Library

Notes: Changes in chemical shifts of olefinic protons in a number of α,β- and α,β,γ,δ-unsaturated carboxylic acids caused by ionization of the COOH group were investigated. The ionization shifts of α-H-atoms are -0.09 to 0.07 ppm, those of β-H-atoms are 0.32-0.47 ppm. The ionization shifts of δ-H-atoms are substantially larger than those of γ-H-atoms. The ionization shifts can be used for immediate determination of the esterification site in monoesters of (2E,4Z)-2,4-hexadienedioic (muconic) acid, which are of interest in connection with synthetic studies on verrucarins. Thus, isomerization by heating in aqueous solution of monoesters of (2Z,4Z)-2,4-hexadienedioic acid yields 1-monoesters rather than 6-monoesters of (2E,4Z)-2,4-hexadienedioic acid, in accordance with the isomerization mechanism involving anchimeric assistance of the free COOH group. Solutions of the ABXY spectra of olefinic protons of monomethyl (2E,4E)- and (2Z,4Z)-2,4-hexadienedioate are reported.

Notes: A highly regio- and stereoselective Diels-Alder reaction between dienophiles of type I and dienes of type II (Scheme 1) gives rise to Diels-Alder adducts of type III. Upon treatment with BF3.Et2O, these adducts are smoothly converted into the corresponding enones (Scheme 6). Under mild acidic conditions, enone (±)-33 gave bicyclic diketone (±)-34 via an intramolecular Michael-type addition. Diketone (±)-34 has the correct relative configuration and a suitable ketone function at C(6) for further conversion into the hexahydrobenzofuran portion of the avermectins and milbemycins.

Notes: The syntheses of 2,3-dimethylidene- and 2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptanes substituted in position C(1) are reported. The 1-dimethoxymethyl group in derivatives 2 and 6 controls the regioselectivity of the Lewis-acid-catalyzed Diels-Alder additions with methyl vinyl ketone and butynone. For the EtAlCl2-catalyzed addition of methyl vinyl ketone to 6, the regioselectivity can be reversed by a small solvent modification. The tetraene 2 is a versatile reagent for regioselective ‘tandem’ cycloadditions.

Notes: Two-dimensional, high-field NMR methods are employed in confirming the relative configuration at the C(20) ethyl side-chain junction as S* in the natural alkaloid tubotaiwine (dihydrocondylocarpine).

Notes: A New Synthesis of (±)-DihydrorecifeiolideEthyl 1-(2′-formylethyl)-2-oxocyclooctane-1-carboxylate (2) prepared by Michael reaction of ethyl 2-oxocyclooctane-1-carboxylate (1) was regioselectively methylated at the aldehyde group with (CH3)2Ti[OCH(CH3)2]2 to give 3 (Scheme 1). The alcohol 3 was treated with Bu4NF to give the deethoxycarbonylated product 4 which by distillation gave the bicyclic enol ether 5. Oxidation (m-chloroperbenzoic acid) of 5 and reduction of the resulting oxolacton 6 yielded the title compound (±)-dihydrorecifeiolide (7) in an overall yield of nearly 50 %. Methylation of the aldehyde 2 with MeLi gave the ring-enlarged lacton 9 in poor yield (13 %). The deethoxycarbonylation reaction 3 → 4 was studied in more detail (Scheme 3).

Notes: Metabolites of Microorganisms. Sulfur-Containing Ansa Compounds of the Naphthomycin TypeFrom a strain of Streptomyces (Tü 2357) in addition to naphthomycin A, 4 new yellow pigments were isolated and their structures determined by spectroscopic comparison with naphthomycin A. Whereas the naphthomycins D and E are simple derivatives of naphthomycin A, having OH and H, respectively, instead of Cl, the naphthomycins F and G contain an N-acetylcysteine residue linked to the aromatic moiety by a thioether group. Degradations with O3 yielded identical products from the naphthomycins A, D, F, and G, showing coincident configurations in parts of the molecules. Naphthomycin F shows some biological activity against gram-positive bacteria and fungi, although much weaker than naphthomycin A. The naphthomycins D, E, and G are inactive against microorganisms.

Notes: The crystal structure of (±)-corynoline (1) has been determined by X-ray diffraction methods. The rings B and C form the half-chair and the twist-half-chair conformations, respectively. The B/C ring conjunction exists in an anti-cis conformation, with a N … H—O intramolecular H-bond. Conformational energy calculation by the CNDO/2 method show that the conformations of 1, (+)-chelidonine (2), and their acetates, observed in crystal structures, are all in the one of total energy minimum.

Notes: (2S,4S)-2-(tert-Butyl)-5-oxo-1,3-dioxolan-4-acetic acid (1) was dilithiated to the enolate 2 in toluene and THF with lithium diisopropylamide (LiN(i-Pr)2) under various conditions. Deuteration experiments with 2 showed that two different stable forms of the enolate could be produced, depending on whether the deprotonation of 1 had been carried out in toluene or THF. The generated (i-Pr)2NH was coordinated to the enolate and, hence, served as a strong lipophilic solvating agent. LiN(i-Pr)2 could substitute the amine ligands of the two species to a different extent. THF was partially able to displace (i-Pr)2NH that solvated the species produced in toluene, but the coordination of the amine to the one produced in THF was quantitive. Correlations with given explanations are made.

Notes: The synthesis of a mononuclear Rh(III) complex, as a representative example of a series of related species, containing two cyclometallating ligands ppy (2-phenylpyridine) and one diimine bpy (2,2′-bipyridine) from a binuclear Cl-bridged compound is described. The absorption spectrum shows a maximum at 364 nm (ε = 7000), with a very weak shoulder (ε = 10) at 454 nm. This band is tentatively assigned to a metal-to-ligand charge-transfer transition. A reversible, one-electron reduction appears in the cyclic voltammogram at E1/2 = -1.41 V (vs. NHE) and a irreversible oxydation at Ep = + 1.1 V. A detailed NMR analysis including 13C-NMR, NOE, SFORD as well as deuteration of the bpy ligand indicates the formation of only one isomer, having a C2 axis, bisecting the bpy ligand, with the two carbon ligands in cis-position. 103Rh, 13C and 103Rh,H couplings are observed.

Notes: Synthesis and Reactivity of Lumazine-7-sulfenic AcidsThe chemical synthesis of the pteridine-7-sulfenic acids 13-16 is described (Scheme 1). The 1,2,3,4-tetrahydro-1,3,6-trimethyl-2,4-dioxopteridine-7-sulfenic acid (14) was isolated as a stable crystalline solid. Its chemical reactivity was investigated and the physical properties determined. In the solid state, the S-oxide form 14A predominates, but in protic solvents the S-OH tautomer 14 exists most likely. In basic medium, the pteridine-7-sulfenate species is stable, whereas a low pH gives rise to a disproportionation to the disulfide 10 and the corresponding pteridine-7-sulfinic acid 37 (Scheme 4). Reaction of 14 with ethyl propiolate leads, under cis-addition, to 36, oxidation with KMnO4 forms 1,2,3,4-tetrahydro-1,3,6-trimethyl-2,4-dioxopteridine-7-sulfonic acid (38) and NaBH4 reduction the corresponding 7-mercaptopteridine dione 18 (Scheme 4).

Notes: CO and H2 are photogenerated simultaneously by visible-light irradiation of systems containing a photosensitizer, the [Ru(bpy)3]2+ complex, Co(II) species as homogeneous catalysts, which mediate CO2 and H2O reduction by intermediate formation of Co(I), a tertiary amine as electron donor, which provides the electrons for the reduction, and an organic solvent which also facilitates dissolution of CO2. The efficiency of (CO + H2) gas production and the selectivity CO/H2 markedly depend upon the composition of the medium, the nature of the tertiary amine, the solvent, and the ligand of the Co ions. 2,9-Dimethyl-1,10-phenanthroline is particularly effective in promoting CO and H2 formation, giving a quantum yield of 7.7% in (CO + H2) (1.2% for CO and 6.5% for H2). The process consists of two catalytic cycles: a photocatalytic cycle for the Ru complex and a double dark reaction pathway for the Co species; oxidative and/or reductive quenching of the excited state of the photosensitizer lead to the formation of Co(I) species which reduce either CO2 or H2O to CO or H2, respectively.

Notes: Estimation of preferred conformation, orientation, and accumulation of adrenocorticotropin (1-24)-peptide at an aqueous-hydrophobic interface produced a model that agreed with that developed from experimental observations with lipid membranes. Thus, the N-terminal message segment (residues 1-11) was incorporated into the hydrophobic phase as an α-helical, perpendicularly oriented domain with an apparent dissociation constant of ca. 5 · 10-5 M. The C-terminal address segment (residues 12-24) remained in the aqueous phase as a random-coil domain. Three parameters proved sufficient to define the model: the Gibbs free energy of hydrophobic association, the molecular amphiphilic moment, and the molecular electric dipole moment. For estimating interactions with biologic membranes (that carry a net negative charge), the Boltzmann distribution of charged peptides was also considered. The estimations were extended to adrenocorticotropin (1-10)-peptide and α-melanotropin. In the first case, the prediction agreed with the earlier observations, in the second, it awaits its experimental proof. The estimated membrane structures were compared with available biologic data. As for opioid peptides, it appears that the amphiphilic moment is an important new parameter for determining quantitative structure-activity relationships (QSAR) in receptor selection and biologic potency.

