Molecular structures and ab initio molecular orbital calculations of the optically active derivatives of 1-aminocyclopropane-1-carboxylic acid

The novel optically active derivatives of 2,2′-disubstituted-1-aminocyclopropane-1-carboxylic acid (−)-2 and (+)-3 were synthesised from the spiro-azlactone (+)-1. Oxidation of the diol moiety of (+)-3 gave by ring enlargement the racemic mixture of 2,3-dihydrofuran derivative (±)-6. This conversion is explained by stepwise rearrangement of the initially formed tetrasubstituted cyclopropanecarbaldehyde 4 through zwitterionic's reactive intermediate 5. The formation of (±)-6 is preferred energetically as established by ab initio calculations of the ground states and possible intermediates for that rearrangement. The crystal structure and absolute configuration of the compounds (+)-1, (−)-2, (+)-3 and (−)-7 were determined by single-crystal X-ray diffraction method. All four compounds possess Z-configuration of the cyclopropane ring. The dioxolane ring in the structures (+)-1 and (−)-2 adopts half-chair conformation, while the cyclopropane ring and geminally substituted groups in the structures (−)-2, (+)-3 and (−)-7 possess the anticlinal conformation. The molecules of the compound (+)-1 are connected by very weak intermolecular hydrogen bond of C-H?O type. In the compounds (−)-2, (+)-3 and (−)-7inter- and intramolecular hydrogen bonds of N-H?O type were observed. The spiro-compound (+)-1 exhibited a more pronounced inhibitory activity against the proliferation of murine leukemia and human T-lymphocytes cells than other type of tumor cell lines and normal human fibroblast cells.     

New silatranes possessing urea functionality: Synthesis, characterization and their structural aspects

The present work aims at the synthesis of various novel silatranes bearing substituted urea functionality. Nucleophilic addition of various amines (morpholine, aniline, ethylenediamine and 3-aminopropyltriethoxysilane) to 3-isocyanatopropyltriethoxysilane resulted in the four triethoxysilanes; N-[3-(triethoxysilyl)propyl]morpholine-4-carboxylic acid amide (1), 1-[3-(triethoxysilyl)propyl]-3-phenylurea (2), 1,2-bis{N′-[3-(triethoxysilyl)propyl]ureido}-ethane (3) and N-[3-(triethoxysilyl)propyl]-N′-[3-(triethoxysilyl)propyl]urea (4), respectively. In the presence of a base the resulting silanes undergo transesterification reaction with triethanolamine, thus forming the corresponding silatranes, N-(3-silatranylpropyl)morpholine-4-carboxylic acid amide (5), 1-(3-silatranylpropyl)-3-phenylurea (6), 1,2-Bis[N′-(3-silatranylpropyl)ureido]-ethane (7) and N-(3-silatranylpropyl)-N′-(3-silatranylpropyl)urea (8), respectively. Among these are four novel compounds (5-8), which were characterized by elemental analysis, IR, multinuclear (¹H, ¹³C and ²⁹Si) NMR and mass spectroscopy. Structures of compounds 5 and 6 were deduced by X-ray crystallography. Single crystal X-ray studies revealed distorted trigonal bipyramidal coordination about Si in 5 and 6 with Si-N bond distance of 2.121(1) Å and 2.189(2) Å, respectively.     

Synthesis of 1-fluoroindan-1-carboxylic acid (FICA) and its properties as a chiral derivatizing agent

1-Fluoroindan-1-carboxylic acid (FICA) (1) was designed and synthesized as its methyl ester (FICA Me ester) (4) in order to develop an efficient chiral derivatizing agent (CDA) which excels α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA) in capability. FICA Me ester (4) was prepared by fluorination of methyl 1-hydroxyindan-1-carboxylate (3) with (diethylamino)sulfur trifluoride (DAST) and derived to the esters of racemic secondary alcohols by ester exchange reaction. The resulting Δδ_F value was large in the case of 2-butyl ester of FICA (5a), whereas not detectable in the case of the corresponding MTPA ester (6a). The magnitude of the Δδ_H values was similar to that of MTPA esters. The diastereomers of (R)-(−)-8-phenylmenthyl ester of FICA (5i) was separated and their ¹H NMR analyses revealed that the concept of the modified Mosher's method was successfully applied to 5i.     

