Studies on penem and carbapenem. I. Syntheses and oral absorption of ester-type prodrugs of sodium (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3-c arboxylat e

Acyloxyalkyl esters (2a-d), alkyloxycarbonyloxyalkyl esters (2e-g) and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (2h) of (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3- carboxylic acid (1) were synthesized. Enhanced oral absorption was observed in mice reflecting increased lipophilicity, compared with the parent 1 itself. Among them, the ester 2h showed a prolonged plasma level and a large area under the blood concentration-time curve (AUC) in rats. These ester-type prodrugs of penem 1 in phosphate buffer (pH 6.86) were much more stable than those of cephalosporins which easily degraded via isomerization to delta 2 cephalosporins.     

Terpsichorean movements of pentaammineruthenium on pyrimidine and isocytosine ligands

Pentaammineruthenium moves on ambidentate nitrogen heterocycles by both rotation and linkage isomerization, which may affect the biological activity of potential ruthenium metallopharmaceuticals. The rapid rotation rates of [(NH3)5RuIII] coordinated to the exocyclic nitrogens of isocytosine (ICyt) and 6-methylisocytosine (6MeICyt) have been determined by 1H NMR. Since these rotamers can be stabilized by hydrogen bonding between the coordinated ammines and the N1 and N3 endocyclic nitrogens, rotamerization is under pH control. Spectrophotometrically (UV-vis) measured pKa values for the two endocyclic sites for the ICyt complex are 2.78 and 9.98, and for 6MeICyt are 3.06 and 10.21, which are probably weighted averages for ionization from N3 and N1, respectively. Activation parameters for the rotamerizations were determined by variable-temperature NMR at pKa1 < pH < pKa2 for the complexes with (ICyt-kappa N2)-, (6MeICyt kappa N2)-, and 2AmPym kappa N2. For [(6MeICyt kappa N2)(-)-(NH3)5RuIII]2+, delta H* = 1.6 kcal/mol, delta S* = -37 cal/mol K, and Ea = 2.2 kcal/mol. Due to strong RuIII-N pi-bonding, the activation enthalpies are approximately 10 kcal lower than the expected values for the free ligands. Rotameric structure is correlated with pKa values, pH-dependent reduction potentials, and 1H NMR parameters. Linkage isomers of [(2AmPym)(NH3)5Ru]n+ are reported in which RuII is coordinated to the endocyclic nitrogen (N1) and RuIII to the exocyclic nitrogen (N2). The rate constant for the kappa N2-->kappa N1 isomerization as part of an ECE mechanism is 3.9 s-1 at pH 3. The pH dependence of the acid-catalyzed hydrolysis of [(2AmPym kappa N1)(NH3)5Ru]2+ is determined.     

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).     

Five new nortropane alkaloids and six new amino acids from the fruit of Morus alba LINNE growing in Turkey

Investigation of the constituents of the fruits of Morus alba LINNE (Moraceae) afforded five new nortropane alkaloids (1-5) along with nor-psi-tropine (6) and six new amino acids, morusimic acids A-F (7-12). The structures of the new compounds were determined to be 2alpha,3beta-dihydroxynortropane (1), 2beta,3beta-dihydroxynortropane (2), 2alpha,3beta,6exo-trihydroxynortropane (3), 2alpha,3beta,4alpha-rihydroxynortropane (4), 3beta,6exo-dihydroxynortropane (5), (3R)-3-hydroxy-12-[(1S,4S)-4-[(1S)-1-hydroxyethyl]-pyrrolidin-1-yll-dodecanoic acid-3-O-beta-D-glucopyranoside (7), (3R)-3-hydroxy-12-[(1S,4S)-4-[(1S)-1-hydroxyethyl]-pyrrolidin-1-yll-dodecanoic acid (8), (3R)-3-hydroxy-12-1(1R,4R,5S)-4-hydroxy-5-methyl-piperidin-1-yll-dodecanoic acid-3-O-beta-D-glucopyranoside (9), (3R)-3-hydroxy-12-[(1R,4R,5S)-4-hydroxy-5-methyl-piperidin-1-yll-dodecanoic acid (10), (3R)-3-hydroxy-12-[(1R,4R,5S)-4-hydroxy-5-hydroxymethyl-piperidin-1-yl]-dodecanoic acid-3-O-beta-D-glucopyranoside (11), and (3R)-3-hydroxy-12-[(1R,4S,5S)-4-hydroxy-5-methyl-piperidin-1-yl]-dodecanoic acid (12) on the basis of spectral and chemical data.     