Notes: The syntheses of 2,3,5-trimethylidenebicyclo[2.2.1]heptane (1) and 2,3,5,6,7-pentamethylidenebicyclo[2.2.2]-octane (2) are reported. The Diels-Alder additions of the diene moieties of these polyenes can be regioselective, probably because of a possible transannular interaction between the homoconjugated methylidene and s-cis-buta-diene groups.

Notes: The N(1)- and N(2)-(2′-deoxyribofuranosides) 1 and 2, respectively, of 8-aza-7-deazaguanine were prepared via phase-transfer glycosylation in the presence or absence of Bu4NHSO4 as catalyst of 6-amino-4-methoxy-lH-pyrazolo[3,4-d]pyrimidine (7c) with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (10). On a similar route, but without catalyst and employing THF as organic phase, the 6-amino-4-chloronucleosides 11b and 12b were synthesized from 7a and converted into the N(1)-and N(2)-substituted 4-thioxo analogues 17a and 18a, respectively. The ratio of N(1)- to N(2)-glycosylation was 2:1 for 7c and 1:1 for 7a, viz. depending on the nucleobase structure. The rate of the H+-catalyzed N-glycosyl hydrolysis was strongly decreased for the N(2)-(β-D-2′-deoxyribofuranosides) as compared to the N(1)-compounds. However, the N(1)-nucleoside 1, which is an isostere of 2′-deoxyguanosine, is sufficiently stable to be employed later in solid-phase oligonucleotide synthesis.

Notes: Synthesis of Betenamine and of Betalaine Model SubstancesFor comparisons of color, spectroscopic properties, pKa values, and stabilities, a number of model substances containing the 1,7-diazaheptamethinium chromophore 8 of the yellow and red betalaine plant pigments were prepared by the thermal or photolytic ring opening of simple pyridine derivatives (such as 2 and 14-16), followed by the introduction of amines. Among the novel compounds prepared were betenamine perchlorate (5), the ‘naked’ ring system of the beet-pigment betanine (C) as well as two 1,7-diazaheptamethinium salts 25 and 27 with terminal amono acids. The synthesis of 5 started with 4-(2-aminoethyl)pyridine (1) and proceeded via 2, ring opening with indoline to 4, saponification, and intramolecular amine replacement (Scheme 1). The syntheses of 25 and 27 involved only one step, namely ring opening of γ-picoline using (S)-cyclodopa (24) and (S)-proline (26), respectively (Scheme 3).

Notes: Synthesis of Pentafulvalene by Oxidative Coupling of Cyclopentadienide with Copper(II) ChlorideStarting with a nearly quantitative coupling of cyclononatetraenide 7 to 1, 1′-dihydrononafulvalene 8 by means of AgBF4, a simple general synthetic concept for fulvalenes is outlined (Scheme 2), consisting in an oxidative coupling of ‘Hückel anions’ like 2 and 7 to 1, 1′-dihydrofulvalenes 10 with Ag(I) or Cu(II) salts, followed by deprotonation (→11) and oxidation (→12); it has been realised in the case of pentafulvalene (1; overall yield 61%; Scheme 3) and 1,2:5,6-dibenzopentafulvalene (18; overall yield 66%, Scheme 4). NMR-spectroscopic investigations show that 1 is a non-aromatic compound with strongly alternating bond-lengths, its π-system being even more localised than that of simple pentafulvenes. In fact, 1 is extremely reactive in concentrated solutions above -50°. Besides of polymerisations, Diels-Alder dimerisation 1→19 followed by a rearrangement 19→20 takes place (Scheme 5).

Notes: Ab initio calculations of structure, properties, and tautomerization reactions of triazene (1) at the HF/3-21G//3-21G, HF/6-31G*//6-31G*, HF/6-31G**//6-31G*, and MP2/6-31G*//6-31G* levels led to the following conclusions and predictions: (a) Calculations of the ground-state structure of (E)- and (Z)-triazene (1a and 1b, respectively) at various levels of theory show for both isomers C1 geometry with a rather flat pyramidal configuration at N(3), and small energy differences (0.2-7.2 kJ/mol) between C1 and Cs geometry, i.e. inversion at N(3) is a quasi-free process. With all levels of calculations, 1a is found to be of lower energy than 1b by 23-30 kJ/mol. (b) Comparison of vibrational frequencies of (E)-diazene (3) calculated at the HF/3-21G level with experimental values reveals that HF/3-21G calculations are reliable for the prediction of vibrational frequencies of polyaza compounds, if corrected by a factor of 0.91. On this basis, the harmonic vibrational frequencies of 1a and 1b were predicted. (c) For the rotation around the N(2) - N(3) bond of 1a two conceivable transition states, 5a (syn) and 5b (anti) were located (HF/3-21G). The energy differences between 5a or 5b, and 1a are in the order of magnitude of 50-56kJ/mol and show a slight preference for the anti-mode, i.e. energy barriers for the N(2) - N(3) rotation are obtained comparable to those observed experimentally with substituted (E)-triazenes (4). (d) Protonation of 1a at N(1), N(2), or N(3) leads to 6a, 6b, and 6c, respectively -the last one resembling an intermediate of formation of 1 from hydrogendiazonium ion (7) and ammonia (8). Energetically, the conjugate acids of 1a follow the sequence 6a 〈 6c 〈 6b. (e) The preference of N(1) protonation of 1a is also reflected in the relatively high gain of energy in the formation of H-bonded dimers of 1a with H-bonds from N(3) - H to N(1). Calculations of three different H-bonded dimers 9a-c of 1a with the 3-21G basis show that an eight-membered cyclic dimer 9c with two H-bonds from N(3)—H to N(1) is energetically most favoured (67.5 kJ/mol below two separate molecules of 1a). This dimer might well be the starting situation of double intermolecular H-transfer leading to an automeric dimer 9c via an energetically low-lying transition state 12, thus offering a low-energy pathway for the known easy tautomerization of mono- or disubstituted (E)-triazenes. For 9c⇄9c, the activation energy including correction for polarization and correlation effects as well as for vibration zero-point energy is estimated to be ca. 54kJ/mol. (f) A six-membered cyclic dimer 9b of 1a with two H-bonds from N(3)—H to N(2) might be involved for double H-transfer via a transition state 11 to a dimer 10 of (E, Z)-azimine (2). This process, however, turns out to be energetically highly disfavoured (estimated energy barrier for 9b→10: 232 kJ/mol) in contrast to the reverse reaction (10→9b via 11: 4 kJ/mol). This leads to the prediction that azimines bearing an H-atom at N(2) might be kinetically too instable for isolation, being, instead, easily tautomerized to triazenes by bimolecular H-transfer.

Notes: On the Photochemistry of (Z,Z)-2,7-Cyclodecadien-1-one and 4,8-Cyclododecadien-1-one. Synthesis and Properties of Tricyclo[5.3.0.02,8]decane SystemsIrradiation of (Z,Z)-2,7-cyclodecadien-1-one (3) yields (Z,Z)-3,7-cyclodecadien-1-one (12) or tricyclo-[5.3.0.02,8]decan-4-one (16), depending on the reaction conditions. Irradiation of 4,8-cyclododecadien-1-one (28) results also in a light-induced transannular [2 + 2] cycloaddition, yielding tetracyclo[7.3.0.02,1003,6]dodecan-1-one (30). Starting from 16, the preparation of tricyclo[5.3.0.02,8]dec-4-ene (19), tricyclo[5.3.0.02,8]dec-4-ene (21) and tricyclo[5.3.0.02,8]deca-3,5-diene (24) is described. The 1H-NMR and 13C—NMR spectra of the newly prepared compounds are discussed. In the case of 19, 21, and 24, the electronic structure is discussed on hand of their PE spectra.

Notes: 1,3-Butadienyl Thiocyanates in the Diels-Alder Reaction Followed by a [3,3]-Sigmatropic Shift(E)- and (Z)-1,3-Butadienyl thiocyanates 3, 4, and 12-15 have been synthesized selectively. Their use as dienes for Diels-Alder reactions followed by a [3,3]-sigmatropic shift to obtain an isomeric isothiocyanate has been studied. The butadienyl thiocyanates are, unfortunately, not very reactive in Diels-Alder reactions. This disadvantage can be overcome, if a trapping reaction with EtOH is added to the two-step sequence. This sequence allows to get good yields of the O-ethyl thiocarbamates 18-23, even if the first two reactions have not favorable equilibrium constants.

Notes: (S,S)-N,N′ -Bis(aminoacyl)ethane- and (S,S)-N,N′ -bis(aminoacyl)propanediamines (AA-NN-2 and AA-NN-3, respectively, AA = alanine, phenylalanine, valine) were synthesized as the dihydrochlorides, and their complexes with Cu(II) studied potentiometrically. Since these ligands in the presence of Cu(II) are able to perform chiral resolution of D,L-dansylamino acids in HPLC (reversed phase), in a certain pH range (6.5-8.5), it is important to know the equilibria existing between ligands and copper in aqueous solution. For AA-NN-2, four species, CuLH3+, CuL2+, Cu2L2H-22+, and CuLH-2, were detected, whereas for AA-NN-3, only CuLH3+, CuL2+, and CuLH-2 were found. The aim is to find out which complexes may be involved in the recognition process.

