ALBERT

Notizen: The benzyl-protected glycosyl acetates 1, 6, 11, and 15 react with MeOPPh2 under catalysis by TMSOTf to yield diastereoselectively the glycosylphosphine oxides 2, 3, 8, 12, 13, and 16, with a strong preference for the 1,2-cis-configurated anomers. Hydrogenolysis of the major products gave the crystalline, unprotected phosphine oxides 4, 9, 14, and 17, of which 4 was transformed in to the acetate 5, and 9 into the benzoate 10. The benzylated phosphine oxides 4, 8, 12, and 16 were reduced with Cl3SiH in the presence of a tertiary amine to form the phosphines 18, 21, 24, and 26, which were transformed into the phosphine sulfides 19, 22, 25, and 27. Moreover, 18 and 21, were characterized as the borane adducts 20, and 23. The structure of the (arabinofuranosyl)phosphine oxide 12, the corresponding sulfide 25, and of the borane complex 20 were established by X-ray analysis. According to NMR spectroscopy, the equatorial pyranosylphosphine oxide 8, the sulfide 22, and the borane complex 23 adopt a 4C1 conformation. The axial phosphine oxide 2 is a flattened 4C1, the sulfide 19 exists as a B2,5, and the borane complex 20 is a flattened 4C1 in the solid sate and a B2,5 in solution. Thus, the conformational behavior of these α-D-glucopyranose derivatives reflects the steric requirement of the P-substituents.

Notizen: High-yield chemical syntheses of phosphoramidite building blocks of the four arabinonucleosides aUrd (1), aCyd (2), aAdo (3), and aGuo (4), suitable for (3′-5′)oligoarabinonucleotide synthesis are described. The problem of 2′-hydroxy group protection was solved by introduction of the versatile 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) residue, which was also used for aglycon protection.

Notizen: Formaldehyde reacts with substituted nitrosobenzenes giving the corresponding N-phenylhydroxamic acids. A mechanism involving three sequential steps in this reaction is proposed. The first step is the nucleophilic attack of the nitroso group on the carbonyl group which leads to the formation of the unstable tetrahedral zwitterionic intermediate. This step is followed by the proton transfer to the zwitterionic intermediate to form more stable nitrosocarbinolic cation intermediate, which in the subsequent step undergoes the rate-controlling elimination of proton from the C-atom of nitrosocarbinolic group, leading to the final product, hydroxamic acid. The first and the second step appear to be reversible. The experimental evidence obtained, which is the basis for such a description of the investigated reaction, includes: (a) the order of reactivity of substituted nitrosobenzenes, as demonstrated by the plot of log kobs vs. σ Hammett parameters with slope of -1.74; (b) the observation of a general-acid catalysis; (c) the observation of the inverse solvent deuterium isotope effect of ca. 1.8 in the reaction; (d) the observation of kinetic primary deuterium isotope effect of ca. 8 related to the ‘water’ reaction in the reactions of formaldehyde with substituted nitrosobenzenes; (e) the observation of general-base catalysis in the reaction; (f) the observation of the kinetic primary deuterium isotope effect of ca. 2.1 for the acetate-ion-catalyzed reaction.

Notizen: The Diels-Alder adducts 8 of furan to 1-cyanovinyl acetate were converted into (Methyl 3-chloro)-5-O-(3-chlorobenzoyl)-2, 3-dideoxy-α-dl-arabino-hexofuranosid)uronic acid ((α)-18a) and into (methyl 3-azido-5-O-(3-chlorobenzoyl_-2,3-dideoxy-α-dl-ribo-hexofuranosid)uronic acid ((α)-41a). These compounds were condensed to (3S)-3-[(1′S)-1′-amino-3′-methylbutyl]-3,4-dihydro-8-hydroxyisocoumarin hydrochloride ((-)-2); the resulting mixtures of diastereoisomeric amides were transformed and separated to give the gastroprotective substance AI-77-B((-)-1) and analogues.

Notizen: Aryl-halo-diazirines react under basic conditions with 1,3-cis-, 1,2-cisand 1,2-trans-diols to give acetals. Yields are high. Diastereoselectivities depend upon the diol and upon the reaction conditions. Thus, reaction of the 1,3-cis-diol 1 (Scheme 1) with 2 gave 3 as a single diastereoisomer. The 1,2-cis-diols 4 and 7 led to the endo- and exo-acetals 5/6 (93:7) and 8/9 (ca.10:1), respectively, The 1,2-trans-diols 10, 16, and 19 reacted with 2 to afford 11/12 (90:10), 17/18 (1:1), and 20/21 (6:1), respectively. Reaction of the (4-nitrophenyl)diazirine 13 with 10 at higher temperatures yielded 14/15 (6:4). The uracil moiety, the acetamido group, and the enol-ether moiety are compatible with the reaction conditions. The diastereoselectivity is rationalized on the basis of a reaction sequence involving alkoxy-halogen exchange, which is regioselective or not, thermolysis of the ensuing alkoxydiazirine(s), protonation of the alkoxycarbene to form an (E)-configurated oxycarbenium ion, and attack of the neighboring oxy or hydroxy group, which is only possible for a limited range of conformers.

Notizen: Synthesis of Chiral Cobalt Complexes with Planoid-Tetradentate Ligand SystemThe synthesis of a series of Cbl-related, achiral CoIII complexes 9a-c as well as enantiomerically pure, C2-symmetric CoIII complexes 15 and 18, is reported (Schemes 3, 5, and 7). The crystal structures of 9c and 15 were determined. Complex 18 acts as an enantioselective catalyst in the isomerization of 1,4-epiperoxides to hydroxycycloalkenones.

Notizen: Enantioselective Synthesis of Allyl- and Propargylamines via Nucleophilic 1,2- Addition to Chiral AldininesThe asymmetric Synthesis of allylamines and propargylamines 5 in high enantiomeric purity (e.e. ≤ 97%) is described. Key step is the 1,2-addition of organocerium reagents to chiral α,β-unsaturated aldimines 3 to produce secondary animes 4. The Chiral auxiliary (S,S)-2 is removed in three steps, affording the title compounds 5, useful bifunctional building blocks and compounds of pharmaceutical interest.

Notizen: The synthesis of a series of novel acetylenic compounds 1-7, isolated recently from the fungus Eutypa lata, is described. The crucial step is the coupling reaction between a protected aryl halogenide and the acetylenic chain as a cuprous acetylide (Scheme 1). A more efficient method using bis(triphenylphosphine)palladium dichloride ([Pd(PPh3)2Cl2]) as catalyst was also carried out with success.

Notizen: Fumaramides 3b and 3c bearing the C2-symmetrical pyrrolidine moieties (2R,5R)-2,5-bis(methoxymethyl)pyrrolidine (2b) or 1,3:4,6-di-O-benzylidene-2,5-dideoxy-2,5-imino-L-idit (2c), respectively, as a chiral auxiliary lead to high diastereoselectivities in radical reactions (‘tin method’;Scheme 1). Removal of the chiral auxiliaries affords the corresponding alkylated fumaric acids Scheme 2. Single-crystal X-ray structures of 3b and 3c support arguments that lead to the model of 1,4-stereoinduction.

Notizen: 14O-Ethyl-5m-ethylnaloxone (7) and 14O-ethyl-5-methylnaltrexone (8) have been prepared starting from 14O-ethyl-5-methyloxycodone (9) in several steps. Both, 7 and 8, were found to be opioid antagonists in vitro and in vivo. Compound 7 exhibited some selectivity for μ opioid receptors, whereas compound 8 did not show selectivity for any of the receptor types. In the AcOH-writhing antagonism test, 8 was not able to antagonize morphine-induced antinociception, but antagonized fentanyl- and sufentanil-induced antinociception.

Notizen: Reported here are the novel free porphyrins corallistin B, C, D, and E, isolated as methyl esters 2a, 3a, 4a, and 5a, respectively, from the sponge Corallistes sp. (Lithistida) collected at the basis of the south New Caledonian coral reef. A protocol is also established for formylation of their NiII complexes, which show a different reactivity pattern toward DMF/POCl3 from metal complexes of deuteroporphyrins. Together with corallistin A, Previously isolated as the methyl ester 1a, and the known deuteroporphyrin IX (isolated as 6a) also present in the sponge, the new corallistins, which may be thought to derive from protoporphyrin via heme, account for an amazing 60% of the EtOh extract from the sponge.

Notizen: Synthesis of Selectively N-Functionalized Polyamine DerivativesA threefold differently protected derivative 8 of the triamine spermidine (2) has been prepared in three steps starting from propane-1,3-diamine (1). The protected spermidine derivative 8 was converted to its spermine analogue 12, a useful polyamine intermediate. In a convergent way, the fourfold differently protected derivative 18 of the tetraamine spermine (3) has been obtained by coupling the two different and separately prepared propane-1,3-diamine units 15 and 17. Spermidine derivative 19 and spermine derivative 20, both selectively protected at both primary amino groups, have been Prepared from the free polyamines 2 and 3, respectively, in a direct approach.

Notizen: Cucl2-Induced oxidative coupling of 2-(tert-butyl)-6,6-dimethylpentafulvenyl anion 9 predominantly takes place at C(7) and C(5) to give [7-7] and [7-5] coupling products 15 and 16 in 35 and 47% yields, respectively (Scheme 3) whose structures are elucidated from 1D- and 2D-NMR analysis. Compared with the product distribution observed for 6,6-dimethylpentafulvenyl anion 2 (Scheme 1), no coupling at C(2)/C(3) of 9 is observed. This means that, besides electronic effects, steric effect are also important in oxidative couplings of fulvenyl anions. The same couplings occur in the case of 2,3-bis(6,6-dimethylfulven-2-yl)-2,3-dimethylbutane dianion 10 as well but, due to electronic as well as conformational effects (Scheme 5), intermolecular coupling (to give polymers 17, Scheme 4) is strongly favored over intermolecular coupling. Mechanisms explaining base-catalyzed isomerization 15a ⇄ 15b ⇄ 15c (Scheme 6) as well as isomerization 16a ⇄16b (Scheme 7) are proposed.

Notizen: The Rh1(diolefin)complexes [Rh(nbd)(2)][PF6] [Rh(1,5-cod)(2)][PF6], and [Rh((Z)-α -acetamidocinnamic acid)(2)][PF6] (2 = the chiral P,N-ligand (S)-1-[bis(p-methylphenyl)phospino]-2-[p-methoxybenzyl)amino]-3-methylbutane have been prepared and characterized. These complexes exit as a mixture of isomers arising from different five-membered-ring conformations and diastereoisomers due to both the prochiral nitrogen and olefin ligands. The three-dimensional solutions structures of these complexes have been studied with the specific aim of understanding how the chiral pocket is built. Aspects of the exchange dynamics and their possible relevance to homogeneous hydrogenation are discussed The solid-state structure for the nbd complex, [Rh(nbd)(2)][PF6], as well as detailed one- and two-dimensional 31P-, 13C-, and 1H-NMR results are presented.

Notizen: The 8-amino-5,6,7,8-tetrahydronaphth-2-oic acid (1), 8-(aminomethyl)-5,6,7,8-tetrahydronaphth-2-oic acid (2), and 8-(aminomethyl)naphth-2-oic acid (3) were synthesized in their protected forms as turn-inducing dipeptide mimics. Two of them (2 and 3) were incorporated into a novel type of cyclic, peptide-based structures (see 21 and 34-36) designed as templates for the synthesis of TASP molecules.

