Syntheses and structural characterization of some mono- and di-p-nitrophenyl[3]ferrocenophanes: X-ray structure of [3]ferrocenophane, 3-p-nitrophenyl[3]ferrocenophane, and 3,4′-bis-(p-nitrophenyl)[3]ferrocenophane; DFT calculations on ferrocene derivatives

[3]Ferrocenophane (3a) reacts in a Gomberg reaction with diazotized p-nitroaniline to give a mixture of mono- and di-substituted products. The isomeric pairs of 3- and 2-(p-nitrophenyl)[3]ferrocenophanes (4 and 5), as well as 3,4′- and 3,4-bis-(p-nitrophenyl)[3]ferrocenophanes (6 and 7) were separated from the mixture by column chromatography on Al₂O₃ and characterized by means of mass, IR, UV, ¹H-NMR spectroscopy, and by X-ray analysis (4 and 6). PM3/tm and density functional theoretical calculations on ferrocene (1) and ferrocenophane derivatives are reported. A refined X-ray structure determination of [3]ferrocenophane (3a) is given.     

Asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine

An asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine (1R and 1S) is presented. Trifluoromethylation involves nucleophilic aromatic substitution of halobenzene 4 most likely via a copper mediated CF₃ anion equivalent generated in situ. The asymmetric step involves conversion of 3,4-dimethoxy-2-trifluoromethylbenzaldehyde (5) to silyl cyanohydrin (6R and 6S) using a chiral salen catalyst in the presence of titanium. 1R and 1S are potential alternatives to currently used vasoconstrictors in local anesthetic formulations.     

First straightforward synthesis of 1-hydroxy-3,4-dihydro-1H-benz[g]isochromene-5,10-dione and structure revision of a bioactive benz[g]isochromene-5,10-dione from Psychotria camponutans

For the first time, a synthesis of 1-hydroxy-3,4-dihydro-1H-benz[g]isochromene-5,10-dione (3), which is claimed to be a bioactive compound isolated from Psychotria camponutans, was achieved with a phthalide annulation reaction using 3-cyano-1(3H)-isobenzofuranone (5) and 5,6-dihydropyran-2-one (6) and subsequent reduction of the lactone moiety in the key steps. However, full spectral characterization of the synthesized target compound revealed that the isolated compound is not 1-hydroxy-3,4-dihydro-1H-benz[g]isochromene-5,10-dione (3). Structure revision shows the previously isolated compound to be the known psychorubrin (2).     

Imino Diels-Alder reaction of boronates. Preparation and characterization of new 3,4-dihydroquinoline and 1,2,3,6-tetrahydropyridine derivatives

The preparation of 3,4-dihydroquinolines (2a-d and 3a,b,d), as well as 1,2,3,6-tetrahydropyridines (4a-e) by imino Diels-Alder reaction of boronates (1a-e) with 2,3-dimethylbutadiene is reported. Boronates (1a-d) containing substituents meta and para relative to the imino fragment lead to diastereomeric mixtures of 4-methyl-4-ethenyl-3,4-dihydroquinolines (2, 3) and tetrahydropyridines (4). In contrast, the presence of an electron withdrawing substituent at the para position (1e), favors the iminodienophile behavior giving 4,5-dimethyl-1,2,3,6-tetrahydropyridine (4e) as the main product. The results show that boronates derived from Schiff bases are electron deficient species which can act either as dienophiles or dienes in the reaction with 2,3-dimethylbutadiene to give 3,4-dihydroquinolines and 1,2,3,6-tetrahydropyridines. All products were characterized by NMR and X-ray diffraction analysis of 2b, 2d, 3d and 4c allowed to assign the relative configuration of the newly formed stereogenic centers.     

A convenient synthesis of 1′-H-spiro-(indoline-3,4′-piperidine) and its derivatives

A simple synthetic route has been developed to prepare 1′-H-spiro(indoline-3,4′-piperidine) (1d). Dialkylation of 2-fluorophenylacetonitrile with N-(tert-butyloxycarbonyl)-bis(2-chloroethyl)amine (5) gave 6. Deprotection of Boc followed by cyclization resulted 1d in 67% overall yield. Selective Boc or Cbz protection of 1′-N gave 1a or 1b with 90 and 85% yield, respectively. Thus, in a five-step procedure, 1a and 1b were synthesized from commercially available reagents in over 50% overall yield. All 3 compounds (1a, 1b and 1d) can be utilized as templates to synthesize compounds for GPCR targets.     

