bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acid induced decomposition of coenzyme B12 and variants
Authors: Gerards L. E. H. , Balt S. 
Published: September 2010

AbstractThe acid catalyzed heterolytic cleavage of the CoC bond in coenzyme B12 (1) was studied using the ‘excess acidity’ functions of Cox and Yates. The results are compared to the acid induced decomposition of (methyl‐5‐deoxy‐ribofuranosyl)‐(2) and (2‐ethoxyethyl)cobalamin (3). Evidence is presented to view the CoC bond cleavage in the compounds (1) and (2) as an A2 mechanism with water as the nucleophile or as an Ia substitution at Co3+, and in (3) as an A1 mechanism. Volumes of activation are consistent with the proposed mechanism.
1H NMR conformational analysis of (3‐aminopropyl)triethoxysilane
Authors: de Brabander‐van den Berg Ellen M. M. , Ippel Johannes H. , Lugtenburg Johan , Jenneskens Leonardus W. 
Published: September 2010

AbstractThe 1H NMR spectrum of (3‐aminopropyl)triethoxysilane (1) was analyzed to gain insight into the population distributions of the anti and gauche conformers: xa and xg, respectively, across the carboncarbon bonds (C(1)‐C(2) (bond I) and C(2)‐C(3) (bond II) of the 3‐aminopropyl group. Values of xa of 0.76/0.71 [bond I, 3J(AB)/3J(A′B)] and 0.57/0.53 [bond II, 3J(BC)/3J(B′C)], respectively, were calculated. The absence of solvent dependence of the anti‐gauche equilibria indicates that specific solute‐solvent complexation does not contribute to the intramolecular interactions.
Synthesis of L‐glucose derivatives from D‐glucose and L‐arabinose
Authors: Smid P. , Noort D. , Broxterman H. J. G. , van Straten N. C. R. , van der Marel G. A. , van Boom J. H. 
Published: September 2010

AbstractL‐Glucose derivatives are prepared by two different routes. The first involves a modification of the previously reported multi‐step approach by Shiozaki8, starting from a D‐glucurono‐1,5‐lactone derivative, resulting in the isolation of 2,3,4,6‐tetra‐O‐benzyl‐L‐glucopyranose. The other route comprises the synthesis of penta‐O‐acetyl‐L‐glucopyranose via a highly stereoselective addition of [(phenyldimethylsilyl)methyl]magnesium chloride with 2,3,5‐tri‐O‐benzyl‐L‐arabinofuranose.
Synthesis and receptor‐affinity profile ofN‐hydroxytryptamine derivatives for serotonin and tryptamine receptors. A molecular‐modeling study
Authors: Dijkstra Gerard D. H. , Tulp Martin Th. M. , Hermkens Pedro H. H. , van Maarseveen Jan H. , Scheeren Hans W. , Kruse Chris G. 
Published: September 2010

AbstractThe synthesis and the affinities for serotonin and tryptamine receptors of a series ofN‐oxy derivatives of tryptamine (6–8, 13–14) are reported. It was found thatN‐hydroxytryptamine (6) is a relatively selective ligand for the 5‐HT1Creceptor. The receptor‐binding data are interpreted by a molecular modeling study in which the binding sites of the 5‐HT1Aand 5‐HT1Creceptors are compared. An asparagine residue present in helix 7 of 5‐HT1Abut absent in 5‐HT1Cplays a crucial role. On the basis of a three‐dimensional model of the seven transmembrane regions of the 5‐HT1Areceptor a hydrogen‐bond interaction is predicted between this asparagine residue and one of the oxygens of an aspartic acid residue on helix 3, leaving only one oxygen atom for ligand interaction. In the 5‐HT1Cboth oxygens of the aspartic acid residue on helix 3 are free to interact via a doubly hydrogen‐bonded complex with theN‐hydroxy moiety of6.N‐Methoxy derivative13lacks this additional hydrogen‐bond possibility and is devoid of binding affinity, presumably as a result of electrostatic repulsion.
Synthesis and pharmacological evaluation of 5,6,7,8‐tetrahydro‐6‐[propyl[2‐(2‐thienyl)ethyl]amino]‐1,2‐naphthalenediol: A novel non‐selective dopamine‐receptor agonist
Authors: Copinga Swier , Dijkstra Durk , de Vries Jan B. , Grol Cor J. , Horn Alan S. 
Published: September 2010

