Asymmetric Synthesis and DNA Intercalation of (-)-6-[[(Aminoalkyl)oxy]methyl]-4-demethoxy-6,7- dideoxydaunomycinones(1)(,)

The BF(3).Et(2)O-promoted Diels-Alder addition of 1-acetylvinyl RADO(Et)-ate (RADO(Et)-ate = 3-ethyl-2-oxo-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate) to 1-(dimethoxymethyl)-2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptane led to one major monoadduct that added to 1,2-didehydrobenzene and was converted into (-)-4-demethoxy-7-deoxydaunomycinone and (2R)-12-acetoxy-2-acetyl-5-(bromomethyl)-1,2,3,4-tetrahydronaphthacen-2-yl RADO(Et)-ate. The latter compound was used to construct (8R)-8-acetyl-6,8-dihydroxy-11-[[(3'-[(aminopropyl)oxy]-, -4'-[(aminobutyl)oxy], and -5'-[(aminopentyl)oxy]methyl]-7,8,9,10-tetrahydronaphthacene-5,12-dione hydrochloride (-)-8, (-)-9, (-)-10, respectively, as well as (8R)-8-acetyl-6,8-dihydroxy-11- [[[2'-[(3"-aminopropyl)amino]ethyl]oxy]- ((-)-11) and -[[3'-[(3"-aminopropyl)amino]propyl]oxy]methyl]-7,8,9, 10-tetrahydronaphthacene-5,12-dione hydrochloride ((-)-12). (8R)-8-Acetyl-6,8-dihydroxy-11-[[(alpha-L-daunosaminyl)oxy]methyl]-7,8,9,10-tetrahydronaphthacene-5,12-dione hydrochloride ((-)-13), a mimic of idarubicin, was also prepared. Absorbance and fluorescence titration experiments showed (-)-8, (-)-9, and (-)-10 to intercalate calf thymus DNA whereas (-)-11, (-)-12, and (-)-13 did not. The best intercalator was (-)-9 (K(b) = (1.1 +/- 0.1) x 10(5) M(-)(1)) with the [(4'-aminobutyl)oxy]methyl chain. Inhibition of topoisomerase II-induced DNA strand religation was observed for (-)-8 at a concentration of 50 &mgr;M.     

Studies on the constituents of Broussonetia species X. Six new alkaloids from Broussonetia kazinoki Sieb.

Six new alkaloids, broussonetines W, X, M1, U1, J3, and J2 (1-6) were isolated from the branches of Broussonetia kazinoki SIEB. (Moraceae) as minor constituents. They were formulated as (2R,3R,4R,5R)-2-hydroxy-methyl-3,4-dihydroxy-5-17-(cyclohexy-2-on-1(6)-enyl)heptyllpyrrolidine (1), (2R,3S,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-17-(cyclohexy-2-on-1(6)-enyl)heptyl]pyrrolidine-4-O-beta-D-glucopyranoside (2), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(9R)-9,13-dihydroxytridecyl]- pyrrolidine (3), (2S,3S,4S)-2-hydroxymethyl-3,4-dihydroxy-5-(10-oxo-13-hydroxytridecyl)-5- pyrroline (4), (2R)-2-[(IS,2S)-1,2-dihydroxy-8-1(2R,3R,4R,5R)-5-(2-hydroxymethyl-3,4-dihydroxy-1-acetylpyrrolidinyl)loctyl]piperidine (5), (2R)-2-[(1S,2S)-1,2-dihydroxy-8-[(2R,3R, 4R,5R)-5-(2-hydroxymethy]-3,4-dihydroxypyrrolidinyl)]octyl]piperidine (6).     

Stereochemistry of the cyclization-rearrangement of (+)-copalyl diphosphate to (-)-abietadiene catalyzed by recombinant abietadiene synthase from Abies grandis

[reaction: see text] Syntheses and enzymatic cyclizations of 8alpha-hydroxy-17-nor copalyl diphosphate (8a), (15R)-[15-2H1] 8b, and (15R,17E)-[15-3H1,17-2H1] copalyl diphosphate ([2H,3H] 2) catalyzed by recombinant abietadiene synthase (rAS) gave 17-nor manoyl oxide (9a), (16E)-[16-2H1] 9b, and (15S,16R)-[16-2H1,16-3H1] abietadiene ([2H1,3H1] 4), respectively. These and other results indicate that conversion of CPP (2) to abietadiene (4) occurs by anti S(N)' cyclization to a sandaracopimar-15-en-8-yl carbocation intermediate (13+, 13beta-methyl) followed by hydrogen transfer and methyl migration suprafacially on the si face of the vinyl group.     

