Prof. Dr. Peter Metz
Selected recent publications
[an error occurred while processing this directive]
"A conceptually novel construction of the 6a-hydroxypterocarpan skeleton – Synthesis of (±)-variabilin"
P. Ciesielski, P. Metz, Bioorg. Med. Chem., in press.
A new access to the 6a-hydroxypterocarpan variabilin was established. Key step of this concise total synthesis is a challenging cyclization of a haloketone via halogen–metal exchange and subsequent intramolecular addition to the carbonyl function.
"Toward the Synthesis of (-)-Codeine by Chiral Auxiliary-Mediated Nitrone Cycloaddition"
J. Rautschek, P. Metz, Heterocycles, in press.
Application of a C2-symmetric dioxolane moiety as chiral auxiliary for an asymmetric intramolecular nitrone cycloaddition was studied as a possible key step for the enantioselective synthesis of (-)-codeine. A cycloaddition precursor bearing a 1,2-diphenylethylene acetal was selected that was readily accessible in ten steps from isovanillin. It underwent nitrone cycloaddition and after a consecutive transformation, an isoxazolidine intermediate with the absolute and relative configuration required for (-)-codeine was obtained.
"An Eco-Friendly Synthesis of Some Novel 4-Methyl-4-hetaryl Chromene and Pyrano[2,3-c]pyrazole Derivatives"
F. M. Abdelrazek, P. Metz, A. Jäger, N. H. Metwally, J. Heterocyclic Chem., in press.
Some novel chromene and pyrano[2,3-c]pyrazole derivatives could be achieved successfully by reacting cyclic ?-diketones with 2-acetylfuran/2-acetylthiophene and malononitrile in a one-pot synthesis. Active methylene pyrazolones reacted with 2-(1-furan-2-yl-ethylidene)- and 2-(1-thiophen-2-yl-ethylidene)-malononitrile derivatives to afford the desired pyrano[2,3-c]pyrazole derivatives. Structures of all new compounds were established based on analytical and spectral data as well as x-ray crystallography. A plausible mechanism for the reaction is suggested. The solvents and catalyst used are environmentally benign, no hazardous solvents or heavy metals were involved.
"A Facile Synthesis and Drug Design of Some New Heterocyclic Compounds Incorporating Pyridine Moiety and Their Antimicrobial Evaluation"
F. M. Abdelrazek, S. M. Gomha, A. H. Abdelrahmana, P. Metz, M. A. Sayed, Lett. Drug Des. Discov., in press.
3-(Dimethylamino)-1-(pyridin-4-yl)prop-2-en-1-one (2) underwent regioselective 1,3-dipolar cycloaddition with nitrilimines 4 to afford the corresponding pyrazoles 6. The reaction of the latter pyrazoles with hydrazine hydrate afforded the corresponding pyrazolo[3,4-d]pyridazines 7. The enaminone 2 reacts also with 6-aminothiouracil 8 to yield respective thione 9. The reaction of thione 9 with hydrazonoyl chlorides 3 yielded pyrido-triazolo-pyrimidinone derivatives 13. Furthermore, pyridine analogs substituted in the 4-position with a pyranone 17 or pyridinones 18, pyridinone 20, 22 or naphthofuran 24 were also synthesized. The structures of the newly synthesized compounds were confirmed by spectral data and elemental analyses. The antimicrobial activity of the synthesized compounds was assayed against two fungi species and two bacterial species; one Gram positive and one Gram negative. Compounds 24 and 18 showed the most inhibitory effect among all tested compounds. Molecular docking study predicted the best binding mode between compound 24 and the enoyl-[acyl-carrier-protein]reductase [NADH] (InhA) (total binding energy -4.7 kcal/mol).
"Alkoxide-Directed Hydride Addition to α,β-Unsaturated Sultones"
K. M. Dawood, A. Bramborg, A. F. Darweesh, K. Spinde, V. Rogachev, A. Jäger, P. Metz, Heterocycles, in press.
Seven- and eight-membered β,γ-unsaturated sultones were readily prepared by ring closing metathesis. Epoxidation of these sultones and of an analogous six-membered sultone furnished the corresponding β,γ-epoxy sultones efficiently. Treatment of these epoxides with a suitable base gave α,β-unsaturated γ-hydroxy sultones in high yields. Reduction of both the α,β-unsaturated γ-hydroxy sultones and the epoxy sultones by Red-Al is likely to proceed in a hydroxyl-directed fashion via a mixed aluminate as the reactive intermediate.
"Synthesis of Some Novel 1,4-Phenylene-bis-Thiazolyl Derivatives and Their Anti-hypertensive α-blocking Activity Screening"
F. M. Abdelrazek, S. M. Gomha, P. Metz, M. M. Abdalla, J. Heterocyclic Chem. 2017, 54, 618-623.
A series of novel 1,4-phenylene-bis-thiazolyl derivatives was synthesized and evaluated for their anti-hypertensive activities as α-blocking agents and some of them showed promising activities.
"3-(3,5-Dimethyl-1H-Pyrazol-1-yl)-3-Oxopropanenitrile as Precursor for Some New Mono-Heterocyclic and Bis-Heterocyclic Compounds"
N. H. Metwally, F. M. Abdelrazek, S. M. Eldaly, P. Metz, J. Heterocyclic Chem. 2017, 54, 289-294.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-oxopropanenitrile 1 was used as a cyanoacetylating agent for synthesis of the acetanilide derivative 3. Compound 3 was utilized as a key intermediate for the synthesis of some new mono-chromene and di-chromene derivatives 9 and 13, the dihydrazo derivatives 15, and the dithiazole derivatives 18 via the condensation with o-hydroxybenzaldehyde derivatives, the coupling with aryl diazonium salts, or the reaction with phenyl isothiocyanate in presence of KOH followed by phenacyl bromide derivatives respectively.
