Endo and exo cyclometallated iron carbonyl complexes derived from N-(N′-methyl-2-pyrrolylmethylidene)-2-thienylmethylamine

The reaction of N-(N′-methyl-2-pyrrolylmethylidene)-2-thienylmethylamine (1) with Fe₂(CO)₉ in refluxing toluene gives endo cyclometallated iron carbonyl complexes 2 and 5, exo cyclometallated iron carbonyl complex 3, and unexpected iron carbonyl complex 4. Complexes 2, 3, and 5 are geometric isomers. Complex 5 differs from complex 2 in the switch of the original substituent from α to β position of the pyrrolyl ring, and the pyrrolyl ring bridges to the diiron centers in μ-(3,2-η¹:η²) coordination mode in stead of μ-(2,3-η¹:η²). In complex 4, the pyrrolyl moiety of the original ligand 1 has been displaced by a thienyl group, which comes from the same ligand. Single crystals of 2, 3, and 5 were subjected to the X-ray diffraction analysis. The major product 2 undergoes: (i) thermolysis to recover the original ligand 1; (ii) reduction to form a hydrogenation product, 6, of the original ligand; (iii) substitution to form a monophosphine-substituted complex 7; (iv) chemical as well as electrochemical oxidation to produce a carbonylation product, γ-butyrolactam 8.     

Synthesis of E-deoxypukalide, and its biomimetic conversion into deoxypseudopterolide by photochemical ring contraction involving a 1,3-allylic shift

Irradiation of a solution of synthetic Z-deoxypukalide 10 in acetonitrile (Pyrex; 400 W Hg lamp) resulted in isomerisation, leading to E-deoxypukalide 12, which was isolated recently from the octocoral Leptogorgia spp. Further irradiation of 12, or prolonged irradiation of 10, then gave the ring-contracted product, deoxypseudopterolide 1 (>90%) found in octocorals of the genera Pseudopterogorgia and Leptogorgia. The contraction of the 14-membered rings in 10 and 12 to the 12-membered ring as 1, occurs by way of photochemical [1,3]-sigmatropic rearrangement.     

A simple synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles

A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 8′) as the pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-pyrrolidinone (1). Next, acid-catalysed ‘ring switching’ transformations of 3 with monosubstituted hydrazines 4 gave N-[(1-substituted 5-hydroxy-1H-pyrazol-4-yl)ethyl]benzamides 7a-k and N-[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides 7′l-o. Benzamides 7a-k and 7′l-o were finally hydrolysed by heating in 6 M hydrochloric acid to furnish 1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8a-k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones 8′l-o in good overall yields.     

Some new DTPA-N,N″-bis(amides) functionalized by alkyl carboxylates: Synthesis,complexation and stability properties

A new series of DTPA-N,N″-bis(amide) ligands functionalized by alkyl carboxylates on the amide side-arms (1a–1l) and their Gd(III) complexes of the type [Gd(1)(H₂O)] · xH₂O (2a–2l) were synthesized and characterized by analytical and spectroscopic techniques. Potentiality of 2a–2l as contrast agent for magnetic resonance imaging (MRI CA) was investigated by measuring some relevant physicochemical properties such as (i) the protonation constants of 1a–1l, (ii) thermodynamic and conditional stability constants of 2a–2l, (iii) the selectivity (pGd) of 1a–1l for the Gd(III) ion over the endogenous metal ions such as Zn(II), Ca(II), and Cu(II), and (iv) the relaxivities (R₁ and R₂) of 2a–2l in aqueous and aqueous HP-β-CD solutions. Comparative studies reveal that most of new Gd(III) complexes show enhanced thermodynamic stability and selectivity as compared with those of [Gd(DTPA-BMA)(H₂O)] (DTPA-BMA = N,N″-di(methylcarbamoylmethyl)diethylenetriamine-N,N′,N″-triacetate). Also enhanced with 1a–1l (except 1f and 1h) is affinity for Gd(III) as compared with [DTPA-BMA]³⁻ under physiological conditions. The relaxivities (R₁ and R₂) of aqueous solutions of 2a–2l, on the other hand, drop significantly as compared with [Gd(DTPA-BMA)(H₂O)] although they increase dramatically (6–10 fold) in aqueous hydroxypropyl-β-cyclodextrin (HP-β-CD) solutions.     

Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-component domino reaction

An efficient, three-component domino reaction of dimedone 1, aromatic aldehydes (2a–o), and 1,3-cyclohexanedione 1a in the regio-selective synthesis of 3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones (3a–o) is reported. The desired product, 3 is efficiently promoted by ascorbic acid as an organo catalyst.     

Cycloaddition of methyl 2-(2,6-dichorophenyl)-2H-azirine-3-carboxylate to electron-rich 2-azadienes

tert-Butyldimethylsililoxy-2-aza-1,3-butadienes react with 2H-azirine 3 leading to Diels-Alder cycloadducts in moderate yields. The reactions are endo- and regioselective with the azirine being added by its less hindered face. There is only one product in the case of 1b, 4b. There are two isomers (4 and 5) from 1a, 1c and 1d. A different result was obtained with the diene 1e. Diene 1e formed products 4e and 8. Some of compounds 4 and 5 have been hydrolysed leading to functionalised aziridines 7. Compound 8 gave aziridine 9.     

A Pd[0]-catalyzed Ullmann cross-coupling/reductive cyclization approach to C-3 mono-alkylated oxindoles and related compounds

The Pd[0]-catalyzed Ullmann cross-coupling of o-nitrohaloarenes 1a-e with the brominated heterocycles 2a-f delivers the expected products 3a-j in good to excellent yields. The reductive cyclization of such products, as well as N-acyl derivatives 3k, l, and m, has been investigated and provided the C-3 mono-substituted oxindoles 5a-d, f, g, k, and m, the direct reduction products 4i and j or indole 5l.     

From lithium ketazides to isomeric silylketazine-rings - imine-enamine tautomerism

Di(tert-butylmethyl)ketazine (I) reacts with n-BuLi in a 1:1 molar ratio to give a monolithium salt (II). The reaction of II with ^tBu₂SiF₂ in n-hexane leads, even in a 1:1 molar ratio, to the formation of the isomeric five- and four-membered ring compounds 1 and 2. Compound 1 has an endocyclic imine and an exocyclic enamine unit. The opposite is found for 2. The acyclic monosubstitution product, ^tBu₂SiFCH₂-C^tBuN-NC^tBuCH₃ (III) could not be isolated. It reacts with the lithium ketazide to give 1 or 2. I is reformed. The reaction in THF yields only the four-membered ring 2. In a comparable reaction of the lithium ketazide and (H₃C)₂SiF₂, the substitution product 3 could be isolated. A possible formation mechanism for 2 includes an intermediate silene IV. Both compounds 1 and 2 react with H₃C-OH under cleavage of the endocyclic Si-N-bond to give the addition product 5. The reaction mechanism includes a hydrogen shift from a nitrogen atom to a carbon atom via an imine-enamine tautomerism. In a 2:1 molar ratio, n-BuLi and the di(tert-butylmethyl)-ketazine (I) form the dilithium salt, 6. Compound 6 crystallizes from THF as trimer with four imine and two enamine units. A seven-membered ring (7) isomeric to 1 and 2 is the result of the reaction of 6 with ^tBu₂SiF₂. Compound 7 contains one imine and one enamine unit in the ring skeleton.The comparable reaction of the (CH₃)₃Si-substituted dilithium-di(tert-butylmethyl)ketazide and ^tBu₂SiF₂ yields the five-membered ring compound 8 with one endocyclic imine and one exocyclic enamine unit.Quantum chemical calculations of 1, 2, 7 and the intermediate silene IV have been carried out and show a low energy difference between the cyclic silyl-ketazine isomers.     

Tabularisins A-D, phragmalin ortho esters with new skeleton isolated from the seeds of Chukrasia tabularis

Tabularisins A-D (1-4), a new class of phragmalins incorporating a cyclopropanyl ring, were isolated from Chukrasia tabularis. Compounds 1 and 2 are also the first examples of phragmalins with an 8,9,11-ortho ester. The structures of 1 and 3 were confirmed by single crystal X-ray studies. The absolute configuration of 2 was determined by CD exciton chirality method on its benzoate (2a), and those of 1, 3, and 4 were proposed by correlating with 2 chemically and biogenetically.     