Selaginellin A and B, two novel natural pigments isolated from Selaginella tamariscina

Two new unusual natural pigments were first isolated from the whole herbs of Selaginella tamariscina. The structure of selaginellin A (1) was established as (R,S)-4-[(4'-hydroxy-3-((4-hydroxyphenyl)ethynyl)biphenyl-2-yl)(4-hydroxyphenyl)methylene]-2,5-cyclohexadien-1-one and selaginellin B (2) as (R,S)-4-[(4'-methoxy-4-(methyl)-3-((4-methoxyphenyl)ethynyl)biphenyl-2-yl)(4-methoxyphenyl)methylene]-2,5-cyclohexadien-1-one, along with four known biflavonoids, amentoflavone (3), hinokiflavone (4), heveaflavone (5), and 7'-O-methylamentoflavone (6). Their chemical structures were elucidated by spectral analysis of electrospray ionization mass spectroscopy (ESI-MS), one-dimensional nuclear magnetic resonance spectroscopy (1D-NMR) and two-dimensional-nuclear magnetic resonance spectroscopy (2D-NMR) including (1)H-NMR, (13)C-NMR, distortionless enhancement by polarization transfer (DEPT) and heteronuclear multiple bond coherence (HMBC), and single-crystal X-ray diffraction techniques.     

Trialkylsilyl group-directed regioselective transformations of 2-(alk-1-yn-1-yl)-2-(trialkylsilyl)-1,3-dithianes to alkynylcyclopropanes and enynes

[reaction: see text] The Cp(2)Ti[P(OEt)(3)](2)-promoted reaction of 2-(alk-1-yn-1-yl)-2-(trialkylsilyl)-1,3-dithianes with 1-alkenes regioselectively produced [(trialkylsilyl)ethynyl]cyclopropanes with a formal allylic rearrangement. The reaction of the thioacetals with ketones proceeded with the same regioselectivity to produce 1-(trialkylsilyl)alk-3-en-1-ynes predominantly. It is suggested that these reactions proceed via the formation of titanium alpha-(silylethynyl)carbene complexes Cp(2)Ti=C(R)CCSi in preference to their regioisomers, alpha-silylalkynylcarbene complexes Cp(2)Ti=C(Si)CCR.     

Simiranes A and B: erythroxylanes diterpenes and other compounds from Simira eliezeriana (Rubiaceae)

The first phytochemical study of Simira eliezeriana Peixoto (Rubiaceae) allowed the isolation and structural determination of two new diterpenes named simirane A [(5R,6R,8R,9R,10S,11S,13S)-6β,11β-dihydroxy-2,4(18),15-erythroxylatrien-1-one] (1) and simirane B [(5S,8R,9R,10S,11S,13S)-11β-hydroxy-2,4(18),15-erythroxylatrien-1-one] (2), together with seven known compounds: sitosterol (3), stigmasterol (4), campesterol (5), coniferaldehyde (6), vanillin (7), pinoresinol (8) and harman (9) from the bark of the plant. The structures of the compounds were established on the basis of spectroscopic methods, including 1-D and 2-D NMR, HRESI-MS and CD analysis and comparisons with available literature data of known compounds.     