"Enantioselective Synthesis of 2'- and 3'-Substituted Natural Flavans by Domino Asymmetric Transfer Hydrogenation/Deoxygenation"
A. Keßberg, P. Metz, Org. Lett., 2016, 18, 6500-6503.
A concise and highly enantioselective synthesis of the natural flavans kazinol U and (2S)-7,3'-dihydroxy-4'-methoxyflavan is reported for the first time. The key transformation is a single-step conversion of a racemic flavanone to a flavan by means of an asymmetric transfer hydrogenation/deoxygenation cascade with kinetic resolution.
"A Metathesis Route to (+)-Orientalol F, a Guaiane Sesquiterpene from Alisma Orientalis"
M. Zahel, Y. Wang, A. Jäger, P. Metz, Eur. J. Org. Chem., 2016, 5881-5886.
The synthesis of (+)-orientalol F (1) started with aldehyde 6, which is available from (R)-limonene in two steps. Wittig reaction of 6 with unsaturated ylide 7 to give a tetraene, and subsequent ring-closing metathesis yielded hydroazulene 4, selective epoxidation of which gave epoxy ester 3. After generation of the requisite isopropyl unit and regioselective reductive epoxide opening, the derived dienol 2 was used for the installation of the oxygen bridge through intramolecular oxymercuration followed by oxidative demercuration. The resulting allylic alcohol epimers 15 and 16 were readily converted into the target natural product 1 by oxidation/reduction sequences.
"Enantioselective Synthesis of Guaianolides in the Osmitopsin Family by Domino Metathesis"
A. Barthel, F. Kaden, A. Jäger, P. Metz, Org. Lett., 2016, 18, 3298-3301.
Relay metathesis enabled an improved access from (S)-citronellal to the marine trisnorguaiane (-)-clavukerin A. This hydroazulene was applied as an advantageously functionalized building block for the asymmetric synthesis of the sesquiterpene lactone osmitopsin and the proposed structure of 4,5-epoxyosmitopsin using a chemo-, regio-, and diastereoselective diepoxide opening as the key step.
"Synthesis of Some Novel Thiazole, Thiadiazole and 1,4-Phenylene-bis-thiazole Derivatives as Potent Antitumor Agents"
S. M. Gomha, F. M. Abdelrazek, A. H. Abdelrahman, P. Metz, Heterocycles 2016, 92, 954-967.
A novel series of 2-ethylidenehydrazono-5-arylazothiazoles 5a-h and 2-ethylidenehydrazono-5-arylazothiazolones 9a-d were prepared by cyclocondensation of hydrazonyl halides 3a-h and 7a-d with ethylidenethiosemicarbazide 2. In addition, reaction of 2 with N-phenyl-carbohydrazonyl chloride (14) afforded 1,3,4-thiadiazole derivative 17 as the end product. Moreover, the thiosemicarbazide derivative 2 was reacted with various bromoacetyl compounds 19a-d and 1,1'-(1,4-phenylene)bis(2-bromoethanone) (21) furnished the respective thiazole derivatives 20a-d and 1,4-phenylene-bis-thiazole derivative 22. The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences and their alternative syntheses. The newly synthesized compounds were evaluated for their antitumor activities against hepatocellular carcinoma (HepG2) cell line and the results revealed promising activities of compounds 5h, 5d, 5g, 5f and 5e with IC50 equal 2.23 ± 0.28, 2.48 ± 0.34, 2.49 ± 0.24, 4.03 ± 0.11, and 5.32 ± 0.27 μM, respectively.
"Utilizing an o-Quinone Methide in Asymmetric Transfer Hydrogenation: Enantioselective Synthesis of Brosimine A, Brosimine B, and Brosimacutin L (Nutzung eines o-Chinonmethids in der asymmetrischen Transferhydrierung: enantioselektive Synthese von Brosimin A, Brosimin B und Brosimacutin L)"
A. Keßberg, P. Metz, Angew. Chem. 2016, 128, 1173-1176; Angew. Chem. Int. Ed. 2016, 55, 1160-1163..
You got much flava: A concise and highly enantioselective synthesis of the flavonoids brosimine A, brosimine B, and brosimacutin L is reported for the first time. The key transformation is a single-step conversion of a flavanone into a flavan by means of an asymmetric transfer hydrogenation/deoxygenation cascade.
"Reactions of 2,4-diphenyl-butadiene-1,4-sultone with some 1,2- and 1,3-nitrogen binucleophiles"
K. A. Ali, A. Jäger, P. Metz, Arkivoc, 2016, (iii), 15-22.
Treatment of 2,4-diphenylbutadiene-1,4-sultone with hydrazine in boiling EtOH gives 1-amino-2,4-diphenyl-1H-pyrrole. On treatment of 2,4-diphenylbutadiene-1,4-sultone with phenyl hydrazine in glacial acetic acid, 4,5-dihydro-5-methyl-1,3,5-triphenyl-1H-pyrazole was isolated. On the other hand, 2,4-diphenylbutadiene-1,4-sultone reacts with 4H-1,2,4-triazol-3-amine and 5-amino-3-phenyl-1H-pyrazole to afford the novel heterocyclic compounds 2-(2,2-dioxo-4-phenyl-3,4-dihydro-8H-2λ6-[1,2,4]triazolo[5,1-c][1,2,4]thiadiazin-4-yl)-1-phenylethan-1-one, the structure of which was established by X-ray crystallography, and 2-(2,2-dioxo-4,7-diphenyl-3,4-dihydro-6H-pyrazolo[5,1-c][1,2,4]thiadiazin-4-yl)-1-phenylethan-1-one.
