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Publications - Bioorganic Chemistry

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Publications

Schrekker, H.; Micskei, K.; Hajdu, C.; Patonay, T.; de Bolster, M.; Wessjohann, L.; Involvement of an Oxidation-Reduction Equilibrium in Chromium-Mediated Enantioselective Nozaki–Hiyama Reactions Adv. Synth. Catal. 346, 731-736, (2004) DOI: 10.1002/adsc.200404021

Ligand induced enantioselective versions of the chromium(II)‐mediated Nozaki–Hiyama reaction to homoallyl alcohols proved to be very difficult to achieve, especially if any other nucleophile than the parent allylchromium(III) species was applied. Also, the reaction is frequently accompanied by the formation of oxidation side products, predominantly allyl ketones. This can be explained by an Oppenauer–(Meerwein–PonndorfVerley) type mechanism (OMPV reaction). The addition of an enantiopure ligand to racemic chromium homoallyl alcoholate intermediates produced enantiomerically enriched homoallyl alcohols with an enantiomeric excess of up to 32%. This observation not only supports that the proposed OMPV oxidation‐reduction equilibrium plays a crucial role in Nozaki–Hiyama reactions, but also proves its involvement in enantioselective versions.
Publications

Schneider, P.; Schrekker, H.; Silveira, C.; Wessjohann, L.; Braga, A.; First Generation Cysteine- and Methionine-Derived Oxazolidine and Thiazolidine Ligands for Palladium-Catalyzed Asymmetric Allylations Eur. J. Org. Chem. 2004, 2715-2722, (2004) DOI: 10.1002/ejoc.200300675

A new series of enantiopure oxazolidine‐thioether and thiazolidine‐alcohol ligands have been synthesized from L ‐cysteine, S‐methyl‐L ‐cysteine, and L ‐methionine in a straightforward manner that allows numerous structural variations to be formed. These types of ligands have not previously been used in asymmetric palladium‐catalyzed allylations and their efficacy was explored in the reaction of rac‐1,3‐diphenyl‐2‐propenyl acetate with dimethyl malonate. The reaction proceeds in excellent yield and with good enantioselectivity. The palladium catalyst derived from N‐benzyl‐2,2‐dimethyl‐4‐(2‐thiapropyl)oxazolidine (12 ) provides the allylation product in a quantitative yield and with an enantiomeric excess of 94%.
Publications

Scheid, G.; Ruijter, E.; Konarzycka-Bessler, M.; Bornscheuer, U. T.; Wessjohann, L. A.; Synthesis and resolution of a key building block for epothilones: a comparison of asymmetric synthesis, chemical and enzymatic resolution Tetrahedron: Asymmetry 15, 2861-2869, (2004) DOI: 10.1016/j.tetasy.2004.06.048

The asymmetric synthesis and kinetic resolution of a series of acyloins (α-hydroxy ketones) suitable as building blocks for the northern half of epothilones was studied. Three methods were applied to obtain nonracemic compounds at the eventual epothilone C15-position: asymmetric synthesis with Evans’ auxiliary, chemical resolution and enzymatic resolution. The success rate in small scale applications increased in the order given, and the enzymatic resolution was studied in more detail. Out of a set of nine lipases and esterases, lipases from Burkholderia cepacia, Pseudomonas sp., lipase B from Candida antarctica and recombinant esterases from Streptomyces diastatochromogenes exhibited the highest enantioselectivities with E-values ranging from 60 to >200. Pig liver esterase exhibited inverse enantiopreference and only with recombinant enzyme could a moderate selectivity (E = 50, commercial PLE: E = 8) be observed.
Publications

Poeaknapo, C.; Fisinger, U.; Zenk, M. H.; Schmidt, J.; Evaluation of the mass spectrometric fragmentation of codeine and morphine after 13C-isotope biosynthetic labeling Phytochemistry 65, 1413-1420, (2004) DOI: 10.1016/j.phytochem.2004.05.005

All major fragment ions of codeine and morphine were elucidated using LC–electrospray MS/MS and high resolution FT-ICR-MS combined with an IRMPD system. Nanogram quantities of labeled codeine were isolated and purified from Papaver somniferum seedlings, which were grown for up to 9 days in the presence of [ring-13C6]-l-tyrosine, [ring-13C6]-tyramine and [1,2-13C2], [6-O-methyl 13C]-(R,S)-coclaurine. The labeling degree of codeine up to 57% into morphinans was observed.
Publications