Diversity of coordination modes in the polymers based on 3,3′,4,4′-biphenylcarboxylate ligand

Four new compounds [Ni₂(4,4′-bpy)(3,4-bptc)(H₂O)₄]_n (1), [Ni(4,4′-bpy)(3,4-H₂bptc)(H₂O)₃]_n (2), [Mn₂(2,2′-bpy)₄(3,4-H₂bptc)₂] (3) and {[Mn(1,10-phen)₂(3,4-H₂bptc)]·4H₂O}_n (4) (3,4-H₄bptc=3,3′,4,4′-biphenyltetracarboxylic acid, 4,4′-bpy=4,4′-bipyridine, 2,2′-bpy=2,2′-bipyridine, 1, 10-phen=1, 10-phenanthroline), have been prepared and structurally characterized. In all compounds, the derivative ligands of 3,4-H₄bptc (3,4-bptc⁴⁻ and 3,4-H₂bptc²⁻) exhibit different coordination modes and lead to the formation of various architectures. Compounds 1 and 2 display the three-dimensional (3D) framework: 1 shows a 3,4-connected topological network with (8³)(8⁵·10) topology symbol based on the coordination bonds while in 2, the hydrogen-bonding interactions are observed to connect the 1D linear chain generating a final 3D framework. 3 exhibits the 2D layer constructed from the hydrogen-bonding interactions between the dinuclear manganese units. Complex 4 shows the double layers motif through connecting the 1D zigzag chains with hydrogen-bonded rings. The thermal stability of 1-4 and magnetic property of 1 were also reported.     

One pot,three-component synthesis of novel 3,4-dihydrophthalazin-2(1H)-yl-4-phenyl-4H-pyrans

Green and efficient one pot, three-component synthesis of novel 2-amino-6-(1,4-dioxo-3,4-dihydrophthalazin)-2(1H)-yl-4-phenyl-4H-pyran-3,5-dicarbonitriles 6 has been developed by condensing 3-(1,4-dioxo-3,4-dihydrophthalazin-(1H)-yl)-3-oxopropanenitrile 3, benzaldehydes 4 and active methylene compounds 5 using l-proline as catalyst in EtOH at RT.     

Synthesis of substituted 2-aroyl-3-methylchromen-4-ones from isovanillin via 2-aroyl-3-methylchroman intermediates

The synthesis of substituted 2-aroyl-3-methylchromen-4-one from isovanillin is described. O-Allylphenol (2) prepared from isovanillin (1) was allowed to react with various α-bromoacetophenone (3) to produce 2-(2-allyl-3,4-dimethoxy)phenoxy-1-aroylethanones (4). The resultant 4 were treated with 2 equiv of potassium tert-butoxide to afford the substituted 2-aroyl-3-methylchromans (5) through an isomerization of an allylic double bond and a carbanion-olefin intramolecular 6-endo-trig cyclization reaction. Subsequently, resultant 5 were oxidized with DDQ to yield the title compound 6, in good over-all yields.     

Syntheses of metabolites of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (TAK-603)

Convenient and efficient syntheses of ethyl 4-(3-hydroxy-4-methoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (1d) and 10-(3,4-dimethoxyphenyl)-7,8-dimethoxy-2H-pyridazino[4,5-b]quinolin-1-one (1e), metabolites of TAK-603 (1), have been achieved. Use of the methanesulfonyl as a protective group of the phenolic hydroxy for Friedel-Crafts reaction enabled a new simpler synthetic route of 1d in high yield. Chloromethyl derivative (23) was converted to formyl derivative (32) using the Kröhnke reaction, followed by cyclization with hydrazine, which formed a novel compound 1e.     

Zamamidine C, 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A, and 3,4-dihydromanzamine J N-oxide, new manzamine alkaloids from sponge Amphimedon sp.

New manzamine alkaloids, zamamidine C (1), 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A (2), and 3,4-dihydromanzamine J N-oxide (3), have been isolated from an Okinawan marine sponge Amphimedon species. The structures and stereochemistries of 1-3 were elucidated from the spectroscopic data and chemical derivatization. Zamamidine C (1) is a new manzamine alkaloid possessing a second β-carboline ring via an ethylene unit at N-2 of manzamine D, while 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A (2) is the first manzamine alkaloid possessing an epoxide ring at C-10 and C-11. Zamamidine C (1) showed significant antitrypanosomal activity against Trypanosoma brucei brucei, the parasite associated with sleeping sickness, and antimalarial activity against Plasmodium falciparum, the causative agent of malaria in vitro.     

The first asymmetric synthesis of all four isomers of cis- and trans-3,4-dihydroxy-3,4-dihydromollugin

Asymmetric synthesis of all the four stereoisomers of cis-3,4-dihydroxy-3,4-dihydromollugins 4 and 6 and trans-3,4-dihydroxy-3,4-dihydromollugins 5 and 7 was achieved. The O-methoxymethyl mollugin derivatives were dihydroxylated to (−)- and (+)-cis-3,4-dihydroxy-3,4-dihydromollugin derivatives using both AD-mix-α and AD-mix-β. Deprotection of the MOM-ethers of cis-dihydroxy compounds resulted in the targeted stereoisomers (−)-(3R,4R)-cis-3,4-dihydroxy-3,4-dihydromollugin 4, (−)-(3R,4S)-trans-3,4-dihydroxy-3,4-dihydromollugin 5, (+)-(3S,4S)-cis-3,4-dihydroxy-3,4-dihydromollugin 6 and (+)-(3S,4R)-trans-3,4-dihydroxy-3,4-dihydromollugin 7. These routes were paved with difficulties, for example, incompatibility of the substrates with AD-mixes, the unexpected formation of trans-dihydroxy compounds and failures in deprotection protocols.     