Notizen: The stereospecific synthesis of the monoterpene alkaloids (-)-α-skytanthine ((-)-2), (-)-N -demethyle-δ-sky-tanthine((-)-7), and (+)-epidihydrotecomanine (+)-4 was achieved from a common intermediate 22, which in turn was obtained from (1R,4S,1′S)-2-(1′-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene (10),via a ketene aza-Claisen rearrangement. The piperidine derivative (+)-31, formally the aza-analogue of (+)-isoiridomyrmecin, was also obtained from the same intermediate 22.

Notizen: A kinetic study on the alkaline hydrolysis of cephaloridine (1) at pH 10.5 and 37° was carried out using ion-pair reversed-phase HPLC. The main resulting degradation products, the 7-epimer 2 of 1, the Δ2-isomer 3 of 1, and the 3-methylidene compound 4 were identified. The presence of a pyridinio group at C(31) results in a slightly increased formation constant for the 3-methylidene compound 4 and the 7-epimer 2, and introduces a new reaction: the isomerization of the double bond at C(3) in the dihydrothiazine ring to C(2).

Notizen: Treatment of ten monocyclic dienols 8-11 with an excess of fluorosulfonic acid in 2-nitropropane at -90° afforded diastereoisomeric mixtures of racemic tricyclic ethers 12-14 in 81-91% yield (see tables 1 and 2). These transformations represent further examples of biomimetic acid-mediated cyclisations in which an OH group serves as the internal nucleophilic terminator. A non-synchronous process is postulated, and the examples described strongly re-inforce our working mechanistic hypothesis, whereby the stereochemical course of cyclisation is directed by the orientation of the side chain vicinal to the intermediate cyclohexyl cation (see Schemes 4 and 5). It is also demonstrated that the efficiency of this process is independent of the nature of the OH group, which may be primary, secondary, or tertiary. In addition, the organoleptic properties of 12-14, Me homologs of known odorants such as Ambrox® ((-)-3a) and its diastereoisomer, are briefly discussed.

Notizen: Strong bases (lithium diisopropylamide (LDA) or BuLi) convert cyclosporin A (CS) to hexalithio derivative containing a Li alkoxide, four Li azaenolate, and one Li enolate units. The Li6 compound is solubilized in tetrahydrofuran (THF) by addition of excess LDA or LiCl. Reactions with electrophiles (alkyl halides, aldehydes, ClCO2R, CO2, (RS)2, D2O) at low temperatures give products containing new side chains in amino-acid residue 3 of the cyclic undecapeptide (see 1-13, Schemes 1, and 2, and Figs. 1 and 2) in moderate to high yields and, with Re- or Si-selectivities, depending upon the conditions of lithiation of up to 7:1, Pure CS derivatives (Scheme 2, Table 1 in the Exper. Part) can be isolated by column chromatography. N-Alkylations or cleavage of the peptide backbone by carbonyl addition occur only at higher temperatures and/or with prolonged reaction times (see 14 and 15 in Scheme 4). Very little or no epimerization of stereogenic centers occurs under the conditions employed. Possible reasons for the feasibility of these surprizing conversions of CS are discussed (Schemes 4 and 5 and Fig. 3). For comparision, [MeAla3]CS (2b) and [D-MeAla3]CS (2a) were also prepared by conventional peptide synthesis in solution (Schemes 6 and 7). Their 1H- and 13C-NMR spectra are compared with those of CS (Table 2 in the Exper. Part).

Notizen: On Diels-Alder Reactions of the C60-FullereneWe report on the regioselective [4+2] cycloaddition of Buckminsterfullerene C60(1) at room temperature with 2,3-dimethylbuta-1,3-diene and with the monoterpene 7-methyl-3-methylideneocta-1,6-diene (= myrcene) and on the spectroscopic characterization of the corresponding crystalling monoadducts 2 and 3. According to these experiments, 1 acts as a reactive dienophile, which can be functionalized regioselectively under mild and controlled conditons.

Notizen: The Mass Spectral Loss of Water from Macrocyclic Amino-ketonesMacrocyclic oxo-lactams containing an N-alkylamino side chain are stable natural products. Their electron-impact mass spectra are characterized by intensive [M - H2O]+ signals, the molecular ion signal itself is missing. Under electrospray ionization conditions, on the other hand, the [M + 1]+ ion is the only detected signal. The loss of water is explained in terms of an internal (thermal) Schiff-base formation, leading to a e.g. bicyclo[11.9.4]-system. The alcohol corresponding to the macrocyclic ketones and/or lactams show an expected mass-spectral behavior following well known rules.

Notizen: Rigorous regio- and stereospecific labeling experiments are performed to demonstrate the operation of the previously suggested operation of ‘isotopically sensitive branching’ in FeI-mediated C—H bond activation. For the hexane-1,6-diol/Fe+-complex, it is shown that dehydrogenation involves specifically the central C(3)/C(4) position, and the study of the stereospecifically labeled D,L- and meso-[3,4-D2]-isotompomers 1e and 1f demonstrates that dehydrogenation proceedes via two competing pathways (i.e. ‘anti’- vs. ‘syn’-route). The contribution of these routes to the product formation is - due to a kinetic isotope effect - controlled by the relative configuration at the labeled positions C(3)/C(4). For the D,L-form 1e, we estimate a ratio of 49:1 in favor of the ‘anti’-route; due to an isotope effect, this ratio drops to 4.3:1 for the meso-form 1f.

Notizen: Preparation of PQQ in the kag ScaleThe improvement of the PQQ synthesis according to the method of Corey and Tramontano allows the preparation of the triester of this cofactor in the kg scale with an overall yield of 13% (average 78% per step), without a bottleneck in the sequence and with crystalline, analytically pure intermediates. The new purification of free PQQ from conc. H2SO4 is remarkable with respect to the application as well as to the stability of this natural product.

Notizen: The cyclic octapeptide cyclo(-Pro-Pro-Tyr-Val-ProLeu-Ile-Ile-) (1), isolated from the Hymeniacidon sponge, was synthesized and examined conformationally using NMR and molecular-dynamics simulations. Most structural parameters of synthetic 1 are in accord with those reported for the isolated material. Our study indicates some small but significant differences in the assignment of the 1H- and 13C-NMR resonances from those of the natural material. The Conformation was determind in both CHCl3 and DMSO using 1H-NMR and molecular-dynamics simulations. Both NOE's and coupling constants were used as experimental restraints during the simulations which utilized explicitly the same solvent as in the NMR study. The differences in the interaction of the solvent with 1 were examined, providing insight into the observed differenced in conformation. The dominant conformation contains a ßVIa turn about Ile8-Tyr3 including a Pro1-Pro2 cis-peptide bond and a ßI or ßII turn about Val4-Ile7 in CHCl3 and DMSO, respectively.

Notizen: The Diazo-quinone of PQQ as a Possible Reagent for Mapping Quinoproteins by Photo-affinity LabelingPQQ is an organic redox cofactor found in a class of enzymes called quinoproteins. The synthesis and the photochemistry of the diazo-quinones of PQQ and PQQ-triester are described. The photogenerated Wolff-rear-rangement products have been caught with water and methanol as model nucleophiles. The products show a strong fluorescence. The diazoquinone of PQQ may be considered as possible reagent for mapping quinoproteins by photo-affinity labeling.

Notizen: A variety of 2-deoxy-1-O-diphenoxylphosphoryl-hexopyranoses were generated in situ by a radical 2→1 migration of the phosphate group. The structures of the reactive rearrangement products were fully elucidated by NMR spectroscopy. Rate constants for this new rearrangement were determined fro a variety of substrates.

Notizen: Formation of derivatives of PQQ and PQQ-Triester for the Detection of PQQPQQ is an organic redox/cofactor found in a class of enzymes called quinoproteins. It has been reported that materials like milk, egg yolk, vinegar, beer, serum, urine, and biological tissues contain little amounts of PQQ. To facilitate studies on PQQ, a simple detection of PQQ could be extremely useful. For this purpose, we describe in this paper some adducts of PQQ or PQQ-triester with 1,2-diamines, 2,4-dihydroxyaniline, pyrrole, indole as well as an oxidation product of PQQ. UV and fluorimetric detections of these colored products show that this method is relatively sensitive. The reaction of PQQ-triester with (MeO)3P to the phosphole adduct 13 is of great importance: the use of [32P]-labeled trialkyl phosphites will make this reaction an extremely sensitive method to detect PQQ.

Notizen: The elimination of H2O from serine residues in peptides was found to be feasible by the following two steps: O-acylation with AcCl/pyrideine in CH2Cl2 and treatment with an imidine base (DBU or DBN) in THF in the presence of large amounts of LiClO4 (10 examples). Other Li salts such as LiBr and LiCl can also be used. No epimerization of the amino acid residues in te peptide could be detected under these conditions. Thus, a simple method for the preparation of peptides with dehydroalanine residues in high yield, directly from serine-containing precursors, is available.

Notizen: Syntheses of (±)-2-exo-cyano-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl acetate (1) and of (±)-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one (2) are reported. The additon of PhSeCl to 1 afforded (±)-5-endo-chloro-2-exo-cyano-1-methyl-6-exo-(phenylselenenyl)-7-oxabicyclo[2.2.1]hept-2-endo-yl acetate (6), whereas 2 added to PhSeCl with the opposite regioselectivity giving (±)-6-endo-chloro-1-methyl-5-exo-(phenylselenenyl)-7-oxabicyclo[2.2.1]heptan-2-one (7). These adducts were converted into 5-chloro-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one (9) and 6-chloro-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one (10), respectively.

Notizen: Synthesis of a 1,2-trans-Configurated, Equatorial Glycosylphosphonate Analogue of D-myo-Inositol 1,4,5-TrisphosphateThe diphosphonate analogue 3 of D-myo-inositol 1,4,5-trisphosphate (1), a 1,2-trans-configurated, equatorial glycosylphosphonate, was synthesized and characterized as its hexasodium salt 3a. In a first approach, the silylated galactal 4 (Scheme 1) was transformed into the oxirane 5 and hence, by treatment with Me3SiP(OMe)2, into a mixture of the glycosylphosphonate 6 and its silyl ether 7. This mixture was desilylated and then treated with acetone and FeCl3 to yield 8 and 9 (64 and 22%, resp., from 4). In a second approach, the acetates 11/12(Scheme 2) were treated with P(OMe)3/Me3SiOTf in MeCN to afford the anomeric glycosylphosphonates 16/17 (1:1, 60%), while the trichloroacetimidate 10 gave mostly the αD-anomer 16. The αD-anomer 20 was obtained from 12 and P(OPh)3. The highest yield of a β-Dphosphonate was realized by treating 12 with the cyclic phosphite 15 (→ 18/19, 40% each). The β-D-phosphonate 17 was debenzylated (→21) and protected to give 8. Transformation of 8 into the bromide 22 (43%) proved difficult due to the facile demethylation of thephosphonate, and was best followed by treatment of the crude product with CH2N2 and 2,2-dimethoxyporpane. Phosphorylation of 22 yielded 41% of the (dimethoxyphosphoryl)phosphate 23. The conditions of the Arbuzov reaction slowly converted the bromide 23 into the bis(phosphoryl)phosphate 24 (69%), which was then deprotected. The resulting 3 was purified via the ammonium salt and transformed into 3a (72%).

Notizen: Synthetic Analogues of Low-Molecular-Weight Acyl-polyamine Spider ToxinsLow-molecular-weight spider and wasp toxins are selective inhibitors of glutamate receptors of the central nervous system and consist of a polyamine backbone and one or several carboxylic acids and/or amino acids linked by a peptide-like bond. The syntheses of twelve analogues of spider and wasp toxins are described (10a-c, 15a-c, 20a-c, 25a-c) having the general structure of acyl, arylacyl, or heteroarylacyl → DL-alanyl → ω-aminoacyl → N1-spermidine, with variation in the acyl and the ω-aminoacyl part.

