Library

Notes: To find out whether the 1,4-addition to 1,2:3,4-diepoxides, which so far has been observed only once, is of a more general character, we investigated the reaction of a variety of O-, C-, N-, and S-nucleophiles with the model compound 1,2:3,4-diepoxy-2,3-dimethylbutane (Scheme 4). In several cases, 1,4-addition products could, indeed, be observed besides the expected 1,2-adducts (Table).

Notes: Synthesis and Crystal Structure of the First Quinoid Dihydropterinmolybdenum (IV) ComplexThe first molybdenum(IV) complex with a quinoid dihydropterin, i.e. 2, was isolated and characterized by IR, UV and NMR data and single-crystal X-ray diffraction. The reaction of MoVIO2Cl2 with the biologically important 6β-5,6,7,8-tetrahydro-L-biopterin(2) (7) in MeOH gave almost quantitatively trichloro(1,5-quinoid-7,8-dihydro-6H-L-biopterin)oxomolybdenLim(IV) (2). The complex crystallizes with one molecule of MeOH in the noncentrosymmetric orthorhombic space group P212121 (No. 19) with unit cell dimensions a = 1009.3(3), b = 1104.7(3), and c = 1484.5(4) pm and Z = 4. The Mo-atom has a distorted octahedral geometry (Fig.1). It is coordinated by N(5) and O(4) of the pterin ligand. The distance of the Mo-N(5) bond (202 pm) is unusually short compared to similar complexes. O(4) is located trans to a terminal oxo ligand. The octahedral coordination is completed by three Cl-atoms in a meridional arrangement. Complex 2, with the Mo-atom in the enzyme-relevant oxidation state +IV and the pterin in the intermediate quinoid dihydro form, should lead to an extension of the proposed ‘common molybdenum cofactor’ model.

Notes: UV irradiation of the unsaturated (E)-5,10-secosteroidal ketones 1 and 6 results, in addition to (E/Z)-isomeri-zation, in an intramolecular Pateino-Büchi reaction and, in the case of 1, in transannular cyclization (along with AcOH elimination). The stereochemistry of the observed intramolecular photoprocesses can be explained in terms of ground-state conformations of the (E)-seco-ketones 1 and 6 in solution.

Notes: The ‘Push-Poll’ Effect of ‘Push-Pull’ Oligoacetylenes. A 13C-NMR InvestigationAccording to 13C-chemicaI shifts of ‘push-pull’ oligoacetylenes 1-4, the ‘push-pull’ effect (i.e. π delocalization induced by ‘push-pull’ substituents) rapidly decays in this series. To correct for other than π -charge-density effects, Δδ values of symmetrically placed C-atoms of the oligoacetylene chain are discussed. Stereoelectronic resteffects (SER) of the substituents on terminal C-atoms of PP-ketones 1a-3a and PP-esters 1b-4b are estimated from the residual Δδ of the asymptotes of Fig. 3. Fig. 4 convincingly shows that Δδ values are dramatically decreasing with increasing number n of acetylene units between the push and pull substituents. Assignment problems of ‘push-pull’ triacetylenes 3 have been solved by 13C labelling of the CO group of 3a.

Notes: C-Glycosides of N-Acetylneuraminic AcidThe synthesis of the C-glycosides 8, 15, and 9 of N-acetylneuraminic acid is described. Hydroxymethylation of the Li-ester enolate, derived from 5, yielded the protected C-glycosides 7 and 10 (46%; 3:1), which were deprotected to yield 8 (54%) and 15 (51%; Scheme 2). The mesylate 16 was obtained from 7 (73%) and transformed via the azide 17 (75%) into the acid 18 (66%) and the amino acid 9 (Scheme 3). The configuration at C(2) of 17 was proved by transforming 17 into the bicyclic lactam 19. Both 8 and 15 are very weak inhibitors of Vibrio cholerae sialidase; 9 appears to stimulate this enzyme.

Notes: Based upon our novel concept for the total synthesis of cytochalasans, the model lactams 2-9 were treated with Bu2Cu(CN)Li2. The results of these conversions vary much from those obtained with Ph2Cu(CN)Li2, demonstrating the uncertainty of predictions in cuprate chemistry. The bicyclic compound 20 was prepared in good yield. However, all attempts to convert p-toluenesulfonate 20 into the Ph-substituted derivative 21, an intermediate for the synthesis of cyiochulusm B(1), have failed so far.

Notes: A new approach to ketose-derived nucteosides is described. It is based upon a chain elongation of 1-deoxy-1-nitroaldoses, followed by activation of the nitro group as a leaving group, and introduction of a pyrimidine or purine base. Thus, the nitroaldose 7 was prepared from 3 by pivaloylation (→4), synthesis of the anomeric nitrones 5/6, and ozonolysis of 6 (Scheme 1). Partial hydrolysis of 4 yielded 8/9, which were characterized as the acetates 10/11 and transformed into the nitrones 12/13. Ozonolysis of 12/13 gave 14/15, which were acetylated to 16/17. Henry reaction of 7 lead to 19 and 20, which were acetylated to 21 and 22 (Scheme 2). Michael addition of 7 to acrylonitrile and to methyl propynoate yielded the anomers 23/24 and 25/26, respectively. Similar reactions of 16/17 were prevented by a facile β-elimination. Therefore, the nitrodiol 15 was transformed into the orthoesters 27 and then, by Henry reaction, partial hydrolysis, and acetylation, into 28 and 29 (Scheme 2). The structure of 19 was established by X-ray analysis. It was the major product of the kinetically controlled Henry reaction of 7. Similarly, the β-D-configurated nitroaldoses 23 and 25 were the major products of the Michael addition. This indicates a preferred ‘endo’-attack on the nitronate anion derived from 7. AMI calculations for this anion indicate a strong pyramidalization at C(1), in agreement with an ‘endo’-attack. Nucleosidation of 21 by 31 afforded 32 and 33. Yields depended strongly upon the nature and the amount of the promoter and reached 77% for 33, which was transformed into 34, 35, and the known ‘psicouridine’ (36; Scheme 3). To probe the mechanism, the trityl-protected 30 was nucleosidated yielding 37, or 37 and 38, depending upon the amount of FeCl3. Nucleosidation of the nitroacetate 28 was more difficult, required SnCl2 as a promoter, and yielded 39 and 40. The β-D-anomer 40 was transformed into 36. Nucleosidation of 23 (SnCl4) yielded the anomers 41 and 42, which were transformed into 43 and 44, and hence into 45 and 46 (Scheme 4). Similarly, nucleosidation of 25 yielded 47 and 48, which were deprotected to 49 and 50, respectively. The nucleoside 49 was saponified to 51. Nucleosidation of 21 by 52 (SnCl2) afforded the adenine nucleosides 53 and 54 (Scheme 5). The adenine nucleoside 53 was deprotected (→55→56) to ‘psicofuranine’ (1), which was also obtained from 58, formed along with 57 by nucleosidation of 28. The structure and particularly the conformation of the nitroaldoses, nitroketoses, and nucleosides are examined.

Notes: Chiraspher, a polymer of ethyl N-acryloylphenylalanine on spherical silica gel, is used for the preparative separation by recycling chromatography of the enantiomers of oxazolidinones rac-5, thioxolanone rac-6, per-hydropyrimidinone rac-7, and dioxinones rac-9 and 10 derived from the acids listed in the title (Figs. 1-5). The oxazolidinones rac-1a, -2, and -4 show a peculiar peak of the separation efficiences upon lowering the Chiraspher-column temperature to 15° (Fig. 6). In some cases, multigram amounts of enantiomerically pure heterocycles could thus be prepared. The absolute configurations of most enantiomers are assigned. First applications of the tert-butyl 5-oxo-2-phenyloxazolidine-3-carboxylate (5) as a nucleophilic chiral glycine building block are described (products 13-16, Scheme 2). A list of enantiomerically pure 1,3-dioxinones is presented (Table 1), showing a correlation between their absolute configuration, sense of optical rotation, and elution behavior on Chiraspher.

Notes: The synthesis of phospholipids 1n-3n, rationally designed for two-dimensional crystallization of progesterone and estradiol receptors, is reported. The structure of these lipids provides them with essential properties such as fluidity and stability when spread into monolayers at the air/H2O interface, affinity for the protein to be crystallized, and accessibility of the ligand under the lipid monolayer.

Notes: Solution studies of the Cu2+ complex with 11-(3-aminopropyl)-1,4,7,11-tetraazacyclotetradecane(L) indicate that, depending on the pH and on the age of the solution, different species are present. Dissolving the solid [CuL](ClO4)2 in slightly acidic solution gives the protonated complex AH, characterized by an absorption maximum at 574 nm, by a relatively fast proton-induced dissociation kinetics and by the typical colour change in basic solution to give the deprolonated form A with coordinated side chain. AH slowly interconverts in acidic solution to a new species BH, which has an absorption maximum at 547 nm, and which is kineticaily more stable against acid dissociation and shows no coordination of the amino group of the side chain. In alkaline solution, however, the deprotonated form B deliver A in a base induced reaction. The X-ray diffraction studies of A and BH allow to determine the geometry of the metal ion and the configuration of the macrocycle. In A, the Cu2+ is pentacoordinated by the five N-atoms of the ligand and the macrocycle is in the RRSR configuration, whereas in BH the Cu2+ is octahedrally coordinated by the four N-atoms of the macrocycle and two axial perchlorate O-atoms with the macrocycle in the RRRS configuration. The amino group of the side chain is protonated and not coordinated. Thus, the on/off equilibrium of the side chain not only changes the geometry of the metal ion, as is generally found, but also alters the macrocyclic moiety.

