Synthesis of Scopin Acetate and 6,7‐Didehydrohyoscyamin. Intramolecular Phenylsulfenylation of a Nonactivated Methylene Group of Ethyl N‐Demethyl‐3‐O‐(phenylthio)tropine‐N‐carboxylate

The synthesis of scopin acetate ( 6b ) and 6,7‐didehydrohyoscyamine ( 17 ) was achieved by using tropine ( 5 ) as the starting compound. Formal (phenylthio)‐radical transfer to the nonactivated 6‐position of ethyl N‐demethyl‐3‐O‐(phenylthio)tropine‐N‐carboxylate ( 9 ) by irradiation in the presence of hexabutyldistannane is a key step of this synthetic approach, involving ethyl 6,7‐didehydro‐N‐demethyltropine‐N‐carboxylate ( 15 ) as a synthetic intermediate (Schemes 3 and 5). The reaction of 9 with tributylstannane in the presence of ethyl acrylate, as a radicophilic olefin, involves Michael‐type alkylation at C(6) of the tropine skeleton affording ethyl N‐demethyl‐N‐(ethoxycarbonyl)tropine‐6‐propanoate ( 18 ) (Scheme 6).     

Spiro[4H‐2,3‐dihydropyran‐3,3′‐oxindoles] derived from 1,2,3,4‐tetrahydroquinoline

Knoevenagel condensation of 5,6‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinoline‐1,2‐dione 3 with aryl cyanomethyl ketones 9 generates 3‐(aroyl(cyano)methylidene)oxindoles 10 that react with cyclic 1,3‐diketones 11 to generate polycyclic hemiacetal spiro[4H‐2,3‐dihydropyran‐3,3′‐oxindoles] 13 .     

Synthesis of 9‐Halogenated 9‐Deazaguanine N7‐(2′‐Deoxyribonucleosides)

The syntheses of N⁷‐glycosylated 9‐deazaguanine 1a as well as of its 9‐bromo and 9‐iodo derivatives 1b , c are described. The regioselective 9‐halogenation with N‐bromosuccinimide (NBS) and N‐iodosuccinimide (NIS) was accomplished at the protected nucleobase 4a (2‐{[(dimethylamino)methylidene]amino}‐3,5‐dihydro‐3‐[(pivaloyloxy)methyl]‐4H‐pyrrolo[3,2‐d]pyrimidin‐4‐one). Nucleobase‐anion glycosylation of 4a – c with 2‐deoxy‐3,5‐di‐O‐(p‐toluoyl)‐α‐D ‐erythro‐pentofuranosyl chloride ( 5 ) furnished the fully protected intermediates 6a – c (Scheme 2). They were deprotected with 0.01M NaOMe yielding the sugar‐deprotected derivatives 8a – c (Scheme 3). At higher concentrations (0.1M NaOMe), also the pivaloyloxymethyl group was removed to give 7a – c , while conc. aq. NH₃ solution furnished the nucleosides 1a – c . In D₂O, the sugar conformation was always biased towards S (67–61%).     

Synthesis and Cytotoxicity Evaluation of Certain α‐Methylidene‐ γ‐butyrolactones Bearing Coumarin,Flavone, Xanthone,Carbazole, and Dibenzofuran Moieties

The cytotoxicities of α‐methylidene‐γ‐butyrolactones, which are linked to coumarins (see 15 and 16 ) and to potential DNA‐intercalating carriers such as flavones, xanthones, carbazole, and dibenzofuran (see 9a – e , 10a – e , 11 , and 12 ), were studied. These compounds were synthesized via alkylation of their hydroxy precursors followed by a Reformatsky‐type condensation (Scheme). These α‐methylidene‐γ‐butyralactones were evaluated in vitro against 60 human tumor cell lines derived from nine cancer cell types and demonstrated a strong growth‐inhibitory activity against leukemia cancer cells (Tables 1 and 2). For flavone‐ and xanthone‐containing α‐methylidene‐γ‐butyrolactones 9a – e and 10a – e , respectively, the overall potency (mean value) decreased on introduction of an electron‐withdrawing substituent at the γ‐phenyl substituent and increased with an electron‐donating substituent. Comparing the different chromophores established the following order of decreasing potency (log GI₅₀): dibenzofuran ( 12 , −6.17) > flavone ( 9a , −5.96) > carbazole ( 11 , −5.80) and xanthone ( 10a , −5.77) > coumarin ( 15 , −5.60; 16 , −5.65). Among them, the dibenzofuran derivative 12 showed not only strong inhibitory activities against leukemia cancer cell lines with an average log GI₅₀ value of −7.22, but also good inhibitory activities against colon, melanoma, and breast cancer cells with average log GI₅₀ values of −6.23, −6.31, and −6.39, respectively.     