Notes: The synthesis of 4-methylumbelliferyl α-D-glycoside 13 of N-acetyl-4-deoxyneuraminic acid and its behaviour towards bacterial sialidases is described. N-Acetyl-4-deoxyneuraminic acid (1) was transformed into its methyl ester 2 and then acetylated to give the anomeric pentaacetates 3 and 4 of methyl 4-deoxyneuraminate and the enolacetate 5 (Scheme). A mixture 3/4 was treated with HCl/AcCl to give the glycosyl chloride, which was directly converted into the 4-methylumbelliferyl α-D-glycoside 9 of methyl 7-O,8-O,9-O,N-tetraacetylneuraminate and into the 2,3-dehydrosialic acid 11. The ketoside 9 was de-O-acetylated to 12 with NaOMe in MeOH. Saponification (NaOH) of the methyl ester 12 followed by acidification gave the free 13, which was also converted into the sodium salt 14 by passage through Dowex 50 (Na+). The 4-deoxy α-D-glycoside 13 is not hydrolyzed at significant rates by Vibrio cholerae and Arthrobacter ureafaciens sialidase. Neither the free N-acetyl-4-deoxyneuraminic acid (1), nor the α-D-glycoside 13 inhibit the activity of these sialidases.

Notes: Succesive treatment of chiral esters 1 with LiN(i-Pr)2/Me3SiCl and di(tert-butyl) azodicarboxylate/TiCl4/Ti(i-PrO)4 gave N,N′ -di[(tert-butoxy)carbonyl]hydrazino esters 9 which on deacylation, hydrogenolysis, transesterification, and acidic hydrolysis furnished (2S)-α-amino acids 6 in high enantiomeric purity with efficient recovery of the auxiliary alcohol 7.

Notes: The hydroxylation of geraniol (8) by cytochrome P-450 (P-450Cath.) from the subtropical plant Catharanthus roseus (L.) G. DON was optimised to give 8-hydroxygeraniol (9) as the single product in 35% yield. Incubations of different 13C- and 2H-labelled geraniols revealed that H-abstraction is completely regioselective in favour of the CH3 group trans to the chain at C(6) of 8. An intramolecular isotope effect kH/kD = 8.0 was determined, suggesting that H-abstraction is one of the major rate-contributing steps; however, the intermolecular isotope effect was surprisingly inverse at low conversion kH/kD = 0.50, indicating the existence of rate-contributing steps preceding the first irreversible, isotope-sensitive reaction in the sequence.

Notes: Nitrocyclohexene undergoes facile SnCl4-induced, [4 + 2]-cycloadditions with simple cycloalkenes to produce nitronates. The nitronates can be transformed sterospecifically into a number of other functional groups (alcohol, ketone, oxime, amine) by hydrolytic, reductive, and oxidative processes. The mechanism of the [4 + 2]-cycloaddition is believed to involve formation of a zwitterionic intermediate which can collapse via competing pathways to form the observed products. 1,3-Dipolar cycloadditions of the nitronates are described.

Notes: It is shown that (-)-(S)-N,N-dimethyl-2-(1′-methylallyl)aniline ((-)-(S)-4), on direct irradiation in MeCN at 20°, undergoes in its lowest-lying triplet state an aromatic di-π-methane (ADPM) rearrangement to yield (-)-(1′R,2′R)- and (+)-(1′R,2′S)-N,N-dimethyl-2-(2-methylcyclopropyl)aniline ((-)-trans- and (+)-cis-7) in an initial trans/cis ratio of 4.71 ± 0.14 and in optical yields of 28.8 ± 5.2% and 15 ± 5%, respectively. The ADPM rearrangement of (-)-(S)-4 to the trans- and cis-configurated products occurs with a preponderance of the path leading to retention of configuration at the pivot atom (C(1′) in the reactant and C(2′) in the products) for (-)-trans-7 and to inversion of configuration for (+)-cis-7, respectively. The results can be rationalized by assuming reaction paths which involve the occurrence of discrete 1,4- and 1,3-diradicals (cf. Schemes 10, 12, and 13). A general analysis of such ADPM rearrangements which allows the classification of these photochemical reactions in terms of borderline cases is presented (Scheme 14). It is found that the optical yields in these ‘step-by-step’ rearrangements are determined by the first step, i.e. by the disrotatory bond formation between C(2) of the aromatic moiety and C(2′) of the allylic side chain leading to the generation of the 1,4-diradicals. Moderation of the optical yields can occur in the ring closure of the 1,3-diradicals to the final products, which may take place with different trans/cis-ratios for the individual 1,3-diradicals. Compounds (-)-trans-7 as well as (+)-cis-7 easily undergo the well-known photochemical trans/cis-isomerization. It mainly leads to racemization. However, a small part of the molecules shows trans/cis-isomerization with inversion of configuration at C(1′), which is best explained by a photochemical cleavage of the C(1′)-C(3′) bond.

Notes: [fac-Re(bpy) (CO)3Cl] (bpy = 2,2′-bipyridine) is an efficient homogeneous catalyst for the selective and sustained photochemical or electrochemical reduction of CO2 to CO. A quantum yield of 14% and a faradic efficiency of 98% were measured in the presence of excess Cl- ions. The photochemical process took place under visible-light irradiation and consumed a tertiary amine as electron donor. A formato-rhenium complex was isolated in the absence of excess Cl- ions. Substitution by Cl- ion generated free formate, but no CO was detected. Luminescence measurements showed that the tertiary amine quenches the metal-to-ligand charge-transfer excited state of the rhenium complex via a reductive mechanism, with a rate constant of 3.4 × 107M-1S-1. The 19e-complex [Re(bpy) (CO)3X]- produced either photochemically or electrochemically appears to be the active precursor in the CO-generation process. Detailed spectroscopic studies on 13C-enriched carbonyl-rhenium and formato-rhenium complexes derived from 13C-enriched CO2 were performed in order to confirm the origin of the products and to study the exchange of the ligands. A mechanism for the present CO2 photoreduction process is presented; it involves separate pathways for CO and formate generation, in which the [Re(bpy) (CO)3X] complex plays the role of both the photoactive and the catalytic center.

Notes: Reaction of 3-(Dimethylamino)-2H-azirines with 1,3-Thiazolidine-2-thioneReaction of 3-(dimethylamino)-2H-azirines 1 and 1,3-thiazolidine-2-thione (6) in MeCN at room temperature leads to a mixture of perhydroimidazo[4,3-b]thiazole-5-thiones 7 and N-[1-(4,5-dihydro-1,3-thiazol-2-yl)alkyl]-N′,N′-dimethylthioureas 8 (Scheme 2), whereas, in i-PrOH at ca. 60°, 8 is the only product (Scheme 4). It has been shown that, in polar solvents or under Me2NH catalysis, the primarily formed 7 isomerizes to 8 (Scheme 4). The hydrolysis of 7 and 8 leads to the same 2-thiohydantoine 9 (Scheme 3 and 5). The structure of 7a, 8c, and 9b has been established by X-ray crystallography (Chapt. 4). Reaction mechanisms for the formation and the hydrolysis of 7 and 8 are suggested.

Notes: Six sesquiterpenoids 1-6, formally derived from (+)-(S)-nerolidol by oxidative cyclization, have been isolated for the first time from commercial cabreuva oil. Whereas the two tetrahydrofurans 5 and 6 have already been described, the four bicyclic ethers (cabreuva oxides A-D) 1-4 are new. The structures of 1-4 are confirmed by synthesis and their absolute configurations are shown to be 3S. The organoleptic properties of the synthetic cabreuva oxides are discussed.

Notes: Three new bidesmosidic saponins 1-3 have been isolated from the berries of Phytolacca dodecandra L′HERIT (Phytolaccaeae). The structures have been established by spectroscopic (1H-NMR, 13C-NMR, FAB-MS, DCI-MS, and GC/MS) and chemical methods (acid, basic, and enzymatic hydrolysis). Saponins 1 and 3 are tetra- and pentaglycosides of oleanolic acid, whereas 2 is a tetraglycoside of bayogenin. The corresponding prosapogenins 1a-3a, obtained by cleavage of a glucose unit esterified at C(28), exhibited strong molluscicidal activity against schistosomiasis-transmitting snails.

Notes: A new method for alkaloid synthesis is described. The rhodium(II)-acetate-catalyzed decomposition of 3-(4-acetoxyphenyl)-1-diazo-4-(pyrrol-1-yl)-2-butanone (5d) gave 6-(4-acetoxyphenyl)-5,6-dihydro-7(8H)-indolizinone (6d) in 82% yield via an intramolecular carbenoid reaction. The latter compound was converted in four steps in 13% overall yield to (±)-ipalbidine (1b).

Notes: Separation of Enantiomers by Partition between Liquid Phases. Enantioselectivity of Diastereoisomeric Dimenthyl Tartarates towards α-Aminoalcohol SaltsThe enantioselectivity of the easily obtainable diastereoisomeric dimenthyl tartarates I and II towards the salts of a series of α-aminoalcohols 1-10 was investigated by partition between aqueous and lipophilic phase. The measured enantiomer distribution constants Q (=KA/KB) confirm the previously observed configurational relationships between the lipophilic tartarates and the preferentially extracted enantiomer of the hydrophilic ammonium slat. However, the (R,R)-ester I is appreciably more selective than its (S,S)-diastereoisomer II or other previously investigated esters. The tartarates I-III transport norephedrin salts through bulk lipophilic membranes with enantioselectivity comparable to that observed in partition experiments. The most enantioselective ester I can be used as an efficient mobile phase for preparative separation of norephedrine enantiomers by flash partition chromatography.