Notizen: The reaction of 4-hydroxycoumarin and certain aliphatic aldehydes affords 1:1 or complex 2:2 adducts besides (or in place) of the expected 2:1 bis(coumarin) adducts. Reaction with heptanal, cyclohexanecarbaldehyde, and pivalaldehyde are reported as representative. The structure of the reaction products was established by spectroscopical techniques, including X-ray analysis, and their formation was mechanistically rationalized. Some of the 1:1 adducts are synthetically useful for the preparation of 3-alkyl-4-hydroxycoumarins.

Notizen: The enantioselective copper-catalyzed 1,4-addition of Grignard reagents to α,β-unsaturated carbonyl compounds was studied with the following CuI compounds as catalyst precursor and 1,2:5,6-di-O-isopropylidene-3-thio-α-D-glucofuranose (Hsiig) as chiral ligand: CuI, iodo[bis(dibutylsulfide)]copper(I), [Cu(siig)], [Cu(siig)(pp)] (pp =1,2-bis)(diphenylphosphinoethene), and tetrakis[iodo(tributylphosphine)]copper(I). The addition of BuMg halides to cyclohex-2-en-1-one was tested under several reaction conditions. The chemical yields and regioselectivities for this reaction were, in all cases, larger than 90 and 98%, respectively, and independent of the experimental conditions. The enantioselectivity was strongly dependent on the reaction conditions and reached a maximum of 60%. Several other substrates were also tested in the above reaction. The X-ray crystal structure for [Cu(siig)(pp)] was determined by X-ray crystallography.

Notizen: From the aerial parts of Scrophularia ilwensis, four new triterpene saponins, ilwensisaponins A-D (1-4) were isolated. The structures of the compounds were elucidated using chemical and spectral data as 13β, 28-epoxy-3-β-{{[β-D-glucopyranosyl-(1→2)]-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→3)]-β-D-fucopyranosyl}-oxy} olean-11-en-23-ol (1), 3-β-{{[β-D-glucopyranosyl-(1→2)]-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→3)]-β-D-fucopyranosyl}oxy}olena-11, 13(18)-diene-23, 28-diol (2), 3-β-{{[β-D-glucopyranosyl-(1→2)]-[α-L-rhamnopyranosyl-(1→4)-β-Dglucopyranosyl-(1→3)]-β-Dfucopyranosyl}oxy}-11α-methoxyolean- 12-ene-23, 28-diol (3), and 3-β-{{[β-D-glucopyransoyl-(1→2)]-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→3)]-β-D-fucopyranosyl}oxy}olean-12-ene-11α,23,28-triol(4).

Notizen: Two new enantioselective syntheses of the naphthopyranquinone antibiotic frenolicin B (1), of its enantiomer 2, and of its diastereoisomers 3 and 4 were accomplished using two different routes from optically active β-Hydroxy esters (R)- and (S)-11 and 18. β-Hydroxy esters (R)- and (S)-11 were prepared stereoselectively from optically active sulfenylacetates (S)- and (R)-10, respectively (Scheme 2, Method A). Alternatively, compound 18 was obtained in excellent yield by enantioselective hydrogenation of the corresponding β-keto ester 17, using a chiral ruthenium-complex catalyst (Scheme 3, Method B). Subsequently, compounds (S)-11 and 18 were transformed into frenolicin B (1). In analogy, Stereoisomers 2-4 were prepared from (S)- and (R)-11 in good yields.

Notizen: The 2′-deoxyisoguanosine phosphonates 3a and 4a and the phosphoramidites 3b and 4b were prepared as building blocks for solid-phase oligonucleotide synthesis. The diphenylcarbamoyl (dpc) residue was introduced as 2-oxo protecting group which stabilizes the N-glycosylic bond against hydrolysis and prevents the molecule from side reactions. The dpc-protected building blocks 4a, b were employed in solid-phase synthesis and were found to be much more efficient than the unprotected compounds 3a, b. Oligonucleotides with alternating (11) or consecutive isoguanine residues (13-15) were synthesized. They form duplexes with parallel chain orientation. The aggregate d(T4-iG4-T4) (15) containing four consecutive 2′-deoxyisoguanosine is shown to be a tetramer similar to that of d(T4-G4-T4).

Notizen: Khusimone (1), one of the main odor-donating compounds of vetiver oil is subject of the following study on structure/odor relationship. The omittance of the ethano bridge of the tricyclic khusimone leads to a bicyclic system. The stereoselective approach to this degraded structure is described, and the olfactory properties are studied. The key step of the synthesis of the hydrindane nucleus is based on a highly diastereoselective conjugate addition to a chiral oxo-cyclopentene-2-carboxylate.

Notizen: The (2-dansylethoxy)carbonyl (= {2-{[5-(dimethylamino)naphthalen-l-yl]sulfonyl}ethoxy}carbonyl; dnseoc) group was employed for protection of the amino functions of the aglycone residues. The lactam function of 2′-deoxyguanosine was on the one hand unprotected and on the other hand alkylated at O6 of the aglycone with the 2-(4-nitrophenyl)ethyl (npe) and 2-(phenylsulfonyl)ethyl (pse) group, respectively. The syntheses of monomeric building blocks, both phosphoramidites and nucleoside- functionalized supports, are described for the three common 2′-deoxynucleosides (2′-deoxycytidine, 2′-deoxyadenosine, 2′-deoxyguanosine). As kinetic studies with the tritylated nucleosides showed, the dnseoc group is more labile towards DBU cleavage than the corresponding 2-(4-nitrophenyl)ethyl-(npe) and [2-(4-nitrophenyl)ethoxy]carbonyl(npeoc)-protected analogues (see Table 2). These results were confirmed by the very fast deprotection rate of the dnseoc groups at some oligonucleotides.

Notizen: The absolute configuration of 3-methylpyrrolidine alkaloids isolated from the poison gland of ants Leptothoracini was determined as (3R). The enantiomeric separation by chiral gas chromatography and unambiguous structural assignment of the target compounds are described.

Notizen: The synthesis of π-substituted heptalenecarboxylates or -dicarboxylates, starting with the easily available dimethyl 9-isopropyl-1, 6-dimethylheptalene-4, 5-dicarboxylate (2b), are described. Treatment of 2b with t-BuOK and C2Cl6 at -78° leads to the chemoselective introduction of a Cl substituent in Me-C(1) (see 5b in Scheme 1). Formation of the corresponding triphenylphosphonium salt 7b via the iodide 6b (Scheme 2) allowed a Wittig reaction with cinnamaldehyde in the two-phase system CH2Cl2/2N NaOH. Transformation of the 4, 5-dicar-boxylate of 2b into the corresponding pseudo-ester 10b allowed the selective reduction of the carbonyl function at C(4) with DIBAH to yield the corresponding 4-carbaldehyde 11b (Scheme 3). Wittig reaction of 11b with (benzyl) triphenylphosphonium bromide led to the introduction of the 4-phenylbuta-1, 3-dienyl substituent at C(4). The combination of both Wittig reactions led to the synthesis of the 1, 4-bis(4-phenylbuta-1, 3-dienyl)-substituted heptalene-5-carboxylate (all-E)-17b (Scheme 5). In a similar manner, by applying a Horner-Wadsworth-Emmons reaction, followed by the Wittig reaction, the donor-acceptor substituted heptalene-5-carboxylate (E;E)-22b was synthesized (Scheme7). Most of these new heptalenes are in solution, at room temperature, in thermal equilibrium with their double-bond shifted (DBS) isomers. In the case of (all-E)-17b and (E;E)-22b, irradiation of the thermal equilibrium mixture with light of λ -(439 ± 10) nm led to a strong preponderance ( 〉 90%) of the DBS isomers 17a and (E;E)-22a, respectively (Schemes 6 and 7). Heating of the photo-mixtures at 40° re-established quickly the thermal equilibrium mixtures. Heptalenes-carboxylates (all-E)-17a and (E;E)-22a which represent the off-state of a 1,4-conjugative switch (CS) system show typical heptalene UV/VIS spectra with a bathochromically shifted heptalene band III and comparably weak heptalene bands II and I which appear only as shoulders (Figs. 4 and 5). In contrast, the DBS isomers (all-E)-17b and (all-E)-22b, equivalent to the on-state of a 1,4-CS system, exhibit extremely intense heptalene bands I and, possibly, II which appear as a broad absorption band at 440 and 445 nm, respectively, thus indicating that the CSs (all-E)-17a⇌(all-E)-17b and (E;E)-22a⇌(E;E)-22b are perfectly working.

Notizen: Configurational and Conformational Isomeric Antiaromatic [28]Tetraoxaporphyrinoids(4.2.4.2) and Aromatic [26]Tetraoxaporphyrin(4.2.4.2) Dications. A New Type of Molecular Dynamics in Macrocyclic SystemsThe [28]tetraoxaporphyrinoids(4.2.4.2) 6 are synthesized by cyclizing Wittig reaction of (E, E)-5, 5′-(buta-1, 3-diene-1, 4-diyl)bis[furan-2-carbaldehyde] (8) with (E, E)-{(buta-1, 3-diene-diyl)bis[(furan-5, 2-diyl)methylene]}bis-[triphenylphosphonium] dibromide (9) and 3, 3′-{[(E)-ethene-1, 2-diyl]bis(furan-5, 2-diyl)}bis[(E)-prop-2-enal] (22) with (E)-{(ethene-1, 2-diyl)bis[(furan-5.2- diy)methylene]}bis[triphenylphosphonium] dibromide (23). An alternative path to get 6 is the McMurry condensation of 8. Four different configurational isomers of 6 could be isolated and characterized by 1H-NMR spectroscopy. The (Z, EE, Z, EE)-isomer 6a is the first macrocyclic system where the inner and outer protons of the (E, E)-dienediyl bridges exchange by rotation around the adjacent single bonds. In the (Z, EE, E, EE)-isomer 6b, the (E)-ethenediyl bridge is rotationally active, while in the (E, ZE, E, EZ)-isomer 6c and in the (E, EZ, E, EZ)-isomer 6e, the rotation of both (E)-ethenediyl bridges is observed. When in the dynamic systems the rotation of the active (E)-double bonds at temperatures T 〈 -90° is frozen, all configurational isomers of 6 appear to be antiaromatic and paratropic. The oxidation of the [28]tetraoxaporphyrinoids 6c and 6e with DDQ yields the aromatic, diatropic [26]tetraoxaporphyrin(4.2.4.2) dications 21e/21e′ both with (E, EZ, E, EZ)-configuration but different fixed conformations. (Z, EE, Z, EE)-Isomer 6a is oxidized to give the (Z, EE, Z, EE)-dication 21a, while the oxidation of 6b yields a mixture of 21a and 21e/21e′. The standard formation enthalpies of the obtained and expected [28]tetraoxaporphyrinoids 6 and [26]tetraoxaporphyrin dications 21 have been calculated with the AM1 method, showing good accordance with the experimental results.