"Further studies on sultones derived from carbene cyclization cycloaddition cascades"
T. Groß, T. Herrmann, B. Shi, A. Jäger, P. Chiu, P. Metz, Tetrahedron, 2015, 71, 5925-5931.
A sulfonyl-stabilized diazoketone underwent an efficient rhodium-catalyzed cascade reaction with an internal vinylsulfonate unit to give a tricyclic sultone as a single diastereomer. Nucleophilic addition of a vinyl Grignard reagent to the ketone of the resultant arylsulfonyl-substituted cycloadduct was stereocomplementary with respect to vinyl Grignard addition to corresponding ester-substituted substrates. The latter tricyclic compounds were chemoselectively transformed into vinylsultones via β-elimination in good yield.
"Insights into the Pamamycin Biosynthesis (Einblicke in die Pamamycin-Biosynthese)"
Y. Rebets, E. Brötz, N. Manderscheid, B. Tokovenko, M. Myronovskyi, P. Metz, L. Petzke, A. Luzhetskyy, Angew. Chem., 2015, 127, 2309-2313; Angew. Chem. Int. Ed., 2015,54, 2280-2284.
Pamamycins are macrodiolides of polyketide origin with antibacterial activities. Their biosynthesis has been proposed to utilize succinate as a building block. However, the mechanism of succinate incorporation into a polyketide was unclear. Here, we report identification of a pamamycin biosynthesis gene cluster by aligning genomes of two pamamycin-producing strains. This unique cluster contains polyketide synthase (PKS) genes encoding seven discrete ketosynthase (KS) enzymes and one acyl-carrier protein (ACP)-encoding gene. A cosmid containing the entire set of genes required for pamamycin biosynthesis was successfully expressed in a heterologous host. Genetic and biochemical studies allowed complete delineation of pamamycin biosynthesis. The pathway proceeds through 3-oxoadipyl-CoA, a key intermediate in the primary metabolism of the degradation of aromatic compounds. 3-Oxoadipyl-CoA could be used as an extender unit in polyketide assembly to facilitate the incorporation of succinate.
"Studies on the Reaction of Cycloalkanones with Malonodinitrile"
F. M. Abdelrazek, N. H. Metwally, N. A. Kassab, M. T. Jaafar, P. Metz, A. Jäger, J. Heterocyclic Chem., 2014, 51, 1785-1790.
Cyclopentanone reacts with malononitrile catalyzed by piperidine or sodium acetate to afford under any case cyclopentylidenemalononitrile dimer: 5-aminospiro-[2,6,7,7a-tetrahydroindene-7,1'-cyclopentane]-4,6,6-tricarbonitrile (7) as the sole product. Contrary to this behavior, cyclohexanone reacts with malononitrile catalyzed by piperidine to afford the analogous cyclohexylidenemalononitrile dimer: 2-aminospiro-[3,4,5,6,7,4a-hexahydronaphthalene-4,1'-cyclohexane]-1,3,3-tricarbonitrile (11); whereas when the reaction is catalyzed by sodium acetate, it afforded 9,10-diaza-8,11-dioxo-tricyclo-[4.3.3.01,6]-dodecane-7,12-dicarbonitrile (12). The structures of these products were established on the basis of their elemental analysis and spectral data, and plausible mechanism has been postulated to account for their formation. X-ray crystallography was carried out as a further evidence for structures 7 and 12.
"An Approach to the Bicyclic C5-C17/C19-C20 (BC) Portion of Neoclerodane Diterpenes by Intramolecular Diels-Alder Reaction"
Y. Wang, V. Rogachev, M. Wolter, M. Gruner, A. Jäger, P. Metz, Eur. J. Org. Chem., 2014, 4083-4088.
Using a highly diastereoselective intramolecular acrylate [4+2] cycloaddition as the key step, a short route from 3-furaldehyde to a bicyclic building block for the synthesis of neoclerodane diterpenes was developed. A first attempt featuring a conjugate methylation of a dienyl lactone failed, but a streamlined sequence using an all-encompassing intramolecular Diels–Alder reaction of a sterically congested 1,3-diene was successful.
"Synthesis of Some New Pyrazole, Pyrimidine, Pyridazine and Their Fused Derivatives from 3-Oxo-3,N-diphenylpropionamide"
F. M. Abdelrazek, Y. M. Elkholy, A. M. Salah, N. M. Abdelazeem, P. Metz, J. Heterocyclic Chem., 2014, 51, 824-829.
The title compounds were obtained from the reactions of 3-oxo-3,N-diphenylpropionamide 3 with dimethylformamide dimethylacetal followed by hydrazine to afford the pyrazole 7, condensation with benzaldehyde followed by cyclocondensation with guanidine to afford the pyrimidine derivative 13, condensation with active methylenes followed by azo coupling of the products followed by cyclization to afford the pyridazines 17a,b. The pyridazinone 17b was explored for the synthesis of some novel pyridazine-fused heterocyclic compounds 19, 21, 24a,24b, 24c and 26. All structures were proved via their elemental analyses and spectral data.
"Synthesis of m-Terphenyl Derivatives via Domino Diels-Alder / Retro-Diels-Alder Reaction of 1,3-Dienic δ-Sultones with Alkynes"
J. Gaitzsch, V. Rogachev, M. Zahel, P. Metz, Synthesis 2014, 46, 531-536.
A highly regioselective synthetic method based on the domino Diels-Alder/retro-Diels-Alder reaction (DA/RDA) of 1,3-dienic δ-sultones with alkynes provides substituted m-terphenyls by elimination of SO3. A variety of δ-sultones and alkynes were examined to determine the scope of the reaction. The de novo synthesized aromatic products were obtained using thermal, microwave and high pressure activation.