Notes: A synthesis of 1,2-cis-configurated, non-isosteric phosphonate analogues of aldose-1-phosphates is described. Treatment of 1-O-acyl-glycoses 1, 7, 13, and 19 with trialkyl phosphite in the presence of trimethylsilyl trifluoromethanesulfonate gave the 1,2-cis-configurated glycosylphosphonates 2, 4, 8, 10, 14, 16, 20, and 22 as the major anomers and the 1,2-trans-configurated glycosylphosphonates 3, 5, 9, 11, 15, 17, 21, and 23 as the minor anomers. The 1,2-cis-configurated phosphonates 4, 10, 16, and 22 were deprotected to give the (β-D-glucopyranosyl)phosphonate 6, the (β-D-mannopyranosyl)phosphonate 12, the (β-D-ribofuranosyl)phosphonate 18, and the (β-D-arabinofuranosyl)phosphonate 24, respectively, in high yields. The preferred formation of 1,2-cis-configurated phosphonates is explained by postulating an equilibrium between the anomeric phosphonium-salt intermediates (such as 25 and 26) and a stabilization of the cis-configurated salts through formation of a pentacoordinated species (such as 28).

Notes: The synthesis of the cyclopropyl silyl ketones 1-4 is described. The trimethylsilyl ketone 1 was prepared from geraniol ((E)-5) in ca. 10% overall yield by cyclopropanation leading to 6, CrO3 oxidation to the aldehyde 8, reaction of the latter with trimethylsilyl anion to 14A+B, and CrO3 oxidation to 1. Also for the (t-butyl)dimethylsilyl ketones 2-4, an efficient four-step synthesis with overall yields of 48%, 85%, and 13%, respectively, was elaborated, starting from the allylic alcohols (E)-5, and 23. The method of preparation involves as the key step a Wittig rearrangement of the silylallyl ethers ((E/Z)-20, 24) to the silyl alcohols ((E/Z)-21, 25), subsequent cyclopropanation (19A + B, 22A + B, 26), and oxidation to the cyclopropyl silyl ketones 2-4.

Notes: The optical resolution of (RS)-pantolactone (1) is carried out through formation of diastereoisomeric amides. These are separated by a single hot washing with CH2C12 or CHC13. The used asymmetric amine, (1R)-3-endo-aminoborneol (4), is readily accessible and can be recovered almost quantitatively after resolution.

Notes: The conformation in the crystalline state and in solution of the sterically congested tetramethylpiperidinederived amide group of the symmetric diamide I formed from 2,2,6,6-tetramethylpiperidine (b) and 1,2,5-thiadiazole-3,4-dicarbonyl dichloride (c), and of the mixed diamide II derived from b, c, and piperidine (a) has been investigated. In crystals, as observed with II, this group is strongly bent out-of-plane at both the N-atom and the carbonyl C-atom, and there is also a sizable twisting around the amide bond. Furthermore, the amide bond is abnormally long (1.37 Å). In CD2Cl2 (or CDCl3) solution, the group is apparently planar in its ground-state conformation, but the energy barrier to rotation around the amide bond is low. This conclusion is based on low-temperature 1H-NMR measurements on I, II, and on the symmetric diamide III derived from a and c.

Notes: A New Synthesis of the Vinblastine Derivatives 20′-Deethyl-20-deoxyvinblastine and 20′-Deethyl-20′-deoxy-C′-homovinblastineA new synthesis of vinblastine derivatives is described. In the key step, the chloroindolenine derivative 14 was reacted with vindoline (2) to give, after cyclization, stereospecifically 17/I and 20′-deethyl-20′-deoxyvinblastine (17/II). In an analogous manner, the epimeric C′-homovinblastine derivatives 21/I-21/IV were synthesized.

Notes: The first syntheses of 9-bromo- and 9-chlorobicyclo[4.2.1]nona-2,4,6-trienes were each achieved in three stereoselective steps from the 9,9-bis(selenophenyl) derivative 9 in 79% overall yield for the bromide and 64% for the chloride. A deuterium-labeling experiment reveals the first rearrangement of a bicyclo[4.2.1]nonatriene which leaves the ring system intact.

Notes: The Gas-Flow Thermolysis of 1-Isobutenyl Alkynyl and 2-Methylphenyl Alkynyl Ketones. Synthesis of Methylenomycin BThe gas-flow thermolysis of 1-isobutenyl alkynyl or 2-methylphenyl alkynyl ketones were found to lead to phenols and cyclopentenones or to naphthols and indanones, respectively. These conversions involve two cyclization processes so far unknown with α-alkynones; they are interpreted as intramolecular additions of an allylic or a benzylic C,H bond to a triple bond which may occur in two directions. In addition, the cyclopentenones formed by the α-alkynone cyclization, a known carbene process yielding 5-rings, were also found. The available evidence ruled out a carbene process yielding 6-rings. The addition process yielding 5-rings was applied to a short (but low yield) synthesis of methylenomycin B.

Notes: The synthesis of a series of phosphine-functionalised macrocycles, 1-6, is described. The combination of N-and O-sites with P- and S-sites provides ligands which may bind transition or non-transition metal ions; as a consequence, they give access to dinuclear complexes containing both a Lewis acid and a redox metallic site. Compounds 1,2 and 6 are heterodinucleating ligands capable of binding two dissimilar metals in proximity. Macrocycles 3-5 are homotopic ligands which may form homodinuclear complexes of transition metals.

Notes: At pH 4.5 (citrate buffer), D-gluconhydroximo-lactone (2), the N-methylurethane 3 and the N-phenylurethane 4 inhibit competitively the hydrolysis of p-nitrophenyl β-D-glucopyranoside by emulsin. The IC50 values of 2, 3, and 4 were 1.6 × 10-4, 1.0 × 10-4, and 5.8 × 10-6 M, respectively. The Ki values of 2 and 4 were 9.8 × 10-5 and 2.3 × 10-6 M, respectively, while D-glucono-1,5-lactone (1) showed IC50 = 1.1 × 10-4 M and Ki = 3.7 × 10-5 M.

Notes: A novel highly substrate-specific Rauwolfia enzyme, raucaffricine β-D-glucosidase, was isolated from cell-suspension cultures of R. serpentina. The enzyme has been purified ca. 1350-fold, its major characteristics such as Mr = 66600 ± 5%, pH optimum 5.1, temperature optimum 38°, and inhibition of its activity by glucose and fructose were investigated. Its limited distribution in different cell cultures and differentiated plants indicates that the enzyme is present in significant amounts exclusively in cultured Rauwolfia cells.

Notes: On Dien-Ketenes from o-Quinol-AcetatesA detailed picture of the photochemistry of o-quinol-acetates is presented. (RS)-6-Acetoxy-6-methyl-, (RS)-6-acetoxy-2,6-dimethyl-, (RS)-6-acetoxy-5,6-dimethyl-, (RS)-6-acetoxy-2,4,6-trimethyl-, (RS)-6-acetoxy-2,3,4,6-tetramethyl-, and (RS)-6-acetoxy-2,3,4,5,6-pentamethyl-2,4-cyclohexadien-1-ones serve as representative educts. There are two separate main photochemical routes conveniently designated as 1(π*, n) or 3(π*, π) tracks. The latter may also be attained by sensitization and leads to phenols. The former, by α-cleavage furnishes dienketens as indispensable phototransients. Photolysis of dien-ketens follows one or more of three reaction channels, each of which yields a particular type of photoproduct: heat-induced monocyclization affords 2,4-cyclohexadien-1-ones, heat-induced bicyclization stereoselectively furnishes bicyclo[3.1.0]hex-3-en-2-ones, and multi-step addition of protic nucleophiles stereoselectively gives 1,4-, 1,6- and/or 1,2-adducts. By X-ray analysis or NOE studies, the structure of isolated photoproducts is established. Conventional spectroscopy at low or flash spectroscopy at normal temperature yield information on the formation and decay of kinetically unstable intermediates. Photoproduct composition depends on the pattern of substitution of the educts, on the solvents, and on the nucleophiles that might be present. Substituents primarily exert an influence upon the population of the various conformers of the dien-keten. Solvents affect the rate of the divers reaction paths competing for the phototransient. Nucleophiles play more than a trivial role when adducts are formed. With the detailed view of a dien-keten's role on hand, the photoproduct from a given o-quinol-acetate or more general from a linear conjugated cyclohexadienone is now predictable.

Notes: On π,π*-excitation of the epoxyenone (E)-1 (λ = 254 nm, MeCN), in addition to the previously isolated compounds 2-9, the new products 10-12, derived from the ylide intermediate c were isolated. Further evidence for the ylide c was obtained by the rapid racemization of the optically active epoxyenone (-)-(E)-1.