A new ergostane-type cholesterol biosynthesis inhibitor isolated from Hormoconis resinae

A new ergostane-type steroid, 3β-hydroxy-1,11-dioxo-ergosta-8,24(28)-diene-4α-carboxylic acid (1) was isolated from the mold Hormoconis resinae as a cholesterol biosynthesis inhibitor in the Chang liver cell. The absolute stereostructure of 1 was established based on the spectroscopic analyses and modified Mosher's method.     

Synthesis and reactions of 2-hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-but-2-enoic acid methyl ester

2-Hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-but-2-enoic acid methyl ester (1) was synthesized by the reaction of pentafluoroacetophenone with dimethyl oxalate in the presence of sodium methylate. Subsequently, reactions of compound 1 with aniline, o-phenylenediamine, and o-aminophenol were investigated. In addition, the thermal cyclization of ester 1 was studied and led to the formation of 5,6,8-trifluoro-7-methoxy-4-oxo-4H-chromene-2-carboxylic acid methyl ester (6) due to nucleophilic substitution of the 3-fluoro group. Hydrolysis of compound 1 and subsequent cyclization by treatment with SOCl₂ gave 5-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-furan-2,3-dione (3). Thermal decarbonylation of compound 3 under mild conditions resulted in the formation of 3-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-propene-1,3-dione (4) which dimerized to pyranone 5.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

cis/trans-Isochromanones. DMAP induced cycloaddition of homophthalic anhydride and aldehydes

Homophthalic anhydride (1) reacts with wide variety of aromatic aldehydes, in the presence of chloroform and DMAP (N,N-dimethyl-4-amino-pyridine) at room temperature, to give in high yields cis- and trans-1-oxo-isochroman-4-carboxylic acids. Under these conditions, the trans-isomer is predominant and formation of Perkin-type products was not observed in contrast to the reaction carried out in the presence of pyridine. The unexpected trans-6-oxo-11-thiophen-2-yl-11,12-dihydro-6H-dibenzo[c,h]chromene-12-carboxylic acid methyl ester (8) was isolated when the reaction between 1 and thiophene-2-carbaldehyde was carried out in pyridine.     

A novel and convenient method for the synthesis of new derivatives of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione

A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine derivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via peptide coupling of l-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-pyridopyrrolodiazepines derivatives 5a-m, 6a-i, 7, and 8a-c. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.     

De-novo approach for a unique spiro skeleton-1,7-dioxa-2,6-dioxospiro[4.4]nonanes

2-Oxoglutaric acid (1) underwent facile indium mediated allylation with allyl bromide (2), and ethyl 4-bromocrotonate (3), cinnamyl bromide (4) and subsequent in situ dehydration to provide respective 5-oxotetrahydrofuran-2-carboxylic acids 5-7 (90-95%). The reaction of 1 with 3 and 4 proceeded with high regio and stereo selectivity to provide only γ-addition products with syn stereochemistry as ascertained from their cyclic products. Compounds 5-7 underwent diastereoselective iodocyclization to provide respective 1,7-dioxa-2,6-dioxospiro[4.4]nonanes 8-13. The relative stereochemistries have been ascertained by single crystal X-ray structures, NOE experiments and coupling constants in ¹H NMR spectra.     

Synthesis of the spiroacetal fragment of broussonetine H

(2S,6S)-2-(3-Bromopropyl)-1,7-dioxaspiro[5.5]undecane 3 was prepared by the addition of the acetylide derived from (4S)-4-benzyloxy-7-tert-butyldiphenylsilyloxyhep-1-yne 8 to δ-valerolactone 6 followed by treatment with hydrogen and palladium on charcoal which effected hydrogenation of the alkyne, hydrogenolysis of the benzyl ether and subsequent spiroacetal formation. The (4S)-stereochemistry in acetylene 8 was established by addition of trimethylsilylacetylene 10 to (2S)-epoxide 9, which in turn is derived from l-glutamic acid 11.     