AbstractBased on the hypothesis that simultaneous stimulation of dopamine D1and ‐D2receptors could be beneficial for the treatment of Parkinson's disease7,13, we prepared 5,6,7,8‐tetrahydro‐6‐[propyl[2‐(2‐thienyl)ethyl]amino]‐1,2‐naphthalenediol (PTAT.4), the diol analogue of N‐0437 (3), as a potential mixed D1/D2‐receptor agonist. The synthesis of4was carried out via a new strategy. The crucial step in this strategy was the conversion of 1‐diazo‐4‐(2,3‐dimethoxyphenyl)‐2‐butanone (15) to the key intermediate 5,6‐dimethoxy‐2‐tetralone (9) via a rhodium(II)‐ acetate‐catalysed cyclisation, followed by transformation under the influence of trifluoroacetic acid. Pharmacological evaluation of the dopaminergic properties of PTAT (4) revealed that this compound displays high affinity for both D1and D2receptors and has the same ability as DPAT (1), a mixed D1/D2‐receptor agonist, to induce locomotor activity in mice rendered acutely akinetic with reserpine.
Monoamine re‐uptake inhibiting 1‐[2‐[(phenoxyphenyl)methoxy]ethyl]‐ piperazines as potential antidepressants
Authors: Wieringa J. , van den Meerendonk A. , Steenvoorden J. , Heeres G. , van Bakel F. , Roeters T. , van der Hulst R. , Den Blanken A. , Leysen D. , Plate R. , de Boer Th. , Rijk H. 
Published: September 2010

AbstractA series of 1‐[2‐[(2‐phenoxyphenyl)methoxy]ethyl]‐4‐(3‐phenylpropyl)piperazines 17–50 (Figure 1) were prepared and tested as inhibitors of biogenic amine re‐uptake. In our search for antidepressants, the relationship between their in vitro and in vivo activity as dopamine‐reuptake inhibitors is described quantitatively by using Retention Index values determined by reversed‐phase liquid chromatography.
Homology model‐building studies of human thrombin: Optimisation of modelling protocol and comparison with X‐ray structure
Authors: Koymans Luc M. H. , Grootenhuis Peter D. J. , Haasnoot Cornelis A. G. 
Published: September 2010

AbstractThe present paper evaluates the effect of several parameters on the accuracy of homology model‐built structures of human thrombin. In order to appraise the merits of such a homology model‐building study as a practical basis for direct drug‐design purposes, this study was limited to the widely used “standard” alignment and loop‐modelling methods implemented in the Quanta/CHARMm 3.0 software. The parameters studied were the alignment method, the choice of the template protein, and the molecular dynamics refinement protocol. The resulting models were energy‐minimised and compared with the energy‐minimised crystal structure of thrombin. It was found that the method of alignment is the dominating parameter: the alignment algorithm giving the most accurate models is one that is based upon the three‐dimensional overlap of structurally conserved regions in related proteins. The choice of the template protein structures, which all showed a ± 30% sequence identity with thrombin, turned out to be less important for the accuracy of the final model. In our hands, molecular dynamics simulations at 300 and 1000K failed to improve the predictive value of the models. The overall root‐mean‐square deviation between the best model and the minimised crystal structure of thrombin amounted to 2.9 Å. Detailed comparison of the models with the experimentally determined 3D structure of thrombin leads to the conclusion that although a homology‐building study may result in a three‐dimensional model that yields a good general idea of the protein structure, rather large structural uncertainties in the proximity of insertions of more than 4 amino acids limit its practical use for direct drug‐design efforts.
Towards a rational design for resolving agents. Part V: Substituent effects in the resolution of ephedrine using a series of cyclic phosphoric acids
Authors: van der Haest Albertus D. , Wynberg Hans , Leusen Frank J. J. , Bruggink Alle 
Published: September 2010

AbstractThe effects of various aromatic substituents in both ephedrine and a cyclic phosphoric acid on the quality of resolution via diastereomeric salt formation are investigated. The diastereo‐selective synthesis of a novel series of chloro‐substituted ephedrines is described. These chloroephedrines can be resolved efficiently with some of the cyclic phosphoric acids. By studying the physical properties of nineteen pairs of diastereomeric salts, we show that the quality of the resolution depends mainly on the aromatic substituent of the cyclic phosphoric acid, whereas substituents at the phenyl ring of ephedrine play a secondary role.
Novel rearrangement during dehydration. Construction of the guaianolide skeleton
Authors: Banerjee Ajoy K. , Vera William 
Published: September 2010