"Metathesis Reactions in Domino Processes"
K. M. Dawood, P. Metz, in: Domino Reactions – Concepts for Efficient Organic Synthesis (Ed.: L. F. Tietze), WILEY-VCH, Weinheim, 2014, pp. 31-66.
"Synthesis of some new pyrazole-based 1,3-thiazoles and 1,3,4-thiadiazoles as anticancer agents"
K. M. Dawood, T. M. A. Eldebss, H. S. A. El-Zahabi, M. H. Yousef, P. Metz, Eur. J. Med. Chem. , 2013, 70, 740-749.
N-(4-(Pyrazol-4-yl)thiazol-2-yl)-N'-phenylthiourea derivative 2 was synthesized and then treated with variety of hydrazonoyl chlorides under basic condition at reflux to afford the corresponding 2-(4-(pyrazol-4-yl)thiazol-2-ylimino)-1,3,4-thiadiazole derivatives 6, 10a-e and 17a-e. Reaction of 2 with ethyl chloroacetate and with 3-chloro-2,4-pentanedione gave the thiazolidin-4-one 22 and 1,3-thiazole 25 derivatives, respectively. Condensation of thiazolidin-4-one 22 with aldehydes gave their 5-arylidene derivatives 23a-f. Most of the synthesized compounds were tested for anticancer activity against human hepatocellular carcinoma HepG2, human breast cancer MCF-7 and human lung cancer A549. Their SAR was studied and variously affected by the electronic factor of electron donating and withdrawing groups. Many of the tested compounds showed moderate to high anticancer activity.
"Ein praktischer Zugang zu hoch enantiomerenreinen Flavanonen durch katalytische asymmetrische Transferhydrierung (A Practical Access to Highly Enantiomerically Pure Flavanones by Catalytic Asymmetric Transfer Hydrogenation)"
M.-K. Lemke, P. Schwab, P. Fischer, S. Tischer, M. Witt, L. Noehringer, V. Rogachev, A. Jäger, O. Kataeva, R. Fröhlich, P. Metz, Angew. Chem. 2013, 125, 11865-11869; Angew. Chem. Int. Ed. 2013, 52, 11651-11655.
A surprisingly selective, non-enzymatic kinetic resolution of readily available, racemic β-chiral ketones enabled the title process, which was applied to a rapid synthesis of several bioactive flavanones in virtually enantiopure form.
Highlighted in: Synfacts 2014, 58 (DOI: 10.1055/s-0033-1340441)
"An Efficient Gold-Catalyzed Domino Process for the Construction of Tetracyclic Ketoethers"
T. Groß, P. Metz, Chem. Eur. J. 2013, 19, 14787 – 14790.
Au, yeah! Catalytic amounts of gold(III)chloride allow a mild and efficient oxidative domino cyclization/cycloaddition of enyne carbonyl compounds 1 and 4 to give the tetracycles 2 or 5, respectively, in the presence of pyridine N-oxide 3.
"A concise enantioselective synthesis of the guaiane sesquiterpene (–)-oxyphyllol"
M. Zahel, P. Metz, Beilstein J. Org. Chem. 2013, 9, 2028-2032.
(–)-Oxyphyllol was prepared in only 4 steps from an epoxy enone that already served as an intermediate for the total synthesis of the anticancer guaiane (–)-englerin A. A regio- and diastereoselective Co(II)-catalyzed hydration of the olefin and a transannular epoxide opening were used as the key reactions.
"Eine kurze enantioselektive Totalsynthese von (–)-Englerin A (A Short Enantioselective Total Synthesis of (–)-Englerin A)"
M. Zahel, A. Keßberg, P. Metz, Angew. Chem. 2013, 125, 5500-5502; Angew. Chem. Int. Ed. 2013, 52, 5390-5392.
Selective oxidations of dienone 2 as well as a ring-closing metathesis to give the hydroazulene framework enabled the 12-step preparation of title compound 1 from (–)-photocitral A (3), which is in turn rapidly available from (–)-isopulegol through dual catalysis.
Highlighted in: Synfacts 2013, 692 (DOI: 10.1055/s-0033-1339205)
"Synthesis and Application of an Enantiomerically Pure Triflate Analogue of Microbially-Derived 3-Halo-cis-1,2-dihydrocatechol Acetonides"
F. Sun, P. Metz, Synlett 2013, 24, 457-460.
(1S,2S)-3-Trifloxy-cis-1,2-dihydrocatechol acetonide, a useful chiral building block, was prepared from D-ribose in good overall yield using a carbonyl allylation and a ring-closing metathesis as the key C–C bond forming steps. Negishi cross-coupling of this triflate with a serine-derived organozinc iodide proceeded efficiently to afford an α-amino acid derivative as a potential precursor for scabrosin esters (ambewelamides).
"Synthetic Studies with 3-Oxo-N-[4-(3-oxo-3-phenylpropionylamino)-phenyl]-3-phenylpropionamide"
F. M. Abdelrazek, N. A. Sobhy, P. Metz, A. A. Bazbouz, J. Heterocyclic Chem. 2012, 49, 381-387.
3-Oxo-N-[4-(3-oxo-3-phenylpropionylamino)-phenyl]-3-phenylpropionamide 1 and its derivative 2-benzoyl-N-[4-(2-benzoyl-3-(dimethylamino-acryloylamino)-phenyl]-3-dimethylaminoacrylamide 12 are used for the synthesis of the hitherto not known bis-heterocyclic amine and bis-heterocyclic carboxamide derivatives. Plausible mechanisms are discussed for the formation of the new compounds.
