A facile synthesis of functionally complex isoxazole derivatives

Metalation of 2(4′-Isoxazolyl)-Δ²-oxazolines takes place initially and selectively on the C-5′-alkyl group. Subsequent metalation also proceeds at this position. Selective deprotection of the oxazoline was accomplished without disturbing the isoxazole ring.     

The preparation of perfluoroaryl substituted isoxazoles via nucleophilic aromatic substitution with lithioalkylisoxazoles

The lithioalkylisoxazoles obtained from C-5 lateral metalation of alkylisoxazoles, 1 , add to hexafluorobenzene. When the C-4 substituent was an electron withdrawing tertiary amide moiety, the yields were highest for mono-perfluoroarylation to give 5-pentafluorophenylmethylisoxazoles, 2 .     

On the Karplus relation for 3J(POCC) of nucleotides

The original Karplus parameters for analysing ³J(POCC) magnitudes of nucleotides in terms of conformational properties of the O? C bond were taken from results for 3′,5′-nucleotides and applied to 3′→ 5′-oligonucleotides; the parameters were later modified to take account of ‘largey’ magnitudes of ³J(POCC) observed in 2′ → 5′-oligonucleotides. In this work the origin of this discrepancy is explained in terms of substituent electronegativity effects at C-1′, and quantified using the ¹³C NMR results of 2′,3′-cyclic mononucleotides. A new set of Karplus parameters suitable for analysing ³J(POCC) magnitudes in 3′- and 5′-nucleotides and 3′ → 5′-oligonucleotides is determined from ¹³C NMR measurements on 3′-nucleotides and available results for 3′,5′-cyclic mononucleotides. A method of dealing with J(P, C-1′) coupling in 2′-nucleotides, 2′,3′-cyclic nucleotides and 2′ → 5′-oligonucleotides using the same Karplus relationship is suggested.     

1H- und 13C-NMR-Untersuchungen zur Struktur N-substituierter Tetrazole—Die Strukturen des N-Methoxycarbonyl-, N-Acetyl- und N-(Tri-n-butylstannyl)-tetrazols sowie Substituenteneffekte auf δ13C und 1J(CH)

The ¹H and ¹³C NMR spectra of several isomeric N-substituted tetrazoles have been investigated. ¹³C NMR is shown to be more useful for distinguishing between structural isomers of N-substituted tetrazoles except for those carrying electropositive substituents like SnBu₃. Correlations of δC-5 (inverse) and ¹J(C-5,H) with s?₁ found for 1-substituted tetrazole allowed the identification of the N SnBu₃ derivative as 1-(tri-n-butylstannyl)tetrazole. The phenyl carbon chemical shift difference ΔC′ = δC-3′-δC-2′ is insignificant for structure elucidation and conformational studies of N-substituted 5-phenyltetrazoles; ΔH′ from ¹H NMR spectra seems to be more useful.     

Investigation of the torsional angle at the glycosidic bond in 5′-amino-5′-deoxythymidine derivatives by carbon-13 n.m.r. spectroscopy

The conformational preference of the thymine base ring with respect to the sugar ring in β,β,β,-trichloroethyl 5′amino-5′-deoxythymidine-5′-phosphate has been studied by ¹³C n.m.r. spectroscopy. The magnitude of the three bond vicinal coupling constant, J(C-2, H-1′), for β,β,β-trichloroethyl 5′-amino-5′-deoxythymidine-5′-phosphate and the similarity between the chemical shifts for the furanose carbons C-1′, C-2′, and C-3′ in β,β,β-trichloroethyl 5-′-amino-5′-deoxythymidine-5′-phosphate and in β,β,β-trichloroethyl thymidine 5′-phosphate indicate that the amino analogue exists in aqueous solution predominantly in the anti conformation, as is the case with natural nucleotides.     

