Synthesis of 1,2,5,6‐/1,2,3,6‐tetrahydropyridinyl‐tetrahydro‐cyclopentaisoxazole derivatives

Fused tetrahydrocyclopenta‐isoxazoles were synthesized by 1,3‐dipolar cycloaddition reactions with pyridinealdoxime or tetrahydropyridinealdoxime and cycloalkenes.     

A theoretical study on the conformation of 3‐phosphinoxido‐ and 3‐phosphono‐1,2,3,4,5,6‐hexahydrophosphinine 1‐oxides

The title compounds ( 2 and 4 ) obtained by the diastereoselective hydrogenation of the corresponding 1,2,3,6‐tetrahydrophosphinine oxides ( 1 and 3 ) were subjected to a detailed quantum chemical study. The possible chair conformers were calculated at the HF/6‐31G* level of theory, according to which, the 1‐phenyl‐3‐P(O)Y₂‐substituted products ( 2 ) exist in the trans₁ form, in which all substituents are equatorial. At the same time, the 1‐ethoxy‐3‐dialkylphosphono compounds ( 4 ) adopt the cis conformations, in which the 1‐ethoxy group is axial and the 3‐P(O)(OR)₂ moiety is equatorial. The major diastereomer ( 4–1 ) is cis₃, in which the 5‐methyl group is axial, while the minor one is cis₁ with an equatorial methyl substituent. It is noteworthy that the rotational position of the exocyclic P(O)Z₂ function affected the energy content of the chair conformer to a high extent. The possibility of the involvement of the twist conformers was also considered. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:520–524, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20148     

Synthesis of N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines as potential nonsteroidal anti‐inflammatory agents

Fourteen novel N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines 9 were synthesized in fair to good yields. 4‐Ethylpyridine 5 reacted with O‐mesitylenesulfonylhydroxylamine (O‐MSH) 4 to furnish N‐amino‐4‐ethylpyridinium mesitylenesulfonate 6 . The reaction of 6 with substituted acid chlorides 7 gave the stable crystalline pyridinium ylides 8a‐8n . A sodium borohydride reduction of 8 in absolute ethanol furnished the target compounds N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines 9a‐9n .     

New isomeric 2‐ortho‐(meta‐ and para‐) chloro‐(bromo and nitro‐)benzylthio‐6‐aminouracils

Ten new ortho, meta and para substituted derivatives of 2‐benzylthio‐6‐aminouracils have been prepared. Electron Impact (EI) induced mass spectral fragmentation of these compounds was investigated. Fragmentation pathways are proposed on the basis of accurate mass and metastable transition measurements. The correlation between the intensities of the M⁺‐ and the selected fragment ions of these compounds is discussed. The data obtained create the basis for dinstinguishing isomers. The ¹H and ¹³C NMR spectra of these compounds were assigned unambiguously using a combination of heteronuclear (HETCOR) spectra the chemical shifts. The data derived from these spectra can be used to differentiate the isomers.     

New P‐ligands: The aromaticity and reactivity of 2,4,6‐trialkylphenylphospholes

A further member of 2,4,6‐trialkyl‐phenyl‐phos‐pholes, the ditertbutylmethylphenyl derivative ( 1c ) was characterized by Bird index and by the sum of angles at the phosphorus atom to describe the flattening of the P‐pyramid. Both numbers suggested a slight aromaticity. The reaction of arylphospholes with phosphorus tribromide was extended to phosphole 1c leading this occasion, after further steps, to the mixture of 3‐ and 2‐substituted products ( 3c‐1 and 3c‐2 , respectively). A triisopropylphenyl‐2H‐phosphole ( 4 ) formed by sigmatropic rearrangement was utilized in the preparation of new 1‐phosphanorbornene derivatives, such as sulfide 6 and hemi‐oxides 8‐1 and 8‐2 . Further oxidation of the latter species ( 8‐1 and 8‐2 ) led to the decomposition of the dimeric structure ( 11 ). 4 could also be trapped by benzaldehyde to afford the oxaphosphanorbornene ( 10 ) as one diastereomer. Finally, the reversible formation of 2H‐phosphole 4 from 1H‐phosphole 1a at 150°C was proved. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:104–222, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20077     

Synthesis,structure and biological activities of [α‐(alkylcarbonyl)‐2‐(1,2,4‐triazol‐1‐yl)]ethyl‐N,N‐dialkydithiocarbamate derivatives

Seven 1,2,4‐triazole compounds containing the N,N‐dialkyldithiocarbamate group were designed and synthesized. Their structures were identified using infrared spectroscopy, element analysis, ¹H NMR spectroscopy and mass spectrometry, and in two cases by single crystal X‐ray diffraction. The result of the biological test showed that the seven compounds all have fungicidal and plant growth‐regulating activities.     