AbstractOn treatment with phosphorus oxychloride, the decalin derivative 6 underwent rearrangement yielding principally the perhydroazulene derivative 8. Similar rearrangement was also observed on dehydration of the decalin derivative 9.
Gas‐phase oxychlorination of benzene
Authors: Born Jan G. P. , van der Wart Hans W. A. , Mulder Peter , Louw Robert 
Published: September 2010

AbstractHomogeneous gas‐phase oxychlorination of benzene has been examined in a flow system between 722 and 1174K. Experiments were performed at atmospheric pressure with nitrogen as an inert carrier gas, containing about equal molar amounts of oxygen, HCl and benzene. Apart from chlorobenzene, substantial amounts of o‐ and p‐chlorophenol are produced. Using benzonitrile rather than benzene, the three isomers of ClC6H4CN are formed in about equal amounts. These findings suggest a homolytic mechanism with aryl radicals as key intermediates. Thermokinetic analysis points to formation of chlorophenols via reaction of phenoxyl (formed from phenyl and oxygen) with HOCl. Chlorination, C6 H6 → C6H5Cl, is explained by reaction between phenyl radicals and HOCl. With increasing temperature (and, therefore, oxygen consumption), slow combustion is replaced by pyrolysis as the major reaction channel. As a result, above ca. 1000K, the production of chlorobenzene diminishes, [C6H5Cl] ultimately being governed by the equilibrium: C6H6 + HCl ⇌ C6H5Cl + H2.
Reactivity of zinc dialkyldithiocarbamates towards halogen‐substituted olefins
Authors: Versloot P. , Dargan P. , Haasnoot J. G. , Reedijk J. , van Duin M. , Put J. , Goubitz K. 
Published: September 2010

AbstractThe reaction of bis(dimethyldithiocarbamato)zinc(II) [Zn(dmtc)2] with halogen‐substituted 2,3‐dimethyl‐2‐butene (e.g., 1‐bromo‐2,3‐dimethyl‐2‐butene; tme‐Br) causes substitution of bromide by the dmtc ligands. Depending on the polarity of the solvent, this results either in a complex ZnBr2 (tme‐dmtc)2, in which the coupling product remains coordinated to the metal, or in the liberation of the ligand, producing ZnBr2 and tme‐dmtc. Crystals of tme‐dmtc have been obtained from methanol solution. An X‐ray structure of this solid has been determined; relevant data: C9H17NS2, Mr = 204.4, monoclinic, P21, a = 8.2087(5), b = 7.3551(5), c = 10.2791(8) Å, β = 106.437(6)°, V = 595.25(8) Å3, Z = 2, Dx = 1.14 g·cm−3, λ(CuKα) = 1.5418 Å, μ(CuKα) = 36.25 cm−1, F(000) = 222, room temperature. Final R = 0.069 for 853 observed reflections.
The influence of the 5‐methyl group in bacteriorhodopsin
Authors: Groesbeek M. , de Vries E. F. J. , Berden J. A. , Lugtenburg J. 
Published: September 2010

AbstractAll‐E‐5‐bromo‐5‐demethylretinal was prepared in 6% yield starting from 4,4‐dimethyl‐2‐cyclohexenone via 2‐bromo‐6,6‐dimethyl‐1‐cyclohexenecarboxaldehyde. The crucial step in the preparation of the intermediate is a 2,3 Wittig rearrangement. 5‐Bromo‐5‐demethylbacteriorhodopsin is easily formed from all‐E‐5‐bromo‐5‐demethylretinal and bO. Due to the fact that the bromo substituent has about the same steric requirements as the 5‐methyl group, the influence of electronic factors on the properties of bacteriorhodopsin could be studied. We conclude that the contribution of the 5‐methyl group in bR to the proton‐pump action and opsin shift is due to its electron‐donating properties.
Coordination properties of the didentate N,O ligand 1‐(2‐hydroxyethyl)‐3,5‐dimethylpyrazole (hl). Crystal structure of [Cu(HL)2(NO3)2] and [Cu(L)Br]2
Authors: Driessen W. L. , Gorter S. , Haanstra W. G. , Laarhoven L. J. J. , Reedijk J. , Goubitz K. , Seljée F. R. 
Published: September 2010