Nitrosylated iron-thiolate-sulfinate complexes with {Fe(NO)}6/7 electronic cores: relevance to the transformation between the active and inactive NO-bound forms of iron-containing nitrile hydratases

The five-coordinated iron-thiolate nitrosyl complexes [(NO)Fe(S,S-C6H3R)2]- (R = H (1), m-CH3 (2)), [(NO)Fe(S,S-C6H2-3,6-Cl2)2]- (3), [(NO)Fe(S,S-C6H3R)2]2- (R = H (10), m-CH3 (11)), and [(NO)Fe(S,S-C6H2-3,6-Cl2)2]2- (12) have been isolated and structurally characterized. Sulfur oxygenation of iron-thiolate nitrosyl complexes 1-3 containing the {Fe(NO)}6 core was triggered by O2 to yield the S-bonded monosulfinate iron species [(NO)Fe(S,SO2-C6H3R)(S,S-C6H3R)]- (R = H (4), m-CH3 (5)) and [(NO)Fe(S,SO2-C6H2-3,6-Cl2)(S,S-C6H2-3,6-Cl2)]2(2-) (6), respectively. In contrast, attack of O2 on the {Fe(NO)}7 complex 10 led to the formation of complex 1 accompanied by the minor products, [Fe(S,S-C6H4)2]2(2-) and [NO3]- (yield 9%). Reduction of complexes 4-6 by [EtS]- in CH3CN-THF yielded [(NO)Fe(S,SO2-C6H3R)(S,S-C6H3R)]2- (R = H (7), m-CH3 (8)) and [(NO)Fe(S,SO2-C6H2-3,6-Cl2)(S,S-C6H2-3,6-Cl2)]2- (9) along with (EtS)2 identified by 1H NMR. Compared to complex 10, complexes 7-9 with the less electron-donating sulfinate ligand coordinated to the {Fe(NO)}7 core were oxidized by O2 to yield complexes 4-6. Obviously, the electronic perturbation of the {Fe(NO)}7 core caused by the coordinated sulfinate in complexes 7-9 may serve to regulate the reactivity of complexes 7-9 toward O2. The iron-sulfinate nitrosyl species with the {Fe(NO)}6/7 core exhibit the photolabilization of sulfur-bound [O] moiety. Complexes 1-4-7-10 (or 2-5-8-11 and 3-6-9-12) are interconvertible under sulfur oxygenation, redox processes, and photolysis, respectively.     

Binding and redox properties of iron(II) bonded to an oxo surface modeled by calix[4]arene

The syntheses of the parent compounds [(p-Bu(t)-calix[4]-(O)2(OR)2)Fe-L] [R = Me, L = THF, 5; R = Bu(n), L = THF, 6; R = PhCH2, L = THF, 7; R = SiMe3, L = none, 8] have been performed by reacting the protonated form of the dialkylcalix[4]arene with [Fe2Mes4] [Mes = 2,4,6-Me3C6H2]. All of them undergo one-electron oxidative functionalization. By use of different oxidizing agents, the following iron(III) derivatives have been obtained: [(p-Bu(t)-calix[4]-(O)2(OR)2)Fe-X] [X = Cl, R = Me, 9; X = I, R = Me, 10] and [(p-Bu(t)-calix[4]-(O)2(OR)2)2Fe2(mu-X] [X = O, R = Me, 11; X = O, R = Bu(n), 12; X = S, R = Me, 13], 9 and 10 being particularly appropriate for a further functionalization of the metal. The last three display typical antiferromagnetic behavior [J = -78.6 cm-1, 11; J = -64.1 cm-1, 13]. In the case of 7 and 8, the reaction with O2 led to the dealkylation of one of the alkoxo groups, with the formation of a dimeric iron(III) derivative ([mu-p-Bu(t)-calix[4]-(O)3(OR))2Fe2] [R = PhCH2, 14; R = SiMe3, 15] [J = -9.8 cm-1]. The reaction of the parent compounds with ButNC and diazoalkanes led to the formation of [Fe=C] functionalities supported by a calix[4]arene oxo surface. The following compounds have been isolated and characterized: ([p-Bu(t)-calix[4]-(O)2(OR)2)Fe=CNBut] [R = SiMe3, 16, nu CN = 2175 cm-1], ([p-Bu(t)-calix[4]-(O)2(OR)2)Fe=CPh2] [R = Me, 17; R = PhCH2, 18; R = SiMe3, 19]. The three carbene complexes 17-19 display quite an unusual high-spin state, which is a consequence of the formation of a weak pi interaction between the metal and the carbene carbon, as confirmed by the extended Hückel calculations. The carbene functionality has been removed from the iron center in the reaction with O2 and HCl. The proposed structures have been supported by X-ray analyses of complexes 8, 9, 12, 14, 16, 17, and 19.     