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.     

Influence of chirality of the preceding acyl moiety on the cis/trans ratio of the proline peptide bond

We report that the cis/trans ratio of the proline peptide bond can be strongly influenced by the chirality of the acyl residue preceding proline. Acyl moieties derived from (2S)-2,6-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (8) and (2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoic acid (5) in acyl-Pro molecules influence isomerization of the proline peptide bond constraining the omega dihedral angle to the trans orientation. Structures of benzyl (2S)-1-([(2S)-2,6-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl)-2-pyrrolidinecarboxylate (3) derived from 2D (1)H NMR conformational analysis and crystallographic data exhibit only the trans conformation of proline peptide bond. On the other hand the diastereomer 4, which contains an (R) acyl moiety, exhibits two sets of signals in (1)H NMR spectra. The signals were assigned to trans (72%) and cis (28%) conformers. Crystallographic analysis of 4 showed that only the cis conformation is present in the crystalline state. The (1)H NMR chemical shift pattern of three sets of signals observed in 2 was observed also in benzyl (2S)-1-[(2R/S)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoyl]-2-pyrrolidinecarboxylate. (R)-Carboxylic acid 5, after coupling with (S)-ProOBn, yielded benzyl (2S)-1-[(2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoyl]-2-pyrrolidinecarboxylate (6), which in DMSO-d(6) exhibited only the trans conformation of the proline peptide bond. These results suggest that in these particular cases acyl-Pro peptide bond isomerization is strongly influenced by the stereochemistry of the acyl residue preceding proline. (2S)-2,6-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (8) and (2R)-3-methoxy-2-methyl-2-(4-methyl-2-nitrophenoxy)-3-oxopropanoic acid (5) are promising chiral peptidomimetic building blocks that can be used as acyl moieties to force the proline peptide bond into the trans conformation in a variety of acyl-Pro molecules.     

Mononucleotide recognition by cyclic trinuclear palladium(II) complexes containing 4,7-phenanthroline N,N bridges

Reaction of [(dach)Pd(NO3)2] entities (dach = (R,R)-1,2-diaminocyclohexane, (S,S)-1,2-diaminocyclohexane) and 4,7-phenanthroline (phen) providing, respectively, 90 and 120 degrees bond angles, leads to the formation of two novel positively charged homochiral cyclic trinuclear metallacalix[3]arene species [((R,R)-1,2-diaminocyclohexane)Pd(phen)]3(NO3)6 (2a) and [((S,S)-1,2-diaminocyclohexane)Pd(phen)]3(NO3)6 (2b). These species have been characterised by 1)H NMR and X-ray diffraction methods (2b), showing that they possess accessible cavities suited for supramolecular recognition processes. We prove, indeed, from 1H NMR studies the inclusion of mononucleotides inside the cavity of the trinuclear species [(ethylenediamino)Pd(phen)]3(6+) (1), [((R,R)-1,2-diaminocyclohexane)Pd(phen)]3(6+) (2a) and [((S,S)-1,2-diaminocyclohexane)Pd(phen)]3(6+) (2b) in aqueous solution. Association constants (K(ass)) range from 85 +/- 6 M(-1) for the interaction between [(ethylenediamine)Pd(phen)]3(6+) and adenosine monophosphate to 37 +/- 4 M(-1) for the interaction between [(1,2-diaminocyclohexane)Pd(phen)]3(6+) and thymidine monophosphate. We invoke the synergy of electrostatic, anion-pi and pi-pi interactions to explain the recognition of mononucleotides inside the cavity of the metallacalix[3]arenes.     

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.     

Chiral Cyclopentane-Based Mimics of D-myo-Inositol 1,4,5-Trisphosphate from D-Glucose