Thermal decomposition of the tert-butyl perester of thymidine-5′-carboxylic acid. Formation and fate of the pseudo-C4′ radical

Thermal decomposition of the tert-butyl perester of thymidine-5′-carboxylic acid 1 carried out at 85 °C in different solvents affords the tert-butylacetal 4a, deriving from in cage decomposition, and pseudo C4′ radicals 2. Radicals 2 can be reduced to 5 by hydrogen atom abstraction from thiol (thiophenol or glutathione) or THF, or can be oxidized to cations 8 by dioxygen or perester 1 itself. Cations 8 are stereoselectively trapped by the nucleophilic solvent (tert-butanol, methanol, water) to give acetals 4a-c.     

Syntheses and crystal structures of diorganotin (IV) moieties with 3-hydroxy-2-pyridinecarboxylic acid

A series of new organotin (IV) complexes with 3-hydroxy-2-pyridinecarboxylic acid (3-OH-2-picH) of two types: R₂SnCl(3-OH-2-pic) (I) (R = Me 1, n-Bu 2, Ph 3, PhCH₂4) and R₂ Sn(3-OH-2-pic)₂ (II) (R = Me 5, n-Bu 6, Ph 7, PhCH₂8)have been synthesized by reactions of diorganotin (IV) dichloride with 3-hydroxy-2-pyridinecarboxylic acid in the presence of sodium ethoxide. All complexes are characterized by elemental analyses, IR spectra and NMR spectra analyses. Among them, complexes 1, 5, 6 and 7 are also characterized by X-ray crystallography diffraction analyses. Complex 1 is a 1D polymeric chain with six-coordinate tin atoms and the packing of complex 1 is stabilized by the C-H?Cl intermolecular weak interactions, thus a 2D network of 1 is formed. Complex 5 is also a 1D polymeric chain with seven-coordinate tin atoms. Complex 6 is a zigzag polymeric chain linked by Sn?O intermolecular weak interactions. Complex 7 is a monomeric complex with distorted octahedral geometry.     

Ag and Zn complexes with possible application as NLO materials - Crystal structures and properties

Four novel Ag^I-complexes with DL-mandelic acid (MA) (1), squaric acid (H₂Sq) (2), 3-pyridin aldehyde (3PyA) (3) and 2-amino-8-hydroxyquinoline (2A8H) (4) as well as two Zn^II-ones with 3PyA (5) and 2A8H (6) are synthesized, isolated, spectroscopic and structural characterized by single crystal X-ray diffraction, UV-vis-NIR, and IR-spectroscopy. The experimental data of the complex (1) were compared with the analogous of the neutral MA. Quantum chemical calculations are carried out, and the electronic structures and optical properties of neutral MA and its anion, with a view to assign the vibrational properties of (1).     

A novel oxidative decarboxylation—synthesis of 2-amino-1,2-dihydroisoquinoline-3(4H)-one and its amide derivatives from tetrahydroisoquinoline-3-carboxylic acid

A convenient method of synthesizing 2-amino-1,2-dihydroisoquinoline-3(4H)-one and its amide derivatives (4 or 5) is described through sydnone intermediate (3) derived from TIC (1) (tetrahydroisoquinoline-3-carboxylic acid) under acidic conditions in good yield.     

Microwave assisted synthesis of novel imidazo [2,1-b]thiazole derivative attached to quinoxalinones

3-(6-Phenylimidazo[2,1-b]thiazol-5-yl)quinoxalin-2(1H)-ones (qunoxalinone) (6a-q) have been synthesized by the reaction of ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) with suitably substituted o-phenylenediamines (5a-f) under microwave heating. The ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) were prepared by the reaction of 6-phenylimidazo[2,1-b]thiazoles (3a-e) with ethyl chlorooxoacetate in refluxing 1,4-dioxane whereas the thiazoles (3a-e) were synthesized by the reaction of 2-bromo-1-phenylethanones (2a-e) with thiazol-2-amine in refluxing acetone.     