Direct synthesis of polyamides by N-acyl phosphoramidites

A variety of N-acyl phosphoramidites were prepared from chlorophosphites and amide derivatives, and their structures were determined with the aid of ¹H-, ¹³C-, and ³¹P-NMR, and IR spectroscopies. These phosphoramidites were employed in direct polycondensation reaction of dicarboxylic acids and diamines under various conditions resulting in polyamides with inherent viscosities of 0.1 to 1.13. The best results were obtained when aliphatic dicarboxylic acids and aromatic diamines were condensed by 2-(N-methylacetamido)-1,3,2-dioxaphospholane in nitriles.     

New synthetic route to alternating copoly(aromatic ester–aliphatic amide)s

The preparation of three novel alternating copoly(aromatic ester–aliphatic amide)s containing the same ordered amide–amide–ester–ester (AAEE), the same para-disubstituted phenyl, and the different long methylene chain structure were described. 1,1′-(Adipoyl)bisbenzotriazole (AdBBT), 1,1′-(suberoyl)bisbenzotriazole (SuBBT), and 1,1′-(sebacoyl)bisbenzotriazole (SeBBT) were synthesized. These diacylbenzotriazoles were preferred to aminoethanol at the amino group because of the selective N-acylation of active acylamide of benzotriazole in excellent yield at room temperature to give diol monomers such as N,N′-bis(2-hydroxyethyl)adipic amide (HEAdA), N,N′-Bis(2-hydroxyethyl)subaric amide (HESuA), and N,N′-bis(2-hydroxyethyl)sebacic amide (HESeA). Polycondensation of 1,1′-(teraphthaloyl)bisbenzotrizole (tPBT) with HEAdA, HESuA, and HESeA gave the corresponding alternating copoly(aromatic ester–aliphatic amide)s: P(tPE–AdA), P(tPE–SuA), and P(tPE–SeA), respectively. The alternating copoly(aromatic ester–aliphatic amide)s were characterized by ¹H-NMR spectra. The resulting polymers have two different chain units; one is chain unit of poly(ethylene terephthalate) and the other is a chain unit of polyamide-2,6, polyamide-2,8, and polyamide-2,10; both are linked via a C? N bond.     

Mannich reactions of heterocycles with dimethyl(methylene) ammonium chloride: A high yield,one-step conversion of estazolam to adinazolam

The readily prepared ammonium salt, (CH₃)₂N⁺ = CH₂Cl^?, 4 , functionalized heterocycles differently, but in a predictable fashion, under neutral, basic or acidic conditions. Triazolo- and imidazobenzophenones 1b ′ and 5 , which primarily underwent intramolecular isomerization to indolols 2a ′ and 6a rather than intermolecular electrophilic substitution under conditions of the normal aqueous Mannich reaction, were converted with 4 to the desired benzophenone derivatives, 1c ′ and 7 , respectively, in moderate yields. The 1-unsubstituted triazolo- or imidazobenzodiazepines, 10a (estazolam) and 10b , were transformed to the corresponding 1-(dimethylamino)methyl derivatives, 11a (adinazolam) and 11b , in good to moderate yields (61% and 32%, respectively.) Under acidic reaction conditions, 1-methyl triazolobenzodiazepine, 10d (alprazolam), afforded 12e , the product of attack at C-4 of the triazolo[4,3-a][1,4]benzodiazepine ring system. Under strongly basic conditions in which the anion of 10d was generated prior to reaction with 4 , both 12e and its isomer, 15 , were formed. These results complement the report that 4 may be used to functionalize the 1-methyl position of triazolobenzodiazepines, and further demonstrate the versatility of reagent 4 in heterocyclic synthesis.     