AbstractThe didentate N,O donor ligand 1‐(2‐hydroxyethyl)‐3,5‐dimethylpyrazole (N‐hed) renders two kinds of coordination compounds, viz. [M(N‐hed)2(NO3)2] with M=Co, Ni, Cu, and Zn, [Ni(N‐hed)2(NCS)2], and [Cu(N‐hed)2Cl2] in which the ligand is neutral, and [Cu(N‐oed)X]2 with X=Cl, Br, and NO3 in which the ligand N‐hed is in its deprotonated form, viz. 1‐(2‐oxidoethyl)‐3,5‐dimethylpyrazole (N‐oed).The crystal structure of [Cu(N‐hed)2(NO3)2] shows it to be mononuclear, with the copper ion at a centre of symmetry. Monoclinic, space group P21/c, a = 7.8176(8), b = 14.93(2), c = 8.4076(8) Å, β = 92.62(2)°, Z = 2; R = 0.036 (Rw = 0.038) for 2132 significant reflections. The copper(II) ion is in a tetragonal‐distorted, elongated‐octahedral environment of two trans pyrazole nitrogen atoms at 1.974(2) Å, two trans hydroxyl oxygen atoms at 1.991(2) Å, and two trans oxygen atoms of monodentate coordinated nitrate anions at 2.561(2) Å. The structure is stabilized by strong intramolecular hydrogen bonds between the hydroxyl group of the coordinated ligand and an oxygen atom of the coordinated nitrate ion with a short O‐O distance of 2.599(2) Å. The metal ions in the compounds [M(N‐hed)2X2] are octahedrally surrounded by two nitrogen and two oxygen atoms of the ligand and by two anion donor atoms (respectively O, N, or Cl).The crystal structure of [Cu(N‐oed)Br]2 shows it to be dinuclear. Triclinic, space group P2/1, a = 4.5213(6), b = 8.484(1), c = 13.052(7) Å, α = 81.50(3), β = 85.79(4), γ = 77.79(2)°, Z = 1, R = 0.148 (Rw = 0.224) for 1534 reflections. The copper ions are bridged by two oxo atoms of the deprotonated ligands with a Cu‐Cu distance of 3.042(4) Å. Each Cu(II) ion is in a distorted square‐planar O2NBr environment. The compounds [Cu(N‐oed)X]2 are diamagnetic and EPR‐silent.
Binding of water and solvent molecules in a 25‐membered‐ring host compound
Authors: Vögtle Fritz , Brodesser Gisela , Nieger Martin , Rissanen Kari 
Published: September 2010

AbstractThe macrocyclic 15‐ and 25‐membered‐ring pyridine oligomers1and2containing three and five methoxy substituents in the 4‐position of the pyridine rings were prepared byMüller‐Röscheisencyclization and then isolated by chromatography. They are attractive as synthetic endobasic receptor molecules. X‐ray structure analysis exhibits the inclusion of hydrogen‐bonded solvent molecules (water and trichloromethane) inside the pentameric macrocycle2.
Catalytic cyclophanes VII. Esterase activity of a bisimidazolyl‐cyclophane
Authors: Chao Ito , Diederich François 
Published: September 2010

AbstractWe report the synthesis of the novel tetraoxa[6.1.6.1]paracyclophane 3 with two imidazole residues attached to the benzene rings of one of the two diphenylmethane spacers that shape the macrocyclic cavity. Four acetic acid residues diverge from the central carbon atoms of the two spacer units and ensure solubility of 3 in water and binary aqueous solvent mixtures. Cyclophane 3 forms stoichiometric inclusion complexes with nitronaphthyl acetates in aqueous phosphate buffers (pH 8) and catalyzes the hydrolysis of bound substrates under turnover conditions.
Synthesis, conformations and redox properties of diametrical calix[4]arenediquinones
Authors: Casnati Alessandro , Comelli Emma , Fabbi Massimo , Bocchi Vittorio , Pochini Andrea , Ungaro Rocco , Mori Giovanni , Ugozzoli Franco , Lanfredi Anna Maria Manotti 
Published: September 2010