Notes: Three macrocyclic hexaamines 1, 2, and 4, and the acyclic tetraamine 5 and hexaamine 6 have been synthesized. The hexaamines 1, 2, and 4 are ditopic coreceptor molecules containing two triamine subunits which may bind anionic substrates when protonated. The stability constants of the complexes between the protonated forms of the macrocyclic polyamines and terminal dicarboxylates -O2C-(CH2)m- CO2- as well as amino-acid and dipeptide dicarboxylates have been determined by pH-metric measurements. Around neutral pH, 1 and 2 give mainly complexes of the fully protonated species 1·6H+ and 2·6H+, whereas 4 yields predominantly complexes of 4·5H+ and 4·4H+. The stability sequences of the complexes formed indicate preferential binding of the dianionic substrates whose length is compatible with the separation of the triammonium binding subunits in the protonated receptor molecules 1, 2, and 4. This selectivity pattern corresponds to a process of linear molecular recognition based on ditopic binding between the two ammonium subunits of the coreceptor and the terminal carboxylates of the substrate of complementary length. The complexes of the acyclic ligands 5 and 6 are much weaker and much less selective, indicating a marked macrocyclic effect on both stability and selectivity of binding, i.e. on recognition.

Notes: The synthesis of the ansa chain of rifamycin S (1), corresponding to the C(19) to C(27) moiety, epimeric at C(23), is described starting from dimethyl xylo-3-hydroxy-2,4-dimethylglutarate (4). The diester 4 was transformed to the C10-diester 16 by two threo-aldol condensations with 2,6-dimethylphenyl propionate (5).

Notes: Steady-state polarization curves, representative of the electrochemical reduction of HCO3- ions at a smooth palladium cathode, obtained in CsHCO3 and NaHCO3 solutions, are compared. The net current densities, associated with the electroreduction of HCO3- anions, measured in 1M CsHCO3 solution are shown to be up to 9 times larger than those observed in 1M NaHCO3 solution. This result is interpreted in terms of a direct involvement of the Cs+ cations in the reaction at the cathode through the formation of ion pairs with the HCO3- anions.

Notes: C45- and C50-Carotenoids: Synthesis of Optically Active Cyclic C20-Building Blocks and of (2R,2′R)-2,2′-Bis(4-hydroxy-3-methyl-2-butenyl)-β,β-carotene ( = C.p. 450)The synthesis of the optically active C20-building blocks (R)-26 and (R)-39 and of the optically active cyclic C50-carotenoid C.p. 450 (3) starting from (-)-β-pinene is reported.

Notes: The Thermal, Catalytic, and Photochemical Denitrogenation of 1-Diazo-3-(1-methylcyclopenta-2,4-dienyl)-2-propanoneThe synthesis of the title compound 12 is described. This diazoketone, distinguished by its Cs-symmetry and by a built-in cisoid diene unit, gives 5-methyltricyclo[3.3.0.02,8]oct-6-ene-3-one (13) when subjected to thermal or catalytic denitrogenation with rhodium (II) acetate or copper (II) acetylacetonate. Direct irradiation of 12 at 350 nm causes Wolff rearrangement, whereas the benzophenone-sensitized photolysis gives again ketone 13. A 1,4-carbene or carbenoid addition was never observed under the conditions described. The ketone 13 equilibrates thermally or under base catalysis with 1-methyltricyclo[3.3.0.02,8]oct-6-ene-3-one (17). The key step of this apparent CH3 migration is shown to be a Cope rearrangement of the corresponding enols (hydroxysemibullvalenes).

Notes: The unstable neutral enol, 1-buten-3-yn-2-ol, and its deuterium-labelled analogues were generated in the gas phase by high-vacuum flash pyrolysis of the corresponding 2-exo-ethynylnorborn-5-en-2-ols, or alternatively from 1-ethynylcyclobutanol. The ionization energy of the enol was measured as 8.92 ± 0.03 eV. The cation radical (HC≡C(OH)=CH2)+· was prepared by electron-impact ionization of the neutral enol, or by dissociative ionization of 1-hexyn-3-ol and 1-ethynylcyclobutanol, and its heat of formation was determined as 944 kJ·mol-1. The heat of formation of the neutral enol was assessed as 83 ± 7 kJ·mol-1 in good agreement with MNDO calculations. Cation radicals HC≡C—C(OH)=CH2+· undergo four main unimolecular fragmentations due to losses of the OH H-atom, a CH3 group incorporating the C(1) methylene and the OH H-atom, CO, and H2O. The structure of the neutral enol and the mechanisms of the ionic decompositions are discussed.

Notes: From bergamot oil (Citrus bergamia RISSO), (-)-(4S, 8R)-8-epi-α-bisabolol (2) and (-)-(4R, 8S)-4-epi-β-bisabolol (3) were isolated. The absolute configuration of their stereoisomers 4 and 5 was established by an enantioselective synthesis starting from (-)-(S)-p-mentha-1,8-dien-4-ol.

Notes: Poly(dipeptamidinium) Salts: Definition and Methods of PreparationPoly(dipeptamidines) are polypeptide derivatives in which the carbonyl oxygen of each second backbone amide group is replaced by an imine nitrogen (see A). So far, such derivatives have been unknown. Polyprotonated salts of them ( = poly(dipeptamidinium) salts) are of interest in view of their intrinsic constitutional relationship to the structure of polynucleotides: the number of covalent bonds between neighboring centers of positive charge in poly(dipeptamidinium) salts is identical to the number of covalent bonds between neighboring centers of negative charge in natural polynucleotides (see D). Poly(dipeptamidinium) polycations and polynucleotide polyanions are constitutionally and electrostatically complementary structures. Since poly(dipeptamidines) are (formally) polymers of dipeptide nitriles, and, since they can be expected to give polypeptides on hydrolysis, the relationship mentioned above deserves attention and experimental study in context with the problem of designing chemical models of biogenesis.This paper describes methods for the chemical preparation, the spectral characterization, and some chemical properties of homodipeptidic poly(dipeptamidinium) salts in the L-alanyl-glycyl and L-phenylalanyl-glycyl series. The methods of preparation include a stepwise construction of defined lower oligomers (up to hexamer) as well as, in the L-alanyl-glycyl series, a one-operation poly-condensation procedure leading to polymers containing an average of ca. 20 dipeptamidinium units (Schemes 4,6 and 7).

Notes: Hydrogenation of the ketone group in di-O-benzylderivative (8) of the known macrocyclic lactone zeralenone (7) using a novel chiral borane complex 3. BH3, prepared in situ, proceeded at lower temperatures with moderate diastereoselectivity (∼40%, d. e. at -60°). Unsaturated diastereomers 9 and 10 were separated, and 9 converted into zeranol (11), a known anabolic agent. Restricted conformational mobility at lower temperatures is assumed for the intermediate 8 on the basis of the temperature-dependent CD spectra of its acetyl congeners 18 and 19. X-Ray structure analysis of 7-O-acetylderivative (13) of 11 revealed the (R)-configuration at C(7). Two crystallographically independent H2O molecules are involved in the H-bonds, one of them (O(21)) rises the helices of the molecules of 13 along b. Small positive torsional angle [C(16)-]C(161)-C(1) [=O] (+19.3°), transoid(E) conformation of the lactone group, and nearly achiral arrangement of the C(11)-C(12) bond (torsional angle [C(11)-]C(12)-C(121)[C(161)] is -93°) are the main conformational features that differentiate the macrocylic RAL (resorcinic-acid lactone) derivatives from the 6-membered lactone derivative 20, studied earlier by CD. Consequently, the rules developed for the CD effects within conjugation band (around 270 nm), and n→π* band (around 255 nm) of the latter compound, cannot be applied the macrocyclic lactones.

Notes: 2-Aza-1,3-dienes. A New Approach to Substituted 2-AminopyrazinesTreatment of enamines by tosylated isonitrosomalono derivatives gives access to 5-dialkylamino-1, 1-dicyano 2-aza-1,3-dienes (or 1-methoxycarbonyl analogous) which are precursors of various regiospecific 5,6-substituted 2-amino-3-cyano (or methoxycarbonyl) pyrazines. Some examples of utilisation of these intermediates for synthesis of lumazines, pteridines, and other bicyclic skeletons are described.

Notes: Reactions of 1,3-Thiazole-5(4H)-thiones with Grignard- and Organolithium Compounds: Carbophilic and Thiophilic AdditionsOrganolithium compounds and 1,3-thiazole-5(4H)-thiones 9 reacted via thiophilic addition on the exocyclic S-atom. The intermediate anion E has been trapped by protonation to give 12 and by alkylation to yield 16, respectively (Schemes 5 and 6). In competition with protonation of E, a fragmentation to benzonitrile and a dithioester 14 was observed (Scheme 5). In some cases, the alkylation of E led to the formation of dithioacetals 17 instead of 16 (Scheme 6). Methyl, ethyl, and isopropyl Grignard reagents and 9 in THF underwent again a thiophilic addition yielding 4,5-dihydro-1,3-thiazoles of type 12 (Scheme 3). In contrast to this result, MeMgI reacted with 9a in Et2O via carbophilic addition to 11. Again a carbophilic attack at C(5) of 9 was observed with allylmagnesium and 2-propynylmagnesium bromide, respectively, in Et2O.