3,4-seco-Diterpenoids from Trigonostemon flavidus

Phytochemical investigation on the stems of Trigonostemon flavidus resulted in the isolation of five new 3,4-seco-diterpenoids, trigoflavidones A-E (1-5), structurally related to the main co-occurring known 3,4-seco-sonderianic acid (6) and 3,4-seco-sonderianol (7). Compound 4 possesses new 3,4-seco rearranged ent-pimarane skeletal type, characteristic of a vinyl group at C-8, while 5 features a unique five-membered ring (C₁) fused with a cyclopropane ring (C₂). The structures of the new compounds were established by a combination of spectroscopic data and computational methods. Compounds 1-7 were tested for their cytotoxicities on HL-60, SMMC-7721, A-549, MCF-7, and SW480 human tumor cell lines.     

Preparation of both enantiomers of β-(3,4-dihydroxybenzyl)-β-alanine, higher homologues of Dopa

β²-(3,4-Dihydroxybenzyl)-β-alanine [β²-Homo-Dopa, 1] is a novel β-amino acid homologue of Dopa, the most successful therapeutic agent in the treatment of Parkinson's disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of β-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired β-amino acids were purified by silica gel chromatography. Alternatively, enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-chain β-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary α-phenylethylamine. Finally, nearly enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-3-aminopropionic acid, rac-12, with (R)- or (S)-α-phenylethylamine, followed by catalytic hydrogenolysis.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

The acid-mediated intramolecular 1,3-dipolar cycloaddition of derived 2-nitro-1,1-ethenediamines for the synthesis of novel fused bicyclic isoxazoles

The discovery of a novel synthesis of new fused bicyclic isoxazoles, for example, N-methyl-3-phenyl-5,6-dihydro-4H-isoxazolo[3,4-c]azepin-8-amine (2a), N-methyl-3-phenyl-4,5-dihydroisoxazolo[3,4-c]pyridin-7-amine (2b) and N-methyl-3-phenyl-4H-pyrrolo[3,4-c]isoxazol-6-amine (2d) in high yield is reported. We speculate that the reaction proceeds via acid-mediated intramolecular 1,3-dipolar cycloaddition from 2-nitro-1,1-ethenediamines 1a,b,d.     

Two novel sesquiterpenes from the roots of Taiwania cryptomerioides Hayata

Two novel 3,4-secocadinane and 4,5-seco-8(7→6)-abeoguaiane skeletons, namely taiwaninones A (1) and B (2), together with khusinodiol (3) and 4β,6β-dihydroxy-1α,5β(H)-guai-9-ene (4) were isolated from the roots of Taiwania cryptomerioides. Their structures were elucidated by the spectral methods. The biotransformations of 1 and 2 were proposed from 3 and 4, respectively.     

A non-catalytic regioselective approach to the synthesis of (E)-stilbenes from suitably functionalized 2H-pyran-2-ones

Highly functionalized (E)-stilbenes 3a-m and 4-aryl-6-styryl-pyran-2-ylidineacetonitriles 4a-b have been prepared and delineated through the ring transformation of 6-aryl-3,4-disubstituted-2H-pyran-2-ones 1 with commercially available (E/Z)-4-phenyl-3-buten-2-one 2 without the use of any catalyst.     

Total synthesis of benzo[c]phenanthridine alkaloids based on a microwave-assisted electrocyclic reaction of the aza 6π-electron system and structural revision of broussonpapyrine

Total syntheses of the des-N-methyl (nor) type of benzo[c]phenanthridine alkaloids 1a-f and 19 and benzo[c]phenanthridine alkaloids, chelerythrine (2d), and broussonpapyrine (2f) were achieved. The key step was the construction of tetracyclic 10,11-dihydrobenzo[c]phenanthridines using a microwave-assisted electrocyclic reaction of the 2-cycloalkenylbenzaldoxime methyl ether 4 as an aza 6π-electron system, which was derived in two steps from a Suzuki-Miyaura cross-coupling reaction of 2-bromobenzaldehyde 6 with 2-(3,4-dihydro-6,7-methylenedioxynaphthyl)boronic acid pinacol ester 7. In addition, the exact structure of broussonpapyrine (2f) (2,3,9,10-tetraoxygenated type) was determined to be chelerythrine (2d).     

Synthesis of the fungal natural product (−)-xylariamide A

The first synthesis of the fungal natural product (−)-xylariamide A 1 is reported. N,O-Bis(trimethylsilyl)acetamide induced coupling of d-tyrosine with (E)-but-2-enedioic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester 5 produced the dechloro natural product 6, which was subsequently monochlorinated using oxone and KCl to yield synthetic 1. (−)-Xylariamide A 1, (+)-xylariamide A 2 and (−)-dechloroxylariamide A 6 displayed no cytotoxic or antimicrobial activity.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.