Notizen: The synthesis of substituted cyclododeca-1,6-diallenes.( = cyclododeca-1,2,6,7-tetraenes) from cyclododeca-5,11-diyne-1,4-diols is described (Schemes 1 and 3). The ca. 1:1 mixtures of the stereoisomers of the cyclododeca-1,6-diallenes were formed in high yields from the ca. 1:1 diastereoisomer mixtures of the 1,4-disubstituted cyclododeca-5,11-diynes by reactions with Me2CuLi or t-BuMgCl/CuII. In mechanistically relevant experiments with the pure diastereoisomers of 1,4-dimethylcyclododeca-5,11-diyne-1,4-diol, it is demonstrated that the configuration is conserved in these reactions. The first synthesis of a 1-substituted cyclododeca-2,8-diyne bearing only one propargylic leaving group gives access to a mixed 12-membered allen-yne (Scheme 5).

Notizen: This study was designed to unravel lipophilicity changes associated with the oxidation state of the S-atom in model compounds, drugs, and metabolites, special attention being given both to intermolecular and intramolecular effects. The methods used were experimental (potentiometry, CPC, and shake-flask techniques to measure lipophilicity, 13C-NMR spectroscopy to investigate tautomeric equilibria) and computational (quenched molecular dynamics and molecular lipophilicity potential). Simple, monofunctional model compounds were used to assess intermolecular forces, as revealed by the Δlog Poct-alk and Δlog Poct-chf parameters. Drugs and their metabolites proved to be good probes to study intramolecular effects in both neutral and anionic forms, as revealed by the difference between calculated and experimental log Poct values (the diff(log Pexp-calc) parameter). Sulindac and its metabolites showed a normal partitioning behavior, whereas the lipophilicity of sulfmpyrazone and its metabolites' was markedly affected by tautomeric and conformational equilibria.

Notizen: The synthesis of (E)-hex-3-ene-l, 5-diynes and 3-methylidenepenta-1, 4-diynes with pendant methano[60]-fullerene moieties as precursors to C60-substituted poly(triacetylenes) (PTAs, Fig. 1) and expanded radialenes (Fig. 2) is described. The Bingel reaction of diethyl (E)-2, 3-dialkynylbut-2-ene-1, 4-diyl bis(2-bromopropane-dioates) 5 and 6 with two C60 molecules (Scheme 2) afforded the monomeric, silyl-protected PTA precursors 9 and 10 which, however, could not be effectively desilylated (Scheme 4). Also formed during the synthesis of 9 and 10, as well as during the reaction of C60 with thedesilylated analogue 16 (Scheme 5), were the macrocyclic products 11, 12, and 17, respectively, resulting from double Bingel addition to one C-sphere. Rigorous analysis revealed that this novel macrocyclization reaction proceeds with complete regio- and diastereoselectivity. The second approach to a suitable PTA monomer attempted N, N′-dicyclohexylcarbodiimide(DCC)-mediated esterification of (E)-2, 3-diethynylbut-2-ene-l, 4-diol (18, Scheme 6) with mono-esterified methanofullerene-dicarboxylic acid 23; however, this synthesis yielded only the corresponding decarboxylated methanofullerene-carboxylic ester 27 (Scheme 7). To prevent decarboxylation, a spacer was inserted between the reacting carboxylic-acid moiety and the methane C-atom in carboxymethyl ethyl 1, 2-methano[60]fullerene-61, 61-dicarboxylate (28, Scheme 8), and DCC-mediated esterification with diol 18 afforded PTA monomer 32 in good yield. The formation of a suitable monomeric precursor 38 to C60-substituted expanded radialenes was achieved in 5 steps starting from dihydroxyacetone (Schemes 9 and 10), with the final step consisting of the DCC-mediated esterification of 28 with 2-[1-ethynyl(prop-2-ynylidene)]propane-1, 3-diol (33). The first mixed C60-C70 fullerene derivative 49, consisting of two methano[60]fullerenes attached to a methano[70]fullerene, was also prepared and fully characterized (Scheme 13). The Cs-symmetrical hybrid compound was obtained by DCC-mediated esterification of bis[2-(2-hydroxy-ethoxy)ethyl] 1, 2-methano[70]fullerene-71, 71-dicarboxylate (46) with an excess of the C60-carboxylic acid 28. The presence of two different fullerenes in the same molecule was reflected by its UV/VIS spectrum, which displayed the characteristic absorption bands of both the C70 and C60 mono-adducts, but at the same time indicated no electronic interaction between the different fullerene moieties. Cyclic voltammetry showed two reversible reduction steps for 49, and comparison with the corresponding C70 and C60 mono-adducts 46 and 30 indicated that the three fullerenes in the composite fullerene compound behave as independent redox centers.

Notizen: By the tether-directed remote functionalization method, a series of bis- to hexakis-adducts of C60, i.e., 1-7 (Fig. 1), had previously been prepared with high regioselectivity. An efficient method for the removal of the tether-reactive-group conjugate was now developed and its utility demonstrated in the regioselective synthesis of bis- to tetrakis(methano)fullerenes ( = di- to tetracyclopropafullerenes-C60-Ih) 9-11 starting from 4, 5, and 7, respectively (Schemes 2, 4, and 5). This versatile protocol consists of a 1O2 ene reaction with the two cyclohexene rings in the starting materials, reduction of the formed mixture of isomeric allylic hydroperoxides to the corresponding alcohols, acid-promoted elimination of H2O to cyclohexa-1,3-dienes, Diels-Alder addition of dimethyl acetylenedicarboxylate, retro-Diels-Alder addition, and, ultimately, transesterification. In the series 9-11, all methano moieties are attached along an equatorial belt of the fullerene. Starting from C2v-symmetrical tetrakis-adduct 15, transesterification with dodecan-1-ol or octan-1-ol yielded the octaesters 16 and 17, respectively, as noncrystalline fullerene derivatives (Scheme 3). The X-ray crystal structure of a CHCl3 solvate of 11 (Fig. 3) showed that the residual conjugated π-chromophore of the C-sphere is reduced to two tetrabenzopyracylene substructures connected by four biphenyl-type bonds (Fig. 5). In the eight six-membered rings surrounding the two pyracylene (= cyclopent[fg]acenaphthylene) moieties, 6-6 and 6-5 bond-length alteration (0.05 Å) was reduced by ca. 0.01 Å as compared to the free C60 skeleton (0.06 Å) (Fig. 4). The crystal packing (Fig. 6) revealed short contacts between Cl-atoms of the solvent molecule and sp2- and sp3-C-atoms of the C-sphere, as well as short contacts between Cl-atoms and O-atoms of the EtOOC groups attached to the methano moieties of 11. The physical properties and chemical reactivity of compounds 1-11 were comprehensively investigated as a function of degree and pattern of addition and the nature of the addends. Methods applied to this study were UV/VIS (Figs. 7-11), IR, and NMR spectroscopy (Table 2), cyclic (CV) and steady-state (SSV) voltammetry (Table 1), calculations of the energies of the lowest uunoccupied mmolecular orbitals (LUMOs) and electron affinities (Figs. 12 and 13), and evaluation of chemical reactivity in competition experiments. It was found that the properties of the fullerene derivatives were not only affected by the degree and pattern of addition but also, in a remarkable way, by the nature of the addends (methano vs. but-2-ene-1, 4-diyl) anellated to the C-sphere. Attachment of multiple thano moieties along an equatorial belt as in the series 8-11 induces only a small perturbation of the original fullerene π-chromophore. In general, with increasing attenuation of the conjugated fullerene π-chromophore, the optical (HOMO-LUMO) gap in the UV/VIS spectrum is shifted to higher energy, the number of reversible one-electron reductions decreases, and the first reduction potential becomes increasingly negative, the computed LUMO energy increases and the electron affinity decreases, and the reactivity of the fullerene towards nucleophiles and carbenes and as dienophile in cycloadditions decreases.

Notizen: Crystal and solution structures of the enantiomerically pure and the racemic pairs of (η3-allyl) {2-[2′-(diphenylphosphino)phenyl]-4,5-dihydro-4-phenyloxazole}palladium(II) hexafluorophosphates (1, and rac-1, resp.) and tetraphenylborates (2, and rac-2, resp.) as well as (η3-allyl){2-[2′-(diphenylphosphino)phenyl]-4,5-dihydro-4-isopropyloxazole}palladium(II) tetraphenylborate (3) were characterized by X-ray crystallography and 1H-NMR spectroscopy. In the solid state, rac-1 and rac-2 proved to be disordered with both diastereoisomeric complexes in the crystal. The complexes 2 and 3 exist only in the ‘exo’ form. The X-ray structures show that the [PdII(η3-allyl)] moiety may adopt different configurations between a nearly symmetrical three-electron PdII(π3-allyl) system and an asymmetrical allyl group with a η1- and a η2-bonding to the metal center. The [PdII(η3-allyl)] system of rac-1 and of ‘endo’ rac-2 is closer to the former, and that of 2, ‘exo’-rac-2, and 3 closer to the later geometry. The 1H-NMR spectra of the hexafluorophosphates 1 and rac-1 show two sets of signals of the allylic protons in an ‘exo’/‘endo’ ratio of 2:3. The tetraphenylborates 2, rac-2, and 3 give only one set of broad signals of the allylic protons.

Notizen: ‘Acetyleno-oligosaccharides’ in which two terminal ethynyl substituents enclose an angle (significantly) below 180° are building blocks for the preparation of cyclodextrin analogues. This is illustrated by the preparation of a cyclotrimer and a cyclotetramer; the C3-symmetrical cyclotrimer 18 (Scheme 1) was synthesized in 13 steps (7.7%) and the C4-symmetrical cyclotetramer 51 (Scheme 3) in 14 steps (4.3%) from the known dialkyne 21. The solubilities of 18 and 51 in H2O were determined by gravimetry; a saturated solution is 130 mM in the trimer 18 and 12.8 mM in the tetramer 51. The dependence of the optical rotation of 18 and 51 in H2O on the concentration, and the concentration dependence of the 1H-NMR chemical shift of the signals of the 1CH groups of 51 (D2O) suggest that there is no significant self-association of 18 and 51.

Notizen: The chiral biyclic bis-lactams of structures 3 and 4 were synthesized from the key intermediate 2′b, the N,N′-bis(4-methoxybenzyl) derivative of 2 (X = MeO) (Scheme 6). The synthesis of this intermediate involved two key steps: (1) a double condensation of glyoxylic acid/anisamide (= oxoacetic acid/4-methoxybenzamide) adduct 11c with veratrole (1,2-dimethoxybenzene; 10) allowed the introduction of two glycine units at the 4,5-positions of the veratrole ring to give 18c (Schemes 3 and 4); (2) in order to circumvent the hydrolysis of 4-methoxybenzoyl protective groups which proved to be unfeasible, these groups were transformed into 4-methoxybenzyl groups through a sequence involving thiocarbonylation followed by reduction (Scheme 5). Thereafter, the double intramolecular cyclization of the resulting diamino diester 22c proceeded easily to afford 2′b. This intermediate may be transformed via the tetrol 2′g or the diol 2′h into the N-protected derivatives of 2 (X = OR) and of 3 (X = OCOR). Cleavage of the 4-alkuxybenzyl groups was achieved by ceric ammonium nitrate. However, when the aromatic ring bore ether functions (N-protected 2), this normal reaction was accompanied by the oxidative ring cleavage to give the diene-diester structure 4 (Schemes 5 and 6).