Notes: [(l-6):(1′-6′)-η-Pentaphenyltriphosphane(5)]chromium (8), which is formed from bis(lithio-η6-benzene)-chromium and dichlorophenylphosphane, and which is prepared more rationally from bis(chloro-η6-benzene)-chromium and K2P3Ph3, is the first sandwich complex featuring an interannular oligophosphane bridge -(PPh)n-, n ≥ 2; 31P{1H}- and 1H-NMR spectra suggest that the stereoisomer 8-meso1 is formed exclusively and that the -(PPh)3- link in this triphospha[3]chromocyclophane is non-fluxional in the range 193 〈 T 〈 348 K.

Notes: The neutral molecules nitrosoformaldehyde (1a), 1-nitrosoacetaldehyde (1b), and 2,2,2-trifluoro-1-nitrosoacetaldehyde (1c) have been generated and detected by neutralization-reionization mass spectrometry (NR-MS).

Notes: The 9-(2′-deoxy-à-D-threo-pentofuranosyl)adenine (=9-(2′-deoxy-à-D-xylofuranosyl)adeninc, xAd; 2) was protected at its 6-NH2 group with cither a benzoyl (5a) or a (dimethyfamino)methylidcnc (6a) residue and with a dimethoxytntyl group at 5′-OH (5b, 6b). Compounds 5b and 6b were then converted into the 3′-phosphonates 5c and 6c; moreover, the 2-cyanoethyl phosphoramidite 6d was synthesized starting from fib. The DNA building blocks were used for solid-phase synthesis of d[(xA)122-A] (8). The latter was hybridized with d[(xT)12-T] (Tm = 35°); in contrast, with d(T12), complex formation was not observed. Moreover, xAd and xTd were introduced into the self-complementary dodccamcr d(G-T-A-G-A-A-T-T-C-T-A-C) (12) at different positions lo give the oligomcrs 13-16. All oligonucleotides were characterised by temperature-dependent CD and UV spectroscopy, and in addition, 14 by T-jump experiments. From concentration-dependent Tm measurements, the thermodynamic paraneters of the melting as well as the tendency of hairpin formation of the oligonucleotides were deduced. Oligemer 14 was hydrolyzed by snake-venom phosphodiesterase in a discontinuous way implying a fast hydrolysis of unmodified 3′- and 5′-flanks followed by a slow hydrolysis of the remaining modified tetramer. In contrast to this, oligonucleotide 16 was hydrolyzed in a continuous reaction. In both cases, calf-spleen phosphodiesterase hydrolyzed the oligomer only marginally.

Notes: The thermal isomerizations of N-[α-(alkylthio)alkyl]- and N-[α-(arylthio)alkyl]benzotriazoles have been investigated under N2 atmospheres (i) in toluene, xylene, MeOH, or EtOH, in the presence of acid catalysts and (ii) in the absence of solvent. The sulfide isomerization rates depend on the number of H-atoms carried by the C-atom attached to the N-atom of the benzotriazole: tertiary (no hydrogen) 〉 secondary (1 hydrogen) 〉 primary (2 hydrogens). The results support an isomenzation mechanism involving a heterolytic N—C bond cleavage with formation of sulfonium/carbonium and benzotriazolate ions.

Notes: The reaction of cyclosporin A (CsA) with Lawesson's reagent under different conditions yields various thiocyclosporins, in which carbonyl O-atoms and/or the hydroxy O-atom of the MeBmt residue are replaced by an S-atom. The position of the S-atom is determined by NMR spectroscopy, and the conformations of the products are studied by NMR spectroscopy and X-ray crystallography. Some of the thiocyclosporins show interesting conformational properties. Whereas one conformation strongly dominates for CsA in CDCL3, two conformers A and B, in a ratio 58:42 are found for [1ψ2, CS-NH]CsA. Extensive NMR studies including new 2D and 3D heteronuclear techniques and restrained MD calculations using ROE effects demonstrate that the major conformer A is identical to CsA, while the minor conformer B contains an additional cis peptide bond between the Sar3 and MeLeu4 residues. [4ψ5, CS—NH; 7ψ8, CS-NH]CsA exhibits a conformation very similar to crystalline CsA. However, the D-Ala8NH, MeLeu6Co γ-turn H-bond is not present in this dithio analogue. Also different is the MeBmt1side-chain conformation, the dithio conformation showing a strong MeBmt1OH, Sar3CO H-bond. Immunosuppressive activities of thiocyclosporins are measured in IL-2 and IL-8 reporter gene assays. Their activities are discussed in relation to their conformations.

Notes: Diazo transfer from trifluoromethanesulfonyl azide (TfN3) to 2-amino-2-deoxy-glycoses constitutes a high-yielding, simple procedure for the preparation of partially protected or unprotected 2-azido-2-deoxy-aldoses. Thus, the D-allosamine derivative 2 gave 93% of 3, while diazo transfer to D-glucosamine, D-mannosamine, and D-galactosamine, followed by acetylation, yielded the azides 5, 7, and 9 in yields of 74-91, 65, and 70%, respectively.

Notes: Radical anions often monocyclic and bicyclic azoalkanes containing the azo group in (Z)-conformation, have been fully characterized by their hyperfine data with the use of ESR, ENDOR, and general-TRIPLE-resonance spectroscopy. These azoalkanes are represented by 3,3,5,5-tetramethyl-1-pyrazoline (1), 2,3-diaza-bicyclo[2.2.1]hept-2-ene (4), and 2,3-diazabicyclo[2.2.2]oct-2-ene (9), as well as by their derivatives 2,3, 5-8, and 10. For all radical anions 1″-10″, the 14N-coupling constant, aN, is in the range of +0. 83 to +0. 97 mT; this finding indicates that the spin population is essentially restricted to the π system of the azo group. The 14N-hyperfine anisotropy largely affects the width of ESR lines, particularly at low temperatures. Substantial coupling constants of 7Li-, 23Na-, 39K-, and 133Cs-nuclei point to a close association of the radical anions with their alkali-metal counterions. With the exception of 39K, these nuclei give rise to readily observable ENDOR signals which appear along with those stemming from protons. The prominent hyperfine features of 1″-10″ are discussed.

Notes: The benzyl- and the acyl-protected glyconolactone tosylhydrazones 6, 9, 12, 16, and 19 (Scheme 1) were prepared in good yields by treating the hemiacetals 4, 7, 10, 14, and 17 with N-tosylhydrazine, to give the N-glycosylhydrazines 5, 8,11,15, and 18, and by oxidizing these hydraz tries with N-bromosuccinimide (NBS) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), with CrO3-dipyridine complex or with pyridinium dichromate. Photolysis of the sodium sail 20 of 6 (Scheme 2) in the presence of N-phenylmaleimide, dimethyl fumarate, or acrylonitrile gave the corresponding cyctopropanes 21-28 in satisfactory yields. Phololytic or thermolytic glycosidation of phenol and 4-melhoxyphenol by 20 yielded the anomeric glycosides 29/30 and 31/32, yields being marginally higher for the Ihermolytic process. Phololytic glycosidation of propan-2-ol gave the glycosides 33 and 34 in low yields only. Yields and ratios of products were compared to those obtained with the diazirine 1 as a source of glycosylidene carbenes. While the yields from 20 are lower, the ratios of products obtained in the photolytic reactions are in agreement with the formation of a common intermediate from both carbene precursors.

Notes: Naturally occurring (-)-(R,R)-α-necrodol ((-)-1) and its C(4)-epimer (-)-2 are obtained in 84 and 44% yields, respectively, by lithium ethylenediamide (LEDA) treatment of the corresponding β-necrodols (-)-3 and (-)-4 (Scheme 1, Table), both readily available from (-)-campholenyl acetate ((-)-i) by an efficient stereoselective synthesis. The thermodynamically preferred (-)-(R)-γ-necrodol ((-)-5) becomes the major product (≥ 80% yield) after either prolonged treatment with LEDA or exposure of α- and β-necrodols to BF3·Et2O. In an alternative route, (+)-5 is prepared starting from (+)-campholenal ((+)-ii) via Pd-catalysed decarbonylation to (-)-(S)-1,4,5,5-tetramethylcyclopent-l-ene ((-)-6) and subsequent application of an acid-catalysed CH2O-addition/rearrangement sequence (Scheme 2).

Notes: The sodium and europium cryptates of the new macrobicyclic ligands 2 and 3 incorporating the 2,2′-bipyri dine 1,1′-dioxide and 3,3′-biisoquinoline 2,2′-dioxide units, respectively, have been prepared. The EuIII complexes present characteristic 1H-NMR spectra, showing large shifts, and are strongly luminescent in aqueous solution. These markedly improved luminescent properties, compared to the europium cryptate of the parent macrobicyclic ligand 1, may be ascribed at least in part to a better shielding of the bound cation by the N-oxide sites.