Two succinic acid derivatives of 2‐ethyl‐6‐methylpyridin‐3‐ol

Crystals of bis(2‐ethyl‐3‐hydroxy‐6‐methylpyridinium) succinate–succinic acid (1/1), C₈H₁₂NO⁺·0.5C₄H₄O₄²⁻·0.5C₄H₆O₄, (I), and 2‐ethyl‐3‐hydroxy‐6‐methylpyridinium hydrogen succinate, C₈H₁₂NO⁺·C₄H₅O₄⁻, (II), were obtained by reaction of 2‐ethyl‐6‐methylpyridin‐3‐ol with succinic acid. The succinate anion and succinic acid molecule in (I) are located about centres of inversion. Intermolecular O—H...O, N—H...O and C—H...O hydrogen bonds are responsible for the formation of a three‐dimensional network in the crystal structure of (I) and a two‐dimensional network in the crystal structure of (II). Both structures are additionally stabilized by π–π interactions between symmetry‐related pyridine rings, forming a rod‐like cationic arrangement for (I) and cationic dimers for (II).     

A Practical and Enantiospecific Synthesis of (−)‐(R)‐ and (+)‐(S)‐Piperidin‐3‐ols

A highly enantiospecific, azide‐free synthesis of (?)‐(R)‐ and (+)‐(S)‐piperidin‐3‐ol in excellent yield was developed. The key step of the synthesis involves the enantiospecific ring openings of enantiomerically pure (R)‐ and (S)‐2‐(oxiran‐2‐ylmethyl)‐1H‐isoindole‐1,3(2H)‐diones with the diethyl malonate anion and subsequent decarboxylation.     

Semisynthesis of 3′(2′)‐O‐(Aminoacyl)‐tRNA Derivatives as Ribosomal Substrate

An efficient synthesis of (3′‐terminally) 3′(2′)‐O‐aminoacylated pCpA derivatives is described, which could lead to the production of (aminoacyl)‐tRNAs following T4 RNA ligase mediated ligation. The tetrahydrofuranyl (thf) group was used as a permanent protective group for the 2′‐OH of the cytidine moiety which can be removed during the purification of the 3′(2′)‐O‐aminoacylated‐pCpA. This approach allowed for a general synthesis of (3′‐terminally) 3′(2′)‐O‐aminoacylated oligonucleotides. The fully protected pCpA 14 was synthesized by phosphoramidite chemistry and treated with NH₃ solution to remove the 2‐cyanoethyl and benzoyl groups (→ 15 ; Schemes 1 and 2). The 2′‐O‐thf‐protected‐pCpA 15 was coupled with α‐amino acid cyanomethyl esters, and the products 20a – c were deprotected and purified with AcOH buffer to afford 3′(2′)‐O‐aminoacylated pCpA 21a – c in high yields. The 3′(2′)‐O‐aminoacylated pCpA were efficiently ligated with tRNA(? CA) to yield (aminoacyl)‐tRNA which was an active substrate for the ribosome.     

2‐[(E)‐(4‐Hydroxy‐3‐methoxybenzylidene)amino]‐N‐(2‐methylphenyl)‐4,5,6,7‐tetrahydro‐1‐benzothiophene‐3‐carboxamide

The title compound, C₂₄H₂₄N₂O₃S, exhibits antifungal and antibacterial properties. The compound crystallizes with two molecules in the asymmetric unit, with one molecule exhibiting `orientational disorder' in the crystal structure with respect to the cyclohexene ring. The o‐toluidine groups in both molecules are noncoplanar with the respective cyclohexene‐fused thiophene ring. In both molecules, there is an intramolecular N—H...N hydrogen bond forming a pseudo‐six‐membered ring which locks the molecular conformation and eliminates conformational flexibility. The crystal structure is stabilized by O—H...O hydrogen bonds; both molecules in the asymmetric unit form independent chains, each such chain consisting of alternating `ordered' and `disordered' molecules in the crystal lattice.     