Synthesis of (−)‐Pinellic Acid and Its (9R,12S,13S)‐Diastereoisomer

The total synthesis of (?)‐pinellic acid with (9S,12S,13S)‐configuration and its (9R,12S,13S)‐diastereoisomer was achieved in high overall yields from a common intermediate derived from (+)‐L ‐diethyl tartrate.     

1H and 13C chemical shifts for acridines: Part XVIII. 9‐Chloroacridine and 9‐(N‐allyl)‐ and 9‐(N‐propargyl)acridinamine derivatives

The¹H and ¹³C NMR resonances for acridine derivatives 9‐substituted with chloro, allylamino and propargylamino groups were completely assigned using a concerted application of gs‐COSY, gs‐HMQC and gs‐HMBC experiments. 9‐(N‐Allyl)‐ and 9‐(N‐propargyl)acridinamine derivatives present amino–imino tautomerism including a large broadening of ¹H and ¹³C NMR signals at room temperature. To obtain suitable resolution, therefore, these latter compounds were studied at 370 K in DMSO‐d6 solutions and showed a complete shift towards the imino tautomers. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and Antiplatelet‐Activity Evaluation of α‐Methylidene‐γ‐butyrolactones Bearing 3,4‐Dihydroquinolin‐2(1H)‐one Moieties

In continuation of our search for potent antiplatelet agents, we have synthesized and evaluated several α‐methylidene‐γ‐butyrolactones bearing 3,4‐dihydroquinolin‐2(1H)‐one moieties. O‐Alkylation of 3,4‐dihydro‐8‐hydroxyquinolin‐2(1H)‐one ( 1 ) with chloroacetone under basic conditions afforded 3,4‐dihydro‐8‐(2‐oxopropoxy)quinolin‐2(1H)‐one ( 2a ) and tricyclic 2,3,6,7‐tetrahydro‐3‐hydroxy‐3‐methyl‐5H‐pyrido[1,2,3‐de][1,4]benzoxazin‐5‐one ( 3a ) in a ratio of 1 : 2.84. Their Reformatsky‐type condensation with ethyl 2‐(bromomethyl)prop‐2‐enoate furnished 3,4‐dihydro‐8‐[(2,3,4,5‐tetrahydro‐2‐methyl‐4‐methylidene‐5‐oxofuran‐2‐yl)methoxy]quinolin‐2(1H)‐one ( 4a ), which shows antiplatelet activity, in 70% yield. Its 2′‐Ph derivatives, and 6‐ and 7‐substituted analogs were also obtained from the corresponding 3,4‐dihydroquinolin‐2(1H)‐ones via alkylation and the Reformatsky‐type condensation. Of these compounds, 3,4‐dihydro‐7‐[(2,3,4,5‐tetrahydro‐4‐methylidene‐5‐oxo‐2‐phenylfuran‐2‐yl)methoxy]quinolin‐2(1H)‐one ( 10b ) was the most active against arachidonic acid (AA) induced platelet aggregation with an IC₅₀ of 0.23 μM . For the inhibition of platelet‐activating factor (PAF) induced aggregation, 6‐{[2‐(4‐fluorophenyl)‐2,3,4,5‐tetrahydro‐4‐methylidene‐5‐oxofuran‐2‐yl]methoxy}‐3,4‐dihydroquinolin‐2(1H)‐one ( 9c ) was the most potent with an IC₅₀ value of 1.83 μM .     