Notes: Investigation of the tubers of Eranthis hyemalis (Ranunculaceae) afforded six chromenone glycosides. Their structures have been elucidated mainly by spectroscopic (FAB-MS, 2D-NMR techniques) and chemical methods (acidic and enzymatic hydrolysis) as 9-{[(β-D-glucopyranosyl)oxy]methyl}-8,11-dihydro-5-hydroxy-2-methyl-4H-pyrano[2,3-g][1]benzoxepin-4-one (1), 9-{[(β-D-gentiobiosyl)oxy]methyl}-8,11-dihydro-5-hydroxy-2-methyl-4H-pyrano[2,3-g][1]benzoxepin-4-one(2), 9-{[(β-D-glucopyranosvl)oxy]melhyl}-8,11-dihydro-5-hydroxy-2-(hydroxy-methyl)-4H-pyrano[2,3-g][1]benzoxepin-4-one(3), 8-{(2E)-4-[(β-D-glucopyranosyl)oxy]-3-methylbut-2-enyl}-5,7-dihydroxy-2-methyl-4H-1-benzopyran-4-one (4), 8-{(2E)-4-[(β-D-glucopyranosyi)oxy]-3-methylbut-2-enyl}-5,7-dihydroxy-2-(hydroxymethyl)-4H-1-benzopyran-4-one (5), and 7-{[(β-D-glucopyranosy1)oxy]methyl}-2,3-dihydro-2-(l-hydroxy-1-methylethyl)-4-methoxy-5H-furo[3,2-g][1]benzopyran-5-one (6). Compound 2 exhibited negative inotropic activity.

Notes: Synthesis of N1,4-Di(p-coiimaroyl)spermine, a Possible Biogenetic Precursor of AphelandrineCoupling of two differently substituted 1,3-diaminopropane units 5 and 6 (Schemes 1 and 2) lead to the key intermediate 8, a tetra-N-protected spermine derivative. By selective deprotection and alkylation with (E)-4-(mesyloxy)cinnamoyl chloride, followed by deprotection, 8 was transformed to the target spermine derivative 19. By an alternative route, the 1,3-diaminopiopanes 10 and 11 were combined to the tri-N-protected tetraamine 12. The intermediates 8 and 12 can be used for the preparation of polyamine derivatives.

Notes: The four photo-cleavable ligands 1-4 of the macrobicyclic-cryptand type have been synthesized by introducing a photo-sensitive 2-nitrobenzyl- or 4,5-dimethoxy-2-nitrobenzyl-ether bond into one of the bridges. These compounds are expected to retain the selective binding features of the parent cryptands and to allow the photolytically induced release of alkali ions in aqueous solution. The crystal structures of the ligand 5-(2-nitro-phenyl)-4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (3) and of its KSCN complex 13 have been determined. They are analogous to those of the corresponding parent species, confirming the macrobicyclic geometry and the cryptate nature of the complex. Spectroscopic properties are reported.

Notes: 2,3-Dihydro-1H-benz[f]indole-4,9-diones are formed in one-step in 45-82% yields by an unprecedented [2+3]-type regioselective photoaddition of 2-amino-1,4-naphthoquinone with various electron-rich alkenes and the [2+3] adducts derived from ammonaphthoquinone with vinyl ethers and vinyl acetate to give 1H-benz[f]indole-4,9-diones including a benzindole-dione with a kinamycin skeleton in 33-72% yields. A probable pathway leading to the formation of the dihydroindole-dione involving air oxidation of an intermediary hydroquinone is proposed.

Notes: Irradiation of dicarbonyl(η5-cyclopentadienyl)iron dimer 1 or decacarbonyldimanganese (2) in the presence of alkyl halides leads to C-centered radicals which can be trappedby alkenes and yields saturated and/or unsaturated addition products. Carbon radicals are generated via halogen abstraction by the initially formed metal-centered radicals resulting from homolysis of the metal-metal bond of dimeric mediators 1 and 2. No reaction occurs using octacarbonyldicobalt (3).

Notes: Carbonyl(cycloheptatrienyl)iodo(phosphorus donor)tungstens ([WI(C7H7)(CO)L]; L = P(OMe)3, 1a; L = P[O(i-Pr)]3, 1b; L = PPh3, 1c) were prepared from dicarbonyl(cycloheptatrienyl)iodotungsten ([WI(C7H7)(CO)2)] via a carbonyl-substitution process. Similarly, bromocarbonyl(phosphorus donor)(1,2,4,6-tetramethylcycloheptatrienyl)tungstens ([WBr(Me4C7H3)(CO)L]; L = P(OMe)3, 6a; L = P[O(i-Pr)]3, 6b; L = PPh3, 6c) were obtained from the reaction of bromodicarbonyl(1,2,4,6)-tetramethylcycloheptatrienyl)tungsten ([WBr(Me4C7H3)(CO)2]; 4) with L. The reduction of 1a-c, 4, and 6a, b with sodiumdihydridobis(2-methoxyethoxy)aluminium in toluene led to stable hydrido complexes [WH(R4C7H3)(CO)L] (R = H, L = P(OMe)3, 2a; R = H, L = P[O(i-Pr)]3, 2b; R = H, L = PPh3, 2c; R = Me, L = P(OMe)3, 7a; R = Me, L = P[O(i-Pr)]3, 7b; R = Me, L = CO, 7d). Complexes 2a and 7b were characterized by X-ray structure analyses.

Notes: The imine obtained by condensing indole-protected 2-(indol-3-yl)acetaldehyde (5) with the terpinylamine derivative (±)-4 was cyclized in 51% yield to the 19-substituted hobartine derivative (±)-20 upon exposure to anhydrous HCOOH. This pivotal intermediate was further elaborated into the indole alkaloids (±)-serratenone ((±)-22) and (±)-sorelline ((±)-29). In the course of these investigations, a novel rearrangement was uncovered; a Lewis acid-catalyzed 1,3-migration of an arylsulfonyl group from the indole N-atom into the benzene ring. The discovery that synthetic (±)-aristotelin-19-one ((±)-34) has decidedly different spectroscopic properties than aristolasicone, a metabolite for which the structure has been recently proposed, led to a revision of the structure of the latter.

Notes: Homolytic dediazoniation of tribromo- and trichloro-benzenediazonium tetrafluoroborates in highly ionizing, low-nucleophilicity solvents (trifluoroethanol and trifluoromethanesulfonic acid (TfOH)) exhibits a strong magnetic-field dependency of dediazoniation products; a more facile singlet-to-triplet intersystem crossing results in increased radical-escape products at higher magnetic fields.

Notes: Synthesis of Enantiomerically Pure Mimulaxanthin and of Its (9Z,9′Z)- and (15Z)IsomersWe present the details of a synthesis of optically active, enantiomerically pure stereoisomers of mimulaxanthin (=(3s,5R,6R,3′S,5′R,6′R)-6,7,6′,7′-tetradehydro-5,6,5′,6′-tetrahydro-β,β-carotin-3,5,3′,5′-tetrol) either as free alcohols 1a and 24a or as their crystalline (t-Bu)Me2Si ethers 1b and 24b. Grasshopper ketone 2a, a presumed synthon, unexpectedly showed a very sluggish reaction with Wittig-Horner reagents. Upon heating with the ylide of ester phosphonates, an addition across the allenic bond occurred. On the contrary, a slow but normal 1,2-addition took place with the ylide from (cyanomethyl)phosphonate but, unexpectedly, with concomitant inversion at the chiral axis. So a mixture of(6R,6S,9E,9Z)-isomers 6-9 was produced {(Scheme 1). However, a fast and very clean 1,2-addition occurred with the ethynyl ketone 12 to yield the esters 13 and 14 (Scheme 2). DIBAH reduction of the separated stereoisomers gave the allenic alcohols 15 and 16 in high yield. Mild oxidation to the aldehydes 17 and 18 followed by their condensation with the acetylenic C10-bis-ylide 19 led to the stereoisomeric 15,15′-didehydromimulaxanthins 20 and 22, respectively (Schemes 3 and 4). Mimulaxanthins 1 and 24 were prepared by partial hydrogenation of 20 and 22 followed by a thermal (Z/E)-isomerization. As expected, the mimulaxanthins exhibit very weak CD curves, obviously caused by the allenic bond that insulates the chiral centers in the end group from the chromophor. On the contrary, some of the C15-allenic synthons showed not only fairly strong CD effects but also a split CD curve which, in our interpretation, results from an exciton coupling between the allene and the C(9)=C(10) bond. We postulate a rotation around the C(8)—C(9) bond, presumably caused by an intramolecular H-bond in 16 or by a dipol interaction between the polarized double bonds in 6, 7, 8, and 17.

Notes: The new axially dissymmetric diphosphines (R)- and (S)-(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(diphenyl phosphine) ((R)- and (S)-5a; ‘MeO-BIPHEP’) and the analogues (R)- and (S)-5b and 5c have been synthesized in enantiomerically pure form. These ligands have become readily available by a synthetic scheme which employs, as key steps, an ortho-lithiation/iodination reaction of the (m-methoxyphenyl)diprienylphosphine oxides 8 and a subsequent Ullmann reaction of the resulting iodides 9 to provide the racemic bis(phosphine oxides) 10. The bis(phosphine oxides) 10 subsequently are resolved with (-)-(2R,3R)- and (+)-(2S,3S)-O-2,3-dibenzoyltartaric acid and reduced to diphosphines 5. The Ullmann reaction constitutes a new and efficient route to 2,2′-bis(phosphinoyl)-substituted biphenyl systems. Absolute configurations were established for (R)-5a by X-ray analysis of the derived Pd complex (R,R)-17a, and for 5b and 5c by means of 1H-NMR comparisons of the derived Pd complexes 16 or 17, respectively, and by means of CD comparisons. The MeO-BIPHEP diphosphine 5a proved to be as efficient as the previously described BIPHEMP diphosphine ((6,6′-dimethylbiphenyl-2,2′-diyl)bis(diphenylphosphine)) in enantioselective isomerizations and hydrogenations.