Conversion of (±)‐3‐ethyl‐3‐methyl phthalides to 3,3‐dimethyl‐3,4‐dihydroisocoumarins. Synthesis of 3‐methylmellein

o‐Lithio yV‐methyl benzamides ( 1a‐f ) upon alkylation with ethyl methyl ketone gave (±)‐3‐ethyl‐3‐methyl phthalides ( 2a‐f ), which upon treatment with concentrated H₂SO₄ or anhydrous A1C1₃ furnished corresponding 3,3‐dimethyl‐3,4‐dihydroisocoumarins ( 3a‐f ) and 3‐methyl mellein ( 3g ).     

Radical and cationic polymerizations of 3‐ethyl‐3‐methacryloyloxymethyloxetane

3‐Ethyl‐3‐methacryloyloxymethyloxetane (EMO) was easily polymerized by dimethyl 2,2′‐azobisisobutyrate (MAIB) as the radical initiator through the opening of the vinyl group. The initial polymerization rate (R_p) at 50 °C in benzene was given by R_p = k[MAIB]^0.55 [EMO]^1.2. The overall activation energy of the polymerization was estimated to be 87 kJ/mol. The number‐average molecular weight (M?_n) of the resulting poly(EMO)s was in the range of 1–3.3 × 10⁵. The polymerization system was found to involve electron spin resonance (ESR) observable propagating poly(EMO) radicals under practical polymerization conditions. ESR‐determined rate constants of propagation (k_p) and termination (k_t) at 60 °C are 120 and 2.41 × 10⁵ L/mol s, respectively—much lower than those of the usual methacrylate esters such as methyl methacrylate and glycidyl methacrylate. The radical copolymerization of EMO (M₁) with styrene (M₂) at 60 °C gave the following copolymerization parameters: r₁ = 0.53, r₂ = 0.43, Q₁ = 0.87, and e₁ = +0.42. EMO was also observed to be polymerized by BF₃OEt₂ as the cationic initiator through the opening of the oxetane ring. The M?_n of the resulting polymer was in the range of 650–3100. The cationic polymerization of radically formed poly(EMO) provided a crosslinked polymer showing distinguishably different thermal behaviors from those of the radical and cationic poly(EMO)s. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 1269–1279, 2001     

Synthesis of 8‐substituted tetrahydro‐γ‐carbolines

The Fischer reaction is applied to the synthesis of 8‐substituted tetrahydro‐γ‐carbolines with electron‐donating or electron‐withdrawing groups, using catalytic or thermal methods. The reaction conditions must be varied according to the nature of the N 1 substituent of the piperidone. The best results are observed when a releasing group is present on the arylhydrazine and a benzyl substituent on the nitrogen of piperidone. Formation of carbolines with a withdrawing substituent is observed in soft acidic conditions; in others, reaction ended at the hydrazone level or did not evolve.     

Synthesis of new 4,5,6,7‐tetrahydro‐3H‐imidazo[4,5‐c]pyridine derivatives

The synthesis of new ligands for the H₃ histamine receptor is described. These new compounds are spinacine derivatives obtained by alkylation or Michael reaction at C6 position.     

Synthesis of the Spermidine Alkaloids (−)‐(2R,3R)‐ and (−)‐(2R,3S)‐3‐Hydroxycelacinnine: Macrocyclization with Oxirane‐Ring Opening and Inversion via Cyclic Sulfamidates

The two epimers (?)‐ 1a and (?)‐ 1b of the macrocyclic lactam alkaloid 3‐hydroxycelacinnine with the (2R,3R) and (2R,3S) absolute configurations, respectively, were synthesized by an alternative route involving macrocyclization with the regio‐ and stereoselective oxirane‐ring opening by the terminal amino group (Schemes 2 and 6). Properly N‐protected chiral trans‐oxirane precursors provided (2R,3R)‐macrocycles after a one‐pot deprotection‐macrocyclization step under moderate dilution (0.005–0.01M ). The best yields (65–85%) were achieved with trifluoroacetyl protection. Macrocyclization of the corresponding cis‐oxiranes was unsuccessful for steric reasons. Inversion at OH? C(3) via nucleophilic displacement of the cyclic sulfamidate derivative with NaNO₂ led to (2R,3S)‐macrocycles. The synthesized (?)‐(2R,3S)‐3‐hydroxycelacinnine ((?)‐ 1b ) was identical to the natural alkaloid.     