Synthesis and chromatographic enantioresolution of anti-HIV quinolone derivatives

The successful enantioseparation of five 6-desfluoroquinolones with three polysaccharide-based stationary phases (namely, the cellulose-based Chiralpak IB and the two amylose-based Chiralpak AD-H and Lux Amylose-2) is herein described. The investigated species differ for the nature of substituents and/or the position of the stereogenic centre on the quinolone scaffold.The effect on the enantioseparation performance exerted by the different morphology of the cellulose-based and amylose-based polymers, was systematically evaluated for all compounds. In this frame, the impact of alternative alcoholic (ethanol, 2-ethoxyethanol, methanol, 2-propanol) and acidic (acetic, methanesulfonic and trifluoroacetic acid) modifiers as well as of a “non-standard” solvent (chloroform), was investigated in normal phase conditions along with the stereo-electronic peculiarities of the selected polymers. While 7-[4-(1,3-benzothiazol-2-yl)-2-methyl-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (1) was enantioresolved with conventional normal-phase conditions by means of the largely employed amylose-based Chiralpak AD-H column, the recruitment of a bulky alcohol (2-ethoxyethanol) succeeded in the enantioresolution of 6-amino-1-methyl-7-[2-methyl-4-(2-pyridinyl)-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (2) and 6-amino-1-[1-(hydroxymethyl)propyl]-4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (3) with the same column. The use of the amylose-based Lux Amylose-2 column, carrying both an electro-withdrawing (chlorine) and an electro-donating (methyl) group on the carbamate residue, allowed to get 6-amino-1-methyl-4-oxo-7-[3-(2-pyridinyl)-1-pyrrolidinyl]-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride (4) enanantioresolved, and 6-amino-1-methyl-4-oxo-7-(3-pyridin-2-ylpiperidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (5) enantioseparated.     

Four new ginkgolic acids from Ginkgo biloba

Four new compounds, 2-hydroxy-6-(12′-hydroxyheptadec-13′(E)-en-1-yl)benzoic acid (1), 2-hydroxy-6-(13′-hydroxyheptadec-11′(E)-en-1-yl)benzoic acid (2), 2-hydroxy-6-(10′-hydroxypentadec-11′(E)-en-1-yl)benzoic acid (3), and 2-hydroxy-6-(11′-hydroxypentadec-9′(E)-en-1-yl)benzoic acid (4) were isolated from the leaves of Ginkgo biloba and the structures of new ginkgolic acids were deduced on the basis of spectroscopic methods and chemical means. Compounds 1 and 2, and 3 and 4 examined as an inseparable mixture of hydroxyl and double bond positional isomers, were ultimately defined by total synthesis. Compounds 1–4 showed moderate lipid droplets accumulation inhibitory activity on mouse pre-adipocyte cell line, MC3T3-G2/PA6.     

Reaction of guaiazulene with o-formylbenzoic acid in diethyl ether (or methanol) in the presence of hexafluorophosphoric acid: comparative studies on H and C NMR spectral properties of 3-guaiazulenylmethylium- and 3-guaiazulenium-ion structures