Notes: Reactions of 3-[2-(morpholin-4-yl)vinyl]-1H-indole (1), the 1,2-dihydro-9H-carbazole 2, as well as the 3-(tetrahydropyridin-4-yl)-1H-indoles 3a and 3b with some carbo- and heterodienophiles are described. The scope and limitations of the synthetic utility of these amino- (or homoamino)-functionalized 3-vinyl-1H-indoles are reported and some MO calculations for the qualitative prediction of their reactivities are presented. The reactions gave rise to substitution products, redox products, Diels-Alder adducts, ene adducts, and Michael-type adducts (Schemes 2 and 3).

Notes: From the gun resin Ammoniacum, an epimeric mixture 2a/3a of highly functionalized prenylated chromandiones was isolated. Their structure was established by spectral data and single-crystal X-ray analysis. The compounds were isolated as acetates 2b/3b, and these derivatives showed in vivo haemorrhagic activity.

Notes: The sponge Stelletta sp. (Astrophorida, Stellettidae), collected at -700 m in the Coral Sea, is shown to contain sterones and sterols of the stigmastane type with a C(24)=C(25) bond for which there is no precedent in the sea. Structure elucidation of the second abundant of these steroids, stigmasta-4,24(25)-dien-3-one ((+)-1), is based on 1D and 2D NMR spectra and chemical transformation to acetate (-)-5. Stigmasta-4,24(25)-diene-3,6-dione ((-)-3), present in trace amounts in the sponge, was obtained in sufficient quantity for NMR study by oxidation of the also present, inseparable, and abundant 4:1 mixture of stigmasta-5,24(25)-dien-3β-ol (6) and its 5,6-dihydro derivative 7 (Scheme 1). This oxidation also afforded the ketone analogues (+)-8 and (+)-9, which could be separated, thus making structure elucidation possible. The 6β-hydroxystigmasta-4,24(25)-dien-3-one ((+)-4), also present in trace amounts in the sponge, was obtained in sufficient amount for NMR study, together with its C(6) epimer (+)-11, by hydroperoxidation of (+)-8 followed by deoxygenation (Scheme 2). The last trace steroid of the sponge, stigmasta-4,6,24(25)-trien-3-one ((-)-2), was structurally elucidated using limited NMR data and comparison with the other stigmastanes. These stigmastanes, as the only steroids of this sponge, are likely to function as stabilizers of its cell walls; their phytosteroid structure, for a sponge which lives in the dark of deep waters, suggest origin through a complex food chain, possibly followed by bioelaboration in the sponge.

Notes: A new approach to the total, asymmetric synthesis of D-threo-L-talo-octose ((-)-1) and its derivatives is presented. It is based on the chemoselective Wittig-Horner monoolefination of a 5-deoxy-D-ribo-hexodialdose derivative 4 obtained by selective reduction of (-)-5-deoxy-2.3-O-isopropylidene-/β-D-ribo-hexofuranurono-6,1-lactone ((-)-3). Allylic bromination of the resulting methyl (E)-oct-6-enofuranuronate (+)-5 followed by intramolecular nucleophilic displacement of the so-obtained bromides gave a 13.3:1 mixture of (-)-methyl (E)-l,4-anhydro-6,7-dideoxy-2,3-O-isopropylidene-β-L-talo-oct-6-enopyranuronate ((-)-8) and methyl (E)-l,4-anhydro-6,7-dideoxy-2,3-O-isopropylidene-α-D-allo-oct-6-enopyranuronate (9). The double hydroxylation of the enoate (-)-8 followed Kishi's rule and gave the corresponding D-threo-β-L-talo-octopyranuronate derivative (-)-11 with a good diastereoselectivity. Reduction of ester (-)-11 and deprotection led to pure (-)-1.

Notes: The synthesis of 4-chloropyrroIo[2,3-d]pyrimidine and 2-amino-4-chloropyrrolo[2,3-d]pyrimidine α-D- and β-D-2′,3′-dideoxyribonucleosides 6a, b and 7a, b is described (Scheme 1). Glycosylation of the pyrrolo[2,3-d]-pyrimidinyl anions of 1a, b with in situ prepared 2,3-dideoxy-α/β-D-glycero-pentofuranosyl chloride (2) was regioselective but afforded anomeric mixtures of the 2′,3′-dideoxyribonucleosides 3a/4a and 3b/4b, respectively. The glycosylation products were deprotected and subjected to nucleophilic displacement yielding various pyrrolo[2,3-d]pyrimidine 2′,3′-deoxyribonucleosides related to 2′,3′-dideoxyadenosine and 2′,3′-dideoxyguanosine. One-pot phosphorylation gave the corresponding triphosphates. Some of them are strong inhibitors of HIV-1 reverse transcriptase, similar to corresponding purine 2′,3′-dideoxynucleotides, but exhibit a better selectivity index in comparison to DNA polymerases. According to that, the N(7) of the purine moiety is not an essential binding position of ddATP or ddGTP at the active centre of HIV-1 reverse transcriptase.

Notes: The structure of a derivative of coenzyme F430 from methanogenic bacteria, the bromide salt of 12,13-diepi-F430 pentamethyl ester (5, X = Br), was determined by X-ray structure analysis. It reveals a more pronounced saddle-shaped out-of-plane deformation of the macrocycle than any hydroporphinoid Ni complex investigated so far. The crystal structure confirms the constitution proposed for coenzyme F430 (2) and shows that in the epimer 5, the three stereogenic centers in ring D, C(17), C(18), and C(19), have the (17S)-, (18S)-, and (19R)-configuration, respectively. Deuteration and 2D-NMR studies independently demonstrate that native coenzyme F430 (2) has the same configuration in ring D as the epimer 5. Therefore, our original tentative assignment of configuration at C(19) and C(18) [1] has to be reversed. This completes the assignment of configuration for all stereogenic centers in coenzyme F430, which has the structure shown in Formula 2.

Notes: Column chromatography of easy available (±)-physovenine (2) on cellulose triacetate afforded (-)- and (+)-physovenine (2a and 2b, resp.). Alkaloids 2a, b required for pharmacological testing were prepared from eserolincs (3a, b) by an improved procedure. Natural (-)-physovenine (2a) was equally potent in inhibiting AChE and BChE in vitro as natural physostigmine (1a), and twice as potent as the unnatural antipode 2b against AChE and 14 times as potent against BChE. Several carbamate analogs of 2a were at least as potent as the former compound in these assays. None of the compounds tested did bind to different opiate receptor or serotonine receptor preparations. Most of the compounds tested had considerable analgesic activity in the Writhing test.

Notes: The absolute configurations of acetylated bretonin A (= (+}-(R)-1-[(acetoxy)methyl]-2-{[(4E,6E,8E)-dodeca-4,6,8-trienyl]oxy}ethyl 4-acetoxybenzoate; (-)-1b) and isobretonin A (= (+)-(S)-3-{[(4E,6E,8E)-do-deca-4,6,8-trienyl]oxy}-2-hydroxypropyl 4-hydroxybenzoate; (+)-2), previously isolated from an undetermined sponge of the North Brittany sea, were established by comparison with synthetic (+)-lb and (+)-2, obtained from the condensation of commerical (-)-(R)-2,2-dimethyl-1,3-dioxolan-4-yl p-toluenesuifonate ((-)-(R)-15) with a mixture of (4E,6E,8E)- (14e) and (4E,6Z,8E)-dodeca-4,6,8-trien-1-ol (14z). This also allowed confirming the structure and configuration of bretonin B (= (S)-2-{[(4E,6Z,8E)-dodeca-4,6,8-trienyl]oxy}-1-(hydroxy-methyl)ethyl 4-hydroxybenzoate; 3) which was also isolated from the same sponge, albeit in a too small amount for a complete study. As concerns the glyceryl ethers precursors of the bretonins, co-occurrence of the usual (S)-con-figuration (from 1a) with the unusual (R)-configuration (from (+)-2)) poses intriguing biogenetic problems.

Notes: The cluster compounds [Pt3(μ-CO)3(PR3)3] act as Lewis bases towards the metal halides of Group XI, MX, Group XII, MX2, and Group XIII, MX3, to form cluster compounds of the composition [{MXn}{Pt3(μ-CO)3(PR3)3}]. The X-ray crystal structure, NMR and IR data are given for the compound [{ZnI}{Pt3(μ-CO)3(PPh(i-Pr)2)3}].

Notes: The products formed on UV irradiation of several tricyclic compounds (i.e. 3, 6, 8, 15, and 17, Schemes 2-4) were studied in detail. A marked dependence of the reaction course on the type and site of substitution was found. Among the several light-induced transformations, a novel rearrangement, i.e. 11 to 9 (Scheme 3) was identified. The formation of the polycyclic compound 13 on irradiation of 8a (Scheme 3) resulted from an unexpected skeletal rearrangement with dearomatization of one benzene ring. The structures of compounds 10, 11, and 13 were established by X-ray crystallography (Figs. 1-3). An attempt was made to give a general mechanistic picture of all observed photochemical results (Schemes 4-6).