Kristallstrukturen und spektroskopische Eigenschaften von 2λ3‐Phospha‐1, 3‐dionaten und 1, 3‐Dionaten des Calciums ‐ ein Vergleich am Beispiel der 1, 3‐Diphenyl‐ und 1, 3‐Di(tert‐butyl)‐Derivate

Crystal Structures and Spectroscopic Properties of 2λ³‐Phospha‐1, 3‐dionates and 1, 3‐Dionates of Calcium ‐ Comparative Studies on the 1, 3‐Diphenyl and 1, 3‐Di(tert‐butyl) Derivatives A hydrogen‐metal exchange between dibenzoylphosphane and calcium carbide in tetrahydrofuran (THF) followed by addition of the ligand 1, 3, 5‐trimethyl‐1, 3, 5‐triazinane (TMTA) furnishes the binuclear complex bis[(tmta‐N, N′, N″)calcium bis(dibenzoylphosphanide)] ( 1a ) co‐crystallizing with benzene. Similarly, reaction of bis(2, 2‐dimethylpropionyl)phosphane with bis(thf‐O)calcium bis[bis(trimethylsilyl)amide] in 1, 2‐dimethoxyethane (DME) gives bis(dme‐O, O′)calcium bis[bis(2, 2‐dimethylpropionyl)phosphanide] ( 1b ) in high yield. The carbon analogues 1, 3‐diphenylpropane‐1, 3‐dione (dibenzoylmethane) or 2, 2, 6, 6‐tetramethylheptane‐3, 5‐dione (dipivaloylmethane) and bis(thf‐O)calcium bis[tris(trimethylsilylmethyl)zincate] in DME afford bis(dme‐O, O′)calcium bis(dibenzoylmethanide) ( 2a ) and the binuclear complex (μ‐dme‐O, O′)bis[(dme‐O, O′)calcium bis(dipivaloylmethanide)] ( 2b ), respectively. Dialkylzinc formed during the metalation reaction shows no reactivity towards the 1, 3‐dionates 2a and 2b . Finally, from the reaction of the unsymmetrically substituted ligand 2‐(methoxycarbonyl)cyclopentanone and bis(thf‐O)calcium bis[bis(trimethylsilyl)amide] in toluene, the trinuclear complex 3 is obtained, co‐crystallizing with THF. The β‐ketoester anion bridges solely via the cyclopentanone unit.     

13C nuclear magnetic resonance spectroscopy of selected adenine nucleosides: Structural correlation and conformation about the glycosidic bond

Structural correlations have been carried out from ¹³C chemical shifts (δ) and by analysis of ¹J(CH) coupling constants, and the conformation about the glycosidic bond has been studied by means of the ³J(CH) vicinal coupling constants between C-8 and H-1′ of some adenine nucleosides such as adenosine (Ado), N(7)-β-D-ribofuranosyladenine (N(7)-Ado), N(9)- and N(7)-β-D-xylofuranosyladenine (N(9)-xylAde and N(7)-xylAde), N(9)-(3-chloro-3-deoxy-β-D-xylofuranosyl)adenine (3′-Cl-xylAde) and N(9)-(2-chloro-2-deoxy-β-D-arabinofuranosyl)adenine (2′-Cl-araAde). The analysis of the influence on δ¹³C of the nature and configuration of the substituent in the carbohydrate fragment of the molecule has revealed two types of effects, namely, 1,2-cis and 1,2-trans. This approach, as well as the ³J(CH) values and the analysis of the C-3′-endo?C-2′-endo equilibrium of the carbohydrate fragment of nucleosides, and circular dichroism (CD) data, provides important information on the conformation about the glycosidic bond. The magnitudes of ³J(C-4, H) are indicative of the position of attachment of the carbohydrate fragment to the heterocyclic base.     

Aza-Claisen Rearrangement: Synthesis of 5′-branched 5′-aminothymidines

The syntheses of both diastereoisomers of 5′-ethyl-substituted thymidine dimers, the (5′R)- and (5′S)-configurated 33a and 33b respectively, in which the natural phosphodiester linkage is replaced by an amide group (C(3′)-CH₂CONH-CH(5′)(Et)), arc described. Their fully protected derivatives 35a and 35b , respectively, are suitable for incorporation into antisense oligonucleotides. Unexpectedly, an attempted Pd^II-catalysed aza-Claisen rearrangement of trichloroacetimidate 7 provided the diastereoisomerically pure cyclopropane derivative 17 , whose structure was confirmed by X-ray analysis.     