Notes: Self-sensitisation of photo-oxygen evolution occurs in aqueous dispersions of silver zeolites. In presence of Cl-, chlorine is the photoproduct in acidic medium, and the same type of self-sensitisation occurs. Self-sensitisation means that systems which are first insensitive to light of a certain wavelength become photo-active after they have been illuminated by light of higher energy. For a better understanding of silver zeolites, we have carried out EH-MO calculations on the 6-6 subunit (SBU) of a zeolite, on the 6-6 SBU with an Ag-atom in the center, on the 6-6 SBU with one Ag-atom in the center and one outside on top of the hexagon, and finally on another with one Ag-atom in the center and two Ag-atoms outside, each on top of a hexagon. The Ag0 in the cage of the 6-6 SBU is significantly polarized by the 6-6 SBU environment. The energy barrier to escape the 6-6 SBU is 0.8 eV for Ag0 and 0.5 eV for Ag+. The HOMO of the Ag(6-6 SBU) is a totally symmetric 5s* orbital and the LUMO is a 5pz* type. 5pz*←5s* electronic excitation reduces the energy barrier and allows an (Ag0)* to exit the 6-6 SBU, provided the excited-state lifetime is long enough. The MO picture predicts low-energy charge-transfer transitions from the zeolite framework to the 5s* orbital. The highest occupied orbitals of the zeolite framework are localized on the O-atoms. Interactions between an Ag-atom in the 6-6 SBU and one or two external Ag-atoms are discussed.

Notes: Based on a computer-assisted analysis of the three-dimensional structure of the binary complex of E.coli dihydrofolate reductase (DHFR) with methotrexate, 5-(N-arylnortropan-3-yl)- and 5-(N-arylpiperidin-4-yl)-2,4-diaminopyrimidines 2 and 4 were designed as inhibitors of DHFR. Syntheses of the designed compounds have been carried out. The most potent compound 2a inhibited E. coli DHFR with Ki = 0.49.10-9M. The activities within the series of compounds synthesized could be rationalized by molecular-modelling experiments which served as the basis of this work. Several compounds within the presented series exhibit antimalarial activities in vitro and in vivo.

Notes: The fast-atom-bombardment mass spectra (FAB-MS) of a series of ribo- and deoxyribonucleosides and -nucleotides were examined in both positive-ion and negative-ion modes. Behaviour of cytosine analogs having unnatural bases (2(1H)-pyrimidone, 2(1H)-pyridinone, and 4-amino-2(1H)-pyridinone) was similar to that of compounds having naturally occurring bases. Nucleotides protected by dimethoxytrityl and p-chlorophenyl groups were also investigated using this technique. Use of negative-ion mode reduces interference from positive counter-ions (e.g., Na+) and allows rapid sequence determination of simple di- and trinucleotides.

Notes: The title compound 3g is obtained via two different routes, either in a multistep synthesis starting from 2-amino-2-methylpropionic acid (methylalanine) or by light-induced, oxidative dealkylation of the corresponding N-isopropyl derivative 3c.

Notes: Novel Heterocycles: Tetrazinodi(heteroarenes), Synthesis and StructureA series of 7 new symmetric tetrazinodi(heteroarenes) is obtained in a two-step synthesis by N-aminating heterocyclic compounds substituted with a leaving group and by treating the latter with an organic or inorganic base. The new compounds are characterized, and the postulated structures are confirmed by X-ray analysis of a representative example.

Notes: The synthesis of 5-acetamido-4-deoxyneuraminic acid (1) is described. Acetylation of a mixture of the epimeric triols 4 and 5 gave the tetraacetates 7 and 8 (Scheme 1). Ozonolysis of a mixture of these acetates followed by base-promoted β-elimination led to the (E) -configurated α,β-unsaturated keto ester 10, which was hydrogenated to give the saturated keto ester 11. Saponification of 11 and hydrolytic removal of the benzylidene group followed by anion-exchange chromatography gave the 5-acetamido-4-deoxyneuraminic acid (1, Scheme 1 and 2). De-O-acetylation (NaOMe/MeOH) of the keto ester 11 gave a mixture of the tert-butyl ester 12 and the methyl ester 13, which were converted to tert-butyl N-acetyl-4-deoxyneuraminate (14) and to methyl N-acetyl-4-deoxyneuraminate (15), respectively. Hydrogenolysis of the benzylidene acetal 11 followed by de-O-acetylation gave the pentahydroxy ester 16.

Notes: EtAlCl2-promoted additions of organocopper reagents to camphor-derived, conjugated N-enoyl-sultams gave saturated and olefinic β-silylcarboxyl derivatives with high diastereodifferentiation. Nondestructive removal of the chiral auxiliary followed by oxidative Si-C bond cleavage furnished enantiomerically pure acetate-derived aldols and propionate-derived ‘anti’ -aldols (via silyl-directed α-methylation).

Notes: Luteochrome isolated from the tubers of a white-fleshed variety of sweet potato (Ipomoea batatas LAM.) has been shown by HPLC, 1H-NMR and CD spectra to consist of a mixture of (5R,6S,5′R,8′R)- and (5R,6S,5′R,8′S)- 5,6:5′,8′-diepoxy-5,6,5′,8′-tetrahydro-β,β-carotene (1 and 2, resp.). Therefore, its precursor is (5R,6S,5′R,6′S)-5,6:5′,6′-diepoxy-5,6,5′,6′-tetrahydro-β,β-carotene (4). This is the first identification of luteochrome as a naturally occurring carotenoid and, at the same time, gives the first clue to the as yet unknown chirality of the widespread β,β-carotene diepoxide. These facts demonstrate that the enzymic epoxidation of the β-end group occurs from the α-side, irrespective of the presence of OH groups on the ring.

Notes: Structure and Reactivity of Xanthocorrinoids. C(15) Hydroxylation of the Corrin Chromophore on Reaction of Cyanocob(III)alamin with Udenfriend's ReagentHydroxy-corrinoid 4 represents a new type of corrin derivatives whose chromophore is identical with that of products formed on bacterial degradation of cyanocob(III)alamin (1). In vitro, 4 is obtained by O2 oxidation of 1 in the presence of ascorbic acid and cupric ions.

Notes: In continuation of our work on penem antibiotics, novel chiral (5R,6S)-2-(1′-aminoalkyl)-6-(hydroxyalkyl)-derivatives 1 have been synthesized by two essentially different strategies. Whereas the starting materials for 1a-f, azetidinones 2 and 5, were obtained from chiral building blocks (6-aminopenicillanic acid and L-threonine, resp.), the one for 1g, azetidinone 9, was derived from racemic 4-acetoxyazetidinone and, as chiral auxiliary, (2R)-2-mercaptopropan-1-ol. The 2-aminomethyl derivatives 1a (CGP 30 779) and 1f (CGP 31 608) proved the most potent compounds in the antibacterial tests in vitro and showed a well-balanced spectrum of activity by comparison with that of established β-lactams.

Notes: The Mediterranean stolonifer Sarcodictyon roseum ( = Rolandia rosea) (Cnidaria, Anthozoa, Alcyonaria, Stolonifera, Clavulariidae) contains the first example of a chiral, optically active prenyl derivative of a reduced benzoquinone, sarcodictyenone (= (+)-(4R*,5R*)-5-geranylgeranyl-4-hydroxy-2-methylcyclohex-2-en-1-one; (+)-1a).

Notes: Allenic acids are found to add to dicyclohexylcarbodiimide affording, in the presence of secondary amines, the 1,3-oxazine-4-ones. 5. Under neutral conditions, they add to diaryl- or aryl(cyclohexyl)carbodiimides and triphenylketen-imine to give the corresponding tricyclo[5.2.2.01,5]undecatriene-3-ones 7-9 and 12.

Notes: Syntheses and Ring-Enlargement Reactions of 2-(4-Hydroxyalkyl)-2-nitrocycloalkanonesSyntheses of the title compounds were achieved by [Pd{P(C6H5)3}4]-catalyzed reaction of 2-nitrocycloalkanones 3 with vinyloxirane followed by catalytic hydrogenation. By another route, the known methyl 4-(1-nitro-2-oxocycloalkyl)butanoates 6 were reduced to the corresponding aldehydes 7 which by NaBH4 reduction or methylation with (CH3)2Ti(i-Pr)2 were transformed to the alcohols 5 and 8, respectively (Saheme 1). Treatment of 5 and/or 8 with KH/THF under reflux gave, via a 7-membered intermediate, the nitrolactones 12 and oxolactones 13 (Scheme 3). Compared with similar reactions running via 5- or 6-membered intermediates (see 1 and 2), the yields are distinctly lower. The natural occurring 12-tridecanolid (14) was synthesized.

Notes: Synthesis of 3-Nitro-1,1-bis(triisopropylsilyl)-1H-cyclopropabenzene and Derivatives of Azocyclopropabenzene1,1-Bis(triisopropylsilyl)-1H-cyclopropabenzene (4) can be nitrated at C(3) without opening of the three-membered ring. Further functionalized cyclopropabenzenes are available in this way.