Synthesis and Structure of the Ruthenium(II) Complexes [(eta-C(5)Me(5))Ru(NO)(bipy)](2+) and [(eta-C(5)Me(5))Ru(NO)(dppz)](2+). DNA Cleavage by an Organometallic dppz Complex (bipy = 2,2'-Bipyridine; dppz = Dipyrido[3,2-a:2',3'-c]phenazine)

The salts [(eta-C(5)Me(5))Ru(NO)(bipy)][OTf](2) (1[OTf](2)) and [(eta-C(5)Me(5))Ru(NO)(dppz)][OTf](2) (2[OTf](2)) are obtained from the treatment of (eta-C(5)Me(5))Ru(NO)(OTf)(2) with 2,2'-bipyridine (bipy) or dipyrido[3,2-a:2',3'-c]phenazine (dppz) (OTf = OSO(2)CF(3)). X-ray data for 1[OTf](2): monoclinic space group P2(1)/c, a = 11.553 (4) ?, b = 16.517 (5) ?, c = 14.719 (4) ?, beta = 94.01 (2) degrees, V = 2802 (2) ?(3), Z = 4, R1 = 0.0698. X-ray data for 2[OTf](2): monoclinic space group P2(1)/c, a = 8.911 (2) ?, b = 30.516 (5) ?, c = 24.622 (4) ?, beta = 99.02 (1) degrees, V = 6613 (2) ?(3), Z = 8, R1 = 0.0789. Both 1[OTf](2) and 2[OTf](2) are soluble in water where they exhibit irreversible electrochemical oxidation and reduction. A fluorescence-monitored titration of a DNA solution containing 2[OTf](2) with ethidium bromide provides evidence that 2(2+) intercalates into DNA with a binding constant greater than 10(6) M(-)(1). DNA cleavage occurs when the DNA solutions containing 2[OTf](2) are photolyzed or treated with H(2)O(2) or K(2)S(2)O(8).     

Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4- triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]- 3(2H,4H)-1,2,4-triazolone and its analogs

A new route for the synthesis of the optically active antifungal azole TAK-187, 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-tria zol-1- yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4 - triazolone, was established. The key synthetic intermediate, 2-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2,2,3,3- tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (8), was prepared starting from the esters (11a, b) of (S)-lactic acid in a stereocontrolled manner. This optically active propiophenone derivative 8 was converted to the one carbon-elongated (1R,2S)-diol 7, which was then reacted with 1H-1,2,4-triazole to yield TAK-187. This newly developed route was applied to the synthesis of the analogs (25a, b--28a, b) containing an imidazolone or imidazolidinone nucleus.     

Homodinuclear iron thiolate nitrosyl compounds [(ON)Fe(S,S-C6H4)2 Fe(NO)2]- and [(ON)Fe(SO2,S-C6H4)(S,S-C6H4)Fe(NO)2]- with {Fe(NO)}7-{Fe(NO)2}9 electronic coupling: new members of a class of dinitrosyl iron complexes

