Showing papers in "Helvetica Chimica Acta in 1989"

Catechol-O-methyltransferase-inhibiting pyrocatechol derivatives: synthesis and structure-activity studies

Abstract: 3-Nitro- and 3-cyanopyrocatechols bearing electron-withdrawing substituents at C(5) have been found to inhibit the enzyme catechol-O-methyltransferase. Structure-activity studies are discussed on the basis of the pharmocological data of 50 compounds (cf, Chapt. 4, Tables 1–7). Some 3-nitro-5-aroylpyrocatechols (Type A2, Table 1) fulfil the requirements for a clinical candidate, being orally active, specific, reversible, and relatively short-acting. The chemical work involved is illustrated by describing a choice of exemplary syntheses, dealing with compounds 9, 11, 14, 18, 22, 24, 25, 35, 41, and 42(Chapt. 5, Schemes 1–10).

Elektrochemische Decarboxylierung von L.‐Threonin‐ und Oligopeptid‐Derivaten unter Bildung von N‐Acyl‐N, O‐acetalen: Herstellung von Oligopeptiden mit Carboxamid‐oder Phosphonat‐C‐Terminus

Abstract: Electrochemical Decarboxylation of L-Threonine and Oligopeptide Derivatives with Formation of N-Acyl-N, O-acetals: Preparation of Oligopeptides with Amide or Phophonate C-Terminus Derivatives of α-amino acids with two stereogenic centers (cf.L-threonine) and of di-, tri-, and tetrapeptides are electrolyzed in MeOH or AcOH, with formation of N-acyl-N, O-acetals (1b–15b, 20b), in an anodic oxidative substitution of the COOH by an OR group. The amine ends of the oligopeptides may be benzyloxycarbonyl(Z)- or (tert-butoxy)carbonyl(Boc)-protected. With unprotected dipeptides, an electrolytic decarboxylative cyclization to imidazolidinones (18c, 19c) may also occur (in H2O/NH4OAc). The electrolyses are carried out in simple flasks with cooling jackets (‘undivided cell’), using constant current conditions and anodes of Pt or glassy C. The electrolyte is generated in situ by adding 10–20 mol-% of a tertiary amine. Mild acidic hydrolysis of electrolysis products thus obtained may lead to amino-acid amides or peptide amides (10c, 11c, 12c, 17c) with one amino acid less than the starting material. The N, O-acetals from L-threonine and the oligopeptides also react with organometallic nucleophiles such as Grignard compounds (21–26, 29), with formation of products in which the original COOH group has been replaced by alkyl or allyl (sometimes even with moderate stereoselectivity). By treatment of the peptide-derived (open-chain) N, O-acetals with trialkyl or triaryl phosphites/TiCl4 the RO group is replaced by a phosphodiester group in a (non-diastereoselective) Michaelis-Arbuzov-type reaction (1d, 1e, 2d–9d, 5e). Thus, the two-step sequence of electrolysis and phosphonation converts an oligopeptide derivative to an analogue with a phosphonic-acid end group. The diastereoisomeric N-protected dimethyl and diethyl dipeptidephosphonates (also prepared from the corresponding diaryl esters by Ti(OR)4-mediated transesterification) could be separated by preparative HPLC (SiO2, Lichrosorb Si 60, 10 μm); the dextrorotatory isomers of 1d–3d were assigned L, D-, the laevoratory ones L, L-configuration by hydrolysis to and identification of the known amino and aminophosphonic acids. The results described demonstrate a new simple route leading, from a given oligopeptide, to pure peptide analogues of known configuration.