Two routes from D-glucose to chiral, ring-contracted analogs of the second messenger D-myo-inositol 1,4,5-trisphosphate are described. Methyl alpha-D-glucopyranoside was converted by an improved procedure into methyl 4,6-O-(p-methoxybenzylidene)-alpha-D-glucopyranoside (6) and thence into methyl 2-O-benzyl-3,4-bis-O-(p-methoxybenzyl)-alpha-D-gluco-hexodialdopyranoside (1,5) (14) in four steps. In the first ring-contraction method 14 was converted into methyl 2-O-benzyl-6,7-dideoxy-3,4-bis-O-(p-methoxybenzyl)-alpha-D-gluco-hept-6-enopyranoside (1,5) (15), which on sequential treatment with Cp(2)Zr(n-Bu)(2) followed by BF(3).Et(2)O afforded a mixture of (1R,2S,3S,4R,5S)-3-(benzyloxy)-4-hydroxy-1,2-bis[(p-methoxybenzyl)oxy]-5-vinylcyclopentane (16) and its 4S,5R diastereoisomer 17. Removal of the p-methoxybenzyl groups of 16 and subsequent phosphorylation and deprotection afforded the first target compound, (1R,2R,3S,4R,5S)-3-hydroxy-1,2,4-tris(phosphonooxy)-5-vinylcyclopentane (3). In the second route, intermediate 14 was subjected to SmI(2)-mediated ring contraction to give (1R,2S,3S,4R,5S)-3-(benzyloxy)-4-hydroxy-5-(hydroxymethyl)-1,2-bis[(p-methoxybenzyl)oxy]cyclopentane (20). Benzylation of 20 provided (1R,2S,3S,4R,5S)-3-(benzyloxy)-6-[(benzyloxy)methyl]-4-hydroxy-1,2-bis[(p-methoxybenzyl)oxy]cyclopentane (22) and (1R,2S,3S,4R,5S)-3,4-bis(benzyloxy)-5-(hydroxymethyl)-1,2-bis[(p-methoxybenzyl)oxy]cyclopentane (21), which were elaborated to the target trisphosphates (1R,2R,3S,4R,5S)-3-hydroxy-5-(hydroxymethyl)-1,2,4-tris(phosphonooxy)cyclopentane (4) and (1R,2S,3R,4R,5S)-1,2-dihydroxy-3,4-bis(phosphonooxy)-5-[(phosphonooxy)methyl]cyclopentane (5), respectively. Both 3 and 4 mobilized intracellular Ca(2+), but 4 was only a few fold less potent than D-myo-inositol 1,4,5-trisphosphate, demonstrating that effective mimics can be designed that do not bear a six-membered ring.     

Synthetic studies of carbapenem and penem antibiotics. III. A synthesis of a key intermediate for 1 beta-methylcarbapenem.

We synthesized useful intermediates 5 and 6 for 1 beta- and 1 alpha-methylcarbapenems from 4-carboxy-3-[(R)-1-hydroxyethyl]-2-azetidinone 4 as a starting material by using stereoselective hydrogenation and hydroboration, respectively. A practical synthetic route from 4 to the (3S,4S)-4-[(R)-1-carboxyethyl]-3-[(R)-1-hydroxyethyl]-2-azetidinone derivative 1, a useful intermediate for the synthesis of 1 beta-methylcarbapenem antibiotics, was established.     

Stereoselective Synthesis of Ferrocenylamino Acids

Enantiopure ferrocenyl-β, and bis-β-amino acids [(R)-(+)-1 and (R, R)-(+)-2] were prepared from (S)-(+)-sulfinimine (3) and (S, S)-(+)-bis-sulfinimine (4) respectively. The desired sulfinimines [(S)-(+)-3 and (S, S)-(+)-4] were prepared from (S)-Andersen reagent (5) and ferrocenecarboxaldehyde (6) and 1, 1 -ferrocenedicarboxaldehyde (7).     

Design, synthesis, and 1,3-dipolar cycloaddition of (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxides as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones

Optically pure (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1, 4-oxazin-2-one N-oxides [(5R)- and (5S)-2] were designed as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones 1. The nitrones (5R)- and (5S)-2 were synthesized by three-step oxidation of (R)- and (S)-phenylglycinols [(R)- and (S)-3], condensation of the resulting (R)- and (S)-2-hydroxylamino-2-phenylethanols [(R)- and (S)-5] with glyoxylic acid, and cyclization of the intermediary nitrones (R)- and (S)-6b. The nitrone (5R)-2reacted with olefins 7-14 under mild conditions to afford the corresponding cycloadducts 15-22 as the main products via the least sterically demanding exo modes. Cycloadduct 30 obtained from (5S)-2 and cyclopentadiene was effectively elaborated to (1S,4S, 5R)-4-benzyloxycarbonylamino-2-oxabicyclo[3.3.0]oct-7-en-3-one (28), the key synthetic intermediate of carbocyclic polyoxin C.     

Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related alpha-amino acids

The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1), an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74% yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate with (+)-camphorsulfonyloxaziridine at -78 degrees C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-piperidinedicarboxylate ((5R)-5a) under reductive conditions afforded the corresponding 1,2-diol (17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-link (+)-pyridinoline (2a).     

Conformationally tailored N-[(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)carbonyl]proline templates as molecular tools for the design of peptidomimetics. Design and synthesis of fibrinogen receptor antagonists

The proline peptide bond was shown by 2D proton NMR studies to exist exclusively in the trans conformation in benzyl (2S)-1-[[(2S)-2-methyl-6-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-11], benzyl (2S)-1-[[(2S)-2-methyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-9], and in the corresponding 6-amino and 7-amino carboxylic acids (S,S)-3 and (S,S)-4. On the other hand, the diastereomers (R,S)-11 and (R,S)-9 containing an (R)[2-methyl-6/7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety, and the diastereoisomers (R,S)-3 and (R,S)-4 incorporating an (R)[6/7-amino-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety were found to exist as equilibria of trans(63-83%) and cis(17-37%) isomers. These conformationally defined templates were applied in the construction of RGD mimetics possessing antagonistic activity at the platelet fibrinogen receptor.     

Synthesis and pharmacological effects of optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]-ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate hydrochloride

Optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate [(S)-(+)-1 and (R)-(-)-1] hydrochlorides were synthesized with high optical purities from (R)-(-)- and (S)-(+)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)- 3-pyridinecarboxylic acids [(R)-(-)-6 and (S)-(+)-6], which are available from (+/-)-6 by optical resolution using quinidine and cinchonidine, respectively. From pharmacological investigations of (S)-(+)-1 and (R)-(-)-1 such as the antihypertensive effect on spontaneously hypertensive rats and inhibition of [3H]nimodipine binding to rat cardiac membrane homogenate, the active form of 1 was defined to be the (4S)-(+)-enantiomer of 1.     

C3-chiral tripodal amido complexes

A comprehensive study into the coordination chemistry of two C3-chiral tripodal amido ligands has been carried out. The amido ligands contain a trisilylmethane backbone and chiral peripheral substituents. The amine precursors. HC(SiMe2NH[(S)-1-phenylethyl]]3 (1) and HC[SiMe2NH[(R)-1-indanyl]]3 (2) were found to be in equilibrium in solution with the cyclic diamines HC[SiMe2N[(S)-1-phenylethyl]2](SiMe2NH-[(S)-1-phenylethyl]] (3) and HC[SiMe2NH[(R)-1-indanyl]][SiMe2NH[(R)-1-indanyl]) (4), which are generated upon ejection of one molecule of the chiral primary amine. Reaction of these equilibrium mixtures with three molar equivalents of butyllithium instantaneously gave the trilithium triamides HC[SiMe2N(Li)[(S)-1-phenylethyl]]3 (5) and HC[SiMe2N(Li)[(R)-1-indanyl]]3 (6), both of which were characterised by an X-ray diffraction study. Both lithium compounds possess a central heteroadamantane core, in which the two-coordinate Li atoms are additionally weakly solvated by the three aryl groups of the chiral peripheral substituents, the Li-C contacts being in the range of 2.65-2.73 A. Reaction of 5 and 6 with [TiCl4(thf)2] and ZrCl4 gave the corresponding amido complexes [TiCl-[HC[SiMe2N[(S)-1-phenylethyl]]3]] (7), [TiCl(HC[SiMe2N[(R)-1-indanyl]]3]] (8), [ZrCl[HC[SiMe2N[(S)-1-phenylethyl]]3]] (9) and [ZrCl[HC[SiMe2N[(R)-1-indanyl]]3]] (10), respectively. Of these, compound 7 was structurally characterised by X-ray structure analysis and was shown to possess a C3-symmetrical arrangement of the tripod ligand. The chiral anionic dinuclear complex [Li-(OEt2)4][Zr2Cl3[HC[SiMe2N[(S)-1-phenylethyl]]3]2] (11) was isolated from reaction mixtures leading to 9. An X-ray diffraction study established its dimeric structure, in which the chiral amido ligands cap the two metal centres, which are linked through three symmetrically arranged, bridging chloro ligands. Reaction of 9 and 10 with a series of alkyl Grignard and alkyllithium reagents yielded the corresponding alkylzirconium complexes. X-ray structure analyses of [Zr(CH3)[HC[SiMe2N[(S)-1-phenylethyl]]3]] (12) and [Zr(CH3)-[HC[SiMe2N)[(R)-1-indanyl]]3]] (20) established their detailed molecular arrangements. While the reaction of 12 with the aryl ketones PhC(O)R (R = CH = CHPh, iPr, Et) gave the corresponding C-O insertion products, which contain an additional chiral centre in the alkoxy group, with low stereoselectivity (0-40% de). The corresponding conversions with several aryl aldehydes yielded the alkoxo complexes with high stereoselectivity. Upon hydrolysis, the chiral alcohols were isolated and shown to have enantiomeric excesses between 68 and 82%. High stereodiscrimination was also observed in the insertion reactions of several chiral ketones and aldehydes. However, this was shown to originate primarily from the chirality of the substrate. In analogous experiments with carbonyl compounds, the ethyl- and butyl-zirconium analogues of 12 did not undergo CO insertion into the metal-alkyl bond. Instead, beta-elimination and formal insertion into the metal-hydride bond occurred. It was found that the elimination of the alkene was induced by     