Reaction of Fe(CO)2(NO)2 and [(ON)Fe(S,S-C6H3R)2]- (R = H (1), CH3 (1-Me))/[(ON)Fe(SO2,S-C6H4)(S,S-C6H4)]- (4) in THF afforded the diiron thiolate/sulfinate nitrosyl complexes [(ON)Fe(S,S-C6H3R)2 Fe(NO)2]- (R = H (2), CH3 (2-Me)) and [(ON)Fe(S,SO2-C6H4)(S,S-C6H4)Fe(NO)2]- (3), respectively. The average N-O bond lengths ([Fe(NO)2] unit) of 1.167(3) and 1.162(4) A in complexes 2 and 3 are consistent with the average N-O bond length of 1.165 A observed in the other structurally characterized dinitrosyl iron complexes with an {Fe(NO)2}9 core. The lower nu(15NO) value (1682 cm(-1) (KBr)) of the [(15NO)FeS4] fragment of [(15NO)Fe(S,S-C6H3CH3)2 Fe(NO)2]- (2-Me-15N), compared to that of [(15NO)Fe(S,S-C6H3CH3)2]- (1-Me-15N) (1727 cm(-1) (KBr)), implicates the electron transfer from {Fe(NO)2}10 Fe(CO)2(NO)2 to complex 1-Me/1 may occur in the process of formation of complex 2-Me/2. Then, the electronic structures of the [(NO)FeS4] and [S2Fe(NO)2] cores of complexes 2, 2-Me, and 3 were best assigned according to the Feltham-Enemark notation as the {Fe(NO)}7-{Fe(NO)2}9 coupling (antiferromagnetic interaction with a J value of -182 cm(-1) for complex 2) to account for the absence of paramagnetism (SQUID) and the EPR signal. On the basis of Fe-N(O) and N-O bond distances, the dinitrosyliron {L2Fe(NO)2} derivatives having an Fe-N(O) distance of approximately 1.670 A and a N-O distance of approximately 1.165 A are best assigned as {Fe(NO)2}9 electronic structures, whereas the Fe-N(O) distance of approximately 1.650 A and N-O distance of approximately 1.190 A probably imply an {Fe(NO)2}10 electronic structure.     

Total synthesis and structural elucidation of (-)-maurenone

[reaction: see text] The total synthesis of (2S,3S)-2,3-dihydro-6-[(1'S, 2'R)-2-hydroxy-1-methylbutyl]-3,5-dimethyl-2-[(1'S)-1-methylpropyl]-4H-pyran-4-one (3), the (-)enantiomer of the marine polypropionate, maurenone, was achieved in nine linear steps (13% overall yield) from (R)-2-benzylpentan-3-one ((R)-14) and (R)-2-benzoyloxypentan-3-one ((R)-15). Key fragments were synthesized using highly diastereoselective syn and anti boron aldol reactions and were coupled using a lithium-mediated aldol reaction. Trifluoroacetic acid-promoted cyclization/dehydration was then used to install the gamma-dihydropyrone ring. Eight isomers of one enantiomeric series were synthesized by coupling two ketones with each of four aldehydes. Comparison of the 13C NMR data for the eight isomers with that reported for maurenone established the relative stereochemistry of the natural product.     

Asymmetric Synthesis and Crystal Structure of （-）-N-[（3R）-3-Cyclohexyl]-3-phenylpropananoyl]bornane-10,2-sultam

The title compound (-)-N-[(3R)-3-cyclohexyl]-3-phenylpropananoyl]bornane-10,2sultam (C 25 H 35 NO 3 S,M r=429.60),a derivative of camphorsultam,crystallizes in the monoclinic space group P2 1 /c with a=10.3301(7),b=19.4040(13),c=11.8106(8),β=100.5580(10)°,V=2327.3(3) 3,Z=4,D c=1.226 g/cm 3,λ=0.71073,μ(MoKα)=0.165 mm-1 and F(000)=928.X-ray diffraction analysis reveals that the six-membered ring of sultam shows a boat form (Fig.1).The planes constructed by (C(4),C(5),C(6),C(7)) and (C(7),C(8),C(9),C(4)) form a dihedral angle of 69.5°.The C(1)-C(2)-C(3) plane forms dihedral angles to the aforementioned planes of 89.8(1) and 85.9(3)°,respectively.And molecules are linked via hydrogen bonding (C-H···N/O) interactions.     

Vanadium complexes of the N(CH2CH2S)3(3-) and O(CH2CH2S)2(2-) ligands with coligands relevant to nitrogen fixation processes