Nucleotides,Part LXVII,The 2‐Cyanoethyl and (2‐Cyanoethoxy)carbonyl Group for Base Protection in Nucleoside and Nucleotide Chemistry

The amino functions of the common 2′‐deoxyribo‐ and ribonucleosides were blocked by the (2‐cyanoethoxy)carbonyl group on treatment with 2‐cyanoethyl carbonochloridate ( 5 ) or 1‐[(2‐cyanoethoxy)carbonyl]‐3‐methyl‐1H‐imidazolium chloride ( 6 ) leading to 7 , 18 , 8 , 19 , 9 , and 20 . In 2′‐deoxyguanosine, the amide group was additionally blocked at the O⁶ position by the 2‐cyanoethyl (→ 27 ) and 2‐(4‐nitrophenyl)ethyl group (→ 31 , 32 ). Comparative kinetic studies regarding the cleavage of the ce/ceoc and npe/npeoc group by β‐elimination revealed valuable information about the ease and sequential deprotection of the various blocking groups at different sites of the nucleobases. Besides the 5′‐O‐(dimethoxytrityl)‐protected 3′‐(2‐cyanoethyl diisopropylphosphoramidites) 38 and 39 of N⁴‐[(2‐cyanoethoxy)carbonyl]‐2′‐deoxycytidine and N⁶‐[(2‐cyanoethoxy)carbonyl]‐2′‐deoxyadenosine, respectively, the N²‐[(2‐cyanoethoxy)carbonyl]‐2′‐deoxy‐O⁶‐[2‐(4‐nitrophenyl)ethyl]guanosine analog 40 is recommended as building block for oligo‐2′‐deoxyribonucleotide synthesis.     

Nucleotide,XVIII. Synthese und Eigenschaften von (tert-Butyldimethylsilyl)guanosinen,Guanosin-3′-phosphotriestern und Guanosin-haltigen Oligoncleotiden

Nucleotides, XVIII. Synthesis and Properties of (tert-Butyldimethylsilyl)guanosines, Guanosine-3′-Phosphotriesters and Guanosine-containing Oligonucleotides Silylation of N²-benzoyl- (1) and N²-isobutyrylguanosin (2) by tert-butyldimethylsilyl chloride led to the various mono-, di- and tri-O-tert-butyldimethylsilyl derivatives 3–15 . The synthesis of 2′- (24–31) and 3′-phosphotriesters ( 16–23 and 32 ) could be achieved by phosphorylations of partially protected guanosines. The guanosine-3′-phosphodiester 33 and the 5′-OH-guanosine-3′-phosphotriester 34 are used in condensation reactions as 5′- and 3′-terminal components, respectively, to form dinucleoside mono- ( 39 and 40 ) and diphosphates (41–48) in relatively good yields. The various products were characterized by elemental analyses, ¹H-, ¹³C-, and ³¹P-NMR spectra as well as UV and CD spectra.     

COORDINATION OF CU2± BY MONO-AMINOALKYLOXAMIDES IN AQUEOUS SOLUTION

Abstract

Complex formation equilibria of Cu^2± complexes of N-(2-aminoethyl)(oxamide, N-3-aminopropyl)oxamide, 1,8-diamino-3,6-diazaoctane-7,8-dione and 1,10-diamino-4,8-diazaoctane-9,10-dione in aqueous solution at 25°C ± 0.1°C and I = 0.1 mol dm^?3 (KNO₃) have been studied using potentiometric and spectrometric titrimetry. Mixed ligand titrations using 2,2′-bipyridyl as the second ligand have been added in order to obtain unambiguous results. The Cu^2± complexes of the monoalkyl substituted oxamides studied can be classified into three groups: (1) CuLH₁ and CuLH₂ complexes; these complexes have a single deprotonated oxamide group in a trans configuration; (2) a CuLH_?3 complex; this complex has a doubly deprotonated oxamide group in a cis configuration; (3) Cu₂LH_?2, Cu₃L₂H_?4 and Cu₃L₂H_?5 complexs; these polynuclear complexes have the doubly deprotonated oxamide group in a trans configuration. Deprotonation of the primary amide group in the Cu₂LH_?2 complex of these ligands occurs before pH = 5. This unprecedented deprotonation of a primary amide group under these conditions is due to the cooperation of both strong and optimally positioned coordinating groups. The concept of amide oxygen anchoring is introduced.     