AbstractSeveral calix[4]arenediquinones3a‐ehaving quinone moieties in opposite positions (diametrical) have been synthesized by oxidation of 25,27‐dialkoxycalix[4]arenes2a‐ewith Tl(NO3)3· 3H2O in organic solvents. The conformational properties of these compounds have been established in the solid state by X‐ray crystallography and in solution by variable‐temperature dynamic NMR. We found that the calix[4]arenediquinones3a‐eare more flexible than the parent 25,27‐dialkoxycalix[4]arenes2a‐ein solution and tend to assume two different partial cone structures in the solid state, depending on the steric bulkiness of the alkoxy groups. Cyclic voltammetry reveals that the redox properties of calix[4]arenediquinones3a‐edepend on their conformational properties.
Synthesis and X‐ray structure of a novel cavity‐containing dinuclear nickel(II) complex
Authors: Gosling P. A. , Sijbesma R. P. , Nolte R. J. M. , Spek A. L. 
Published: September 2010

AbstractCompounds consisting of a substrate‐binding site and a NiII or MnIII salen moiety have been synthesized. These compounds are able to epoxidise a variety of alkenes in the presence of sodium hypochlorite or iodosylbenzene. The X‐ray structure of the nickel(II) complex is reported.
NMR spectroscopy and molecular‐mechanics calculations in supramolecular chemistry
Authors: Schneider Hans‐Jörg 
Published: September 2010

AbstractThe role of NMR spectroscopy techniques, with emphasis on shielding variations and nuclear Overhauser effects for structural elucidation of host‐guest compounds in solution, is discussed on the basis of selected cyclophane and cyclodextrin associations. Force‐field calculations are shown to be an important prerequisite for such studies, and for evaluation of possible binding modes and mechanisms between host and guest. Present limitations of both computational and NMR spectroscopic methods are pointed out with respect to accurate conformational analyses and to the prediction of association constants.
Dicopper (I) trefoil knots: Demetallation kinetic studies and molecular structures
Authors: Albrecht‐Gary A. M. , Meyer M. , Dietrich‐Buchecker C. O. , Sauvage J. P. , Guilhem J. , Pascard C. 
Published: September 2010

AbstractX‐ray structures of knotted dicopper(I) complexes and demetallation kinetic studies of trefoil knots and related face‐to‐face complexes are presented and discussed.
A new approach to controlling catenated structures
Authors: Amabilino David B. , Stoddart J. Fraser 
Published: September 2010

AbstractA [2]catenane comprised of a macrocyclic polyether, analagous to bisparaphenylene 34‐crown‐10 ‐ but incorporating catechol units in its tetraethyleneglycol chains – and the cyclobis(paraquat‐p‐phenylene) tetracation, has been self‐assembled and shown to exist in solution as a non‐equimolar mixture of translational isomers.
Use of (chloromethyl) dimethylphenylsilane in sugar chemistry. Stereo‐controlled approach to destomic acid and 1‐deoxy‐nojirimycin
Authors: Smid P. , Schipper F. J. M. , Broxterman H. J. G. , Boons G. J. P. H. , van der Marel G. A. , van Boom J. H. 
Published: September 2010

AbstractAddition of [(phenyldimethylsilyl)methyl]magnesium chloride (1d) to 1,2:3,4‐di‐O‐iso‐propylidene‐α‐D‐galacto‐hexodialdo‐1,5‐pyranose, and further processing of the resulting anti‐α‐hydroxy‐silane adduct by a well‐established sequence of reactions, gives a precursor to destomic acid 2. Similarly, addition of the Grignard reagent 1d to 3‐O‐benzyl‐1,2‐O‐isopropylidene‐α‐D‐xylo‐pentodialdo‐1,4‐furanose proceeds with a high degree of stereoselectivity to give, after further elaboration of the syn‐α‐hydroxy‐silane adduct, the antibiotic 1‐deoxynojirimycin.
Mechanistic study of decomposition of cyclohexyl hydroperoxide catalysed by manganese(III) tetraarylporphyrins
Authors: Hansen Carola B. , Mul Guido , Tabor Roland B. J. , Drenth Wiendelt 
Published: September 2010