Notizen: The kinetics of the Cu2+ complexation by macrocycles 1 (4-[(l,4,8,11-tetraazacyclotetradec-1-yl)methyl]-benzoic acid) and 2 (N-propyl-4-[(1,4,8,11-tetraazacyclotetradec-1-yl)methyl]-benzamide) as well as by macrocycle 1 conjugated to bovine serum albumin (bsa) and to ribonuclease A (rnase) were studied by stopped flow techniques. For 1 and 2, the kinetics were followed in the mM range monitoring the d-d* absorption band of the Cu2+ complex. From the pH dependence of kobs, the rate law is v = [Cu2+] (kLH[LH] + kLH2[LH2]), where kLH and kLK2 are the bimolecular rate constants for Cu2+ with the diprotonated (LH2) and monoprotonated (LH1) form of the ligand, respectively. The values are kLH2 = 1.7(1) M-1s-1 and kLH = 2.3(1) 105 M-1s-1 for 1, and kLH2, = 0.28(9) M-1s-1 and kLH = 2.0(1) 105 M-1s-1 for 2. The kinetics of the Cu2+ incorporation into 1,2 and 1 conjugated to bsa and rnase, i.e., 3 and 4, respectively, were also followed using nitroso-R salt as a metal indicator in the μM range, i.e., under conditions typical for the ‘post-labeling’ technique to give radiolabeled monoclonal antibodies. In these cases, the reaction takes place between the 1:1 complex of Cu2+ with nitroso-R-salt and the macrocycle. At pH 6.5, the rates are very similar to each other indicating that the complexation properties of the macrocycle attached to a protein are not very different from those of the free ligand under comparable conditions.

Notizen: The synthesis of a variety of hydroxylactams from ω-phthalimidoalkanoates using a triplet-sensitized photodecarboxylation reaction initiated by intramolecular photo electron transfer is described. Ring sizes available by this method span from 4 (benzazepine-1,5-dione 7) to 26 (cyclodipeptide 26e). Ground-state template formation is proposed as the explanation for the high efficiency of this reaction and for the decrease in reactivity in the presence of organic bases instead of metal carbonates. The crucial step in this macrocyclization reaction seems to be the protonation of the intermediary ketyl radials (Scheme 4). Spacer groups investigated were alkyl chains (C3-C11: 5c-h, 11a, 12), ether (16, 18), ester (20, 22), and amide (26a-f) linkages. Within the detection limits, no dimeric (= decarboxylative coupling) products were observed, indicating the high preference for intra-vs. intermolecular photoelectron transfer. The C,C radical combination step proceeds with low stereoselectivity (cf, products 11 and 12) in contrast to comparable singlet reactions. Except for the lactones 22, all products were stable under the photolysis conditions. Prolonged irradiation of 22 led to the formation of the spiro compounds 23, probably via an intermediary acyliminium betaine (Scheme 8). One serious limitation of the decarboxylative macrocyclization is its incompatibility with the glycine spacer (as in 27a and 27b), probably the consequence of a strong intramolecular H-bond (Scheme 10).

Notizen: A novel tricyclic dipeptide template, formally derived by coupling (2S,4S)-4-aminoproline (Pro(NH2)) and (S)-2-(carboxymethyl)proline (Pro(CH2COOH)) as a diketopiperazine, has been synthesized in a form suitable for solid-phase peptide synthesis using Fmoc chemistry. This template was incorporated into the cyclic molecule cyclo(-Ala1-Asn2-Pro3-Asn4-Ala5-Ala6-Temp-) (Temp = template), whose conformation in H2O was studied by NMR methods. Average solution structures derived by restrained simulated annealing point to a highly populated βI-turn within the Asn-Pro-Asn-Ala motif and also indicate which conformations are likely to be preferred by the template.

Notizen: The syntheses of both diastereoisomers of 5′-ethyl-substituted thymidine dimers, the (5′R)- and (5′S)-configurated 33a and 33b respectively, in which the natural phosphodiester linkage is replaced by an amide group (C(3′)-CH2CONH-CH(5′)(Et)), arc described. Their fully protected derivatives 35a and 35b, respectively, are suitable for incorporation into antisense oligonucleotides. Unexpectedly, an attempted PdII-catalysed aza-Claisen rearrangement of trichloroacetimidate 7 provided the diastereoisomerically pure cyclopropane derivative 17, whose structure was confirmed by X-ray analysis.

Notizen: New Pathways to Precursors of PentalenePentalene dimers 2 and 3 are easily available in moderate yields by CuCl2-induced oxidative coupling of dilithium-pentalenediide (5) (Scheme 1). On the other hand, NBS bromination of 1,5-dihydropentalene (4) or of 1,2-dihydropentalene (8) gives unstable 1-bromo-1,2-dihydropentalene (9), while subsequent in-situ elimination with Et3N exclusively gives syn-cis-pentalene dimer 2 in moderate yields (Scheme 3). NMR-Spectroscopic evidence for compounds 2, 3, and 9 is presented, and mechanistic alternatives for the formation of pentalene dimers 2 and 3 are discussed.

Notizen: Four new iridoid glucosides 1-4, named blumeosides A-D, were isolated from the methanolic stem-bark extract of Fagraea blumei G. DON. (Loganiaceae). They were accompanied by the benzyl-alcohol derivative di-O-methylcrenatin (5) and the flavone C-glucoside swertisin (6). The structures of 1-4 were established by spectroscopic methods, including FAB-MS, and 1H- and 13C-NMR, and by alkaline hydrolysis. Blumeosides A (1) and C (3) are 10-O-(2,5-dihydroxytercphthalo) adoxosidic acid and 10-O-(2-hydroxyterephthalo)adoxosidic acid, respectively. In blumeosides B (4) and D (2), both carboxylic groups of the terephthalic-acid moiety are esterified by adoxosidic-acid units, Blumeosides A-D (1-4) inhibited bleaching of crocin induced by alkoxyl radicals. Blumeosides A (1) and D (2) also demonstrated scavenging properties towards the 2,2-diphenyl-1-picryl-hvdrazvl (CDPPH) radical in TLC autographic and spectrophotometric assays.

Notizen: The kinetic model of column chromatography is revisited to explicitly show that this approach yields, when neglecting axial dispersion, a rather simple analytical expression depending only on two dimensionless parameters, namely a dimensionless kinetic retention parameter and a dimensionless time parameter. An expression for the time corresponding to the maximum of the peak is also proposed.

Notizen: The αv/β3 integrin is implicated in human tumor metastasis and angiogenesis. It has been shown that structures of the sequence cyclo(-Arg1-Gly2-Asp3-D-Phe4-Xaa5-) (I) and cyclo(-Arg1-Gly2-Asp3-Phe4-D-Xaa5-) (II) bind with high affinity and the latter with high selectivity to this receptor. The residues Xaa and D-Xaa accept a broad variety of amino acids. Here, we report on the synthesis, activities, and conformational analysis of cyclic Arg-Gly-Asp (RGD) peptides containing liophilic amino acids Xaa or D-Xaa in position 5. For I, these were (2S)-2-aminohexadecanoic acid (Ahd) and N′-hexadecylglycine (Hd-Gly) and in II, D-Ahd and Hd-Gly, and, for control purposes, Ahd were incorporated (Fig. 1). The enantiomerically pure a-amino acids were obtained by non-enantioselective synthesis and subsequent enzymatic separation of isomers using acylase I (Scheme). Hd-Gly was prepared in a modified procedure according to Stewart from ethyl bromoacetate and hexadecylamine (Scheme). The synthesis and physicochemical properties of the corresponding (9H-fluoren-9-ylmethoxy)carbonyl (Fmoc) derivatives, compatible with solid-phase peptide synthesis, are described. Structure elucidation by NMR reveals that the lipid modification has no significant impact on the template structures when incorporated into them. For peptides I with Xaa = Ahd or Hd-Gly (1 or 2), a βII′/γ-turn-like arrangement with D-Phe in i+1 position of the β-turn is found. Peptides II with D-Xaa = D-Ahd or Hd-Gly (3 or 4) exhibit a βII′/γ-turn conformation with Gly in i+1 position of the β-turn, whereas II with Ahd instead of D-Xaa, i.e., lacking a D-amino acid in position 4 or 5 (5). adopts no defined conformation. However, in assays of receptor specificity employing human αvv/β3 integrin, the compounds exhibit IC50 values ranging from nanomolar to less than millimolar. These results indicate that although the arrangement of the pharmacophoric groups is preserved in the target compounds, the biological activity is highly dependent on spatial requirements of the lipid anchor in the receptor binding pocket. Obviously, only certain positions do not affect the binding.

Notizen: The conformational analysis of naturally occurring cytostatic cyclic heptapeptides axinastatin 2, 3, and 4 was carried out by two-dimensional NMR spectroscopy in combination with distance-geometry (DG) and molecular-dynamics (MD) calculations in explicit solvents. The synthesized secondary metabolites were examined in (D6)DMSO. Axinastatin 2 was also investigated in CD3OH. In all structures, Pro2 is in the i + 1 position of a βI turn and Pro6 occupies the i + 2 position of a βVIa turn about the cis amide bond between residue 5 and Pro6. In all peptides, a bifurcated H-bond occurs between residue 4 CO and the amide protons of residue 1 and 7. For axinastatin 2 and 3, an Asn Ig turn was found about Asn1 and Pro2. We compared these structures with conformations of cyclic heptapeptides obtained by X-ray and NMR studies. A β-bulge motif with two β turns and one bifurcated H-bond is found as the dominating backbone conformation of cyclic all-L-heptapeptides. Axinastatin 2, 3, and 4 can be characterized by six trans and one cis amide bond resulting in a β/βVI(a)-turn motif, a conformation found for many cyclic heptapeptides. Detailed biological tests of the synthetic compounds in different human cancer cell lines indicates these axinastatins to be inactive or of low activity.

Notizen: In the presence of activating agents, the N-acylglycine 8 reacts with electrophilic alkynes via the münchnone9 to the pyrrolopyridines (= indolizines) 10, 18, and 19 (Scheme 1 ), Depending on the nature of the activating agent and the reaction temperature, the formation of the pyrroles was accompanied by partial epimerization to the manna-configurated epimers 16 and 17. The gluco-configurated pyrrolopyridine 10 was deprotected to 12. Silylation of 12, followed by reduction and desilylation, gave the hexol 15. Cycloaddition of 9 to 4-toluenesulfonyl cyanide yielded 53% of the imidazole 23, while cycloaddition to phenyl cyanate gave the phenoxyimidazole 28 in low yields only (Scheme 2). As expected, the deprotected pyrroles 12, 15, 20, and 21 are weak inhibitors of retaining β-glucosidases, while the deprotected imidazole 24 derived from 23 proved a good inhibitor of sweet-almond β-glucosidases and a powerful inhibitor of Caldocellum saccharolyticum β-glucosidase.

Notizen: Tetrahydrobenzo[a]pyrrolizidines (= octahydro-1H-pyrrolo[2,1-a]isoindoles) and tetrahydrobenzo[a]indo-lizidines, (= decahydropyrido[2,1-a]isoindoles) were prepared stereoselectively in four steps through an amineinduced ring-opening of 3-bromo-2,5-dimethylthiophene 1,1-dioxide (1) with L-prolinol (9), piperidine-2-methanol (10), and piperidine-2-ethanol (11), yielding the dienes (2S)-1-[(2E,4Z)-4-bromohexa-2,4-dienyl]pyrrolidine-2-methanol (12), 1-[(2E,4Z)-4-bromohexa-2,4-dienyl]piperidine-2-methanol (13), and 1-[(2E,4Z)-4-bromo-hexa-2,4-dienyl]piperidine-2-ethanol (14; Scheme2), which, after conversion into their α,β-unsaturated esters, cyclized in a TiCl4-catalyzed intramolecular Diets-Alder reaction (Scheme3). A discussion on the mechanism of the ring opening reaction including semiempirical and ab initio calculations is also presented.