Vanadium(III) and vanadium(V) complexes derived from the tris(2-thiolatoethyl)amine ligand [(NS3)3-] and the bis(2-thiolatoethyl)ether ligand [(OS2)2-] have been synthesized with the aim of investigating the potential of these vanadium sites to bind dinitrogen and activate its reduction. Evidence is presented for the transient existence of (V(NS3)(N2)V(NS3), and a series of mononuclear complexes containing hydrazine, hydrazide, imide, ammine, organic cyanide, and isocyanide ligands has been prepared and the chemistry of these complexes investigated. [V(NS3)O] (1) reacts with an excess of N2H4 to give, probably via the intermediates (V(NS3)(NNH2) (2a) and (V(NS3)(N2)V(NS3) (3), the V(III) adduct [V(NS3)(N2H4)] (4). If 1 is treated with 0.5 mol of N2H4, 0.5 mol of N2 is evolved and green, insoluble [(V(NS3))n] (5) results. Compound 4 is converted by disproportionation to [V(NS3)(NH3)] (6), but 4 does not act as a catalyst for disproportionation of N2H4 nor does it act as a catalyst for its reduction by Zn/HOC6H3Pri2-2,6. Compound 1 reacts with NR1(2)NR2(2) (R1 = H or SiMe3; R2(2) = Me2, MePh, or HPh) to give the hydrazide complexes [V(NS3)(NNR2(2)] (R2(2) = Me2, 2b; R2(2) = MePh, 2c; R2(2) = HPh, 2d), which are not protonated by anhydrous HBr nor are they reduced by Zn/HOC6H3Pri2-2,6. Compound 2b can also be prepared by reaction of [V(NNMe2)(dipp)3] (dipp = OC6H3Pri2-2,6) with NS3H3. N2H4 is displaced quantitatively from 4 by anions to give the salts [NR3(4)][V(NS3)X] (X = Cl, R3 = Et, 7a; X = Cl, R3 = Ph, 7b; X = Br, R3 = Et, 7c; X = N3, R3 = Bu(n), 7d; X = N3, R3 = Et, 7e; X = CN, R3 = Et, 7f). Compound 6 loses NH3 thermally to give 5, which can also be prepared from [VCl3(THF)3] and NS3H3/LiBun. Displacement of NH3 from 6 by ligands L gives the adducts [V(NS3)(L)] (L = MeCN, nu CN 2264 cm-1, 8a; L = ButNC, nu NC 2173 cm-1, 8b; L = C6H11NC, nu NC 2173 cm-1, 8c). Reaction of 4 with N3SiMe3 gives [V(NS3)(NSiMe3)] (9), which is converted to [V(NS3)(NH)] (10) by hydrolysis and to [V(NS3)(NCPh3)] (11) by reaction with ClCPh3. Compound 10 is converted into 1 by [NMe4]OH and to [V(NS3)NLi(THF)2] (12) by LiNPri in THF. A further range of imido complexes [V(NS3)(NR4)] (R4 = C6H4Y-4 where Y = H (13a), OMe (13b), Me (13c), Cl (13d), Br (13e), NO2 (13f); R4 = C6H4Y-3, where Y = OMe (13g); Cl (13h); R4 = C6H3Y2-3,4, where Y = Me (13i); Cl (13j); R4 = C6H11 (13k)) has been prepared by reaction of 1 with R4NCO. The precursor complex [V(OS2)O(dipp)] (14) [OS2(2-) = O(CH2CH2S)2(2-)] has been prepared from [VO(OPri)3], Hdipp, and OS2H2. It reacts with NH2NMe2 to give [V(OS2)(NNMe2)(dipp)] (15) and with N3SiMe3 to give [V(OS2)(NSiMe3)(dipp)] (16). A second oxide precursor, formulated as [V(OS2)1.5O] (17), has also been obtained, and it reacts with SiMe3NHNMe2 to give [V(OS2)(NNMe2)(OSiMe3)] (18). The X-ray crystal structures of the complexes 2b, 2c, 4, 6, 7a, 8a, 9, 10, 13d, 14, 15, 16, and 18 have been determined, and the 51V NMR and other spectroscopic parameters of the complexes are discussed in terms of electronic effects.     