Notes: N-Nitroacetyl derivatives of L-proline, L-valine, and L-phenylalanine esters were prepared in two steps under mild conditions (Scheme 2). Regiospecific mono- and bis-allylation of these nitroacetyl derivatives were accomplished in presence of a Pd(0) catalyst. The bis-allyl derivatives 7-9 were obtained in 40-75% yield. The tertiary NO2 group in these compounds could be transformed into an acetylamino group by Zn/AcOH/Ac2O. The final products 11-13 are dipeptides in which the N-terminal glycine residue bears two α-allyl substituents.

Notes: By aromatic nucleophilic substitution followed by intramolecular acylation, 9-oxo-9H-thioxanthene- and 9-oxo-9H-xanthene-dicarboximides were prepared from nitro- or chlorophthalimides and the dianions of thiosalicylic and salicylic acids (Scheme). The 9-oxo-9H-thioxanthene-3,4-dicarboximides were converted to 9-oxo-9H-thioxanthene-3,4-dicarboxylic-acid derivatives such as anhydride, esters, and further imides. Some of these derivatives proved to be excellent photosensitizers with special properties such as liquid aggregation form, H2O solubility, solubility in lipophilic organic solvents and polymers, or bathochromic shifts of the absorption wavelengths.

Notes: The crystal structures of the LiBr complexes of two macrobicyclic ligands, [py.py.bpy]1 and [py.biqi.biqi] 2, have been determined. They confirm the cryptate nature of these species. In 3, the Li+ cation is bound in the shallow cavity of a ligand of flattened shape, whereas in 4, it is buried inside the macrobicycle and surrounded by its three bridges.

Notes: Treatment of methyl 2-(1-hydroxyalkyl)prop-2-enoates 1 with conc. HBr solution afforded methyl (Z)-2-(bromomethyl)alk-2-enoates 2, which were transformed regioselectively into N-substituted methyl (E)-2- (aminomethyl)alk-2-enoates 3 (SN2 reaction) and into N-substituted methyl 2-(1-aminoalkyl)prop-2-enoates 4(SN2′ reaction). Regiocontrol of nucleophilic attack by amine was accomplished simply by choice of solvent, the SN2 reaction occurring in MeCN and the SN2′ reaction in petroleum ether. Hydrolysis and lactamization afforded β-lactams 7 and 8, containing an exocyciic alkylidene and methylidene group at C(3), respectively.

Notes: The original suggestion that a through-space mechanism was operative in the seven-bond J(P, P) coupling constant of 30.3 Hz observed for 3.3′-bis(1,1-dimethylethyl)-2,2′-[3,3′,5,5′-tetrakis(1,1-dimethylethyl)-1,1′-biphenyl-2,2′-diyl]bis(oxy)}bis[1,3,2-oxazaphospholidine] (1a)) was investigated. In the solid-state CP-MAS 31PNMR spectrum of 1a, two nonequivalent P-atoms were observed; sufficient resolution could not be obtained to determine whether P, P coupling was present. The preparation and spectral data of the N-methyl analogue 1b and of the acyclic N-isopropyl analogue 6 (Scheme 1) provided evidence that a) the essentially exclusive formation (R*, R*,S*)-1ain the reaction of the disodium biphenyldiolate 3a with the phosphorochloridite 4a is the result of significant differences in the free energy of activation (ΔG*) for the formation of the various diastereoisomers due to the steric congestion within the molecule and that b) the magnitude of the observed P,P coupling is dependent upon the degree of conformational freedom within the molecule. In the 31P-NMR spectrum of the P-sulfide 7, which was prepared by the reaction of la with sulfur, 2s resonances were observed that strongly suggested that the lone electrons pair on P are involved in the mechanism for the transmission of coupling data. The (4S,5R)-12 and (4R, 5S)-12 of la were prepared in a three-step reaction sequence starting from the corresponding enantiomerically pure norephredine 8 (Scheme 2). Both (4S, 5R)- and (4R, 5S)-12 were obtained as a diastereoisomer mixture that differ by the configuration of the axis of chirality, i.e., (R*R*,R*)- and (R*,S*,R*)-12 were obtained. The major diastereoisomer was obtained upon recrystallization, and the atropisomers were observed to equilibrate in solution by monitoring the H—C(5) resonance in the 1H-NMR with time (ΔG° = 0.4 kcal/mol; Fig. 2). The process observed corresponds to the restricted rotation about the central single bond of the biphenyl system. The isolation of an atropisomer with only a single ortho substituent on each aryl ring is quite rare. In the 13C-NMR spectrum of both (R*,R*,R*)- and (R*,S*,R*)-12, C(5) is two-bond-coupled to the oxazaphospholidine P-atom (2J(C(5),P((2)) = 8.5 Hz) that is further virtually coupled to the P-atom of the other oxazaphospholidine ring (7J(P(2),P(2′)) = 30 Hz; 9J(C(5),P(2′)) = 0 Hz; δ(P(2)) = δ(P(2′)) = 136 ppm. In the 31P-NMR spectrum of (R*,R*,S*)-12, which was prepared from the racemic chloridite (mixture of three diastereoisomers was obtained), a 7J(P(2),P(2′) of 36 Hz was observed. These observations provide strong evidence that seven-bond P,P coupling occurs in all three diastereoisomers of 12. The observed P,P coupling is both independent of the configuration of the chiral axis and the configuration of the asymmetric P-centers. This independence of P,P coupling upon the configuration on P implies also the independence of the observed coupling upon the orientation of the lone-pair of electrons on P provided that the conformations of the diastereoisomers are similar in solution. The X-ray crystal structure of the complex formed from 1a and dichloro(cycloocta-1,5-diene)platinum(II) was obtained and the solid-state structure discussed. The major diastereoisomer of (4S,5R)-12 was used as a chiral ligand in asymmetric hydrosilylation and hydrogenation reactions (Scheme 3).

Notes: The major alkaloid from Rauwolfia serpentina cell-suspension cultures, the glucoalkaloid raucaffricine (2), was enzymatically formed from vomilenine (1) and UDPG in presence of microsomal-bound enzyme. This glucosyltransferase exhibits a relatively high substrate specificity with strong preference for 1 and UDPG. The apparent Km values for 1 and UDPG were 40 μM and 0.8 mM, respectively, for raucaffricine formation. Optimum transferase activity was observed at 50° and pH 6.3. The taxonomic distribution of this enzyme seems to be very limited because transferase can he exclusively detected in raucaffricine-producing plant cells.

Notes: The synthesis of 2′-deoxyisoguanosine (2), and the pyrrolo[2,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine 2′-deoxyribonucleosides 3 and 4 is described. Condensation of the imidazole precursor 5 with benzoyl isocyanate followed by reaction with ammonia gave 2. Its N(7) regioisomer was obtained from 6. Compound 2 was also prepared by the photochemically induced conversion of 2-Chloro- and 2-bromopurine 2′-deoxyribofuranosides 9a and 10, respectively, in aqueous solution, The photo reaction was further used for the synthesis of the compounds 3 and 4 starting with the amino-chloro-2′-deoxynucleosides 9b and 9c, respectively.

Notes: Optical Isomers of Naftidrofuryl( = 2-(Diethylamino)ethyl 2-[(Naphth-1-yl)methyl]-3-(tetrahydrofur-2-yl)propanoate)The four optical isomers of naftidrofuryl (1) were prepared in two ways, by separation and resolution of the two diastereoisomeric racemates and by synthesis from the enantiomers of tetrahydrofuran-2-methanol (6); see Scheme}. The absolute configuration of one of the isomer as a tartrate monohydrate was established by X-ray crystallography thus allowing the deduction of the absolute configurations of the other three optical isomers.

Notes: In higher plants, the two homotcrpenes 4,8-dimethylnona-l,3,7-triene (1) and 4,8,12-trimethyltrideca-1,3,7,11-teiracnc (2) originate from nerolidol (3) or geranyllinalool (4) by anoxidative cleavage of their C-skele-lons. The reaction proceeds with exclusive loss of H8-C(5) of 3 and formal production of a C4 fragment. The site specificity of the enzyme(s) is identical for all of the hitherto examined plant families (Agavaceae, Asclepiadaceae, Asteraceae, Leguminosae, Magnoliaceae, and Saxifragaceae). The enzyme tolerates a wide range of structural modifications at the polar head of 3. Instead of 3, also gcranylacclone 12 and the secondary alcohol 13 can be cleaved to the homoterpene 1 and as yet unidentified carbonyl fragments. The C=C bonds within the aliphatic chain of 3 seem to be essential for the oxidative bond cleavage as well as for recognition and embedding of the substrate into the active center of the enzyme(s). The feed-induced biosynthesis of 1 and 2 in leaves of the Lima bean Phaseolus lunatm infested with the spider mite Tetranychus urticae probably requires a preceding release of nerolidol (3) or geranyllinalool (4) from phylogenic glycosides prior to the fragmentation reaction. The microbial reduction of the trienoic acids 6 and 6ais the key stop for the synthesis of deuterium labelled nerolidol (3RS,5R)-and (3RS,5S)-9.