Recyclization of 5-Amino- oxazoles as a Route to new Functionalized Heterocycles (Developments of V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine)

The recyclizations of 5-amino- and 5-hydrazine-1,3-oxazoles mainly with electron-withdrawing group in 4^th position are considered. The chemical behavior of these heterocycles is due to the presence of two hidden amide fragments; therefore, the recyclization processes include a stage of nucleophile attack on 2^nd or 5^th position of the oxazole cycle. When the nitrile group is present in 4^th position, it is often involved in the recyclization forming α-aminoazoles. 5-Amino/hydrazine-1,3-oxazoles undergo recyclization both in nucleophilic (amines, hydrazine, thionating agents) and electrophilic medium ((trifluoro)acetic acid, other acylating agents). The numerous types of functionalized heterocycles can be easily obtained with the usage of these recyclizations, such as the derivatives of 3-amino-6,7-dihydro-5H-pyrrolo[1,2–a]imidazole, imidazolidine-2,4-dione, 1H-pyrazole-3,4,5-triamine, 5,6-diamino-2,3-diphenylpyrimidin-4(3H)-one, 2-(2-R-7-oxo-5-(trifluoromethyl)oxazolo[5,4–d]pyrimidin-6(7H)-yl)acetic acid, 2-R-4-(5-R′-1,3,4-oxadiazol-2-yl)oxazol-5-amine, (amino(5-amino-1,3,4-thiadiazol-2-yl)methyl)phosphonate.     

Conformation and ortho steric effects in a series of 2-(pyrazol-1-yl)quinolines

Nine 2-(pyrazol-1-yl)-4-methylquinolines bearing substituents on the pyrazole 3- or 5-positions (H, Me, Et, i-Pr, t-Bu) were regioselectively synthesized either using the direct condensation of 2-chloro-4-methylquinoline and sodium salt of 3(5)-substituted pyrazoles or by treatment of 2-hydrazino-4-methylquinoline with an appropriate β-ketoaldehyde. The ¹H and ¹³C chemical shifts were discussed taking into account the preferred conformation about the C-2-N-1′ bond as calculated by the AM1 Hamiltonian. It appears that 5-ethyl and 5-isopropyl substituted derivatives present short C-H-N-1 interactions. Ortho steric effects appear to be responsible for these conformations.     

Antifungal diastereomeric furanones from Mutisia friesiana: structural determination and conformational analysis

Two diastereomeric furanones, (4S,5S)-5-(4′-methyl-3′-pentenyl)-4-hydroxy-5-methyldihydrofuran-2-one 1 and (4S,5R)-5-(4′-methyl-3′-pentenyl)-4-hydroxy-5-methyldihydrofuran-2-one 2 were isolated for the first time from the shrub Mutisia friesiana. The relative stereochemistries of 1 and 2 were ascertained from NOESY NMR data and confirmed by a combination of molecular modeling (molecular mechanics and ab initio molecular orbital calculations) and NMR data. Comparison between experimental and calculated ¹H–¹H vicinal coupling constants revealed that both furanones exist in an equilibrium of two stable conformers of the five-membered ring. Application of Mosher's method suggests that both diastereomeric furanones have the same (S)-configuration at C-(4) and are epimers at C-(5). Furanones 1 and 2 showed antifungal activity against the pathogenic fungus Cladosporium cucumerinum.     