Catalysis of oxo transfer to prochiral sulfides by oxovanadium(v) compounds that model the active center of haloperoxidases

The catalytic properties of a new class of chiral vanadium compounds--[(S,S,S)-VO(OMe)L1] (5), [(S,S)-VO(OMe)L2] (6), [(S,S)-VO(OMe)L3] (7), and [(R,R,R)-VO(OMe)L4] (8), as well as the system VO(OiPr)(3)/(R,R,R)-H(2)L4 [H(2)L1=(S,S)-bis(2-hydroxypropyl)-(S)-1-phenylethylamine, 1; H(2)L2=(S,S)-bis(2-hydroxypropyl)benzylamine, 2; H(2)L3=(S,S)-bis(2-hydroxypropyl)isopropylamine), 3; (H(2)L4)=(R,R)-bis(2-phenylethanol)-(R)-1-phenylethylamine, 4]--in the asymmetric oxidation of prochiral sulfides by organic hydroperoxides have been investigated. Particular attention has been paid to the factors that guide the discrimination between the two prochiral faces of the sulfides (methyl p-tolyl sulfide and benzyl phenyl sulfide), to steric implications stemming from the oxidant (cumyl hydroperoxide and tert-butyl hydroperoxide), and to the specific complex used. As an example, (S)-methyl p-tolyl sulfoxide was obtained in a 31 % enantiomeric excess by use of cumyl hydroperoxide as oxidant and complex 5 as the catalyst, after 150 min at 0 degrees C and with 100 % conversion of the sulfide. The crystal and molecular structures of 5 and 6 reveal the close relationship between these complexes and the active center of vanadate-dependent haloperoxidases: the vanadium is in a slightly distorted trigonal-bipyramidal environment with the nitrogen and the methoxy group in the axial positions, and the oxo and alkoxide functions of L2 and L3 are the plane. The presence and equilibrium situation of isomers of the catalysts in solution has been investigated by (51)V EXSY and variable-temperature multinuclear NMR spectroscopy. An intermediately formed peroxo (ROO(-)) vanadium complex was detected by (51)V NMR spectroscopy.     

Studies on the constituents of Broussonetia species VIII. Four new pyrrolidine alkaloids, broussonetines R, S, T, and V and a new pyrroline alkaloid, broussonetine U, from Broussonetia kazinoki Sieb

Four new pyrrolidine alkaloids, broussonetines R, S, T, and V and a new pyrroline alkaloid, broussonetine U were isolated from the branches of Broussonetia kazinoki SIEB. (Moraceae) in low yield. Broussonetines R, S and T were formulated as (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R)-1-hydroxy-3-[6-(4-hydroxybutyl)-cyclohexy-2-on-1(6)-enyllpropyl] pyrrolidine (1), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R,10S)-1,10,13-trihydroxytridecyl] pyrrolidine (2), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R,5S)-1,5, 13-trihydroxy-10-oxo-tridecyl] pyrrolidine (3). And broussonetines U and V were proposed to be (2S,3S,4S)-2-hydroxymethyl-3, 4-dihydroxy-5-(9-oxo-13-hydroxytridecyl)-5-pyrroline (4), (2R,3S,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(E)-9-oxo-13-hydroxy-3-tridecenyl] pyrrolidine (5), respectively, by spectroscopic and chemical methods.     

Atmospheric pressure chemical ionization multi-stage mass spectrometry in the characterization of stereoisomeric synthons of cyclopropane amino acids

The mass spectrometric behaviour of (1S,2R)-, (1R,2R)-, (1R,2S)- and (1S,2S)-2-[(S)-2,2-dimethyl-1, 3-dioxolan-4-yl]-1-spiro-?4'[2'-phenyl-5'(4'H)-oxazolone]? cyclopropane (2) and (1S,2R)-, (1R,2R)-, (1R,2S)- and (1S, 2S)-methyl-1-benzamido-2-[(S)-2,2-dimethyl-1, 3-dioxolan-4-yl]cyclopropanecarboxylate (3) was studied under atmospheric pressure ionization conditions and by multi-stage mass spectrometric (MS(n)) experiments performed with an ion trap. Interestingly, by using methanol as solvent, compounds 2 lead to [M + H + CH(3)OH](+) ions which, as proved by collisional experiments, exhibit the same structure of the corresponding compound 3. MS/MS of [MH](+) ions allows a clear characterization of the different stereoisomers, which give rise to specific fragmentation pathways, rationalized with respect to the structure of the neutral molecules.     

Asymmetric synthesis of [2,3-(13)C(2),(15)N]-4-benzyloxy-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazine-2-one via lipase TL-mediated kinetic resolution of benzoin: general procedure for the synthesis of [2,3-(13)C(2),(15)N]-L-alanine.