Four new 3,5-cyclosteroidal saponins from Dracaena surculosa

Further search for steroidal compounds contained in Dracaena surculosa (Agavaceae) led to the isolation of two new 3,5-cyclospirostanol saponins (1, 2) and two new 3,5-cyclofurostanol saponins (3, 4). Their structural assignment was established by spectroscopic analysis and a few chemical transformations as (24S,25R)-1beta-[(beta-D-fucopyranosyl)oxy]-6beta-hydroxy-3alpha,5alpha-cyclospirostan-24-yl beta-D-glucopyranoside (1), (24S,25R)-1beta-[(beta-D-glucopyranosyl)oxy]-6beta-hydroxy-3alpha,5alpha-cyclospirostan-24-yl beta-D-glucopyranoside (2), (25S)-1beta-[(beta-D-glucopyranosyl)oxy]-6beta-hydroxy-22alpha-methoxy-3alpha,5alpha-cyclofurostan-26-yl beta-D-glucopyranoside (3), and (25S)-1beta-[(beta-D-fucopyranosyl)oxy]-6beta-hydroxy-22alpha-methoxy-3alpha,5alpha-cyclofurostan-26-yl beta-D-glucopyranoside (4), respectively.     

Three new megastigmane glucopyranosides from the Cardamine komarovii

Three new megastigmane glucopyranosides, komaroveside A [(3S,4R,5Z,7E)-3,4-dihydroxy-5,7-megastigmadien-9-one-3-O-β-D-glucopyranoside] (1), komaroveside B [(3S,4S,5S,6R,7E)-5,6-epoxy-3,4-dihydroxy-7-megastigmen-9-one-3-O-β-D-glucopyranoside] (2) and komaroveside C [(3S,4S,5S,6R,7E,9S)-5,6-epoxy-3,4,9-trihydroxy-7-megastigmen-3-O-β-D-glucopyranoside] (3) were isolated, together with eight known compounds, from Cardamine komarovii. The identification of these compounds and the elucidation of their structures were based on 1D- and 2D-NMR spectral data analysis. The isolated compounds were tested for their cytotoxicity against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, HCT15) in vitro using the sulforhodamine B bioassay.     

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.     

A new, non-iterative asymmetric synthesis of long-chain 1,3-polyols

A new approach to the asymmetric synthesis of pentadeca-1,3,5,7,9,11,13,15-octols and their derivatives is presented. It is based on the Sharpless asymmetric dihydroxylation (AD) of 4,4'-methylene[(1R,1'S,6R,6'S)-6-acetoxycyclohept-3-en-1-yl]bis(4-methoxybenzoate) (9), derived from a double [3+4] cycloaddition of the 1,1,3-trichloro-2-oxyallyl cation with 2,2'-methylenedifuran (1). The diol (-)-10, obtained in 98.4% ee from 9 with "AD-mix-beta(5x), was oxidised into (2R and 2S,4S,6R)-tetrahydro-2-hydroxy-6-((4S,6S)-(6-hydroxy-4-[(4-methoxybenzoyl)oxy]cyclohept-1-en-1-yl)-2-oxopropyl)-2H-pyran-4-yl 4-methoxybenzoates ((-)-18). By the combinations of Evans' anti and Nasaraka's syn reductions of aldol (-)-18 with the double Mitsunobu reaction, 16 diastereomeric pentadeca-1,3,5,7,9,11,13,15-octols and analogues can be obtained, in principle, with high enantio- and diastereoselectivities.