Efficient and regioselective chromium(0)-catalyzed reaction of 2-substituted furans with diazo compounds: stereoselective synthesis of (2E,4Z)-2-aryl-hexadienedioic acid diesters

Pentacarbonyl(η²-cis-cyclooctene)chromium(0) (1) catalyzes efficiently reactions of diazo compounds with electron-rich furans. The reaction of 2-methoxyfuran (2) with alkyl α-diazoarylacetate (3a-g) furnishes the (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g) in excellent yields. These reactions are highly regioselective. The cyclopropanation intermediates formed from 1 and diazo compounds 3a-g always arise from a carbene addition to the less substituted CC bond of 2. The resulting cyclopropanation product undergoes a ring opening reaction to form the corresponding (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g). The pentacarbonylchromium(0)-catalyzed reactions of 2-alkylfuran (5a-b) with ethyl α-diazophenylacetate (3a) and 9-diazo-9H-fluorene (3h) produce the 1(E),3(E)-butadienes (6a-d) in very good yields.     

A novel synthesis of aryl tethered imidazo[4,5-b]pyrazin-2-ones through in situ ring construction and contraction

An innovative synthesis of aryl tethered 1,3-dimethylimidazo[4,5-b]pyrazin-2-ones 4 and 6 has been delineated through base catalyzed ring transformation of 6-aryl-4-(piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1 and methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates 5 with 7-acetyl-1,3-dimethyllumazine 2 with subsequent ring contraction of the fused pyrimidine to an imidazole ring. An additional product, methyl [6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-4-thiophen-2-ylpyran-2-ylidene]acetate 8b, was also isolated from the reaction of 5 and 2, as a minor constituent.     

Synthesis and characterization of boronates derived from non-symmetric amino-bis-phenols

The condensation of 2-[[(2-hydroxyphenyl)amino]methyl]-phenols (1a-1e) with different arylboronic acids led to 12 new monomeric boronates of the type 2-aryl-dibenzo[d,h]-6-aza-1,3-dioxa-2-boracyclononene (2a-2l). The boronates were characterized by ¹H-, ¹³C-, ¹¹B- and 2D-NMR experiments, FT infrared, mass spectra and elemental analyses. The stereochemistry of the H-N → B-Ph fusion is always cis, as established through the NMR spectra, as well as the X-ray structures of four boronates (2a, 2e, 2f and 2l). Hydrogen bonds between the amine proton and the oxygen ester of the five- membered ring are present in three X-ray structures (2a, 2e and 2f), while the supramolecular structure in the derivative possessing a primary amine (2l) is built up through the protons present in this moiety instead of the proton from the H-N → B-Ph fragment.     

Regiochemistry of an ambident cyclic ketene-N,O-acetal nucleophile and its anion toward electrophiles

The five-membered cyclic ketene-N,O-acetal, 2-oxazolidin-2-ylidene-1-phenylethanone 1, and its anion 2, formed on deprotonation, are ambident nucleophiles. Compound 1 was synthesized by benzoylation of 2-methyl-2-oxazoline to give a ring-opened N,C,O-trisbenzoylation product, 9, followed by N,O-double debenzoylation using methanolic KOH. Compound 1 reacted with benzoyl chloride to give N,C,O-trisbenzoylated 9, and reacted with phenyl chloroformate to give the similar ring-opened carbonic acid 3-[(2-chloro-ethyl)-phenoxycarbonyl-amino]-3-oxo-1-phenyl-propenyl ester phenyl ester, 13. In contrast, ambident anion 2 reacted with benzoyl chloride to give the β,β-bisbenzoylated cyclic ketene-N,O-acetal, 16, and reacted with phenyl chloroformate to give the novel heterocycle 3-(2-hydroxy-ethyl)-6-phenyl-[1,3]oxazine-2,4-dione, 17.     