Lipase TL-mediated kinetic resolution of benzoin proceeded to give the corresponding optically pure (R)-benzoin (R)-1. On the other hand, (S)-benzoin O-acetate (S)-7 could be hydrolyzed without epimerization to give (S)-benzoin (S)-1 under alkaline conditions. Furthermore, both enantiomers of benzoin (1) were converted to [(15)N]-(1R,2S)- and (1S,2R)- 2-amino-1,2-diphenylethanol (3a and 3b), respectively, according to the procedure reported previously. [2,3-(13)C(2),(15)N]-(5S,6R)-4-benzyloxy-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazine-2-one (10) was synthesized from ethyl [1,2-(13)C(2)]bromoacetate and (1R,2S)-2-amino-1,2-diphenylethanol (3b) in three steps. Finally, [2,3-(13)C(2),(15)N]-L-alanine (12) was prepared via alkylation of the lactone 10 and hydrogenation of the alkylated product 11.     

Optically active antifungal azoles. XIII. Synthesis of stereoisomers and metabolites of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456)

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone [(1R,2R)-1: TAK-456] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S,2R)-, (1S,2S)- and (1R,2S)-1] of this compound were prepared as authentic samples to determine the enantiomeric and diastereomeric purity of TAK-456 as well as to compare their in vitro antifungal activity. Pharmacokinetic studies of TAK-456 using rats identified the existence of metabolites in the liver homogenate. The structures of the major metabolites were assigned as 4-hydroxy-2-imidazolidinone (3) and/or 5-hydroxy-2-imidazolidinone (4), based on HPLC and LC/MS/MS analyses. These hydroxylated compounds, 3 and 4, were prepared by reduction of the corresponding imidazolidinediones, 11 and 12, and confirmed to be identical to the metabolites by HPLC. In vitro antifungal activities of the three stereoisomers and the synthesized metabolites were considerably weaker than TAK-456.     

Pentamethylcyclopentadienyl-iridium(III) complexes with pyridylamino ligands: synthesis and applications as asymmetric catalysts for Diels-Alder reactions

Reaction of the dimer [(Cp*IrCl)2(P-Cl)2] with chiral pyridylamino ligands (pyam, L1-L5) in the presence of NaSbF6 gave complexes [Cp*IrCl(pyam)][SbF6] 1-5 as diastereomeric mixtures, which have been fully characterised, including the X-ray molecular structure determination of the complexes (S(Ir),R(N),R(C))-[Cp*IrClL1][SbF6] 1a and (R(Ir),S(N),S(C))-[Cp*IrClL5][SbF6] 5a. Treatment of these cations with AgSbF6 affords the corresponding aqua species [Cp*Ir(pyam)(H2O)][SbF6]2 6-10 which have been also fully characterised. The molecular structure of the complex (S(Ir),R(N),R(C))-[Cp*IrL,(H2O)][SbF6]2 6 has been determined by X-ray diffractometric methods. The aqua complexes [Cp*Ir(pyam)(H2O)][SbF6]2 (6, pyam = L2 (7), L3 (8)) evolve to the cyclometallated species [Cp*Ir{kappa3(N,N',C)-(R)-(C6H4)CH(CH3)NHCH2C5NH4}][SbF6] (11), [Cp*Ir{kappa3(N,N',C)-(R)-(C10H6)CH(CH3)-NHCH2C5NH4)}][SbF6] (12), and [Cp*Ir{kappa3(N,N',C)-(R)-(C10H6)CH(CH3)NHCH2C9NH6)}][SbF6] (13) respectively, via intramolecular activation of an ortho C-H aryl bond. Complexes 6-10 are enantioselective catalysts for the Diels-Alder reaction between methacrolein and cyclopentadiene. Reaction occurs rapidly at room temperature with good exo : endo selectivity (from 81 : 19 to 98 : 2) and moderate enantioselectivity (up to 72%). The involved intermediate Lewis acid-dienophile compounds [Cp*Ir(pyam)(methacrolein)][SbF]2 (pyam = L4 (14), L5 (15)) have been isolated and characterised.