Synthesis and NMD A Antagonistic Properties of the Enantiomers of 4‐(3‐phosphonopropyl)piperazine‐2‐carboxylic acid (CPP) and of the unsaturated analogue (E)‐4‐(3‐phosphonoprop‐2‐enyl)piperazine‐2‐carboxylic acid (CPP‐ene)

Abstract: The (R)- and (s)-enantiomers of 4-(3-phosphonopropyl)piperazine-2-carboxylic acid (D- and L-CPP, resp; 15 and 16, resp), and of its unsaturated analogue (E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D- and L-CPP-ene, resp; 13 and 14, resp) were prepared The absolute configuration of the enantiomers was determined by a chemical correlation of the menthyl ester 7 with D-asparagine The affinity of these derivatives for the NMDA receptor was determined by displacement of [3H]CPP in rat cerebral cortical membranes In two functional tests (the frog hemisected spinal cord preparation and the sodium efflux test from rat brain slices), D-CPP-ene appears to be the most potent, enantiomerically pure, competitive NMDA antagonist known to date

Glycosylidene Carbenes a new approach to glycoside synthesis. Part 1. Preparation of glycosylidene-derived diaziridines and diazirines†

Abstract: A new approach towards the synthesis of glycosides based upon a (formal) insertion of glycosylidene carbenes into OH bonds is presented. The synthesis and characterization of the glycosylidene-derived diazirines 25–28, precursors of glycosylidene carbenes, are described. The diazirines were prepared by the rapid, high-yielding oxidation of the diaziridines 20 and 22–24 with I2/Et3N. The diaziridines, the first examples of C- alkoxy-diaziridines, were formed in high yields by the reaction of the [(glycosylidene)-amino]methanesulfonates 14 and 17–19 with a saturated solution of NH3 in MeOH. The diazirines are highly reactive compounds, losing N2 at room temperature or below. The reaction of the gluco-configurated diazirine 25 with i-PrOH yielding a mixture of the α- and β-D-glucosides 29 and 30 illustrates the potential of glycosylidene-derived diazirines as a new type of glycosyl donors.

Structure Determination of New Isomeric Naphtho[2,3‐b]furan‐4,9‐diones from Tabebuia avellanedae by the selective‐INEPT technique

Abstract: ~The stem bark of the South-American tree Tubebuiu avellanedue LORENTZ ex GRISEB., Bignoniaceae (syn. T. impetiginosu MART. ex DC., T. heptuphylla VELL. TOLEDO, and T. I$ MART. ex. SCHUM. [l]), known in folk medicine as Pau d’Arco, IpC Roxo, Taheebo, and Lapacho, is used in North and South America for many years as an anticancer, antifungal, antibacterial, and antiinflammatory drug [2] [3]. Lapachol and dehydro-a -lapachone, the major naphthoquinones of the heartwood of Tubebuiu uvellunedue LORENTZ ex GRISEB., were found to be active against different types of tumors [47]. In viuo antitumor effects were observed using p. 0. administration of 20-30 mg/kg lapachol [8], and de Suntunu et ul. [9] demonstrated in vivo antineoplastic effects on Yoshidu’s sarcoma and Walker 256 carcinosarcoma for the lipophilic extract of the inner bark of T. uvellanedue LORENTZ ex GRISEB. These pharmacological activities, and recent results from our laboratory (Munich) concerning the immunostimulating effects of various naphthoquinones when applied in minute doses [lo] prompted us to initiate a new, thorough investigation of the lipophilic extract of the inner bark of T. uvellunedue LORENTZ ex GRISEB. Results and Discussion. - Column chromatography (CC) of the CHCl, extract of T. uvellunedue LORENTZ ex GRISEB. stem bark on silica gel, using CHC1, as eluent resulted in five fractions (Fr. I-V) which afforded twenty compounds by further CC, prep. HPLC, and prep. TLC (see Scheme). In the present publication, we describe the structure elucidation of the new compounds 8, 12, 13, 15, 16, and 19 which were obtained from Fr. I, IZ, and IV. The other compounds and their biological activities will be described in a forthcoming paper.

New fluorinating reagents. Part II. Preparation and Synthetic Application of a Saccharin Derived N‐Fluorosultam

Abstract: The synthesis of the new saccharin derived N-fluorosultam 1 is described. A comparative study with commercially available N-fluorosulfonamides shows 1 to be a superior fluorinating reagent for the synthesis of α-fluorocarbonyl compounds.