Notizen: The X-ray crystal-structure analyses of two N-enoyl-toluenesultam derivatives 1 are reported. The structural differences with their bornanesultam analogues 2 as well as stereochemical aspects with respect to their [4 + 2] and [3 + 2] cycloadditions are discussed.

Notizen: To get informations on both the structure and dynamics of hydrogen chelates 1 of heteroaromatic systems, a great variety of quinazoline-2-acetonitrile chelates were synthesized (see 2-4). Similarly to the situation of the corresponding H-chelates in the pyrimidine-2-acetonitrile series, the investigation of these new derivatives 2-4 by NMR spectroscopic methods (DNMR, COSY, NOESY, ROESY, EXSY, HMQC, HMBC) confirms the presence of an equilibrium of the two possible H-chelate structures (two ‘rotamers’ I and II, i.e., (E)/(Z) isomers; see Scheme). The corresponding equilibria I ⇌ II were determined by complete 1H-NMR signal assignment at low temperatures (after freezing the rotational processes). In addition, the tautomer equilibria A ⇌ B (relative energies of the two minima of the nonsymmetrical double-well potential) for both ‘rotamers’ are ascertained by H,H and C,H couplings. The results are an important basis for the interpretation of both the UV/VIS absorptions and the dependence of fluorescence and fluorescence quantum yields on temperature.

Notizen: Stereoselective reactions of phthalimido-substituted radicals derived from (±)-threonine with different radical traps are reported (Scheme 3, Table 1). A strong influence of the nature of the radical trap on the stereoselectivity was noticed. Small nucleophilic radical traps gave preferentially the syn products. The observed selectivities are explained with the A1,3 strain model and depend on steric and electronic effects (Fig. 2). Reactions with electrophilic radical traps such as diphenyl diselenide gave the anti diastereoisomers with moderate stereocontrol, presumably due to stereoelectronic effects. The same stereochemical outcome, i.e., preferential formation of the anti products, was observed for the reactions of the related N-phthaloyliminium ion (Scheme 5, Table 2). The stereochemistry of the ionic reaction is rationalized by a Felkin-Anh model (Fig. 3).

Notizen: The cyclopalladation of 1,1′-azonaphthalene (= di(naphthalen-1-yl)diazene; 2) with bis(hexafluoroacetyl-acetonato)palladium(II) (3; [Pd(hfa)2]) yields the ortho-palladated complex (1,1,1,5,5,5-hexafluoropentane-2,4-dionato-κ2O,O′)[1-(naphthalen-1-ylazo-κN2)naphthalen-2-yl-κC2]palladium(II) (4) as well as the peri-palladated complex (1,1,1,5,5,5-hexafluoropentane-2,4-dionato-κ2O,O′)[8-(naphthalen-1-ylazo-κN2)naphthalen-1-yl-κC1]-palladium(II) (5); their structures were corroborated by X-ray analyses. The formation of the novel peri-metallated product 5 containing a six-membered palladacycle strongly depends upon the reaction conditions.

Notizen: The photoisomerization behavior of three mono[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]spermidines, 1, 2, and 3, and three bis[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]spermidines, 4, 5, and 6, are investigated. The synthetic product (E)-1 could be almost quantitatively (〉 96%) converted into its isomer (Z)-1 under UV light irradiation. In the cases of (E)-2 and (E)-3, a mixture of (E)/(Z) ca. 1:2 was obtained, when the same conditions were applied. The comparison of their UV spectra provides the possible explanation for these different behaviors. Furthermore, it was noticed that the (Z) → (E) isomerization of the C=C bond took place during the purification by reverse-phase high-performance liquid chromatography (RP-HPLC), and the (E)/(Z)-mixture is thus inseparable. The same feature could be observed during the isolation of the (Z,Z)-N,N′-bis[3-(4-hydroxyphenyl)prop-2-enoyl]-spermidines, (Z,Z)-4, (Z,Z)-5, and (Z,Z)-6. Nevertheless, the fractions of (Z,Z)-5 and (Z,Z)-6 were in almost pure state collected, and their 1-NMR spectra are presented.

Notizen: Boophiline (1), a new sterol amide was isolated from the cattle tick Boophilus microplus (Ixodidae). The structure was assigned as N-[3-(sulfooxy)-25ξcholest-5-en-26-oyl]-L-isoleucine by detailed 2D NMR investigations in conjunction with FAB mass spectrometry and acidic hydrolyses. Complete assignment of the diastereotopic methylene protons of the ring system could be deduced from the NMR data. In agar dilution assays, 1 exhibited antifungal properties against Cladosporium cucumerinum and antibacterial activity against Bacillus subtilis and Escherichia coli.

Notizen: The classical rules for Cope rearrangements predict a transition state with chair form to be favored over the boat form. On the other hand, bridged homotropylidenes, which allow only a boat-form transition state by steric reasons, have extremely low barriers. A controversy about the correct pathway and the different possible intermediates and transition states of the reaction has gone on for years. In this work, the hypersurfaces of barbaralane, in comparison with the boat- and chair-form of hexa-1,5-diene, are computed by the ab inito CASSCF (6,6)/6-31G** method starting with UMP2/6-31G** natural orbitals (NO's). All three hypersurfaces show characteristic features, and, moreover differ from each other. A hitherto undiscussed intermediate, bicyclo[2.2.0]hexane, was localized on the boat-hexa-1,5-diene pathway. So it is noteworthy that our transition state for the boat-hexa-1,5-diene does not correspond to the transition states found by other authors for this conformation. The computed enthalpies of activation of boat- and chair-hexa-1,5-diene, and barbaralane are in good agreement with the experimental data.

Notizen: As one of the regulatory gene products in the HIV-1 genome, Rev protein must be translocated from the nucleus to the cytoplasm to exert its function. Therefore, inhibition of Rev protein translocation could be a useful target for HIV therapy. An extract from the Streptomyces strain A92-308902 with very potent inhibitory activity was found in the course of a high throughput screening with a Rev translocation assay (RTA). Bioassay-guided fractionation with gel filtration, normal-phase and reversed-phase chromatography yielded six RTA-active metabolites belonging to the leptomycin family, the known leptomycin A (1), leptomycin B (2), kazusamycin B (3), and kazusamycin A (4). and the hitherto unknown dilactonmycin (5) and delactonmycin (6), together with an inactive cyclic hexadepsipeptide L-156,620 (7). The structures were established mainly by spectroscopic methods (UV, FT-IR, FAB-MS, 1H-NMR, 13C-NMR(JMOD), DQ-COSY, ROESY, HSQC, and HMBC). The configuration of all C=C bonds of 1-6 was unambiguously established by analysis of coupling constants and ROESY spectra. All isolated leptomycins 1-6 inhibit Rev translocation at nanomolar concentrations. Six derivatives (2a-c and 4a-c) of leptomycin B (2) and kazusamycin A (4) were also prepared and tested in the RTA for preliminary investigations on structure-activity relationships.

Notizen: The olefins mentioned in the title were copolymerized with CO in the presence of palladium catalysts modified with dicyclohexyl{(R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl}phosphine. Productivities up to 95 g/(gPd · h) were achieved. The obtained copolymers were recovered in the pure, regio- und stereoregular polyketone structures3. The isotactic poly[2-benzyl-1-oxopropane-1,3-diyl] (3a) and its analogues 3b, c were found to isomerize to the corresponding spirocyclic poly[3-(arylmethyl)tetrahydrofuran-2,2-5,5-tetrayl-2-oxy-2-methylene]s 4 in a suspension in CHC13, thus indicating that the spiroketal structure is thermodynamically the most stable for these copolymers. However, the atactic material did not undergo any structural transformation. These results show that regularity at the centers of chirality in the main chain is a prerequisite for the conversion of the polyketone to the spiroketal structure.

Notizen: Methyl 2-acetyl-3-{[2-(dimethylamino)-1-(methoxycarbonyl)ethenyl]amino}prop-2-enoate (4) and phenyl-methyl 2-acetyl-3-{[2-(dimethylamino)-1(methoxycarbonyl)ethenyl]amino}prop-2-enoate (5) were prepared in three steps from the corresponding acetoacetic esters, and used as reagents for the preparation of N3-protected 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 10-12, 5H-thiazolo[3,2-a]pyrimidin-5-one 13, 4H-pyrido[1,2-a]-pyridin-4-one 19 and 2H-1-benzopyran-2-ones 20-23. Free 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 24-26 were prepared from 10-12 by removal of the 2-(methoxycarbonyl)-3-oxobut-1-enyl or 3-oxo-2-[(phenyl-methoxy)carbonyl]but-1-envl as N-protecting group by various methods.

Notizen: Cyclophanes 3 and 4 were prepared as initiator cores for the construction of dendrophanes (dendritic cydophanes) 1 and 2, respectively, which mimic recognition sites buried in globular proteins. The tetra-oxy[6.1.6.1]paracyclophane 3 was prepared by a short three-step route (Scheme 1) and possesses a cavity binding site shaped by two diphenylmethane units suitable for the inclusion of flat aromatic substrates such as benzene and naphthalene derivatives as was shown by 1H-NMR binding titrations in basic D2O phosphate buffer (Table 1). The larger cyclophane 4, shaped by two wider naphthyl(phenyl)methane spacers, was prepared in a longer, ten-step synthesis (Scheme 2) which included as a key intermediate the tetrabromocyclophane 5. 1H-NMR Binding studies in basic borate buffer in D2O/CD3OD demonstrated that 4 is an efficient steroid receptor. In a series of steroids (Table 1), complexation strength decreased with increasing substrate polarity and increasing number of polar substituents; in addition, electrostatic repulsion between carboxylate residues of host and guest also affected the binding affinity strongly. The conformationally flexible tetrabromocyclophane 5 displayed a pronounced tendency to form solid-state inclusion compounds of defined stoichiometry, which were analyzed by X-ray crystallography (Fig. 2). 1,2-Dichloroethane formed a cavity inclusion complex 5a with 1:1 stoichiometry, while in the 1:3 inclusion compound 5b with benzene, one guest is fully buried in the macrocyclic cavity and two others are positioned in channels between the Cyclophanes in the crystal lattice. In the 1:2 inclusion compound 5c, two toluene molecules penetrate with their aromatic rings the macrocyclic cavity from opposite sides in an antiparallel fashion. On the other hand, p-xylene (= 1,4-dimethylbenzene) in the 1:1 compound 5d is sandwiched between the cyclophane molecules with its two Me groups penetrating the cavities of the two macrocycles. In the 1:2 inclusion compound 5e with tetralin (= 1,2,3,4-tetrahydronaphthalene), both host and guest are statically disordered. The shape of the macrocycle in 5a-e depends strongly on the nature of the guest (Fig. 4). Characteristic for these compounds is the pronounced tendency of 5 to undergo regular stacking and to form channels for guest inclusion; these channels can infinitely extend across the macrocyclic cavities (Fig. 6) or in the crystal lattice between neighboring cyclophane stacks (Fig. 5). Also, the crystal lattice of 5c displays a remarkable zig-zag pattern of short Br…O contacts between neighboring macrocycles (Fig. 7).

Notizen: The synthesis, absolute configuration, and olfactive evaluation of (-)-(E)-α-trans-bergamotenone (= (-)-(1′S,6′R,E)-5-(2′,6′-dimethylbicyclo[3.1.1]hept-2′-en-6′-yl)pent-3-en-2-one; (-)-1), as well as its homologue (-)-19 are reperted. The previously arbitrarily attributed absolute configuration of 1 and of (-)-α-trans-bergamotene (= (-)-(1 S,6R)-2,6-dimethyl-6-(4-methylpent-3-enyl)bicyclo[3.1. 1]hept-2-ene; (-)-2), together with those of the structurally related aldehydes (-)-3a,b and alcohols (-)-4a,b, have been rigorously assigned.