"Verfahren zur Herstellung enantiomerenreiner Flavanone"
P. Metz, P. Schwab, P. Fischer, M.-K. Lemke, S. Tischer, DE 11 2007 001 531 B4.
"A short and efficient synthesis of (+)-totarol"
V. Rogachev, T. Löhl, T. Markert, P. Metz, Arkivoc 2012, (iii), 172-180.
A concise route to multigram quantities of the antibacterial diterpene (+)-totarol (1) is reported. (-)-Sclareol (2) was converted to the target compound 1 using either a six- or a seven-step sequence, while only three steps were required to access (+)-totarol (1) starting from (+)-manool (9) or (+)-13-epi-manool (10), respectively. A novel one-pot intramolecular aldol condensation/α-alkylation protocol served as the key operation for streamlining the syntheses of 1.
Arkivoc 2012, (iii), 172-180
"Total Synthesis of Pamamycin-649B"
P. Fischer, M. Gruner, A. Jäger, O. Kataeva, P. Metz, Chem. Eur. J. 2011, 17, 13334-13340.
The first total synthesis of the macrodiolide antibiotic pamamycin-649B (1) was achieved by using sultone methodology. The diethyl substituted larger hydroxy acid fragment was constructed in a concise fashion through domino elimination/alkoxide-directed 1,6-additions of ethyllithium to sultones derived from intramolecular Diels-Alder reaction of furan-containing vinylsulfonates. Intermolecular Yamaguchi esterification of the two hydroxy acid building blocks and subsequent Yamaguchi cyclization eventually provided the target macrocycle 1. Since the final lactonization with formation of the ester linkage between C1' and the C8 oxygen proceeded with complete C2' epimerization, the more readily available C2' epimeric smaller fragment could be used to streamline the synthetic sequence.
"Eine Totalsynthese von (±)-Codein durch 1,3-dipolare Cycloaddition (A Total Synthesis of (±)-Codein by 1,3-Dipolar Cycloaddition)"
T. Erhard, G. Ehrlich, P. Metz, Angew. Chem. 2011, 123, 3979-3981; Angew. Chem. Int. Ed. 2011, 50, 3892-3894.
Nitrone cycloaddition on a dearomatized bicyclic phenol enabled the facile construction of the correctly configured phenanthrene skeleton of codeine. Further steps yielded allopseudocodeine in a completely diastereoselective manner and finally (±)-codeine by allylic transposition through the hydrolysis of chlorocodides.
Highlighted in: Org. Chem. Highlights 2011
"Enantioselektive Totalsynthese der Diterpene Kempen-2, Kempen-1 und 3-epi-Kempen-1 aus dem Abwehrsekret höherer Termiten (Enantioselective Total Synthesis of the Diterpenes Kempene-2, Kempene-1, and 3-epi-Kempene-1 from the Defense Secretion of Higher Termites)"
M. Schubert, P. Metz, Angew. Chem. 2011, 123, 3011-3013; Angew. Chem. Int. Ed. 2011, 50, 2954-2956.
Two rings in one sweep: A domino metathesis of the bicyclic dienyne 4 obtained from a catalytic enantioselective Diels–Alder reaction as the key process enabled the efficient preparation of the tetracyclic diterpenes kempene-2 (1), kempene-1 (2), and 3-epi-kempene-1 (3).
Highlighted in: Synfacts 2011, 580 (DOI: 10.1055/s-0030-1260372)
"A General Access to Zaragozic Acids: Total Synthesis and Structural Elucidation of Zaragozic Acid D and Formal Syntheses of Zaragozic Acids A and C"
Y. Wang, P. Metz, Chem. Eur. J. 2011, 17, 3335-3337.
One for all: The 2,8-dioxabicyclo[3.2.1]octane derivative 1 served as a general building block for the bioactive title compounds. Two chemoselective alkynylations and two ruthenium-catalyzed hydrogenations had key roles in the first total synthesis of zaragozic acid D, a potent ras-farnesyl protein transferase inhibitor.
"Total Synthesis of the Cytotoxic 1,10-seco-Eudesmanolides Britannilactone and 1,6-O,O-Diacetylbritannilactone"
J. Merten, Y. Wang, T. Krause, O. Kataeva, P. Metz, Chem. Eur. J. 2011, 17, 3332-3334.
A natural boost! The first synthetic access to the bioactive title compounds was achieved from the dienyl carboxylic acid 1, which in turn is readily available by using sultone chemistry. The enantioselective route developed here also confirms the relative and absolute configuration of these sesquiterpene lactones.
"Simple and practical one-step synthesis of new 1,3-dienic δ-sultones from terminal alkynes and some synthetic applications of these compounds"
J. Gaitzsch, V. Rogachev, P. Metz, V. D. Filimonov, M. Zahel, O. Kataeva, J. Sulfur Chem. 2011, 32, 3-16.
1,3-Dienic δ-sultones 4,6-diaryl-[1,2]oxathiine 2,2-dioxides were synthesized via a one-step reaction of arylalkynes with dioxane sulfotrioxide. The reactivity of various alkynes in this reaction was investigated. The resulting sultones were brominated with Br2 or N-bromosuccinimide regioselectively α to sulfur and subsequently coupled with phenylacetylene using Sonogashira conditions.