Solubilization of Peptides in Non‐polar Organic Solvents by the Addition of Inorganic Salts: Facts and Implications

Abstract: The solubility of open-chain peptide derivatives (12 examples) in non-polar, ether-type organic solvents may be greatly increased by addition of salts (LiCl, LiBr, LiI, LiBF4, LiClO4, NaI, MgBr2 CaBr2, ZnCl2) or of titanates (Ti(OEt)4, Ti(OCHMe2)4). Examples are reported (Tables 2–6) in which this solubilizing effect leads to peptide concentrations more than one-hundred-fold those in the absence of salt (cf, BocAlaGlyGlyGlyOH in THF from 2g·1−1 to ≥ 300 g·1−1 with 6 equiv. of LiCl), 1H-NMR Spectra of one of these solutions are reported (Fig. 1). There are no indications for epimerizations of stereogenic centres on the peptide backbone. Possible applications of these solutions in peptide chemistry are discussed.

Models for Copper‐Dioxygen Complexes: The chemistry of copper(II) with some planar tridentate nitrogen ligands

Abstract: The solution chemistry of Cu(II) with a series of five planar tridentate nitrogen ligands, 2,6-bis(benzimidazol-2-yl)pyridine (bzimpy, 1), 2,6-bis(l-methylbenzimidazol-2-yl)pyridine (mbzimpy, 2) 2,6-bis(benzothiazol-2-yl) pyridine (bzthpy, 3), 2,6-bis(benzoxazol-2-yl)pyridine (bzoxpy, 4), and 2,2′, 6′, 2″-terpyridyl (terpy, 5) is reported. Electronic and EPR spectra are consistent with the complexes [CuL]2+ having essentially tetragonal structure in solution, with the fourth coordination site in the plane of the ligand occupied by solvent. bzthpy and bzoxpy show smaller ligand-field splittings than bzimpy, mbzimpy, and terpy, and are easily decomplexed from the copper. Substitution of the coordinated solvent molecule in the plane of the ligand is observed with Cl− and OH− (provided that the ligand has no acidic protons) for all ligands except terpy. The reaction between [Cu(mbzimpy)]2+ and imidazole has been studied by potentiometric titration in MeCN/H2O 1:1 and shows strong binding of the imidazole in the plane (log K = 4.5 at 25°), and also the formation of an imidazolate-bridged dinuclear species.

Synthesis of (−)‐Conduritol C (1L‐Cyclohex‐5‐ene‐1,2,3/4‐tetrol)

Abstract: (1R, 2R, 4R)-2-endo-Cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl acetate ((−)-7) has been transformed into the all-cis-configurated 4L-4,5,6/0-trihydroxycyclohex-2-en-1-one derivatives (−)-12 and (−)-19. (−)-Conduritol C ((−)-3) was derived in a stereospecific manner from (−)-12.

Ethylene Biosynthesis part 10. Synthesis and study of racemic, (1R, 2S)-, and (1S, 2R)-1-Amino-2-(hydroxymethyl)cyclopropanecarboxylic Acid

Abstract: The preparation of optically active 1-amino-2-(hydroxymethyl)cyclopropanecarboxylic acid has been achieved by a route involving cycloalkylation of dimethyl malonate with epichlorohydrin and subsequent Hofmann rearrangement. The reaction of epichlorohydrin with nucleophiles may occur al either electrophilic site, epoxide or halide. Based on the absolute configuration of the starting materials and the lactones obtained, it has been shown that the initial step of the cycloalkylation occurs at the epoxide moiety. The 1-amino-2-(hydroxymethyl)-cyclopropanecarboxylic acid, an analogue of the precursor to the plant growth hormone ethylene, is to be used in affinity purification techniques and in generation of antibodies.