Notizen: (-)-(R)-4,4,4,4′,4′,4′-Hexafluorovaline hydrochloride ((R)-5) of 98% ee is prepared from β,β-bis(trifluoromethyl)acrylic acid (= benzyl 4,4,4-trifluoro-3-(trifluoromethyl)but-2-enoate; 1) in 4 steps with an overall yield of 9.6%. Key step is the separation of the TsOH salts of the diastereoisomers obtained by anti-Michael addition of (+)-(R)-1-phenylethylamine (2) to 1 (→ (R,R)-3). In contrast to the published (S)-chirality, the X-ray structure analysis of (R,S)-6 reveals, that (R)-chirality has to be assigned to the levorotatory (-)-4,4,4,4′,4′,4′-hexafluorovaline hydrochloride.

Notizen: The synthesis and characterization of tripodal dodecadentate ligands with salicylamide and bipyridine binding sites for iron(II) and iron(III) are presented.

Notizen: The reaction of CuO'Bu with CO2, and iPr2NH in the presence of PPh3, gives the dialkylcarbamato complex [Cu(O2CNiPr2)(PPh3)2] (1). The CO2/R2NH system (R = Me, Et) in an appropriate organic medium reacts with Ag2O giving the corresponding N,N-dialkylcarbamato complexes of analytical formula [Ag(C2CNR2)] (R = Me, 2; R = Et, 3). The methyl derivative 2 was characterized by X-ray diffraction methods. Crystal data of 2: for [Ag2(O2CNMe2)2], C6H12Ag2N2O4, mol. wt. 391.9; monoclinic, space group P21/c, a = 12.08(1), b = 3.797(2), c = 11.316(7) Å, β = 113.37(6)°, V = 476.3 Å3, Z = 2, Dc = 2.732 g cm-3; μ(MoKα) = 40.64 cm-1, F(000) = 376.0; R = 0.059, Rw = 0.067; g.o.f. 1.27. The structure consists of dinuclear [(Ag2OCNMe2)2] units with slightly distorted linearly two-coordinated Ag-atoms containing bridging carbamato groups to form a substantially planar eight-membered ring with an intra-annular Ag—Ag distance of 2.837(2) Å; the dinuclear units are further joined by Ag—O bonds to form an infinite array. Compound 3, which is presumably dinuclear, as suggested by cryoscopic measurements in benzene, undergoes a structural fission with PPh3, giving the mononuclear triphenylphosphine derivative [Ag(O2CNEt2)(PPh3)2] (4). The amine-catalyzed conversion of Ag2O into Ag2CO3, in the presence of the iPr2NH/CO2 system, is also reported. Cl-Exchange from [AuCl(PPh3)] with [Ag(O2CNEt2)] (3) gives the first N,N-dialkylcarbamato complex of gold, namely [Au(O2CNEt2)(PPh3)] (5), which crystallizes in the monoclinic system: C23H25AuNO2P · 0.5 C7H16, mol. wt. 625.5, space group P21/c; a = 13.212(5), b = 12.25(1), c = 16.795(6) Å, β = 109.09(2)°, V = 2568(2) Å3, Z = 4, Dc, = 1.618 g cm-3; μ(AgKα) = 31.40 cm-1, F(000) = 1236.0; R = 0.058; Rw = 0.064; g.o.f. 2.121. The compound contains two-coordinated Au-atom, namely to the P-atom and to the O-atom of the monodentate carbamato group, the P—Au—O bond angle being 174.7(3)°. The reaction with MeI showed these compounds to react predominantly at the carbamato O-atom giving the corresponding urethanes R2NCO2Me. Evidence was gathered for the transient coordination of CO to Ag in 3.

Notizen: The reactions of α-diazo ketones 1a,b with 9H-fluorene-9-thione (2f) in THF at room temperature yielded the symmetrical 1,3-dithiolanes 7a,b, whereas 1b and 2,2,4,4-tetramethylcyclobutane-1,3-dithione (2d) in THF at 60° led to a mixture of two stereoisomeric 1,3-oxathiole derivatives cis- and trans-9a (Scheme 2). With 2-diazo-1,2-diphenylethanone (1c), thio ketones 2a-d as well as 1,3-thiazole-5(4H)-thione 2g reacted to give 1,3-oxathiole derivatives exclusively (Schemes 3 and 4). As the reactions with 1c were more sluggish than those with 1a,b, they were catalyzed either by the addition of LiClO4 or by Rh2(OAc)4. In the case of 2d in THF/LiClO4 at room temperature, a mixture of the monoadduct 4d and the stereoisomeric bis-adducts cis- and trans-9b was formed. Monoadduct 4d could be transformed to cis- and trans-9b by treatment with 1c in the presence of Rh2(OAc)4 (Scheme 4). Xanthione (2e) and 1c in THF at room temperature reacted only when catalyzed with Rh2(OAc)4, and, in contrast to the previous reactions, the benzoyl-substituted thiirane derivative 5a was the sole product (Scheme 4). Both types of reaction were observed with α-diazo amides 1d,e (Schemes 5-7). It is worth mentioning that formation of 1,3-oxathiole or thiirane is not only dependent on the type of the carbonyl compound 2 but also on the α-diazo amide. In the case of 1d and thioxocyclobutanone 2c in THF at room temperature, the primary cycloadduct 12 was the main product. Heating the mixture to 60°, 1,3-oxathiole 10d as well as the spirocyclic thiirane-carboxamide 11b were formed. Thiirane-carboxamides 11d-g were desulfurized with (Me2N)3P in THF at 60°, yielding the corresponding acrylamide derivatives (Scheme 7). All reactions are rationalized by a mechanism via initial formation of acyl-substituted thiocarbonyl ylides which undergo either a 1,5-dipolar electrocyclization to give 1,3-oxathiole derivatives or a 1,3-dipolar electrocyclization to yield thiiranes. Only in the case of the most reactive 9H-fluorene-9-thione (2f) is the thiocarbonyl ylide trapped by a second molecule of 2f to give 1,3-dithiolane derivatives by a 1,3-dipolar cycloaddition.

Notizen: The synthesis of a series of chiral enantiomerically pure C2-symmetric binucleating ligands is reported. Ligands of type 1-4, which consist of a phenolic or heterocyclic unit bridging two chiral dihydrooxazole rings. are readily accessible from chiral amino alcohols. Ligands 5a and 5b are composed of a cyclic urea or thiourea unit, respectively, and two 3,4-dihydro-2H-pyrrole rings containing a stereogenic center next to the N-atom. Compounds of this type are readily assembled from ethane-1,2-diamine and an imidothioic ester derived from pyroglutamic acid. These new ligands, which can coordinate two metals in close proximity to each other, are of interest regarding possible applications in asymmetric catalysis.

Notizen: Stability constants have been measured for a series of ligands based on a 2,2′-(pyridine-2,6-diyl)bis[1H-benzimidazole] unit which forms dinuclear double-stranded helical complexes with copper(I). Variation of different structural parameters confirms the importance of the coordinate bond, the stacking interactions, and the weakly bridging pyridine units observed by X-ray crystallography. The stabilities of the complexes depend strongly on the solvent, and in MeCN, which is a good solvent for copper(I), the complexes are less stable and assemble in a stepwise manner. The interconversion of the enantiomers may be followed by 1H-NMR and takes place on a millisecond time scale around room temperature. The trends in lability are similar to those found for the stability of the complexes.

Notizen: Oligodeoxyribonucleotides containing 7-deaza-2′-deoxy-8-methylguanosine (m8c7Gd; 2b) were prepared. For this purpose, the phosphonate 3a and the phosphoramidite 3b were synthesized and employed in solidphase oligodeoxyribonucleotide synthesis. The structures and the thermodynamic data of duplex formation of oligodeoxyribonucleotides containing 2b were investigated by temperature-dependent CD and UV spectra and compared with those containing 7-deaza-2′-deoxy-7-methylguanosine (m7c7Gd) or 7-deaza-2′-deoxy-guanosine (c7Gd; 2a). In general, compound 2b reduces the duplex stability. In case of the sequence d(m8c7G-C)4 (18), the B → Z transition was facilitated by the incorporation of 2b. Moreover, a single 7-deaza-8-methylguanine residue present in an oligodeoxyribonucleotide tract of guanine residues destabilizes the dG quadruplex significantly. This destabilization is more pronounced than in the case of 7-deazaguanine or 7-deaza-7-methyl-guanine.

Notizen: Absolute rate constants and their Arrhenius parameters are obtained for the addition of a cyclic malonyl radical derived from Meldrum's acid to 20 mono- or 1,1-disubstituted alkenes in (±)-propylene oxide and for the addition of the open-chain di(tert-butyl)malonyl radical to six mono- or 1,1-disubstituted alkenes in 1,1,2-trichloro-1,2,2-trifluoroethane by time-resolved electron spin resonance spectroscopy. At room temperature, the radicals add at the unsubstituted C-atoms with rate constants ranging from 1.1. 105 M-1S-1 (acrolein) to 2.4. 106 M-1S-1 (1,1-diphenylethene). The frequency factors are in the narrow ranges of log (A/M-1S-1) = 8.7 ± 0.1 for the cyclic and log (A/M-1S-1) = 8.2 ± 0.2 for the open-chain malonyl species, whereas the activation energies vary from 12.9 kJ/mol (1,1-diphenylethene) to 21.7 kJ/mol (acrylonitrile). They correlate with the alkene ionization potentials and, more weakly, with the reaction enthalpy. No correlation was found between the activation energies and the alkene electron affinities. Hence, the results confirm and quantify the electrophilic nature of malonyl radicals in addition reactions.

Notizen: An asymmetric synthesis of (-)-(4R)-dihydroisomyricoidine (28), a 13-membered amino lactam of type A, was performed by a diastereoselective Michael addition between the spermidine derivative 3 and the commercially available optically active ethyl carboxylate 4, and the cyclization of the resulting ω-amino acid 7 using diethyl phosphorocyanidate ((EtO)2POCN), followed by a Wittig reaction to introduce the (Z)-side chain. Some side reactions are also discussed.

Notizen: Natural free carboxylic acids from the hadromerid sponge Diacarnus levii (Kelly-Borges and Vacelet) were esterified to yield the new cyclic norditerpene peroxides ent-muqubilin benzyl ester (= (αR,3S,6R)-α,6-dimethyl-6-[(E)-4-methyl-6-(2,6,6-trimethyl-cyclohex-1-en-1-yl)hex-3-enyl]-1,2-dioxan-3-acetic acid benzyl ester; 6, diacarnoate B methyl ester(= (αS,3R,6R)-α,6-dimethyl-6-{2-(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-3-oxo-2,5,5,8a-tetramethylnaphthalen-1-yl)ethyl}-1,2-dioxan-3-acetic acid methyl ester; 9), and deoxydiacarnoate B benzyl ester (= (αS,3R,6R)-α,6-dimethyl-6-{2-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethyl-1-naphthalenyl]ethyl}-1,2-dioxan-3-acetic acid benzyl ester; 10), which were isolated following extensive chromatography. The relative configuration of the peroxide/α-methylacetate moiety of 6, 9, and 10, was directly determined from their NMR spectra. The absolute configurations of the peroxide/α-methylacetate moiety was deduced from comparative 1H-NMR data of the (S)- and (R)-phenylglycine methyl ester derivatives 7 and 8 as well as 11/13 and 12/14, all obtained from a mixture of the precursors of 3, 6, and 10. The absolute configuration at the carbobicyclic moiety of enone 9 and of 10, is identical, as established by chemical interconversion, 9 and 10 belong to the normal labdane series according to empirical CD rules, applied either directly to 9 or to the parent (+)-sclareolide-derived enone 20. In contrast, molar rotation additivity rules suggest the ent-labdane configuration for 9 and 10. The epidioxides 1-3, 6, and 10 proved active in vitro against the malaria parasite Plasmodium falciparum; especially the previously isolated methyl 3-epinuapapuanoate (2) was active against a chloroquine-resistant strain, and this with a good security index.