"Method for the preparation of (+)-totarol"
T. Löhl, T. Markert, P. Metz, V. Rogachev, EP 2143703 (A1).
"A Concise Catalytic Route to the Marine Sesquiterpenoids (-)-Clavukerin A and (-)-Isoclavukerin A"
S. Knüppel, V. O. Rogachev, P. Metz, Eur. J. Org. Chem. 2010, 6145-6148.
Using a combined organocatalytic/metal-catalyzed strategy, the enantiopure title hydroazulenes were prepared in only four steps from (S)- and (R)-citronellal, respectively. A catalyst-controlled diastereoselective Michael addition of these aldehydes to methyl vinyl ketone followed by chemoselective dibromoolefination and one-pot Wittig olefination/alkyne formation afforded the key dienynes that underwent regioselective domino metathesis to yield the target natural products.
"Facile Access to Biaryls and 2-Acetyl-5-arylbenzofurans via Suzuki Coupling in Water under Thermal and Microwave Conditions"
A. F. Darweesh, M. R. Shaaban, A. M. Farag, P. Metz, K. M. Dawood, Synthesis 2010, 3163-3173.
The phosphine-free Suzuki-Miyaura carbon-carbon cross-coupling reactions of activated and deactivated aryl halides and 2-acetyl-5-bromobenzofuran with various aryl- or heteroarylboronic acids were investigated. A benzothiazole-based palladium(II) complex was used as a precatalyst for the reactions under both thermal and microwave conditions in air using water as a solvent.
"The Reaction of 2-Dimethylaminomethylene-3-oxo-N-phenylbutyramide with Active Methylene Nitriles"
F. M. Abdelrazek, M. F. Sharaf, P. Metz, A. Jäger, J. Heterocyclic Chem. 2010, 47, 528-533.
2-Dimethylaminomethylene-3-oxo-N-phenylbutyramide 1 reacts with malononitrile 2a to afford the pent-2-enedioic acid 1-amide 5-phenylamide derivative 6, which could be cyclized to give the 6-methylpyridone derivative 7. Compound 1 reacts with cyanoacetamide 2b to afford the same pyridone 7 and with cyanothioacetamide 2c to afford the analogous pyridinethione 12. Compound 12 reacts with DMAD to afford the pyridine derivative 15 and with N,N-dimethylchloroacetamide 16 to afford the thieno[2,3-d]pyridine derivative 18. Compound 18 reacts with morpholine-4-carboxaldehyde 19, N,N-dimethylformamide 20, and 2,5-dimethoxy-tetrahydrofuran 21 to afford the fully aromatic thieno[2,3-d]pyridine derivatives 22, 23, and 24, respectively.
"Synthesis of Some Novel Polyaza Fused Heterocyclic Compounds"
F. M. Abdelrazek, N. H. Metwally, N. A. Kassab, N. A. Sobhy, P. Metz, A. Jäger, J. Heterocyclic Chem. 2010, 47, 384-388.
2-(1-Aryl-ethylidene)-malononitriles 1a-d undergo self dimerization in ethanol catalyzed by sodium ethoxide to afford 2-[4,6-diaryl-3-cyano-6-methyl-5,6-dihydropyridin-2(1H)-ylidene]-malononitrile derivatives 3a-d respectively. The structure of the dimer was elucidated by X-ray crystallography and a plausible mechanism for its formation is depicted. Compound 3a couples with arene diazonium salts 4a-d to afford the hydrazo derivatives 5a-d; and reacts with hydrazine hydrate and phenylhydrazine 6a,b to afford the pyrazolo[3,4-h][1,6]naphthyridine derivatives 7a,b; and with urea and thiourea 8a,b to afford the pyrimido[4,5-h][1,6]naphthyridine derivatives 9a,b respectively.
"Prenylation has a compound specific effect on the estrogenicity of naringenin and genistein", G. Kretzschmar, O. Zierau, J. Wober, S. Tischer, P. Metz, G. Vollmer, J. Steroid Biochem. Mol. Biol. 2010, 118, 1-6.
A variety of plant derived substances, so-called phytoestrogens (PEs), although structurally not related to steroids, produce effects similar to the mammalian estradiol. However, little is known so far about the structural requirements which determine PE activities. Taking into consideration that prenylation reactions are relatively common in plant secondary metabolism, the activity of a set of three PE derivatives of genistein and naringenin, namely genistein, 8-prenylgenistein (8PG), 6-(1,1-dimethylallyl)genistein (6DMAG), naringenin, 8-prenylnaringenin (8PN) and 6-(1,1-dimethylallyl)naringenin (6DMAN) was compared regarding structure–estrogenicity relationships in three functionally different estrogen receptor assays. Strong estrogenic activities were recorded for 6DMAN and 8PN in all assays used, while the parent compound naringenin showed only very weak estrogenicity. In contrast, in the case of genistein derivatives, only genistein itself exhibited estrogenic activity in a yeast based assay. In MVLN breast cancer cells, a bioluminescent MCF-7-derived cell line, the estrogenic activity of all three genistein derivatives was similar. Studying alkaline phosphatase activity in Ishikawa endometrial cancer cells as an estrogenic response marker revealed a similar pattern of estrogenicity of the genistein derivatives compared to the yeast based assay although a slight estrogenic effect of 6DMAG and 8PG was apparent. In summary, this study demonstrates that prenylation often found in plant secondary metabolism differentially modifies estrogenic properties of PEs depending on the basic structure of the respective PE.
"The Rhodium-Catalyzed Carbene Cyclization Cycloaddition Cascade Reaction of Vinylsulfonates"
B. Shi, S. Merten, D. K. Y. Wong, J. C. K. Chu, L. L. Liu, S. K. Lam, A. Jäger, W.-T. Wong, P. Chiu, P. Metz, Adv. Synth. Catal., 2009, 351, 3128-3132.