Acid‐Catalyzed Cyclization Reactions of Substituted Acetylenic Ketones: A new Approach for the Synthesis of 3‐Halofurans, Flavones, and Styrylchromones

Abstract: Acetylenic acetals of type I(Scheme 1) and acetylenic ketones of type III(Scheme 1), 37 and 38(Scheme 7) are versatile synthetic precursors for the synthesis of various heterocycles by acid-catalyzed cyclization reactions. By this way, substituted 3-halofurans of type II and IV(Scheme 1) and flavones and styrylchromones (Scheme 7) can be synthesized in good-to-excellent yields. The high degree of regioselectivity in the synthesis of the 3-halofurans (Scheme 4) is the result of the regioselective β-addition of HX (X = Cl, Br, I) to the acetylenic aldehyde and acetylenic ketone moieties. A possible mechanism is depicted in Scheme 5. Since 3-halofurans can easily be metalated and substituted, this approach constitutes a new synthesis of highly substituted furans.

Aplysinopsin-type alkaloids from Dendrophyllia sp., a scleractinian coral of the family dendrophylliidae of the philippines, facile photochemical (Z/E) photoisomerization and thermal reversal

Abstract: The dendrophylliid Dendrophyllia sp. of Palawan contains the indole alkaloids 2′-demethylaplysinopsin (4) and 2′-demethyl-3′-N-methylaplysinopsin (6) and their 6-bromo analogues in H (Z/E) ratio larger than 95:5; these mixtures undergo facile photoisomerization to give mixtures richer in the (E) stereoisomer which undergo thermal isomerization to give back the original mixtures.

Biologically Active Natural Acetylenic Compounds from Eutypa lata (Pers: F.) TUL

Abstract: Eight new acetylenic compounds have been isolated and identified from the culture medium of the fungus Eutypa lata. Structural elucidation and biological activity are discussed.

Sphinxolide, a 26‐Membered Antitumoral Macrolide Isolated from an Unidentified Pacific Nudibranch

Abstract: It is shown that an unidentified nudibranch of Hawaiian waters contains a 26-membered macrolide, sphinxolide ((−)-1) with potent activity against the KB cell line. The structure of sphinxolide, a 2:1 mixture of (E/Z)-isomers at the formamide moiety, is established to be (–)-1 on the basis of extensive NMR and FAB-MS analysis, in combination with data for the products of mono- ((−)-2) and diacetylation ((+)-3).

Asymmetric Diels‐Alder reactions: X‐Ray crystal‐structure analysis of [N‐((E)‐But‐2‐enoyl)bornane‐10,2‐sultam]tetrachlorotitanium

Abstract: An X-ray diffraction analysis of the crystalline complex 2b (MLn TiCl4) shows a chelation of the carbonyl O-atom and the upper SO2 O-atom by TiCl4, a slightly pyramidal N-atom, and a π -face-stereoselective shielding of the C(α)-Si face by the CH2(3) group. The Ti-atom is in a pseudo-octahedral environment.

Ferroelectric Liquid Crystals. Part 9. Laterally substituted phenyl benzoates incorporating a trans-1,4-disubstituted cyclohexane ring†

Abstract: About 65 diverse phenyl benzoates incorporating a trans-1,4-disubstituted cyclohexane ring and at least one lateral substituent have been synthesised. The dependence of the liquid-crystal transition temperatures of these materials on various lateral substituents (F, Cl, CN, and Br) in different positions of the esters has been investigated systematically. The influence of up to four F-atoms in various positions of a standard ester has been thoroughly studied and the optimum combination for a broad smectic C mesomorphic range established. In consequence, three homologous series incorporating the 4-alkoxy-2,3-difluorobenzoic-acid moiety were prepared. An additional CC bond was introduced into the alkyl chain attached to the cyclohexane ring of some of these esters and the resulting modifications of the transition temperatures determined. Three ester series incorporating a lateral substituent and the optically active (+)-(S)-(1-methylheptyl)oxy substituent have also been synthesised, and similar effects have been observed. These materials can be used as important components of commercial chiral smectic C mixtures for electro-optic display device applications.

New Cell Growth‐Inhibitory Cyclohexadienone Derivatives from Hypericum calycinum L.