Notes: tert-Alkyl sulfides, with an α-(1H-benzotriazol-1-yl) group 6 and 13, are readily prepared from N-[(aryl-thio)methyl]-1H-benzotriazoles 3 and N-(11), respectively, by reaction with BuLi and then with the appropriate electrophile. The tert-alkyl sulfides 6 and 13 are smoothly converted by BF3. OEt2 into vinyl sulfides 5, 7 or 12, respectively, in satisfactory yields.

Notes: Synthesis of the Macrolide Antibiotic (-)-A2677IB Using Photolactonization as a Key Reaction and Computer Simulation as an Effective Aid in OptimizationThe title compound has been synthesized in a sequence of 21 steps starting from phenol. The cyclic skeleton has been built up in the earlier part of the synthesis by photolactonization. This reaction supplies C(6), with a functionality, not present in the target structure, but useful for oxygenation at C(4) and generation of the stereogenic center C(5). The Barton/McCombie reaction provides a product deoxygenated at C(6), but only after an adjacent oxirane ring has been opened at the cost of an increase in the number of overall steps. X-Ray structural information and computational modelling of appropriate molecules proved to be essential to selection of optimal conditions for various transformations.

Notes: We incorporated 6,7-dimethyllumazine chromophores and a [RuII(bathophenanthroline)] complex into different oligodeoxynucleotides, the former via the corresponding phosphoramidites of the 2′-deoxynucleosides and the latter specifically by the phosphonate approach at the 5′-end of synthetic oligonucleotides, directly in the course of their synthesis on solid support. Efficiency measurements of this energy-transfer system with the lumazine as energy donor and the Ru complex as energy acceptor allowed us to distinguish between the hybridized and the non-hybridized state of oligonucleotides. Thus, the approach should be of value in DNA probe technology for the detection of single-stranded DNA targets.

Notes: The antibiotic myxovirescine M2 was synthesized from seven building blocks (1-7, Scheme 1), with the following chiral starting materials being employed: (S)-malic acid, (+)-D-ribonolactone, (S)-2-(hydroxymethyl)butanoate, and (2R,4S)-5-hydroxy-2,4-dimethylpenLanoate. Three new nucleophilic reagents, 8-10, for C-C bond formation have been used. The key steps of the synthesis are: a Suzuki coupling between an alkyl borane and a vinyl bromide (4 + 12e → 13), a Julia olefinalion (14 + 17 → 18), and a Yamaguchi macrolactonizalion to form the 28-membered lactone (18 → 19), This extremely convergenl synthetic approach will allow the preparation of a number of the 31 known myxovirescine molecules.

Notes: The (-)-(2S)-Diethyl 2-Hydroxyhexanedioate, a New Chiral Building Block for Enantioselective Synthesis(-)-(2S)-Diethyl 2-hydroxyhexanedioate ((2S)-3) has been obtained by enantioselective reduction of diethyl 2-oxohexanedioate (1) with baker's yeast. The key intermediate (-)-(5S)-ethyl 5,6-dihydroxyhexanoate ((5S)-5) is proved to be a useful synthon for the synthesis of chiral δ-lactones and a precursor of leukotriene LTB4 ((5S)-13).

Notes: The structure and synthesis of novel irregular C12 terpenoids isolated from quince fruit (Cydonia oblonga MILL.) are described: quince oxepine (= (E)-2,3,6,7-tetrahydro-4-methyl-2-(3-methylbuta-1,3 dienyl)oxepine; 3) and the quince oxepanes as a 1:1 mixture of cis- and trans-isomers (= cis- and trans-(E)-4-methyl-2-(3-methylbuta-1,3-dienyl)oxepane; 4 and 5, resp.). The absolute configurations of the natural compounds have not been determined due to the minute amounts available, but both relative and absolute configurations of synthetic 4 and 5 were established by chemial correlation with (R)-pulegone.

Notes: 1H- and 13C-NMR spectra of a series of 8-R1-substituted as well as of 8,8-R1, R2-disubstituted heptafulvenes, varying from inversely polarized (3l) to unpolar (3h) and polar heptafulvenes with electron-withdrawing groups (3d, e, f), have been analyzed and compared with those of methoxytropylium salt 5a. The results concerning 3J (H,H) values and 13C-chemical shifts are shown in Figs. 5 and 6. It turns out that all the NMR parameters are strongly influenced by substituents R1, R2, but contrary to planar pentafulvenes, no linear correlations of the NMR parameter vs. Hammett substituent constant σ+ are obtained in the series 3l → 3d. 3J coupling constants J(2,3)/J(4,5) and J(3,4) are not much influenced by substituent changes in the series 3l → 3h, but are approaching in the row 3h → 3d. Similarly, signals of the 13C-atoms undergo a moderate shift to higher frequencies in the row 3l → 3h, but are strongly influenced by —M groups, whereby the sensitivity is decreasing in the series C(7) 〉 C(2)/C(5) 〉 C(3)/C(4) 〉 C(1)/C(6). These results are essentially explained by a boat conformation of inversely polarized heptafulvenes of the type 3l and an increasing planarization of the ring on going to polar heptafulvenes of type 3d.

Notes: Several synthetic pathways to the anticonvulsivum gabapentin (1-(aminomethyl)cyclohexaneacetic acid) have been investigated. Advantages and drawbacks of the different routes are discussed, and the most economical and technically most feasible synthesis is pointed out.

Notes: A route for synthesizing C-nucleosides with 2,6-substituted pyridines as heterocyclic aglycones is described. Condensation of appropriately substituted lithiated pyridines with ribono-1,4-lactone derivatives yields hemiacetal 4a-g (Table 1), which can be reduced by Et3SiH and BF3·Et2O to the corresponding C-nucleoside (see Scheme 1 for 4d → β-D-5). Conditions are presented that optimize the amount of the 2,6-dichloropyridine-derived β-D-anomer β-D-5 formed (Table 3). Aminolysis of β-D-5 yields the diaminonucleoside 14 (Scheme 3).

Notes: Information on the hitherto unknown relative configuration and on the conformation of the title compounds in solution can be derived from nuclear Overhauser effects and coupling constants. Whereas the bridged 5-(dimethoxyphosphoryl)-2-methoxy-1,2λ5-oxaphospholan-2-ones 6 and 7 are sterically strained and, therefore, conformationally rigid, the C(3)-unsubstituted compound 1 does not show a preferred solution conformation. Phenyl substituents at C(3) (compounds 2-5) tend to adopt a pseudoequatorial position, this way leading to a definite conformation of the respective compounds. The influence of the conformation on the NMR spectra is discussed. 31P-NMR Spectroscopy is ideally suited for the characterization and quantification of the isomers 2-5 present in the reaction mixture.

Notes: Bicyclic alcohol (±)-2, an advanced intermediate for the synthesis of the methyl ester 1 of pentalenolactone E, has been synthesized in nine operations starting from aldehyde 7. The key step 6 → 9 is a Pd-catalyzed, tandem intramolecular alkyne allylation/carbonylation reaction.

Notes: The readily available alkyl dicyanoacetates 1 reacted with the 1,3-dipolar reagents arenecarbonitrile oxides 2′ and arenecarbonitrile imines 5′ to afford 1,2,4-oxadiazol and 1,2,4-triazol derivatives. The arenecarbonitrile oxides 2′ with electron-donating groups on the arene ring gave products 3a-d resulting from addition on both CN groups of 1, and those with electron-withdrawing groups provided mono-adducts 4a-e (Scheme 1). Arylnitrile imines 5′ reacted with 1 to offer both bis- and mono-addition products (Scheme 2); the bis-adducts 8a,b possess an ester structure, whereas the mono-adducts 6a-d present a ketene-hemiacetal structure.

Notes: Diels-Alder reactions of the (1H-indol-3-yl)-enacetamides and -endiacetamides 1a-d with some carbodieno-philes and 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione give rise to the novel amino-functionalized carbazole; 4-6 and 8 (Scheme 3). Ethenetetracarbonitrile reacts with 1b to furnish the Michael-type adduct 7 (Scheme 3). Structural aspects of the starting materials 1, which exhibit above all 3-vinyl-1H-indole reactivity, are discussed with regard to the prediction of a Diels-Alder process.

Notes: The ketene derivative of the chiral oxazolidinone 1 underwent non-concerted stereo specific [2 + 2] cycloadditions with the (Z)-imine moiety of diazepines 2, leading thereby with good diastereoselection to the trans-β-lactam adducts 3 (major) and 4 (minor). The absolute configuration of the major cycloadduct 3a was determined by an X-ray analysis. Its formation is discussed in terms of minimisation of steric interaction in the two transition states which give sequencially the zwitterionic intermediates and the final cycloadducts.

Notes: The reactions of [Fe2(CO)9] with 2-exo,3-exo-bis(chloromethyl)-5,6-di(methylidene)-7-oxabicycio[2.2.1]-heptane (5) and with 5,6-di(methylidene)-7-oxabicyclo[2.2.1]heptane-2-exo,3-exo-dimethyl bis(methanesulfonate) (6) afforded, together with the corresponding [exo-Fe(CO)3(1,3-diene)] complexes 7 and 8, the products of dimerization in the form of stable [Fe(CO)2{(1,2,3-η:6,7,8-η)-octa-2,6-diene-1,8-diyl}] complexes 9 and 10, respectively, with high stereoselectivity. The structure of 10 was established by means of single-crystal X-ray diffraction.