Velutabularins A-J, phragmalin-type limonoids with novel cyclic moiety from Chukrasia tabularis var. velutina

Velutabularins A-J, ten novel phragmalin-type limonoids, were isolated from the stem bark of Chukrasia tabularis var. velutina. In structures of 1-6, the tetrahydrofuran ring from dehydration of OH-15 and OH-17, ring C and 13/14/18-cyclopropanyl moiety formed an unprecedented 8-oxatricyclo[4,3,1^1,6]decane. Compounds 7-10 are derivates of 1-6 opening the tetrahydrofuran ring. All of these compounds possess a novel C-16/C-30 δ-lactone ring, which were reported in phragmalins rarely. The structures of these novel compounds were elucidated based on extensive 1D and 2D spectroscopic analysis. The absolute configuration of 5 and 9 were determined by the calculated electronic circular dichroism (ECD) method. The anti-inflammatory activities of major compounds (2, 4, 5, 9) were evaluated for inhibitory activity against lipopolysaccharide (LPS) induced nitric oxide (NO) production in macrophage (RAW264.7) cell line.     

A one-pot synthesis of an annelated [a]aza-thieno[3,2-g]naphthalenone through ring transformation followed by photocyclization

A concise synthesis of 4-aryl-10-oxo-1,2,3,10-tetrahydro-9-thia-1,3a-diazadicyclopenta[a,g]naphthalene-6-carbonitriles 5a-f and 5-aryl-11-oxo-1,3,4,11-tetrahydro-2H-10-thia-1,4a-diaza-cyclopenta[b]phenanthrene-7-carbonitriles 5g-i has been delineated through ring transformations of the 2H-pyran-2-one 1, followed by photocyclization of product 4.     

New phlegmarane-type, cernuane-type, and quinolizidine alkaloids from two species of Lycopodium

Two new phlegmarane-type alkaloids, cermizines A (1) and B (2), three new quinolizidine alkaloids, cermizine C (3) and senepodines G (4) and H (5), and a new C₁₆N₂ type alkaloid consisting of a quinolizidine and a piperidine ring, cermizine D (6), as well as two new cernuane-type alkaloids, cernuine N-oxide (7) and lycocernuine N-oxide (8), have been isolated together with cernuine (9) and lycocernuine (10) from the club moss Lycopodium cernuum and L. chinense. The relative stereochemistry of 1-4 and 6, and the absolute stereochemistry of 5, 7, and 8 were elucidated by combination of NOESY correlations, modified Mosher's method, chemical transformations, and computational methods. Cermizine D (6) might be a biosynthetic intermediate of cernuane-type alkaloids such as 7-10.     

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.     

Regioselective synthesis of 4- and 5-oxazole-phosphine oxides and -phosphonates from 2H-azirines and acyl chlorides

A simple and efficient regioselective synthesis of 4-oxazole-phosphine oxides 11 and -phosphonates 12 from 2H-azirine-phosphine oxides 1 and -phosphonates 6 is described. The key step for the synthesis of oxazoles 11 is a base-mediated ring closure of vinylogous α-aminophosphorus compounds derived from phosphine oxides 4 and from phosphonates 8. These derivatives 4 and 8 are obtained by reaction of functionalized azirines 1 and 6 with acyl chlorides 2 and subsequent acid-catalyzed ring opening of N-acylaziridine-phosphine oxides 3 and -phosphonates 7. Regioselective thermal ring cleavage of N-acylaziridine-phosphine oxides 3 leads α-chloro-β-(N-acylamido)-phosphine oxides 13 and their treatment with bases gives 5-oxazole-phosphine oxides 16.     

Withaphysanolide A, a novel C-27 norwithanolide skeleton, and other cytotoxic compounds from Physalis divericata

A novel C-27 norwithasteroid, withaphysanolide A (1) containing a pyran ring was isolated from the aerial parts of Physalis divericata. Four known withaphysalins (2-5) and five physalins (6-10) were also isolated. The structural assignment for 1 was done based on spectroscopic and single-crystal X-ray diffraction data. Logical biosynthetic pathways were postulated. Compounds 6, 7, and 10 displayed potent cytotoxic activity against HCT-116 and H460 human cancer cell lines, with IC₅₀ values less than 2.0 μM.     

Synthesis of the FG ring fragment of pectenotoxins 1-9

The synthesis of the FG ring fragment common to pectenotoxins 1-9 is reported. The successful, convergent synthesis relied on high yielding routes to access two key intermediates; aldehyde 1 and phosphonium salt 2. A Z-selective Wittig reaction gave access to advanced linear precursor 3, which was converted to FG ring fragment 4 using two sequential cyclization reactions.