Abstract: The crude petroleum-ether extract of the aerial parts of Hypericum calycinum L. (Guttiferae) exhibited in vitro growth-inhibitory activity against the Co-115 human colon carcinoma cell line. Bioassay-guided fractionation of this extract allowed the isolation of the cyclohexadienone derivatives 1–5, four of which are previously undescribed compounds. The structures of the known chinesin II (1) and of 2 (hypercalin A) were established by 1H- and 13C-NMR spectroscopy and were confirmed by X-ray analysis of their crystalline mixture which revealed the complete relative configuration of both compounds. The structure of 3 (hypercalin B) was elucidated by means of extensive 1D- and 2D-NMR experiments, including DQ-COSY, HETCOR and LR-HETCOR. The structure of compound 4 (hypercalin C) was established by 1H- and 13C-NMR spectroscopy and confirmed by X-ray analysis to be the 3,5-dihydroxy-4-{[(1R*,2S*, 5S*)-2-hydroxy-2-methyl-5-(1-methylethenyl)cyclopentyl]methyl}-6,6-bis-(3-methylbut-2-enyl)-2-(2-methylpropanoyl)cyclohexa-2,4-dien-1-one. The structures of the higher isomeric homologues 5a/5b were deduced by comparison of their UV, 1H-, and 13C-NMR spectra with those of 4. The isolated compounds appeared to be related to chinesin I and II previously isolated from Hypericum chinense L. and were responsible for the growth-inhibitory activity of the extract against the Co-115 human carcinoma cell line. Moreover, 1/2 and 3 showed molluscicidal activity against the schistosomiasis-transmitting snail Biomphalaria glabrata.

Biosynthesis of Homoterpenes in Higher Plants

Abstract: In higher plants, the two homoterpenes 4,8-dimethyinona-1,3,7-triene (1) and 4,8,12-trimethyltrideca-1,3,7,11-tetraene (2) are synthesized from the regular terpene alcohols nerolidol and geranyllinalool by fragmentation into the homoterpene and butenone. The biosynthetic pathway is evidenced by conversion of (2H)nerolidol in Hoya purpureo-fusca, Magnolia liliiflora nigra, Robinia pseudoacacia, and Philadelphus coronarius.

Application of the gold(I)-Catalyzed aldol reaction to a stereoselective synthesis of (2S, 3R, 4R, 6E)-3-Hydroxy-4-methyl-2-(methylamino)oct-6-enoic Acid ( = MeBmt), Cyclosporin's unusual amino acid†

Abstract: The title compound 8 was prepared in three steps starting from the optically pure aldehyde (2R, 4E)-2-methyl-hex-4-enal (3), thus constituting the shortest synthetic approach reported. Two of the three stereogenic centers in the product were generated in a coupling reaction of 3 with ethyl isocyanoacetate, catalyzed by a gold(I)/chiral ferrocenylphosphine system, giving the dihydrooxazole 5 in 85% diastereoselectivity (mismatchedcase). The weak effect of double stereodifferentiation in this reaction (matched case 90% ds) is discussed. N-Methylation and hydrolytic ring opening of 5 gave the protected form 7 of MeBmt, The X-ray diffraction study carried out on 7 confirms the absolute configuration of the two stereogenic centers formed in the gold(I)-catalytic reaction.

Total Synthesis of L-Allose, L-Talose, and Derivatives

Abstract: (1S, 4R, 5S, 6S)-5-exo, 6-exo-(Isopropylidenedioxy)-7-oxabicyclo[2.2.1]heptan-2-one ((−)-1) was transformed with high stereoselectivity to L-allose. Similarly, enantiomer (+)-1 was transformed into L-talose. The ketones (+)-1 and (−)-1 were derived from furan and 1-cyanovinyl (1S)-camphanate and 1-cyanovinyl (1R)-camphanate, respectively.