Notes: The stereo and face selectivities of the cycloaddition of 1,2,3-trichloro-3-fluorocyclopropene (1a) with acyclic dienes and furans has been re-investigated by X-ray determination and correlation of 19F-NMR data. The isolated adducts of dienes exclusively have exo-configuration, and exo-Configuration predominates with furans. The Cl substituents of the resulting cyclopropane ring are cis-oriented. The face selectivity of the reaction with both types of substrates is attributed to electrostatic interactions between the F and the bridgehead Cl substituents, which destabilize the F-cis-transition state (13 (F-cis)) over 13 (F-trans).

Notes: The syntheses of 1,7-dideaza-2′,3′-dideoxyadenosine (1) and related pyrrolo[2,3-b]pyridine 2′,3′-dideoxyribi and 2′,3′-didehydro-2′,3′-dideoxyribonucleosides (see 2-5) are described. As starting materials, 2′-deoxyribo-nucleosides 6 or 7 were used. The 3′-OH group was removed by Barton deoxygenation or via mesylation follow by elimination and catalytic hydrogenation. Compound 1 was also obtained from the direct glycosylation of 4-nitro-1H-pyrrolo[2,3-b]pyridine (17) with the 2,3-dideoxyribofuranosyl chloride 18. The triphosphate 25 of 1 showed only marginal activity against HIV-1 reverse transcriptase, indicating that purine N(1) is required for the inhibitory activity of the parent 2′,3′-dideoxyadenosine.

Notes: A series of new 2′-5′-oligonucleotide trimers carrying a 9-(2′,3′-anhydro-β-D-ribofuranosyl)-(59), 9-(3′-deoxy-β-D-glycero-pent-3-enofuranosyl)-(63), 9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)-(62), and 9-(3′-halo-3′-deoxy-β-D-xylofuranosyl)adenine (60 and 61) moiety at the 2′-terminal end have been synthesized via the phosphotriester method. The properly protected, modified monomeric building blocks (6, 9, 16, 19, 27, 33, 36, 37, and 43) were obtained, in general, by a sequence of reactions, introducing the protecting groups into the right positions. Their condensations with the intermediary dimeric 2′-terminal phosphodiesters 48 and 49 led to the fully protected 2′-5′-trimers 50-58 which were deblocked to form the free 2′-5′-trimers 59-63. Easy elimination of HBr on deprotection did not allow to form the trimeric (3′-bromo-3′-deoxy-β-D-xylofuranosyl)adenine analogue but only 63 carrying an unsaturated sugar moiety instead. The newly synthesized compounds have been characterized by UV and NMR spectra as well as by elemental analysis.

Notes: To obtain stable derivatives of α-unsubstituted pyrroles, the reaction of the test pyrrole 9 with a series of chalcones 14a-h were studied. Michael adducts 16b-h could be isolated. In order to synthesize coloured derivatives, the reaction of different pyrroles 9, 21, 23, and 25 with diphenylpropynone 19 was investigated. In these cases, too, Michael-addition products were formed. The intense absorption band around 400 nm makes the identification of these derivatives easy.

Notes: (S)-Perilla alcohol (5) was transformed into (S)-7-(phenylthio)-p-menth-1-en-8-amine (11) in five steps. Condensation of this building block with 1-(4-methoxyphenylsulfonyl)-1H-indole-3-acetaldehyde (12) led to the expected imine 15 which cyclized in 54% yield to protected 20-(phenylthio)hobartine 16 upon exposure to anh. HCOOH. Treatment of this intermediate with an alkylating reagent led to (+)-aristofruticosine protected in the indole moiety via an intramolecular, allylic nucleophilic displacement reaction. Subsequent reductive removal of the protecting group completed the first synthesis of the Aristotelia alkaloid (+)-aristofruticosine ((+)-4). This straightforward synthesis confirmed the tentative structure (+)-4, proposed by Bick and Hai, and established the hitherto unknown absolute configuration of this metabolite.

Notes: The tin hydride promoted and the reductive vitamin B12 catalysed radical cyclisation of mixed 2-bromo-acetaldehyde acetals and of (2-bromomethyl)dimethylsilyl ethers of allylic terpenoid alcohols has been investigated: 3-oxadeca-5,9-dien-l-yl radicals undergo 5-‘exo’ cyclisation to oxolanes (Scheme 4), 3-oxa-2-siladeca-5,9-dien-1-yl radicals sequential 6-‘endo’→5-‘exo’ tandem cyclisation to cis-3-oxa-4-silabicyclo[4.3.0]nonanes (Scheme 5), and 3-oxa-2-silatetradeca-5,9,13-trien-l-yl radicals sequential 6-‘endo’→6-‘endo’→5-‘exo’ triple cyclisation to trans-transoid-trans- 12-oxa-11-silatricyclo[7.4.0.02,6] tridecanes (Scheme 6).

Notes: A general strategy for the synthesis of oligobipyridine ligands 2-5 containing from two to five 2,2′-bipyridine subunits, for helical metal complexes is described (sec Scheme). Both the unsubstituted parent strands (a series) as well as their derivatives bearing fester or amide functions in the 4,4′-positions of the bipyridine moieties (b-d series) have been obtained.

Notes: Reduction of tribenzo[a,c,e]cyclooctene (2) and its 2,3- and 1,4-dimethyl derivatives (4 and 5), as well as of 1,1-dimethyl-10,11-propane-2,2-diylidene-1H-benzo[5,6]cycloocta[1,2,3,4-def]fluorene (6) and its 5,6-didehydro derivative (7) was followed by cyclic voltammetry. The radical anions of these compounds and those of their derivatives (D)2, (D)5, and (D)6, deuteratsd at C(9) in 1 and 5 or in the corresponding position of 6, have been characterized with the use of ESR, ENDOR, and TRIPLE-resonance spectroscopy. The cyclic-voltammetric and proton-hyperfine data are consistent with the increasing deviations of the radical anions from planarity in the order These deviations, due to steric or interferences in the peri-positions 1↔14 and 4↔5, are removed in and by the introduction of bridging groups. The non-plalarity affects the thermodynamic and kinetic stabilities of the radical anions and causes a shift in the π-spin distribution away from that benzene ring which is linked to the two others by the essential single bonds C(4a)—C(4b) and C(14a)—C(14b). This finding suggests that the steric hindrance in , and is alleviated by twisting this ring out of coplanarity with the remaining (Z)-stilbene-like π-system.

Notes: A thorough IR and 1H-, 13C-, 31P-, 183W-NMR spectroscopic, and X-ray structural study was carried out on complexes of the type trans, trans-[WH(CO)2(NO)(PR3)2], (R = Et, Me, Ph, i-PrO, MeO, and PhO). Linear correlations could be found between Tolman's parameter X and v(CO), v(WH), v(NO), δ(13C) (CO), as well as 1n(k), k being the H/D exchange rate constant for the hydride in CD3OD. The 1J(183W,31P), 2J(31P,1H), and 2J(31P,13C) as well as the 1J(183W,1H) values are related to the electronegativity of the R groups on the phosphorus ligands. This is also indicated by EHT calculations of s-orbital populations of appropiate W model complexes. The X-ray structures of [WH(CO)2(NO)(PR3)2] (R = Me, Ph, and MeO) were determined. Minor differences were observed in the W—P bond lenghts and in the P—W—P and C—W—C angles. No obvious relationship between X-ray data and spectroscopic parameters could be found. All three structures reveal a bending of both the CO and PR3 ligands towards the hydride atom. The total octahedral distortion is remarkably constant (25.6, 29.4, and 27.0° tilt, respectively), although the ligands individually are very different. This is attributed to redistribution of π-electron density between CO and PR3 groups toward the central W-atom in the three complexes.

Notes: Several 3,6-substituted 1,2,4-trioxan-5-ones have been prepared in good yield by condensing aldehydes and ketones with trimethylsilyl α-[(trimethylsilyl)peroxy]alkanoates in the presence of trimethylsilyl trifluoromethane sulfonate as catalyst.

Notes: Enantiospecific Synthesis of ( - )-(1S,3R,5R)-1,8-Dimethyl-3-ethyl-2,9-dioxabicyclo[3.3.1]non-7-eneThe isomer ( - )-(1S,3R,5R)-1,8-dimethyl-3-ethyl-2,9-dioxabicyclo[3.3.1]non-7-ene ((1S,3R,5R)-8) was synthesized from ( - )-(3R)-methyl 3-hydroxypentanoate with an enantiomeric excess ≥ 96%.

Notes: One-Electron Redox Reactions of Octamethyl[4]radialene: Proof of the Alternancy of Even-Membered RadialenesThe photoelectron spectrum of octamethyl[4]radialene ( = tetrakis(dimethylmethylidene)cyclobutane) yields the rather low first vertical ionization of only 7.30 eV and, therefore, the molecule can be oxidized by AlCl3/CH2Cl2 to its radical cation. The ESR and ENDOR signal patterns recorded are almost identical with those of the radical anion, generated in a [2.2.2]cryptand THF solution by reduction at a potassium metal mirror. Their near congruency is in accord with the alternant π molecular properties of even-membered radialenes as predicted by HMO theory, and larger changes of the D2d structure of C8(CH3)8 during the redox reactions are presumably hindered by the steric overcrowding in persubstituted [4]radialenes.