Vinylsulfonates proved to be excellent dipolarophiles for carbonyl ylides derived from diazoketones in rhodium-catalyzed intramolecular cycloadditions. Polyfunctional substrates, such as 8 and (+)-15, were readily available from hydroxy esters, e.g. 1 and the cyclopenta-1,3-dione 10, respectively, and the resulting polycyclic sultones were formed under mild reaction conditions in high yields with very good diastereoselectivities. A ruthenium-catalyzed asymmetric transfer hydrogenation was found to desymmetrize the meso cyclopenta-1,3-dione 12 efficiently.
"A Symmetry-Based Synthesis of the Heterobicyclic Core of the Zaragozic Acids/Squalestatins"
Y. Wang, O. Kataeva, P. Metz, Adv. Synth. Catal. 2009, 351, 2075-2080.
The pseudo C2-symmetrical diketone 22 was efficiently constructed from furan-3,4-dimethanol (7) using a two-directional route featuring a double asymmetric dihydroxylation. Acidic hydrolysis of the cyclopentylidene acetals of 22 triggered a selective cyclization of the resulting hexaol diketone to generate the 2,8-dioxabicyclo[3.2.1]octane core of the zaragozic acids/squalestatins. Chemoselective oxidative cleavage of a superfluous two-carbon appendage and further functional group manipulations yielded the enantiomerically pure triester 30, which offers itself as a general heterobicyclic building block for naturally occurring zaragozic acids/squalestatins and unnatural analogs.
"New Domino Reactions with Sultones"
A. M. M. Ewas, K. M. H. Dawood, K. Spinde, Y. Wang, A. Jäger, P. Metz, Synlett 2009, 1773-1776.
Hydroxyl-containing α,β-unsaturated δ-sultones undergo a diastereoselective conjugate reduction by Red-Al. This transformation can be extended to a domino elimination/1,4-hydride addition of a tricyclic sultone substrate that is readily available via intramolecular Diels-Alder reaction. Bicyclic γ-keto δ-sultones are converted to diastereomerically pure oxabicyclic ketones in a domino desulfurization/oxy-Michael addition using DBU.
"Enantioselektive Synthese von 4-Desmethyl-3α-hydroxy-15-ripperten (Enantioselective Synthesis of 4-Desmethyl-3α-hydroxy-15-rippertene)"
R. Hennig, P. Metz, Angew. Chem. 2009, 121, 1177-1179; Angew. Chem. Int. Ed. 2009, 48, 1157-1159.
Let it rip: An intramolecular Diels-Alder reaction and two intramolecular aldol condensations allow the efficient preparation of the title compound 2, a close analog of the diterpene 1 which was isolated from the defense secretion of termite soldiers. The synthesis commenced with cyclohexanone 3, which is rapidly available from (-)-isopulegol.
"The first example of a domino Diels-Alder/retro-Diels-Alder reaction of 1,3-dienic δ-sultones with alkynes: a simple synthesis of m-terphenyl dicarboxy derivatives from 4,6-diphenyl-[1,2]oxathiine 2,2-dioxide"
J. Gaitzsch, V. O. Rogachev, P. Metz, M. S. Yusubov, V. D. Filimonov, O. Kataeva, J. Sulfur Chem. 2009, 30, 4-9.
[1,1';3',1'']Terphenyl-4',5'-dicarboxylic acid derivatives were prepared from 1,3-dienic δ-sultone 4,6-diphenyl-[1,2]oxathiine 2,2-dioxide via Diels-Alder/retro-Diels-Alder reaction with dimethyl acetylenedicarboxylate under thermal, microwave or high-pressure activation.
"Enantioselective Synthesis of the Hydroazulene Core of 3α-Hydroxy-15-rippertene"
T. Kreuzer, P. Metz, Eur. J. Org. Chem., 2008, 572-579.
As part of a project directed toward the total synthesis of the tetracyclic diterpene 3α-hydroxy-15-rippertene, a constituent of the defense secretion of higher termites, a fast access to two advanced hydroazulene key intermediates has been achieved starting from (-)-isopulegol. A regio- and diastereoselective formal hydromethallylation and a regioselective ring expansion served as the key steps in the formation of the seven-membered ring. Completion of the bicyclic title compounds was then achieved by cyclopentene annulation via diastereoselective conjugate addition of organocuprates and subsequent intramolecular aldol condensations.
"Desulfurization of sultams with simultaneous methylenation"
V. O. Rogachev, S. Merten, T. Seiser, O. Kataeva, P. Metz, Tetrahedron Lett., 2008, 49, 133-136.
Alkylation of γ- and δ-sultams with (iodomethyl)trimethylsilane followed by treatment of the resultant silanes with tetrabutylammonium fluoride gave rise to sulfur-free unsaturated amines. In particular, N-THP substituted sultams were found to be useful substrates for the alkylation event. A corresponding one-pot transformation involving sultam α-alkylation with (iodomethyl)magnesium chloride is also reported.
"A Symmetry-Based Approach to the Heterobicyclic Core of the Zaragozic Acids – Model Studies in the Pseudo C2-Symmetric Series"
Y. Wang, S. Gang, A. Bierstedt, M. Gruner, R. Fröhlich, P. Metz, Adv. Synth. Catal., 2007, 349, 2361-2367.
Using a two-directional strategy, a concise synthesis of a pseudo C2-symmetric tetrabenzyl ether of a hexaol diketone was accomplished. Hydrogenolysis of this compound in the presence of acetic acid and subsequent peracetylation triggered a group-selective intramolecular acetalization to give the desired 2,8-dioxabicyclo[3.2.1]octane derivative with correct relative and absolute configuration at all stereogenic centers of the heterobicyclic core.