Methyl‐jasmonat: Ein kurzer Weg zum Naturstoff und seinem unnatürlichen Enantiomer via Palladium(0)‐induzierte, enantiodivergente Alkylierung von Cyclopent‐2‐en‐1,3‐diol‐Derivaten

Abstract: Methyl Jasmonate: A Short Synthesis of Naturally Occurring Methyl Jasmonate and its Unnatural Enantiomer via Enantiodivergent Alkylation of Cyclopent-2-ene-1,3-diol Derivatives by Palladium(0)-Induced Reactions Palladium-catalyzed alkylation of cyclopent-2-ene-1,2-diol derivatives like 2 is a useful method for enantiodivergent functionalization, resulting in both enantiomeric series of chiral building blocks. The chiral building blocks 3 and 13 can be transformed to methyl jasmonate (1)and its unnatural enantiomer ent-1, recent statement [1b] that 1 has no odour at all and that ‘methyl jasmonate's’ fragrance is actually due to its cis-isomer ent-11 has been confirmed also for the enantiomeric series.

Asymmetric Diels‐Alder Reaction of 1‐Methoxybuta‐1,3‐diene with (2R)‐N‐Glyoxyloylbornane‐10,2‐sultam

Abstract: Starting from sultam 1, the chiral dienophile (2R)-N-glyoxyloylbornane-10,2-sultam (4) was readily prepared. Non-catalyzed atmospheric- and high-pressure as well as [Eu(fod)3]-promoted [4 + 2] cycloadditions of 1-methoxy-buta-1,3-diene (5) to chiral dienophile 4, leading with high asymmetric induction to 6-methoxy-3,6-dihydro-2H-pyran-2-yl derivatives 6–9, are described. The extent and direction of asymmetric induction in these reactions were established by 1H-NMR analysis and chemical correlation, respectively. Stereochemical models for both non-catalyzed and [Eu(fod)3]-promoted reactions are proposed.

An eclipsed C(sp3)−CH3 bond in a crystalline hydrated tricyclic orthoamide: evidence for C−H••••O hydrogen bonds

Abstract: Accurate, low-temperature (81 K) X-ray analyses have been made for two crystalline modifications of the tricyclic orthoamide 1b: a cubic trihydrate in space group Pa3 (Z = 8), where the molecule has crystallographic threefold rotation symmetry, and an anhydrous monoclinic form in space group P21/c (Z = 8) where two symmetry-independent molecules have different configurations, one ail-trans. (as in the cubic trihydrate), the other cis, cis, trans. In the cubic trihydrate, each orthoamide molecule is attached to a triad of H2o molecules by OH…N H-bonds. A remarkable feature of this structure is the nearly eclipsed conformation about the central C-CH3 bond. In the anhydrous crystal, both types of molecule have the normal staggered orientation of their Me groups. The reversal of the Me orientation in the trihydrate is attributed to CH…O H-bonding, which must be much stronger and more directionally specific than has been previously assumed.

Stoffwechselprodukte von Mikroorganismen. 253. Mitteilung. Hormaomycin, ein neues Peptid‐lacton mit morphogener Aktivität auf Streptomyceten

Abstract: Hormaomycin, a Novel Peptide Lactone with Morphogenetic Activity on Streptomyces A culture identified as Streptomyces griseoflavus (strain W-384) has been found to produce a novel peptide-lactone antibiotic designated hormaomycin (6). The empirical molecular formula of the compound is established to be C55H69ClN10O14. The constituent amino acids of the antibiotic are suggested to be allothreonine (1; 1), isoleucine (2; 1), 3-methyl-phenylalanine (3; 2), and, for the first time identified from a natural source, 4-[(Z)-prop-1-enyl]-proline (4; 1) and 3-(2-nitrocyclopropyl)-alanine (5; 2). The amino acids were delivered by acidic hydrolysis and assigned by high-resolution- GC/MS analysis (after transformation to derivatives) in combination with extended 2D-NMR experiments of the antibiotic itself. From the latter, it became plausible that the N-terminus of the peptide chain is acylated by a Cl-containing derivative of 1H-pyrrol-2-carboxylic acid. Hormaomycin is active against some Gram-positive bacteria. In addition, the antibiotic exhibits potent aerial mycelium-inducing activity and effects the production of antibiotics.