Notes: Monosubstitution of Octa(hydridosilasesquioxane) H8Si8O12 to R′H7Si8O12 by HydrosilylationHydrosilylation of hex-1-ene and of styrene by octa(hydridosilasesquioxanes) catalyzed by hexachloroplatinic acid leads to the first monosubstituted octasilasesquioxane R′H7Si8O12 molecules.

Notes: Molecular-orbital calculations have been performed for the conjugate base cis-[Co(NH3)4(NH2)Cl]+ and trans-[M(NH3)4(NH2)Cl]+ (M = CrIII, CoIII, and RhIII), the hexacoordinated intermediates cis- and trans-[Co(NH3)4(NH2)…Cl]+, the square-pyramidal and trigonal bipyramidal pentacoordinated intermediates apical-[Co(NH3)4(NH2)]2+, basal-[Co(NH3)4(NH2)]2+, and equatorial-[M(NH3)4(NH2)]2+ (M = Co and Rh), respectively, using modified extended Hückel and SCF MS-Xα methods. The LUMO of the conjugate bases is an antibonding metal centered dρ* orbital which is stabilized during the dissociative activation of the M—Cl bond. For the above conjugate bases, separations of the highest doubly occupied MO (HDOMO) and the LUMO of 1.3, 2.5, 1.8, and 2.5 eV, respectively, have been calculated using the SCF MS-Xα model. Only in the conjugate base cis-[Co(NH3)4(NH2)Cl]+ with the smallest HDOMO  -  LUMO gap, the singlet electronic structure of the ground state may be stabilized by changing into a triplet when the Co—Cl bond is activated. This situation is unique to (acidato)(pentaamine)cobalt(III) complexes with deprotonated amine ligand cis to the leaving group and the reason for the existence of intermediates and their reactivity as well. Base hydrolysis of the analogues CrIII and RhIII complexes - the latter taken to represent the second- and third-row transition-metal amines - is unlikely to proceed via intermediates; a concerted substitution process is expected to take place.

Notes: The allylation and deuteration of six-membered cyclic sulfinylated radicals were investigated. For this purpose, radicals with the predefined conformations I and II were generated from 2-(phenylselenenyl)thiacyclo-hexane-1-oxide derivatives 7-10 (Scheme). Steric effects were insufficient to account for all the observed selectivities. The participation of stereoelectronic effects are envisaged to explain the stereoselective axial deuteration of type-II radicals.

Notes: The preparation of a 3:1 complex of hydroquinone (HQ) and C60, (HQ)3C60, is reported and its X-ray crystal structure described. The HQ host builds up a single H-bonded super-polonium network with super-cubes as building blocks, which accommodate the large C60 guest molecules. The enclathration of C60 is rather tight (high density of the complex) owing, in part, to favorable charge-transfer host-guest interactions (π-donor-acceptor complex). Nonetheless, the C60 molecules arc orientationally disordered, and no individual bond lengths could be measured. In contrast, the HQ host network is essentially ordered and well-defined with normal intramolecular geometry. No appreciable (powder) conductivity could be observed for (HQ)3C60, yet ESR spectra of single crystals showed interesting narrow signals.

Notes: Z-Protected diphenyl (decarboxy-dipeptidyl)phosphonates 5a-c with a (decarboxysarcosinyl)phosphonate moiety are prepared from Z-L-alanine (1a). Z-L-valine (1b), and Z-L-phenylalanine (1c) by the following series of steps: coupling with methyl sarcosinate (→2a-c), saponification (→3a-c), Hofer-Moest oxidative decarboxyiation by electrolysis in MeOH (→4a-c), and Arbuzov reaction with P(OPh)3/TiCl4 (Scheme 3). Double deprotonation and alkylation lead to non-stereoselective incorporation of side chains next to the phosphonate group (products of type 6-8, nine examples, see Scheme 4). In the cases of 6a-c and 8c, the diastereoisomers could be separated and the configuration of the newly formed stereogenic center deduced. We assign the L,D-configuration to the diastereoisomers for which the 31P-NMR signal appears at higher field.

Notes: A series of didehydro-3-O-methyl-estrones having a styrenic framework, with the ring-A-conjugated double bond in all three possible positions (8,9-didehydro- (6),9,11-didehydro- (1b), 6,7-didehydro- (9), and the 12,18-di-nor-8,9-didehydroestrone analog 11), were compared for their reactivity towards singlet oxygen. Under dye-sensitized photo-oxygenation conditions, both, products derived from ene-type reactions with the isolation of a stable hydroperoxide and a fragmentation product, were obtained from 6 (see Scheme 3), while only fragmentation took place for 1b (Scheme 1), Kinetic studies indicated that 6 is more reactive towards 1O2 than 1b (β = 9.2·10-3 mol·1-1 vs 3.3·10-2 mol·1-1, resp.). The observed reactivity, apparently, does not match with ene-type reaction and [2 + 2]cycloaddition being in competition, since the most activated substrate 6 preferentially yields ene-type products and their derivatives. Conformational analysis on the structure of 6 and 1b, both calculated by molecular-mechanic techniques (MMPMI) and determined by X-ray diffraction, show that the allylic H-atoms satisfy the orthogonality rule for ene-type reactions. The product distribution is best rationalized by applying Fukui's rule which takes into account a combination of electronic and geometric factors. Substrates 9 and 11 yielded photo-products arising from ene-type reaction with no stable primary products isolated (Scheme 4). Geometric considerations based on the calculated structures by molecular mechanics are consistent with the observed results.

Notes: Treatment of 3,3′-alkylidene-4,4′-dihydroxybis[coumarins] 1 with NaBH3CN in refluxing MeOH affords 3-alkyl-4-hydroxycoumarins 2 and 4-hydroxycoumarin (3; Scheme 1). The reaction might take place via hydride trapping of alkylidenechromandiones C formed from 1 in a retro-Michael reaction. Such a retro-Michael reaction of 1 might be biologically relevant. The presence of C during the reductive fragmentation 1 → 2 is suggested by Diels-Alder and nucleophilic trapping of the alkylidenechromandiones C as well as from cross-over experiments with coumarins other than 3 (see Scheme 2). The reductive fragmentation of 1 allows the chemo- and regioselective synthesis of a variety of 3-alkyl-4-hydroxycoumarins 2 (see Table).

Notes: The fused pentacyclic alkaloid 2-bromoleptoclinidinone (1) isolated from an ascidian possesses a bidentate chelating site. Complexation of 1 with [cis-RuCl2{(D8)bpy}2] · 2H2O forms an octahedral complex which was isolated both as hexafluorophosphate 2 and chloride 3 salts. Intercalation of 3 in calf-thymus DNA was shown to occur as well as photoactivated cleavage of double-strand supercoiled DNA pBR322 under visible-light irradiation.

Notes: The probably most straightforward plan to synthesize the indole alkaloid alloaristoteline (5) failed, because- in marked contrast to the regular Aristotelia series-electrophilic reagents attack with preference C(3) of the indole moiety in the key intermediate allohobartine ((-)-12), instead of C(18). The only product that could be isolated when (-)-12 was treated with mineral acid was isomer (+)-15 of 5 (Scheme 2). As a consequence, the crucial electrophilic site at C(17) was created by taking recourse to the preparation of the stabilized allylic cation VI. Gratifyingly, this alleged intermediate, obtained from precursor (±)-18, cyclized smoothly to protected (±)-18,19-didehydroalloaristoteline (±)-17, which was transformed in two high-yield steps into the racemic form of the target molecule 5 (Scheme 4). This successful alternative provides unambiguous evidence that the recently revised structure of 5 is indeed correct.

Notes: Methods for a stereoselective preparation of compounds of type 2b, a key intermediate of a previous synthesis of the tetracyclic diterpene stemarin (la), have been tested on model compounds 5a, 5c, and 8a. Thus, (±)-(1RS,6SR,8SR,11SR)-hydroxytricyclo[6.2.2.0l,6]dodecan-9-one (5a) was transformed by the Mitsunobu reaction into (±)-(1RS,6SR,8SR,11RS)-11-(benzoyloxy)tricyclot[6.2.2.01,6]dodecan-9-one (6b; Scheme 2). The latter was also obtained from (±)-(1RS,6SR,8SR,11RS)-11-[(4)-toluenesulfonyloxy]tricyclo[6.2.2.01,6]dodecan-9-one (5c) by the action of Et4N (PhCOO) in acetone. Compound 6b was then converted into (±)-(1RS,6RS,8RS,9RS)-tricyclo[6.2.2.01,6]dodecan-9-ol (8b), a model for 2b. Compound 8b was also prepared from its epimer 8a by the Mitsunobu reaction via ester 7b. The inversion of configuration of bicyclo[2.2.2]octan-2-ols or derivates was not previously described. The model studies paved the way to the diastereoselective synthesis of (+)-18-deoxystemarin (1b) via 12β-hydroxy-13-methyl-9β,13β-ethano-9β-podocarpan-15-one (10a) and 13-methyl-9β,13β-ethano-9β-podpcarpan-12α-ol (11b).

Notes: On irradiation with visible light in the presence of air, the zinc complex 1b of pyropheophorbide-a methyl ester (1a) is photo-oxidized at the C(20) methine bridge yielding the corresponding 19-formyl-21H-bilin-1(23H)-one derivative 2. Surprisingly, the cadmium complex Ic is cleaved, under the same conditions, at the C(5) methine bridge affording the same type of bilinone which has been recently characterized as an early product of chlorophyll catabolism in plants.