Poeaknapo, C.; Schmidt, J.; Brandsch, M.; Dräger, B.; Zenk, M. H.; Endogenous formation of morphine in human cells Proc. Natl. Acad. Sci. U.S.A. 101, 14091-14096, (2004) DOI: 10.1073/pnas.0405430101

Morphine is a plant (opium poppy)-derived alkaloid and one of the strongest known analgesic compounds. Studies from several laboratories have suggested that animal and human tissue or fluids contain trace amounts of morphine. Its origin in mammals has been believed to be of dietary origin. Here, we address the question of whether morphine is of endogenous origin or derived from exogenous sources. Benzylisoquinoline alkaloids present in human neuroblastoma cells (SH-SY5Y) and human pancreas carcinoma cells (DAN-G) were identified by GC/tandem MS (MS/MS) as norlaudanosoline (DAN-G), reticuline (DAN-G and SH-SY5Y), and morphine (10 nM, SH-SY5Y). The stereochemistry of reticuline was determined to be 1-(S). Growth of the SH-SY5Y cell line in the presence of 18O2 led to the [18O]-labeled morphine that had the molecular weight 4 mass units higher than if grown in 16O2, indicating the presence of two atoms of 18O per molecule of morphine. Growth of DAN-G cells in an 18O2 atmosphere yielded norlaudanosoline and (S)-reticuline, both labeled at only two of the four oxygen atoms. This result clearly demonstrates that all three alkaloids are of biosynthetic origin and suggests that norlaudanosoline and (S)-reticuline are endogenous precursors of morphine. Feeding of [ring-13C6]-tyramine, [1-13C, N- 13CH3]-(S)-reticuline and [N-CD3]-thebaine to the neuroblastoma cells led each to the position-specific labeling of morphine, as established by GC/MS/MS. Without doubt, human cells can produce the alkaloid morphine. The studies presented here serve as a platform for the exploration of the function of “endogenous morphine” in the neurosciences and immunosciences.
Publications

Page, J. E.; Hause, G.; Raschke, M.; Gao, W.; Schmidt, J.; Zenk, M. H.; Kutchan, T. M.; Functional Analysis of the Final Steps of the 1-Deoxy-d-xylulose 5-phosphate (DXP) Pathway to Isoprenoids in Plants Using Virus-Induced Gene Silencing Plant Physiol. 134, 1401-1413, (2004) DOI: 10.1104/pp.103.038133

Isoprenoid biosynthesis in plant plastids occurs via the 1-deoxy-d-xylulose 5-phosphate (DXP) pathway. We used tobacco rattle virus (TRV) to posttranscriptionally silence the expression of the last two enzymes of this pathway, the IspG-encoded (E)-4-hydroxy-3-methylbut-2-enyl diphosphate synthase (HDS) and the IspH-encoded isopentenyl/dimethylallyl diphosphate synthase (IDDS), as well as isopentenyl/dimethylallyl diphosphate isomerase (IDI), the enzyme that interconverts IPP and DMAPP. TRV-IspG and TRV-IspH infected Nicotiana benthamiana plants had albino leaves that contained less than 4% of the chlorophyll and carotenoid pigments of control leaves. We applied [13C]DXP and [14C]DXP to silenced leaves and found that 2-C-methyl-d-erythritol 2,4-cyclodiphosphate accumulated in plants blocked at HDS while DXP, (E)-4-hydroxy-3-methylbut-2-enyl phosphate and (E)-2-methylbut-2-ene-1,4-diol accumulated in IDDS-blocked plants. Albino leaves from IspG- and IspH-silenced plants displayed a disorganized palisade mesophyll, reduced cuticle, fewer plastids, and disrupted thylakoid membranes. These findings demonstrate the participation of HDS and IDDS in the DXP pathway in plants, and support the view that plastid isoprenoid biosynthesis is metabolically and physically segregated from the mevalonate pathway. IDI-silenced plants had mottled white-pale green leaves with disrupted tissue and plastid structure, and showed an 80% reduction in pigments compared to controls. IPP pyrophosphatase activity was higher in chloroplasts isolated from IDI-silenced plants than in control plant chloroplasts. We suggest that a low level of isoprenoid biosynthesis via the DXP pathway can occur without IDI but that this enzyme is required for full function of the DXP pathway.
Publications