Notizen: 3-Hydroxy-2-cyanoalk-2-enamides, and 2-cyano-2-(tetrahydrofuran-2-ylidene)- and 2-cyano-2-(tetrahydropyran-2-ylidene)acetamides with N-alkyl and N-aryl substituents have been synthesized in three steps from cyanoacetic acid. Their conformations were investigated by X-ray crystallography and 1H-NMR ROESY spectroscopy at room temperature. The enolic compounds 1-3 adopt an extended conformation stabilized by a strong intramolecular O—H … O=C bond both in the solid state and in (D6)DMSO solution. In contrast, the structure of the cyclic derivatives 5a,b-8a,b is solvent-dependent. In the solid state and in CDCl3 solution, the compounds adopt an extended conformation of type I or III, while, in (D6)DMSO solution, their structures undergo time-dependent (Z)/(E)-isomerization structures (of type II or IV). This observation is compatible with a dipolar transition state of rotation. The kinetics of the isomerization are controlled by the N-substituent, the N-(t-Bu) derivatives 7a and 7b having the highest barrier of rotation around the C=C bond. The whole body of experimental evidence together with the results of molecular-mechanics calculations with I-IV, indicate that, in DMSO, two (E)/(Z)-isomers with two conformations are present, and that they undergo interconversion at room temperature with four different constants. The very fast exchange rates kI,II and kIII,IV in the NMR time-scale might be responsible for the detection of only two isomers.

Notizen: A new acylated dimeric secoiridoid glycoside, seemannoside A (2), has been isolated from the aerial parts of Lisianthius seemannii (GRISEB) O. KUNTZE (Gentianaceae). The structure was established by spectroscopic analysis (UV, MS, 1H- and 13C-NMR, and 2D-NMR experiments) and chemical reactions as (E-4′-O-p-coumaroyl)lisianthioside. The structure of the (Z)-isomer (seemannoside B, 3), also present in the plant, was confirmed by LC/UV/1H-NMR analysis. The active principle, 6, responsible for the antifungal activity of the apolar extract against Cladosporium cucumerinum, has been isolated. Its structure has been established by NMR spectroscopy and X-ray crystallographic analysis as a rare type of aglycone monoterpene dimer.

Notizen: Asymmetric Diels-Alder reaction of the pentadienoic and hexadienoic acids 2a,b with the chiral chloronitroso derivative 3 gave the primary adducts 4a,b with good-to-excellent enantioselectivity. Subsequent as- or trans-dihydroxylation and hydrogenolytic cleavage of the N—O bond led to the 5-amino-5-deoxypentono-δ-lactams 13a, 14, 15a, and 16 in the D-ribose, L-arabinose, D-xylose, and L-lyxose series, respectively, and to the 5-amino-5,6-dideoxyhexono-δ-lactams 13b and 15b in the D-allose and D-glucose series, respectively.

Notizen: Photolysis and Ag-benzoate-catalyzed decomposition of the diazo ketones 2 and 4 derived from Z-Ala-OH and Z-Ala-Ala-OH in the presence of oligonucleotide derivatives bearing at the 5′-terminus an NH2 instead of the OH group, or an aminohexyl phosphate group lead to Z-protected 3-aminobutanoyl and to Z-Ala-β-HAla derivatives, respectively (conjugates 12, 13, and 17-23, Schemes 3-5), In solution, this amide-forming acylation reaction could be realized only with oligomers containing up to 8 unprotected nucleotide building blocks (Schemes 3 and 4). With the analogous polymer-bound and protected oligonucleotide derivatives as amino nucleophiles, excellent yields were obtained with all chain lengths tested (up to 15mer Scheme 5), The products were purified by reversed-phase HPLC and characterized by MALDI-TOF mass spectrometry (Figs. 2-4, Table 2) and by capillary gel electrophoresis (Fig.2).

Notizen: We describe a versatile novel approach for the synthesis of 2, 4, 6-trisubstituted pyrimidines on solid support. Thus, polymer-boun J thiouronium salt 2 reacted in high yield in a cyclocondensation reaction with the acetylenic ketones 3 to form, after tert-butyl-ester cleavage, the polymer-bound carboxylic acids 4, which were cleaved by oxidation with 3-chloroperbenzoic acid and pyrrolidine to form the 2-pyrrolidinylpyrimidine-4-carboxylic acids 6a-c in high yields and purities without further purification (Scheme 1). Alternatively, acid 4a was subjected to an Ugi four-component condensation which gave the polymer-bound Ugi products 9a-e in good yields (Scheme 2). Multidirectional cleavage reaction of sulfone 8a with different nucleophiles resulted in the clean formation of pyrimidine-4-carboxamides 10-13 (Scheme 3). This strategy combines efficiently solid-phase chemistry with a multicomponent reaction and a multidirectional cleavage step to form highly diverse pyrimidines in a parallel array.

Notizen: The title compounds 4 are obtained by photolysis of simple N-alkylpyridinium salts in H2O or alcohol. On reaction with [Fe2(CO)9] in THF, 4 gives bicyclic tricarbonyliron complexes 13a-d, which on oxidative decomplexation with ceric ammonium nitrate afford cis-fused cyclopenteno-β-lactams 15a-d.

Notizen: The first crystal structure of a molybdenum complex 9 with a hydrogenated pterin and a sulfur ligand contributes to the discussion about the active center of molybdenum and tungsten enzymes containing a molybdopterin cofactor. Complex 9 was synthesized through a redox reaction of [MoVIO2 (LN-S2)] (8; LN-S2 = pyridine-2, 6-bis(methanethiolato)) with 5, 6, 7, 8-tetrahydropterin (7). 2 HCl (H4Ptr.2 HCl). The complex crystallizes, with a non-coordinating Cl-atom acting as a counterion, in the monoclinic space group C2/c (No. 15) with cell dimensions a = 22.900(5), b = 10.716(2), c = 17.551(4) Å, β = 120.36(3)°, and Z = 8. We interpret 9 as [MoIVO(LN-S2)(H+-q-H2Ptr)]Cl (q = quinonoid; H2Ptr = dihydropterin), i.e., a MoIV monooxo center coordinated by a pyridine-2, 6-bis(methanethiolato) ligand and a protonated dihydropterin. The spectroscopic properties of this new complex are comparable to those of other crystalline molybdenum complexes of hydrogenated pterins without additional S-coordination. The slightly H2O-soluble complex 9 reacts with the natural enzyme substrate DMSO very slowly, possibly due to the lack of easily dissociable ligands at the metal center.

Notizen: The solid-state structures of three stereoisomer, 1-3, of the cyclic tetramer of 3-aminobutanoic acid are presented. These cyclo-β-peptides were found to be highly insoluble materials, and it proved to be impossible to grow crystals of sufficient quality for X-ray single-crystal analysis. The samples of 1-3 were, however, suitable candidates for structure determination from powder diffraction data (Fig. 1), and the application of this method is described. All three isomers have been found to adopt tubular structures (Figs. 2-4) in a fashion similar to those already observed for certain cyclo-α-peptides. The stacks of 16-membered rings are held together by four nonlinear C=O…H—N H-bonds between pairs of molecules (Fig.5).

Notizen: β-Cryptoxanthin (1) was acetylated and then epoxidized with monoperoxyphthalic acid. After hydrolysis, repeated chromatography, and crystallization, (3S,5R,6S)-5,6-epoxy-β-cryptoxanthin (3), (3S,5S,6R)-5,6-epoxy-β-cryptoxanthin (4), (3R,5′R,6′R)-5′,6′-epoxy-β-cryptoxanthin (5), (3S,5R,6S,5′R,6′S)-5,6:5′,6′-diepoxy-β-cryp-toxanthin (6), and (3S,5S,6R,5′S,6′R)-5,6:5′,6′-diepoxy-β-cryptoxanthin (7) were isolated as main products and characterized by their UV/VIS, CD, 1H- and 13C-NMR, and mass spectra. The comparison of the carotenoid isolated from yellow, tomato-shaped paprika (Capsicum annuum var. lycopersiciforme flavum) with 3-5 strongly supports the structure of 3 for the natural product.

Notizen: The 14-membered tetraazamacrocyclic Ni2+ and Cu2+ complexes of 4 (1, 4, 8-trimethyl-11-[(2-methylthio)ethyl]-1, 4, 8, 11-tetraazacyclotetradecane), 5. (1, 4-dimethyl-8, 11-bis[2-(methylthio)ethyl]-l, 4, 8, 11-tetraazacyclotetradecane), and 7 (1, 4, 8, ll-tetrakis[2-(methylthio)ethyl]-1, 4, 8, 11-tetraazacyclotetradecane), with pne, two, and four methylthio-substituted pendant chains, respectively, and the Ni2+ complex of 6 (1, 4-dimethyl-8, 11-bis (2-methoxyethyl)-1, 4, 8, 11-tetraazacyclotetradecane), with two methoxy-substituted pendant chains, were synthesized and their chemistry studied with regard to modelling F430. Solution spectra in H2O, MeCN, and DMF indicate participation of the side chain in metal coordination when the donor group is a thioether, whereas no coordination with the metal ion is observed with the ether group. Similarly the X-ray structures of the thioether-containing compounds [Ni(5)](ClO4)2, [Cu(5)](ClO4)2, and [Cu(7)](ClO4)2 show a coordination number of 5, whereas that of [Ni(6)](ClO4)2 with ether pendant chains, shows a coordination number of 4. Cyclic voltammetry of these complexes in MeCN reveals that Ni2+ is reversibly reduced to Ni+ between -0.64 and -0.77 V vs. SCE, the potential being influenced by the nature and number of the pendant chains. At more negative potentials, the thioether is cleaved, whereby a thiol is formed; the thiol is then oxidized at ca. + 0.8 V vs. SCE, when a glassy carbon electrode is used, or at ca. 0 V vs. SCE at a dropping Hg electrode. No cleavage of the ether bond in [Ni(6)](ClO4)2 is observed under similar conditions.

Notizen: The photochemical synthesis of indole derivatives starting from the indoline-2-thiones 1 is described. Irradiation of indoline-2-thiones 1 in the presence of alkenes 3 gave 2-alkyl-3H-indoles 4-7 or 2-alkylindoles 8-22 through the ring cleavage of the intermediates, spirocyclic amino-thietanes, initially derived by [2 + 2] cycloaddition of the C=S bond of 1 and the C=C bond of 3. Irradiation of 1 in the presence of trialkylamines 26 gave desulfurization products 27-32 and unexpected 3-alkylindoles 33-40. N-Acylindoline-2-thiones 11-p yielded the deacylated products, indoline-2-thiones 1a-b, and ethyl esters 43 through γ-H abstraction by the excited thioamide S-atom when irradiated in CDC13/EtOH or benzene/EtOH. Oxygen analogues 2a-d also underwent intramolecular H abstraction to give the indolin-2-ones 2e-f and ethyl esters 43 in a similar way.