AbstractThe reaction between manganese(III) tetraarylporphyrins and cyclohexyl hydroperoxide has been investigated. Since pyridine increases the decomposition rate of cyclohexyl hydroperoxide, all experiments were performed in the presence of pyridine. Experiments with 2,6‐di‐tert‐butylpyridine showed that pyridine increases the reaction rate by ligation to the manganese porphyrin as well as by acting as a base. Cyclohexyl hydroperoxide is decomposed into cyclohexanol and cyclohexanone. Since neither 3,3,5,5‐tetramethylcyclohexanol nor cyclohexanol‐d12 are oxidized under these reaction conditions, cyclohexanone is formed directly from the peroxide and not by oxidation of the alcohol. During the reaction, a manganese(V)oxo porphyrin complex is formed. This complex may react with (i) the peroxide under formation of cyclohexanol and molecular oxygen, (ii) the solvent cyclohexane, or (iii) manganese(III) porphyrin. The latter reaction leads to destruction of the catalyst. This destruction is prevented by introduction of bulky groups on the ortho positions of the phenyl. The scission of the hydroperoxide is suggested to be heterolytic. It is also base‐catalysed. The rate‐determining step in the decomposition of cyclohexyl hydroperoxide is scission of the oxygenoxygen bond of the manganese peroxyl porphyrin complex. A mechanism in line with the kinetic data is proposed.
Hydrolysis of 4‐nitrophenyl esters of picolinic acid and N‐protected amino acids by metalloenzyme models in vesicular assemblies
Authors: Weijnen John G. J. , Koudijs Arie , Tap Paul G. J. A. , Engbersen Johan F. J. 
Published: September 2010

AbstractMixed vesicles of N‐dodecyl‐N,N‐dimethyl‐1‐octadecanaminium bromide (C18C12) and functionalised 1,10‐phenanthroline ligands having two long alkyl chains and a nucleophilic hydroxymethyl (1), (S)‐2‐(hydroxymethyl)pyrrolidine (2) or ephedrine group (3, 4) at the α position, were investigated for their catalytic activities and enantioselectivities in the hydrolysis of 4‐nitrophenyl esters of picolinic acid (PNPP) and N‐protected leucine [D(L)‐Z‐Leu‐PNP and D(L)‐C12‐Lcu‐PNP] in the presence of metal ions. The ZnII complex of the chiral ligand 2 in C18C12 vesicles exhibits the highest activity toward PNPP. The highest enantioselectivity in the stereoselective hydrolysis of D(L)‐C12‐Lcu‐PNP (kLa,obs/kDa,obs = 3.6) was attained with the metallocatalyst 2‐ZnII, whereas with 2‐CuII an inversion of stereoselectivity was observed (kLa,obs/kDa,obs = 0.68). The composition of the matrix in which catalyst and substrate are concentrated, affects the rate of hydrolysis but not the enantioselectivity. The rate of hydrolysis and the stereoselectivity are discussed in terms of the structure of the ligand, coordination geometry of the metal ion and the position of the metalloamphiphile in the surfactant aggregate.
Reactions of thebaine and 6‐demethoxythebaine anions with carbonyl compounds; novel Diels‐Alder adducts from 5β‐substituted thebaines (chemistry of opium alkaloids, Part XXXIX)
Authors: Woudenberg R. H. , Lie T. S. , Maat L. 
Published: September 2010

AbstractReaction of the anions of thebaine and 6‐demethoxythebaine with 2‐propanone gave the 5β‐(dimethylmethanol)‐substituted analogues 3 and 5 and the isomeric C‐7‐substituted morphinan‐5,8‐dienes 4, 6 and 7, respectively. No reaction took place with methanal. Therefore, thebaine‐5β‐methanol (10) was prepared by reacting the anion with alkyl chloroformate followed by lithium aluminium hydride reduction. Diels‐Alder reaction of diene 10 with ethyl acrylate gave the 6α,14α‐ethenoisomorphinan 11. Of the morphinan‐6,8‐dienes 3 and 5, only diene 5 showed a reaction, namely rearrangement followed by cycloaddition with ethyl acrylate, yielding three adducts. The structure of the major adduct 13 was elucidated using 1D‐ and 2D‐NMR techniques and revealed an aporphine‐like structure. Furthermore, the conversion of 11 into a new etorphine analogue 16 was accomplished by treatment with methylmagnesium bromide followed by 3‐O‐demethylation.