Notes: Rose bengal-sensitized photooxygenation of 4-propyl-4-octene (1) in MeOH/Me2CHOH 1:1 (v/v) and MeOH/H2O 95:5 followed by reduction gave (E)-4-propyl-5-octen-4-ol (4), its (Z)-isomer 5, (E)-5-propyl-5-octen-4-ol (6), and its (Z)-isomer 7. Analogously, (E)-4-propyl[1,1,1-2H3]oct-4-ene (2) gave (E)-4-propyl[1,1,1-2H3]oct-5-en-4-ol (14), its (Z)-isomer 15, (E)-5-[3′,3′,3′-2H3]propyl-5-octen-4-ol (16), its (Z)-isomer 17, and the corresponding [8,8,8-2H3]-isomers 18 and 19 (see Scheme 1). The proportions of 4-7 were carefully determined by GC between 10% and 85% conversion of 1 and were constant within this range. The labeled substrate 2 was photooxygenated in two high-conversion experiments, and after reduction, the ratios 16/18 and 17/19 were determined by NMR. Isotope effects in 2 were neglected and the proportions of corresponding products from 1 and 2 assumed to be similar (% 4 ≍ % 14; % 5 ≍ % 15; % 6 ≍ % (16 + 18): % 7 ≍ % (17 + 19)). Combination of these proportions with the ratios 16/18 and 17/19 led to an estimate of the proportions of hydroperoxides formed from 2. Accordingly, singlet oxygen ene additions at the disubstituted side of 2 are preferred (ca. 90%). The previously studied trisubstituted olefins 20-25 exhibited the same preference, but had both CH3 and higher alkyl substituents on the double bond. In these substrates, CH3 groups syn to the lone alkyl or CH3 group appear to be more reactive than CH2 groups at that site beyond a statistical bias.

Notes: tert-Butyl and 2,6-di(tert-butyl)-4-methylphenyl (BHT) cyclopropanecarboxylates (4, 6, 24, 25) are lithiated with LiN(i-Pr)2 and t-BuLi, respectively. Reactions with alkyl halides, aldehydes, acyl chlorides, and heteroelectrophiles give α-substituted BHT esters which can be cleaved (t-BuOK/H2O/THF) to the corresponding carboxylic acids or reduced (LiAlH4/THF) to the cyclopropanemethanols.

Notes: Synthesis of 6,7-Dihydro-2H-pyrimido[6,1-a]isoquinolin-4(3H)-ones and Analogous Compounds and their Activity as Blood-Platelet InhibitorsThe synthesis of 6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-4(3H)-ones and of analogous compounds is described. These compounds are powerful phosphodiesterase inhibitors and, therefore, inhibit blood-platelet aggregation independent of the agonist. They exhibit, too, cardiac activities. However, there is evidence for selective action. A structure-activity relationship for platelet-aggregation inhibitors is discussed.

Notes: An Uniformly Occurring Aliphatic Benzil-Benzilic-Acid-Type RearrangementTreatment of 6-bromo-2,2,5,5-tetramethylcyclohex-3-enone (2) with aqueous alkaline and air affords 1-hydroxy-2,2,5,5-tetramethylcyclopent-3-enecarboxylic acid (8) as the major product of a benzil-benzilic-acid-type rearrangement. The key compound is 2,2,5,5-tetramethylcyclohex-3-ene-1,2-dione (11). The by-product of the reaction is (E)-2,2,5,5-tetramethylhex-3-enedioic acid (9) as the result of an oxidative cleavage of the 6-membered ring and the isomerization of the double bond.

Notes: Starting from acetates 1 and propionates 6, TiCl4-mediated addition of their silyketene acetals 2 and 7 to aldehydes gave aldols 4 and 9, respectively, with high π-face and ‘anti’ differentiation (Schemes, and Tables 1 and 2). Alternation of the (E/Z)-enolate geometry led to reversed α- and β-inductions (7 → 9b, 8 → 10b). Non-destructive removal of the auxiliary yielded enantiomerically pure β -hydroxycarboxylic acids 13.

Notes: Enantiomerically Pure Pyrrolidine Derivatives from trans-4-Hydroxy-L-proline by Electrochemical Oxidative Decarboxylation and Titanium-Tetrachloride-Mediated Reaction with NucleophilesPreparative electrolysis of N-methoxycarbonyl-O-[(t-butyl)dimethylsilyl]hydroxyproline 4 in MeOH leads to substitution of the COOH by a MeO group (oxidative decarboxylation). The mixture 5 of the two diastereoisomers (ca 1:1) thus obtained was reacted in CH2Cl2 with nucleophilic silylated compounds (such as allylsilane, silyl cyanide and 1-phenyl-1-silyloxyethane) or with trimethyl phosphite in the presence of TiCl4 to give 2-allyl-, 2-cyano-, 2-(2-oxo-2-phenylethyl)- and 2-phosphono-substituted hydroxypyrrolidines, respectively, with high diastereoselectivities (≥ 90%, products 6-12). The configuration of two of the products (6/7 and 8/9) was shown to be cis.

Notes: Comparative results on the reduction of 4,6,7,8-tetrahydro-7,7-dimethyl-2H-1-benzopyran-2,5(3H)-diones 1 are reported. Hydride reduction (LiAlH4 in Et2O or NaBH4 in i-PrOH) affords 2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-ones 5 in 30-60% isolated yield. Photochemical reduction of 1b and 1d (direct irradiation at λ = 300 or 254 nm in i-PrOH, or sensitized irradiation in acetone/i-PrOH or benzene/i-PrOH) gives 3-(6-oxo-1-cyclohexenyl)alkanoic acids 6 in 50-80%, while 1c affords the isomeric 3-(4,4-dimethyl-6-oxo-1-cyclohexenyl)-4-methyl-4-pentenoic acid (9) in 73% isolated yield. Electrochemical reduction (Hg, CH3CN, Bu4N+ClO4-, -2.6 V vs. Ag/Ag+) requires more than 4 Farad/mol for the consumption of 1 without any major product being detected.

Notes: The configurations of the 5,6-double bond in the carbacyclins iloprost (3; (E)) and isoiloprost (4; (Z)) are based on a complete assignment of the 13C and 1H resonances determined by 1D and 2D 13C-NMR and 1H-NMR methods.

Notes: Synthesis and Structure of Two Gold Complexes of Triphenylphosnium [Bis(diphenylphosphino)methylide]Triphenylphosphonium [bis(diphenylphosphino)methylide] (1) reacts with 1 or 2 equiv. of (CO)AuCl in a solvent to give mono- or binuclear Au(I) complexes 2 or 3, respectively. The Au-atoms are bound exclusively to P-atoms, and the ylidic C-atom remins an uncoordinated link between the three P-atoms. Contrary to findings with the free ligand 1, 31P-NMR spectra of 3 are in agreement with free P—C bond rotation in solution. 197Au-Mössbauer data for both complexes indicate the presence of Au(I) centers in a very similar environment. X-Ray structure analysis shows that the basic geometry of the free ligand is essentially retained in the complexes. Apart from the different degree of complexation, the structures of 2 and 3 differ only slightly in the conformation of the phenyl rings.

Notes: Cyclophane-Metal Complexes: Synthesis and Crystal Structure of ([3.3]Paracyclophane)gallium(I) Tetrabromogallate(III)[3.3]Paracyclophane forms 1:1 complexes 2a and 2b with both Ga[GaCl4] and Ga[GaBr4]. The crystalline products obtained from toluene solution at room temperature are much less sensitive to air and moisture than most other arene complexes of Ga(I). Solubilities in standard organic solvents are very low, suggesting coordination polymers. The X-ray diffraction analysis of 2b confirms the presence of a two-dimensional network. Both aromatic rings of each cyclophane molecule are η6-coordinated from the outer side to Ga(I)-atoms. The position of these metal cations is 2.75 Å above the ring centres. The arene rings are parallel within each cyclophane, but tilted by 48.5° with respect to those of the neighbouring cyclophane. The coordination sphere of the Ga(I) centres is completed by two Br-atoms of two GaBr4- anions, which link the Ga(I) cations to give … Ga[GaBr4] Ga[GaBr4]Ga … strands. The double interconnection of the Ga(I)-atoms gives rise to a two-dimensional sheet structure, which is thus different from the structure of the previously described Ga[GaBr4] complex of [2.2]paracyclophane, where a three-dimensional network was observed.

Notes: Butanolides and Butenolides by Intramolecular Ene-Reaction during Thermolysis of Propargyl PropiolatesGas-phase flow thermolysis of 2-butynyl propynoate (1) and 2-propynyl 2-butynoate (2) at 550° afforded 3-ethynyl-2-methyl-2-buten-4-olide (4, 85%) and 2-ethynyl-3-methyl-2-buten-4-olide (5, 80%), respectively. Their formation presumably entails an ene reaction between the methylacetylenic and the acetylenic functions of the diyne esters 1 and 2 to give the two methyliden-vinyliden-butanolides 10 and 11 as intermediates, followed by a [1,5]-H shift to 4 and 5. At 400-450°, the gas phase flow thermolysis of 1 and 2 led to the dimers 16 (77%) and 17 (6%), respectively. These products resulted from the Diels-Alder dimerization of the above mentioned intermediates 10 and 11. The regioselectivity of this dimerization is determined by a ‘head-to-head’ approach, with the double bond conjugated to the carbonyl group acting as the dienophile in both cases. The low yield of 17 from 2 is probably due to a further Diels-Alder reaction of the dimer 17 with its precursor 11, yielding a trimer 18 (8% isolated). This process is not possible when starting with 1, which explains the higher yield of 16. The gas phase flow thermolysis of 2-butynyl 2-butynoate (3) at 550° afforded a mixture of four isomeric products, namely the two monocyclic ethynyl-butenolides 6 and 7 and the two bicyclic vinyl-butenolides 8 and 9. The formations of 6-9 are also rationalizable by initial ene-reactions, in this case two alternative ones, each involving one of the two CH3 groups of 3. This leads to two alkylidene-vinylidene-butenolides, namely 12 and 13. A [1,5]-H shift converts 12 into 6 and 13 into 7. A competing alternative [1,5]-H shift transforms both 12 and 13 to the triene 14, which electrocyclizes to the cyclohexadiene 15. The latter undergoes two alternative [1,5]-H shifts to yield 8 and 9.