Mono- and Dialkylation of Derivatives of (1R, 2S)-2-Hydroxycyclopentanecarboxylic Acid and -cyclohexanecarboxylic acid via bicyclic dioxanones: Selective generation of three contiguous stereogenic centers on a cyclohexane ring†‡

Abstract: Ethyl (1R, 2S)-2-hydroxycyclopentanecarboxylate and -cyclohexanecarboxylate (1a and 2a, respectively) obtained in 40 and 70% yield by reduction of 3-oxocyclopentanecarboxylate and cyclohexanecarboxylate, respectively (Scheme 2), with non-fermenting yeast, are converted to bicyclic dioxanone derivatives 3 and 4 with formaldehyde, isobutyraldehyde, and pivalaldehyde (Scheme 3). The Li-enolates of these dioxanones are alkylated (5a–5i, 5j, 6a–6g), hydroxyalkylated (51, m, 6d, e), acylated (5k, 6c) and phenylselenenylated (7–9) with usually high yields and excellent diastereoselectivities (Scheme 3, Tables and 2). All the major isomers formed under kinetic control are shown to have cis-fused bicyclic structures. Oxidation of the seleno compounds 7–9 leads to α, β-unsaturated carbonyl derivatives 10–13 (Scheme 3) of which the products 12a–c with the CC bond in the carbocyclic ring (exocyclic on the dioxanone ring) are most readily isolated (70–80% from the saturated precursors). Michael addition of Cu(I)-containing reagents to 12a–c and subsequent alkylations afford dioxanones 14a–i and 16a–d with trans-fused cyclohoxane ring (Scheme 4). All enolate alkylations are carried out in the presence of the cyclic urea DMPU as a cosolvent. The configuration of the products is established by NMR measurements and chemical correlation. Some of the products are converted to single isomers of monocyclic hydroxycyclopentane (17–19) and cyclohexane derivatives (20–23; Scheme 5). Possible uses of the described reactions for EPC synthesis are outlined. The observed steric course of the reactions is discussed and compared with that of analogous transformations of monocyclic and acyclic derivatives.

Conformational Analysis of Didemnins. A multidisciplinary approach by means of X-Ray, NMR, molecular-dynamics, and molecular-mechanics techniques

Abstract: We present the application of several homo- and heteronuclear 1D- and 2D-NMR techniques to assign the 1H-NMR chemical shifts of the dominant conformation of didemnin B (2; three different conformations in (D6)DMSO solution in the ratio 8:1:1) and its conformational analysis, as well as the solution conformation of didemnin A (1). The conformations were refined by restrained molecular-dynamics calculations using the GROMOS program and by MOMO, a novel personal-computer-based interactive molecular-graphics and molecular-mechanics package, using experimental distances (via a H…H pseudo potential function) as restraints. The solution structures of 1 and 2 obtained by GROMOS and MOMO calculations were compared with each other and related to the recently solved crystal structure of 2. Focusing on the main conformer, the two kinds of the distance-restrained conformational calculations for 2 yielded a ‘solution structure’ close to the crystal structure. Almost all of the 40 restrained H…H distances coincided (within the estimated standard deviations) with those observed in the crystal structure. One more hydrogen bond was detected in solution involving the lactoyl OH group (disordered in the crystal structure) and the dimethyltyrosine (Me2Tyr5) carbonyl O-atom. The macrocyclic ring system in the modeled solution structure of 1 exhibited a topology close to those of the solution and crystal structures of 2. The main difference between 1 and 2 could be traced back to a significant change in the Ψ angle of the N-methyl-D-leucine (MeLeu7) residue. In 1, the N-methyl moiety of MeLeu7 points inward within the macrocyclic ring toward the 1st and Hip region. We also tested the suitability of structures obtained from NMR data as ‘search fragments’ in the ‘Patterson search approach’ of crystal-structure analysis. It proved possible to resolve the crystal structure of 2 a posteriori with the Patterson search program PATSEE, in this way.