An Efficient Synthesis of 3′‐Amino‐3′‐deoxyguanosine from Guanosine

3′‐Amino‐3′‐deoxyguanosine was synthesized from guanosine in eight steps and 58% overall yield. The 2′,3′‐diol of 5′‐O‐[(tert‐butyl)diphenylsilyl]‐2‐N‐[(dimethylamino)methylidene]guanosine was reacted with α‐acetoxyisobutyryl bromide and treated with 0.5n NH₃ in MeOH to yield 9‐{2′‐O‐acetyl‐3′‐bromo‐5′‐O‐[(tert‐butyl)diphenylsilyl]‐3′‐deoxy‐β‐D ‐xylofuranosyl]‐2‐N‐[(dimethylamino)methylidene]guanine, which was reacted with benzyl isocyanate, NaH, and then 3.0n NaOH, and finally with Pd/C (10%) and HCO₂NH₄ in EtOH/AcOH to afford 3′‐amino‐3′‐deoxyguanosine.     

Structural comparison of three N‐(4‐halogenophenyl)‐N′‐[1‐(2‐pyridyl)ethylidene]hydrazine hydrochlorides

2‐{1‐[(4‐Chloroanilino)methylidene]ethyl}pyridinium chloride methanol solvate, C₁₃H₁₃ClN₃⁺·Cl⁻·CH₃OH, (I), crystallizes as discrete cations and anions, with one molecule of methanol as solvent in the asymmetric unit. The N—C—C—N torsion angle in the cation indicates a cis conformation. The cations are located parallel to the (02) plane and are connected through hydrogen bonds by a methanol solvent molecule and a chloride anion, forming zigzag chains in the direction of the b axis. The crystal structure of 2‐{1‐[(4‐fluoroanilino)methylidene]ethyl}pyridinium chloride, C₁₃H₁₃FN₃⁺·Cl⁻, (II), contains just one anion and one cation in the asymmetric unit but no solvent. In contrast with (I), the N—C—C—N torsion angle in the cation corresponds with a trans conformation. The cations are located parallel to the (100) plane and are connected by hydrogen bonds to the chloride anions, forming zigzag chains in the direction of the b axis. In addition, the crystal packing is stabilized by weak π–π interactions between the pyridinium and benzene rings. The crystal of (II) is a nonmerohedral monoclinic twin which emulates an orthorhombic diffraction pattern. Twinning occurs via a twofold rotation about the c axis and the fractional contribution of the minor twin component refined to 0.324 (3). 2‐{1‐[(4‐Fluoroanilino)methylidene]ethyl}pyridinium chloride methanol disolvate, C₁₃H₁₃FN₃⁺·Cl⁻·2CH₃OH, (III), is a pseudopolymorph of (II). It crystallizes with two anions, two cations and four molecules of methanol in the asymmetric unit. Two symmetry‐equivalent cations are connected by hydrogen bonds to a chloride anion and a methanol solvent molecule, forming a centrosymmetric dimer. A further methanol molecule is hydrogen bonded to each chloride anion. These aggregates are connected by C—H...O contacts to form infinite chains. It is remarkable that the geometric structures of two compounds having two different formula units in their asymmetric units are essentially the same.     

Synthesis of (S)‐3‐heteroaryl‐2‐hydroxy‐l‐propyl benzoates by ‘ring switching’ methodology

(S)‐5‐Benzoyloxymethyl‐3‐[(E)‐(dimethylamino)methylidene]tetrahydrofuran‐2‐one (6), prepared in 5 steps from L‐glutamic acid (1), was used as precursor in a one step ‘ring switching’ synthesis of (S)‐2‐hydroxy‐3‐heteroaryl‐l‐propyl benzoates 13‐18, 23, 24. In the reaction of 6 with 2‐aminopyridine (21) and 2‐amino‐4,6‐dimethylpyrimidine (22) the corresponding dimethylamine substitution products (25, 26) were obtained.     