Notes: The kinetics and product studies of oxidation of eight olefins 1-8 by ClO2 in H2O in the pH range 3-7 are described. The reaction is faster as the pH decreases. At pH 〈 4, ClO2 reacts equimolarly with olefins to yield isomeric mixtures of chlorohydrines and 1,2-dioxygenated products, following the equation: The order of reactivity is: (E)-stilbene 〉 indene 〉 β-methylstyrene 〉 acenaphthylene 〉 α-methylstyrene 〉 styrene 〉 cyclohexene 〉 allylbenzene. A multi-stage radical-cation mechanism is proposed, in which an initial reversible protonation: \documentclass{article}\pagestyle{empty}\begin{document}$$ {\rm ClO}_{{\rm 2}} + {\rm H}^{\rm +} \mathbin{\lower.3ex\hbox{$\buildrel\textstyle\rightarrow\over {\smash{\leftarrow}\vphantom{_{\vbox to.5ex{\vss}}}}$}} \left[{{\rm HClO}_{\rm 2}} \right]^ + $$\end{document} is followed by an electron-transfer stage (rate-determining): The cation-radical thus produced, adds rapidly an additional ClO2 to form dioxygenated products. The chlorohydrines most likely arise from HClO additions to the olefinic double bonds, which, in turn, generate from dismutation of 2 HClO2 into HClO + H+ + ClO3-.

Notes: Since we found certain structural features of triaziridine (1) obtained by MNDO calculations to be in qualitative agreement with those derived earlier from ab initio calculations, we used the MNDO method to derive properties of formyltriaziridine (2) and 1-formyl-2,3-diisopropyltriaziridine (3) as models for the preparatively known 2,3-dialkyl-triaziridine-1-carboxylates 4 and 5. The main results are: (a) The triaziridine N-atoms with H, alkyl, or formyl as substituents (see 2 and 3) are pyramidal. N(1) carrying the formyl group is flatter than N(2) and N(3) with H or alkyl substitent. Bond lengths and angles at N(2) and N(3) are almost identical with those calculated for the N-atoms of 1. (b) The MNDO inversion barriers at the H-substituted N(2) and N(3) of 2 are higher than those at the formyl-substituted N(1), but similar to the ab initio barriers at the N-atoms of 1. (c) The MNDO inversion barriers at N(1) of 2 and 3 are 53 to 92 kJ/mol, whereas the rotation barriers around the N(1)-C(4) bond are 7 to 23 kJ/mol; thus, the previously observed dynamic NMR phenomena in trans-2,3-diisopropyltriaziridine-carboxylates (5) can now be assigned to the slowing down of N(1) inversion rather than N(1)-C(4) rotation.

Notes: (1-Phenylethyl)- and (1-naphthylethyl)ureas, obtained in the reaction of racemic amines with optically pure isocyanates, are separated and then decomposed in refluxing alcohols, to afford optically pure secondary amines and optically pure alkyl carbamates in quantitative yields. The scope of this fragmentation for the resolution of racemic mixtures of amines is illustrated by several examples of biologically important compounds. Carbamates obtained by this fragmentation can readily be recycled.

Notes: Four carotenoids (zeaxanthin 1, astaxanthin 2, and their C50 synthetic isoprene-homologues 3 und 4) have been incorporated into bilayer unilamellar vescles of dimyristoylphospatidylcholine as proved by coelution on a Sepharose column. The incorporation into the bilayer proper has been proved by the sensitivity to phase transition of UV/VIS spectra and circular dichroism. The UV/VIS absorptions of the carotenoids are typical of a lipidic environment. At the temperature of phase transition occur both intermolecular phenomena (aggregation of carotenoid molecules) and intramolecular changes (conformational change). The relative solubilities of the various carotenoids in this phospholipid membrane can be fitted with molecular parameters (length of the lipophilic carotenoid segment vs. lipid bilayer thickness).

Notes: C45-and C50-Carotenoids: Synthesis of (S)-TrisanhydrobacterioruberinThe Synthesis of (S)-trisanhydrobacterioruberin ((S)-1) is reported.

Notes: Mössbauer data recorded at room temperature and 78 K for several binary and two new ternary vanadium sulfides are presented. The results are discussed in comparison with the structures and magnetic susceptibility measurements. A change in the spin state of the Fe-atoms from the Fe2+ high-spin state to the low-spin state is observed in the binary vanadium sulfides. This change is due to a shortening of the crystallographic c-axis which is nearly parallel to short metal-metal distances. In one ternary thallium vanadium sulfide the Fe is in the unusual trivalent low-spin state at room temperature.

Notes: The two bis-macrocycles 4 and 5 in which the tetraaza units are separated by a chain of different length, have been synthesized using 1,4,7-tritosyl-1,4,7,11-tetraazacyclotetradecane as starting compound and bifunctional alkylating agents. The bis-macrocycles give binuclear complexes with Ni2+ and Cu2+, the properties of which have been studied to obtain information about the interaction of the two subunits as a function of the distance. The VIS spectra of the Ni2+ and Cu2+ complexes indicate that both metal ions are in a square-planar geometry as expected from the results of the analogous complexes with 1,4,7,11-tetraazacyclotetradecane 7. Cyclic voltammetry and differential pulse polarography of the binuclear Ni2+complexes in CH3CN show a single two-electron step for ligand 5, whereas two distinct one-electron redox processes can be observed for ligand 4, indicating that the two metal ions interact with each other when the chain length is shorter. Similarly, the EPR studies of frozen solutions of the binuclear Cu2+ complexes clearly show that a magnetic dipolar interaction between the two paramagnetic centers exists, and that the strength of it depends upon the length of the bridge. Finally, from the X-ray structures of the binuclear Ni2+ complexes with 4 and 5, it is seen that the two rings are kept apart as far as possible, the distances between the two metal ions determined in the solid correlate well with the observations in solution.

Notes: Optically Active Lycopene Epoxides and Lycopene Glycols: Synthesis and Chiroptical PropertiesWe present extensive spectral and chiroptical data on the pure and crystalline lycopene diepoxides 1-3 and glycols 4-9. A first synthetic approach to 1-9 with (+)-malic acid as starting material afforded 30 as a complex mixture of isomers (Scheme 1). Pure stereoisomers 1-9 were obtained using the enantiomerically pure epoxygeraniol 31 as starting material (Scheme 2). Differentiation of the (5Z)-from the (all-E)-isomers by 1H-NMR and UV/VIS alone is very difficult.

Notes: The reaction of the meso-diol, Δ,Λ-[(en)2Rh(OH)2Rh(en)2]4+, with aqueous H2O2 and 1 equiv. of NaOH at 90° forms the μ-peroxo-μ-hydroxo-bridged species Δ,Λ-[(en)2Rh(O2,OH)Rh(en)2]3+ in a yield of ca. 50%. The compound was crystallized as perchlorate and trifluoromethanesulfonate salts. The structure of the latter salt was determined by single-crystal X-ray diffraction. The crystals are triclinic with space group P1 and lattice constants a = 11.895(5), b = 12.491(4), c = 13.053(5) Å, α = 103.98(3), β = 92.59(3), γ = 119.52(6)°. The distances of the metal centres to the bridging peroxo ligand are 1.999(8) and 1.983(6) Å. The O—O distance in the peroxo group is 1.521(14) Å, and the dihedral angle of the Rh—O—O—Rh unit deviates 65° from planarity. The peroxo complex reacts reversibly with acid, and spectrophotometric studies suggest that the reaction involves protonation of the peroxo bridge, with pKa = 2.70(2) at 25° in 1M NaClO4.

Notes: Novel (5R,8S,10R)-6-(allyloxy)- and (5R,8S,10R)-6-(propyloxy)ergolines have been synthesized by use of a Meisenheimer [2,3]-sigmatropic rearrangement of a (5R,8S,10R)-6-allyl-ergoline N6-oxide as key step.

Notes: The N,N-dimethyl-8-nitro-1-naphthaleneamine molecule has been observed in seven environments in three crystal modifications. A range of conformations, related by conrotatory motions about the two exocyclic C—N bonds, is observed. In all seven conformations, the lone pair of the amino N-atom is directed approximately towards the nitro N-atom, which is slightly pyramidalized towards the amino group. The NO2 group appears to be a poorer through-space electron acceptor than the carboxylic ester group, in contrast to their through-bond electron-accepting properties.

Notes: 5,6,7,8-Tetrahydro-4H-1,2,5-oxadiazocin-6-ones, Ring Enlargement Products from a 3-Isoxazolidinone and 3-Amino-2H-azirines3-Dimethylamino-2H-azirines 1 and 4,4-dimethyl-3-isoxazolidinone (7) undergo already at room temperature a ring enlargement reaction to yield 5,6,7,8-tetrahydro-4H-1,2,5-oxadiazocines of type 8. The structure of 8a has been confirmed by X-ray crystallography. The conformation of the eight-membered ring with a trans-amide group is of particular interest (Fig. 1 and 2).

Notes: Chiral metals are so far practically unknown. The synthesis of a chiral substrate for possible organic conductors and superconductors is described.