Novel Aplysinopsin-Type Alkaloids from Scleractinian Corals of the Family Dendrophylliidae of the Mediterranean and the Philippines. Configurational-assignment criteria,stereospecific synthesis,and photoisomerization

From the scleractinian coral Tubastraea sp. (Dendrophylliidae) collected at Palawan, Philippines, 3′-deimino-3′-oxoaplysinopsin ( 4 ) and 6-bromo-3′-deimino-3′-oxoaplysinopsin ( 6 ) are now isolated as 5:2 mixtures of (E/Z) stereoisomers. The 3′-deimino-2′,4′-bis(demethyl)-3′-oxoaplysinopsin ( 7 ) and 6-bromo-3′-demino-2′,4-bis(demethyl)-3′-oxoaplysinopsin ( 5 ) are isolated as 2:3 and 1:1 (E/Z) mixtures, respectively, from another dendrophylliid, Leptopsammia pruvoti, collected near Marseille, Mediterranean coast of France. Larger amounts of these and related compounds, needed for a full structural determination, are obtained by synthesis. Thus, condensations of indol-3-carboxaldehyde (9) or of its 6-bromo derivative 14 with hydantoin (15) , 3-methylhydantoin (11) , or 1,3dimethylhydantoin (10) give the prevalent natural aplysinopsins with high stereospecificity. The minor stereoisomers (Z)- 4 , (Z)- 6 , (E)- 7 , and (E)- 5 are obtained by (E/Z) photoisomerization under UV light of the condensation mixtures. The configuration is assigned from larger H? C(8)/C(5′) ¹H, ¹³C couplings in the (E) than in the (Z) isomer, and, in the case of 4 and 6 , from NOE enhancement at Me? N(2′) on irradiation at H? C(8). The stereospecificity of the condensations is attributed to steric inhibition to planarity in the rate-limiting transition states, due to N(2′)/H? C(2) repulsion with (Z)- 4 and (Z)- 6 , or to C(5′)?O/H? C(2) repulsion with (E)–7 or (E)- 5 . As the aplysinopsins undergo (E/Z ) phostoisomerization also under the daylight conditions of the laboratory, their isomeric composition in nature can not be presently assessed.     

Nucleotides. Part L. Aglycone protection by the (2-dansylethoxy)carbonyl (= {2-{[5-(dimethylamino)naphthalen-l-yl]sulfonyl}ethoxy}carbonyl; dnseoc) group a new variation in oligodeoxyribonucleotide synthesis

The (2-dansylethoxy)carbonyl (= {2-{[5-(dimethylamino)naphthalen-l-yl]sulfonyl}ethoxy}carbonyl; dnseoc) group was employed for protection of the amino functions of the aglycone residues. The lactam function of 2′-deoxyguanosine was on the one hand unprotected and on the other hand alkylated at O⁶ of the aglycone with the 2-(4-nitrophenyl)ethyl (npe) and 2-(phenylsulfonyl)ethyl (pse) group, respectively. The syntheses of monomeric building blocks, both phosphoramidites and nucleoside- functionalized supports, are described for the three common 2′-deoxynucleosides (2′-deoxycytidine, 2′-deoxyadenosine, 2′-deoxyguanosine). As kinetic studies with the tritylated nucleosides showed, the dnseoc group is more labile towards DBU cleavage than the corresponding 2-(4-nitrophenyl)ethyl-(npe) and [2-(4-nitrophenyl)ethoxy]carbonyl(npeoc)-protected analogues (see Table 2). These results were confirmed by the very fast deprotection rate of the dnseoc groups at some oligonucleotides.     

Directed Remote Lateral Metalation: Highly Substituted 2‐Naphthols and BINOLs by In Situ Generation of a Directing Group

A general synthesis of highly substituted 2‐naphthols based on a new carbanionic reaction sequence is demonstrated. The reaction exploits the dual nature of lithium bases consisting of consecutive ring opening of readily available coumarins with either LiNEt₂ or LiNiPr₂ into Z‐cinnamamides, thus generating a directing group in situ and allowing, by conformational freedom, a lateral directed remote metalation for ring closure to give the aryl 2‐naphthols in good to excellent yields. These transformations can be combined to provide a more efficient one‐pot process. Mechanistic insight into the remote lateral metalation step, demonstrating the requirement of Z‐cinnamamide, is described. Application of this methodology to the synthesis of highly substituted 3,3′‐diaryl BINOL ligands is also reported.