using the TranSort technique.     

3-羟基-4-甲基-5-乙基-2(5H)-呋喃酮的合成

报道了以草酸二乙酯为原料,制备具有焦糖香味的香料化合物3-羟基-4-甲基-5-乙基-2(5H)-呋喃酮的方法:首先乙基溴化镁与草酸二乙酯通过格氏反应,以约50%产率生成2-氧代丁酸乙酯,然后其在碳酸钾的作用下发生缩合反应,以约94%产率得到3-羟基-4-甲基-5-乙基-5-乙氧羰基-2(5H)-呋喃酮,再通过水解、脱羧反应,得到3-羟基-4-甲基-5-乙基-2(5H)-呋喃酮.路线总收率约36%.     

Synthesis and evaluation of 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid as a linker in solid-phase synthesis monitored by gel-phase (19)F NMR spectroscopy

Gel-phase (19)F NMR spectroscopy is a useful monitoring technique for solid-phase organic chemistry due to the high information content it delivers and swift acquisition times, using standard NMR spectrometers. This paper describes the synthesis of the novel linker 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid in 29% yield over seven steps, using nucleophilic aromatic substitutions on 2,4,5-trifluorobenzonitrile as key steps. Following standard solid-phase synthesis a peptide could be cleaved from the linker using 20% TFA in CH(2)Cl(2) in 30 minutes, in contrast to a previously described monoalkoxy linker that requires 90% TFA in water at elevated temperature. A resin-bound peptide could be successfully glycosylated using only two equivalents of a thioglycoside donor, activated with N-iodosuccinimide and trifluoromethanesulfonic acid, and subsequent cleavage and deprotection gave the target glycopeptide. Direct glycosylation of the linker itself followed by mild acidic cleavage gave a fully protected hemiacetal for further chemical manipulation.     

Synthesis and screening of aromatase inhibitory activity of substituted C19 steroidal 17-oxime analogs

The synthesis and aromatase inhibitory activity of androst-4-en-, androst-5-en-, 1β,2β-epoxy- and/or androsta-4,6-dien-, 4β,5β-epoxyandrostane-, and 4-substituted androst-4-en-17-oxime derivatives are described. Inhibition activity of synthesized compounds was assessed using aromatase enzyme and [1β-3H]androstenedione as substrate. Most of the compounds displayed similar to or more aromatase inhibitory activity than formestane (74.2%). 4-Chloro-3β-hydroxy-4-androsten-17-one oxime (14, 93.8%) showed the highest activity, while 4-azido-3β-hydroxy-4-androsten-17-one oxime (17, 32.8%) showed the lowest inhibitory activity for aromatase.