New Hyperforin Derivatives from Hypericum revolutum VAHL with Growth‐Inhibitory Activity against a Human Colon Carcinoma Cell Line

Abstract: The crude petroleum-ether extract of the root bark of Hypericum revolutum VAHL (Guttiferae) exhibited in vitro growth-inhibitory activity against the Co-115 human colon carcinoma cell line. Activity-guided fractionation of this extract resulted in the isolation of two new hyperforin derivatives 1 and 2. The structure of 1 (hyperevolutin A) was established by X-ray analysis as the 4-hydroxy-8-exo-methyl-5,7-exo-bis(3-methylbut-2-enyl)-1-(2-methyl-1-oxopropyl)-8-endo-(4-methylpent-3-enyl)bicyclo[3.3.1]non-3-ene-2,9-dione. The structure of the homologue 2 was deduced by comparison of its UV and 1H- and 13C-NMR spectra with those of 1.

Novel trinor-eremophilanes (dendryphiellin B, C, and D), eremophilanes (dendryphiellin E, F, and G), and branched C9-carboxylic acids (dendryphiellic acid A and B) from the marine deuteromycete Dendryphiella salina (Sutherland) Pugh et Nicot.

Abstract: Further investigation of global extracts from cultures of the marine deuteromycete Dendryphiella salina leads to the isolation of three novel trinor-eremophilanes esterified by branched C9-carboxylic acids, dendryphiellin B(= (+)-(1R*,2S*,7R*,8aR*)-1,2,6,7,8,8a-hexahydro-7-hydroxy-1,8a-dimethyl-6-oxonaphthalen-2-yl (6R*, 2E, 4E)-6-hydroxy-6-methylocta-2,4-dienoate; (+)-2), dendryphiellin C (=(+)-(1R*, 2S*, 7R*, 8aR*)-1,2,6,7,8,8a-hexa-hydro-7-hydroxy-1,8a-dimethyl-6-oxonaphthalen-2-yl (6S, 2E, 4E)-6-methylocta-2,4-dienoate; (+)-3)), and dendryphiellin D (=(+)-(1R*, 2S*, 7R*, 8aR*)-1,2,6,7(8,8a-hexahydro-7-hydroxy-1,8a-dimethyl-6-oxonaphthalen-2-yl (6R*,2E,4E)-6-(hydroxymethyl)octa-2,4-dienoate; (+)-4). An intact eremophilane, dendryphiellin E (5), and its ethanolysis product dendryphiellin F whose absolute configuration is represented by structural formula (+)-6 are also isolated from the above extracts. Dendryphiellin E exists as an open form 5a in equilibrium with a closed form 5b. A similar equilibrium exists between the open form 8a and the closed form 8b of a non-esterified eremophilane, dendryphiellin G (8), which is isolated too from the above extracts and proves structurally related to the cyclic portion of 5. Finally, the free, branched C9-carboxylic acids dendryphiellic acid A ((+)-9) and B ((+)-10) which correspond to side chains of the above esterified terpenes are also isolated from the above extracts.

Der Zugang zum Antitumor-Antibiotikum CC-1065 mittels Hetero-Cope-Umlagerung von Vinyl-N-phenylhydroxamaten

Abstract: The Access to the Three Subunits of the Antitumor Antibiotic CC-1065 by Hetero-Cope Rearrangement of Vinyl N-Phenylhydroxamates. The use of the hetero-Cope rearrangement of vinyl N phenylhydroxamates to indoles for the preparation of the 1,2-dihydro-3H, 6H-benzo[1,2-b:4,3-b′]dipyrrole skeleton, the structural subunits characteristic of the antitu-mor antibiotic CC-1065 as well as the phosphodiesterase inhibitors PDE-I and PDE-II is described.

Asymmetric Induction on Copper(I) Chloride catalyzed 1,4-addition of alkylmagnesium chlorides to α, β-disubstituted (E)-enoylsultams and subsequent protonation

Abstract: Successive treatment of conjugated N-enoylsultams 2 with alkyl Grignard reagents/CuCl and aq. NH4Cl solution generated selectively two stereogenic centers at C(α) and C(β) providing, after flash chromatography and crystallization, acylsultams 5 in high purity. Mild cleavage afforded the recovered sultam auxiliary 1 and enantiomerically pure carboxylic acids 7.