Reaction of guaiazulene (1) with o-formylbenzoic acid (2) in diethyl ether in the presence of hexafluorophosphoric acid at 25 °C for 90 min gives the corresponding monocarbenium-ion compound, [2-(carboxy)phenyl](3-guaiazulenyl)methylium hexafluorophosphate (3), quantitatively, which upon treatment with aq NaHCO₃ leads to 3-(3-guaiazulenyl)-2-benzofuran-1(3H)-one (5) in 96% isolated yield. Similarly, reaction of 1 with 2 in methanol under the same conditions as the above reaction affords two kinds of inseparable monocarbenium-ion compounds, 3 and (3-guaiazulenyl)[2-(methoxycarbonyl)phenyl]methylium hexafluorophosphate (4) with an equilibrium between them, which upon reaction with a solution of NaBH₄ in ethanol at 25 °C for 30 min leads to 5 in 46% isolated yield and (3-guaiazulenyl)[2-(methoxycarbonyl)phenyl]methane (6) in 37% isolated yield. Along with the ¹H and ¹³C NMR spectral properties of a solution of 5 in trifluoroacetic acid-d₁ at 25 °C, whose molecular structure is converted to a ca. 1:1 equilibrium mixture of 7 possessing a partial structure of the 3-guaiazulenylmethylium-ion and 8 possessing a partial structure of the 3-guaiazulenium-ion, comparative studies on the ¹H and ¹³C NMR spectral properties of 7 and 8 with those of the monocarbenium-ion compound, (3-guaiazulenyl)[4-(methoxycarbonyl)phenyl]methylium hexafluorophosphate (A), 5, and 6 are reported. From these NMR studies, it can be inferred that the positive charge of the 3-guaiazulenylmethylium-ion part of 7 apparently is transferred to the seven-membered ring, generating a resonance form of the 3-guaiazulenylium-ion structure η′, and the same result can be inferred for the previously documented monocarbenium-ion compounds A-I. Moreover, referring to a comparative study on the C-C bond lengths of A observed by the X-ray crystallographic analysis with those of the optimized (3-guaiazulenyl)[4-(methoxycarbonyl)phenyl]methylium-ion structure for A calculated by a WinMOPAC (Ver. 3.0) program using PM3, AM1, or MNDOD as a semiempirical Hamiltonian, the optimized [2-(carboxy)phenyl](3-guaiazulenyl)methylium-ion structure for 3 calculated using PM3 is described.     

The first A-nor-hippuristanol and two novel 4,5-secosuberosanoids from the Gorgonian Isis hippuris

The first A-nor-hippuristanol, A-nor-22-epi-hippurin-2α-carboxylic acid (1), and two 4,5-secosuberosane sesquiterpenoids, isishippuric acids A and B (2 and 3), have been isolated from the gorgonian coral Isis hippuris. Those structures were deduced by extensive 1D and 2D NMR studies. The structure of 1 was further supported by a single crystal X-ray diffraction analysis. Isishippuric acid B has been shown to exhibit potent cytotoxicity toward a limited panel of cancer cells.     

Claisen rearrangements based on vinyl fluorides

2-Fluoroalk-1-en-3-ols (4), available from terminal alkenes (1) by bromofluorination, subsequent dehydrobromination of the 1-bromo-2-fluoroalkanes (2) to form 2-fluoroalkenes (3) and selenium dioxide mediated allylic oxidation with tert-butylhydroperoxide, undergo Johnson-Claisen rearrangement on treatment with trimethyl orthoacetate to give methyl 4-fluoroalk-4-enoates (7) in high yields. In contrast Ireland-Claisen rearrangement of 3-acetoxy-2-fluorodec-1-ene (9b) with triethylamine and TMSOTf in ether failed. Instead of the expected formation of a carboxylic acid, selective C-silylation of the α-position to the carboxyl group to form 14 occurred. However, Ireland-Claisen rearrangement was successful with corresponding chloroacetates 10 and propionates 11 of four 2-fluoroalk-1-en-3-ols (4) to give 2-chloro-4-fluoroalk-4-enecarboxylic acids (15) or its 2-methyl derivatives 16, respectively, in moderate yields. These [3,3]-sigmatropic rearrangements are diastereoselective giving trans-configured double bonds, exclusively. Corresponding esters derived from (Z)-2-fluorocyclododec-2-enol (22), did rearrange to yield mixtures of diastereomers much less selectively. Also 2-fluorodec-2-enol (6), which was prepared by rearrangement of 2-fluoro-2-octyloxirane (5) with TMSOTf and triethylamine, was successfully applied as a starting material for [3,3]-sigmatropic rearrangements. The corresponding 3-(1-fluoroethenyl)alkanoic acid derivatives 17 and 18 were formed in moderate yield.