Synthesis of 3‐(4‐Oxo‐4H‐quinolizinyl‐3) and 3‐(4‐Oxo‐4H‐pyridino[1,2‐a]pyrimidinyl‐3) substituted lactic acid derivatives

A one‐step ‘ring switching’ transformation of (S)‐3‐[(dimethylamino)methylidene]‐5‐(methoxycarbonyl)tetrahydrofuran‐2‐one ( 4 ) with 2‐pyridineacetic acid derivatives ( 5–7 ) and 2‐aminopyridines ( 8, 9 ) afforded the corresponding 3‐(4‐oxo‐4H‐quinolizinyl‐3)‐ (15–17) and 3‐(4‐oxo‐4H‐pyridino[1,2‐a]pyrimidinyl‐3)‐2‐hydroxypropanoates ( 18, 19 ), respectively.     

Synthesis of 11Z‐9‐demethyl‐9‐((3‐indolyl)methyl)retinal

A convenient synthesis of 11Z‐9‐demethyl‐9‐((3‐indolyl)methyl)retinal, which has an amino acid residue of tryptophan at the 9 position in retinal, is described using a tricarbonyliron complex.     

Synthesis of (2S)‐2‐(Benzoylamino)‐3‐(heteroaryl)propyl Benzoates

(3E,5S)‐1‐Benzoyl‐5‐[(benzoyloxy)methyl]‐3‐[(dimethylamino)methylidene]pyrrolidin‐2‐one ( 9 ) was prepared in two steps from commercially available (S)‐5‐(hydroxymethyl)pyrrolidin‐2‐one ( 7 ) (Scheme 1). Compound 9 gave, in one step, upon treatment with various C,N‐ and C,O‐1,3‐dinucleophiles 10 – 18 , the corresponding 3‐(quinolizin‐3‐yl)‐ and 3‐(2‐oxo‐2H‐pyran‐3‐yl)‐substituted (2S)‐2‐(benzoylamino)propyl benzoates 19 – 27 (Schemes 1 and 2).     

Hydroacridines: Part 30. 1H and 13C NMR spectra of 9‐substituted 1,2,3,4,5,6,7,8‐octahydroacridines and of their N‐oxides

The ¹H and ¹³C NMR chemical shifts of 1,2,3,4,5,6,7,8‐octahydroacridine, 12 of its 9‐substituted derivatives, and of the corresponding N‐oxides were determined, assigned, and discussed in terms of 9‐substituent effects and effects of N‐oxidation. A good linear correlation was found between the ¹³C chemical shifts of the aromatic carbons in octahydroacridines and those of respective carbons in the corresponding N‐oxides. Copyright © 2009 John Wiley & Sons, Ltd.     

A Convenient Synthesis of 2,3‐Dihydro‐3‐methylidene‐1H‐isoindol‐1‐ones by Reaction of 2‐Formylbenzo­nitriles with Dimethyloxosulfonium Methylide

A facile method for the synthesis of 2,3‐dihydro‐3‐methylidene‐1H‐isoindol‐1‐one and its derivatives carrying substituent(s) at C(5) and/or C(6) has been developed. The reaction of 2‐formylbenzonitrile ( 1a ) with dimethyloxosulfonium methylide, generated by the treatment of trimethylsulfoxonium iodide with NaH in DMSO/THF at 0°, resulted in the formation of 2,3‐dihydro‐3‐methylidene‐1H‐isoindol‐1‐one ( 2a ) in 77% yield. Similarly, six 2‐formylbenzonitriles carrying substituent(s) at C(4) and/or C(5), i.e., 1b – 1g , also gave the corresponding expected products 2b – 2g in comparable yields.     