Enantioselective Synthesis of (−)‐(R)‐Cordiachromene and (−)‐(R)‐Dictyochromenol Utilizing Intramolecular SNAr Reaction

A simple and efficient enantioselective synthesis of chromene, (?)‐(R)‐cordiachromene ( 1 ), and (?)‐(R)‐dictyochromenol ( 2 ) has been accomplished. This convergent synthesis utilizes intramolecular S_NAr reaction for the formation of chroman ring, and Seebach's method of ‘self‐reproduction of chirality’ should establish the (R)‐configuration of the C(2) side chain as key steps.     

Methyl (±)‐1‐ethyl‐2‐hydroxy‐4‐(4‐methoxybenzoyl)‐5‐(4‐methoxyphenyl)‐3‐oxo‐2,3‐di­hydro‐1H‐pyrrole‐2‐acetate

The title compound, C₂₄H₂₅NO₇, is a racemic mixture of 2,3‐di­hydro‐1H‐pyrrol‐3‐ones. It crystallizes in the triclinic system, space group P1, with Z = 2. The asymmetric unit contains two enantiomorphic mol­ecules and the structure is stabilized by hydrogen‐bond contacts.     

4‐[1‐(Phenylsulfonyl)indol‐3‐yl]‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinoline

In the title compound, C₂₆H₂₂N₂O₂S, the tetra­hydro­pyridine ring has a conformation intermediate between half‐chair and sofa. The tetrahydroquinoline mean plane makes a dihedral angle of 73.3 (1)° with the cyclopentene ring, which adopts an envelope conformation, and an angle of 45.45 (4)° with the indole best plane. The dihedral angle between the benzene and pyrrole rings is 2.6 (1)°. The orientations of the phenyl ring on the sulfonyl group and of the indole are governed by weak C—H?O interactions. The packing of the mol­ecule in the solid state is stabilized by C—H?O and C—H?N hydrogen bonds.     

Synthesis of Boron‐Containing ADP and GDP Analogues: Nucleoside 5′‐(Pα‐Boranodiphosphates)

New 5′‐(P^α‐boronated) analogues of the naturally occurring nucleoside diphosphates ADP and GDP were synthesized in good yields, i.e., adenosine 5′‐(P^α‐boranodiphosphate) (ADPαB; 5a ) and guanosine 5′‐(P^α‐boranodiphosphate) (GDPαB; 5b ). Their diastereoisomers were successfully separated by reversed‐phase HPLC, and chemical structures were established via spectroscopic methods. The isoelectronic substitution of borane (BH₃) for one of the non‐bridging O‐atoms in phosphate diesters should impart an increase in lipophilicity and change in polarity in ADPαB and GDPαB. The boronated nucleoside diphosphates could be employed for investigations of the stereochemical course and metal requirements of enzymatic reactions involving ADP and GDP, and as carriers of ¹⁰B in boron neutron‐capture therapy (BNCT) for the treatment of cancer.     

(−)‐(3S)‐3‐(Tosylamino)butano‐4‐lactone,a Versatile Chiral Synthon for the Enantioselective Synthesis of Different Types of Polyamine Macrocycles: Determination of the Absolute Configuration of (−)‐(R)‐Budmunchiamine A

(−)‐(3S)‐3‐(Tosylamino)butano‐4‐lactone ( 1 ) and its derivative ethyl (−)‐(3S)‐4‐iodo‐3‐(tosylamino)butanoate ( 2 ) are presented as easily accessible chiral building blocks for the construction of a range of different macrolactam frameworks important for the synthesis of naturally occurring polyamine alkaloids as well as for establishing a substance library of such compounds, including S‐containing derivatives for biological tests. In addition to that, the absolute configuration of the spermine alkaloid (−)‐(R)‐budmunchiamine A ( 3 ) from Albizia amara was determined by total synthesis according to the new methodology.