Micskei, K.; Hajdu, C.; Wessjohann, L. A.; Mercs, L.; Kiss-Szikszai, A.; Patonay, T.; Enantioselective reduction of prochiral ketones by chromium(II) amino acid complexes Tetrahedron: Asymmetry 15, 1735-1744, (2004) DOI: 10.1016/j.tetasy.2004.04.017

The reduction of prochiral ketones has been performed by Cr(II) L-amino acid complexes in aqueous DMF solution under mild conditions in good yields and moderate (up to 58%) ee values. The dependence of the yield and enantioselectivity on various factors such as the structure of the ligand, pH and the solvent has also been investigated. A mechanism based on SET from the Cr(II) ion followed by protonation by water and the formation of an organochromium intermediate is also proposed.
Publications

Lübken, T.; Schmidt, J.; Porzel, A.; Arnold, N.; Wessjohann, L.; Hygrophorones A–G: fungicidal cyclopentenones from Hygrophorus species (Basidiomycetes) Phytochemistry 65, 1061-1071, (2004) DOI: 10.1016/j.phytochem.2004.01.023

Twenty new 5-(hydroxyalkyl)-2-cyclopentenone derivatives (hygrophorones) could be isolated from Hygrophorus latitabundus, H. olivaceoalbus, H. persoonii, and H. pustulatus. Their fungicidal activity was exemplarily tested. The hygrophorones have structural similarities to the antibiotic pentenomycin. Chemically, hygrophorones are 2-cyclopentenones with hydroxy or acetoxy substituents at C-4 and/or C-5. An odd-numbered 1′ oxidized alkyl chain (C11, C13, C15, or C17) is attached at C-5. In addition, from H. persoonii the new γ-butyrolactone derivative [5-(E)-2-hydroxytetradexylidene-5H-furan-2-one] could be isolated. Some hygrophorones are responsible for the color reaction of the stipes of these fungi upon treatment with potassium hydroxide solution. Structural elucidations are based on 1D (1H, 13C) and 2D (COSY, NOESY, HSQC, HMBC) NMR spectroscopic analyses as well as HR-FT-ICR-MS investigations.A series of new cyclopentenone derivatives and butyrolactones with antifungical activity could be isolated from fruit bodies of the basidiomyceteous genus Hygrophorus. Structural elucidations are based on 1D and 2D NMR spectroscopic analyses as well as HR-FT-ICR-MS investigations.
Publications

Krelaus, R.; Westermann, B.; Preparation of peptide-like bicyclic lactams via a sequential Ugi reaction––olefin metathesis approach Tetrahedron Lett. 45, 5987-5990, (2004) DOI: 10.1016/j.tetlet.2004.06.052

Bicyclic lactams, suitable for incorporation into conformationally restricted peptide mimics, can be synthesized by using olefinic starting materials for the Ugi multicomponent reaction, setting up an olefin metathesis reaction, that is easily carried out with the Grubbs catalyst. The influence of the different starting materials is evaluated. In addition, the utilization of chiral, nonracemic amines is described.
Publications

Huneck, S.; Feige, G. B.; Schmidt, J.; Chemie von Cladonia furcata und Cladonia rangiformis Herzogia 17, 51-58, (2004)

Eleven collections of Cladonia furcata and fourteen of Cladonia rangiformis, mainly from Saxony Anhalt (Germany) have been analyzed for their lichen substances by HPLC and HPLC-MS. The main compounds of C. furcata are fumarprotocetraric acid, atranorin, protocetraric acid, rangiformic acid, bourgeanic acid, norrangiformic acid and the new lichen metabolite 1-methyl 3,4-dicarboxydecanoate. C. rangiformis is characterized by atranorin, rangiformic acid, norrangiformic acid and 1-methyl 3,4-dicarboxyhexadecanoate, while bourgeanic acid is absent.
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