Planarity of heteroaryldithiocarbazic acid derivatives showing tuberculostatic activity. II. Crystal structures of 3‐[amino(pyrazin‐2‐yl)methylidene]‐2‐methylcarbazic acid esters

Four compounds showing moderate antituberculostatic activity have been studied to test the hypothesis that the planarity of the 2‐[amino(pyrazin‐2‐yl)methylidene]dithiocarbazate fragment is crucial for activity. N′‐Anilinopyrazine‐2‐carboximidamide, C₁₁H₁₁N₅, D1, and diethyl 2,2′‐[({[amino(pyrazin‐2‐yl)methylidene]hydrazinylidene}methylidene)bis(sulfanediyl)]diacetate, C₁₄H₁₉N₅O₄S₂, B1, maintain planarity due to conjugation and attractive intramolecular hydrogen‐bond contacts, while methyl 3‐[amino(pyrazin‐2‐yl)methylidene]‐2‐methyldithiocarbazate, C₈H₁₁N₅S₂, C1, and benzyl 3‐[amino(pyrazin‐2‐yl)methylidene]‐2‐methyldithiocarbazate, C₁₄H₁₅N₅S₂, C2, are not planar, due to methylation at one of the N atoms of the central N—N bond. The resulting twists of the two molecular halves (parts) of C1 and C2 are indicated by torsion angles of 116.5 (2) and −135.9 (2)°, respectively, compared with values of about 180° in the crystal structures of nonsubstituted compounds. As the methylated derivatives show similar activity against Mycobacterium tuberculosis to that of the nonsubstituted derivatives, maintaining planarity does not seem to be a prerequisite for activity.     

A Facile Synthesis of 2‐Imino‐4‐methylene‐1,3‐dithiolanes

A one‐pot synthesis of 2‐imino‐4‐methylidene‐1,3‐dithiolanes via a three‐component reaction of propargyl bromide (=3‐bromoprop‐1‐yne), primary amines, and carbon disulfide (CS₂) is described.     

Synthesis and hydrolysis of p‐toluoyl and acetyl 9‐triptycyl diselenides: A study on generation of triptycene‐9‐selenenoselenoic acid

p‐Toluoyl 9‐triptycyl diselenide ( 9 ) was prepared by reaction of Se‐9‐triptycyl triptycene‐9‐selenoseleninate ( 7 ) with p‐toluenecarboselenoic acid ( 8 ) and by reaction of triptycene‐9‐selenenoselenolate salt with p‐toluoyl chloride. Acetyl 9‐triptycyl diselenide ( 13 ) was prepared by reaction of triptycene‐9‐selenenoselenolate salt with acetyl chloride. Hydrolysis of the two diselenides, 9 and 13 , provided triptycene‐9‐selenol ( 10 ) and di‐9‐triptycyl triselenide ( 12 ), suggesting the generation of triptycene‐9‐selenenoselenoic acid ( 3 ). © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:525–528, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20155     

Intercalating Nucleic Acids with Insertion of 5‐[(Pyren‐1‐yl)methylidene]hydantoin‐Substituted Butane‐1,2‐diol

Isopropylidene‐protected (S)‐4‐O‐(methylsulfonyl)butane‐1,2,4‐triol was used for alkylation of 5‐[(pyren‐3‐yl)methylidene]hydantoin to give the N³‐monoalkylated product 4 in 29% yield together with a dialkylated product 5 in 12% yield. After deprotection, compound 4 was transformed into a dimethoxytrityl (DMT)‐protected phosphoramidite building block 9 for standard DNA synthesis. When inserted as a bulge in the triplex‐forming oligomer, compound 6 stabilizes a DNA triplex, whereas the corresponding DNA/DNA and DNA/RNA duplexes are slightly destabilized. For the triplex, fluorescence enhancement was observed at 500 nm.     

Oxygenated 4‐Methylidene Sterols from the South China Sea Sponge Theonella swinhoei

Two new O‐bearing 4‐methylidene sterols, 9α‐hydroxy‐15‐oxoconicasterol ( 1 ) and 8β‐hydroxy‐B‐norconicasta‐6α‐aldehyde ( 2 ), were isolated from the EtOH extract of the marine sponge Theonella swinhoei collected from the South China Sea. Their structures were elucidated by spectroscopic data and comparison with known compounds. In addition, spectroscopic data reported for the known 4‐methylidene sterol 7α‐hydroxyconicasterol ( 3 ) were revised.