"Synthesis and Molluscicidal Activity of New Chromene and Pyrano[2,3-c]pyrazole Derivatives"
F. M. Abdelrazek, P. Metz, O. Kataeva, A. Jäger, S. F. El-Mahrouky, Arch. Pharm. Chem. Life Sci., 2007, 340, 543-548.
The chromene derivative 4 reacts with acetic anhydride, phenylisothiocyanate and ethyl orthoformate to afford the N-acetyl derivative 6, the chromenopyrimidine 8 and the formimidate 9, respectively. 2-(1H-Indol-3-ylmethylene)-malononitrile 10b reacts with 1,3-cyclohexanedione and dimedone 11a,b to afford the 4(3-indolyl)-chromene derivatives 12a,b, respectively, and with the pyrazolone derivatives 13a-d to afford the arylidene exchange derivatives 14a-c and the pyranopyrazole derivative 15, respectively. The arylidene derivatives 10a,b react also with indane-1,3-dione 16 to afford the arylidene exchange derivatives 18a,b. The molluscicidal activity of the synthesized compounds towards Biomphalaria alexandrina snails, the intermediate host of Schistosoma mansoni, was investigated and most of them showed weak to moderate activity.
"Mechanism of Inhibition of Human Secretory Phospholipase A2 by Flavonoids – Rationale for Lead Design"
J. Lättig, M. Böhl, P. Fischer, S. Tischer, C. Tietböhl, M. Menschikowski, H. O. Gutzeit, P. Metz, M. T. Pisabarro, J. Comput. Aided Mol. Des., 2007, 21, 473-483.
The human secretory phospholipase A2 group IIA (PLA2-IIA) is a lipolytic enzyme. Its inhibition leads to a decrease in eicosanoids levels and, thereby, to reduced inflammation. Therefore, PLA2-IIA is of high pharmacological interest in treatment of chronic diseases such as asthma and rheumatoid arthritis. Quercetin and naringenin, amongst other flavonoids, are known for their anti-inflammatory activity by modulation of enzymes of the arachidonic acid cascade. However, the mechanism by which flavonoids inhibit PLA2 remained unclear so far. Flavonoids are widely produced in plant tissues and, thereby, suitable targets for pharmaceutical extractions and chemical syntheses. Our work focuses on understanding the binding modes of flavonoids to PLA2, their inhibition mechanism and the rationale to modify them to obtain potent and specific inhibitors. Our computational and experimental studies focused on a set of 24 compounds including natural flavonoids and naringenin-based derivatives. Experimental results on PLA2-inhibition showed good inhibitory activity for quercetin, kaempferol and galangin, but relatively poor for naringenin. Several naringenin derivatives were synthesized and tested for affinity and inhibitory activity improvement. 6-(1,1-dimethylallyl)naringenin revealed comparable PLA2 inhibition to quercetin-like compounds. We characterized the binding mode of these compounds and the determinants for their affinity, selectivity and inhibitory potency. Based on our results, we suggest C(6) as the most promising position of the flavonoid scaffold to introduce chemical modifications to improve affinity, selectivity and inhibition of PLA2-IIA by flavonoids.
"Effects of the chemically synthesized flavanone 7-(O-prenyl)narigenin-4'-acetate on the estrogen signaling pathway in vitro and in vivo"
G. Kretzschmar, G. Vollmer, P. Schwab, S. Tischer, P. Metz, O. Zierau J. Steroid Biochem. Mol. Bio.2007, 107,114-119.
The flavanone naringenin is known to possess only weak estrogenic properties, but some of its derivatives such as 8-prenylnaringenin are potent phytoestrogens. The aim of this study was to further clarify structure–function relationships of flavanones regarding their estrogenic or antiestrogenic properties by characterizing the new chemically synthesized naringenin derivative 7-(O-prenyl)naringenin-4'-acetate (7-O-PN). A yeast based reporter gene assay and MVLN cells, a MCF-7-derived cell line that possesses a luciferase reporter gene under the control of a vitellogenin estrogen responsive element, were used to investigate estrogenic actions of 7-O-PN in vitro. Estradiol (E2) has been used as a positive control. Subsequently a 3-day rat uterotrophic assay was performed to test for estrogenic effects. In addition, mRNA expression of estrogen sensitive genes in the uteri of these rats was measured using real time rtPCR. While E2 leads to a strong dose dependent signal in the yeast based reporter gene assay and in MVLN cells, 7-O-PN shows mild E2 antagonistic properties at concentrations 10-8 and 10-7 M, E2 agonistic properties at 10-6 and 10-5 M in MVLN cells and no effects on the yeast based system. In contrast to E2 treatment, 7-O-PN treatment did not increase uterus wet weight compared to the negative control. These findings are supported by mRNA expression studies of proliferation markers. Additionally, mRNA expression studies of estrogen regulated genes revealed very strong antiestrogenic properties of 7-O-PN regarding regulation of complement C3 expression while some estrogenic effects could be observed on the expression of estrogen receptor β, clusterin and possibly on progesterone receptor and vascular endothelial growth factor.
"Selective C-6 Prenylation of Flavonoids viaEuropium(III)-Catalyzed Claisen Rearrangement and Cross-Metathesis"
S. Tischer, P. Metz, Adv. Synth. Catal., 2007, 349, 147-151.
Starting from the readily available parent flavonoids, the flavanone6-prenylnaringenin, the isoflavone 6-prenylgenistein (wighteone, erythrinin B) and a protected derivative of the flavonol 6-prenylquercetin (gancaonin P) have been synthesized in short reaction sequences featuring the title processes as key steps.
"Stereoselective preparation of γ- and δ-sultams by thermal and high-pressure intramolecular Diels-Alder reaction of vinylsulfonamides"
V. O. Rogachev, P. Metz, Arkivoc 2007, ν,167-190.
A range of novel γ- and δ-sultams was prepared by intramolecular [4+2] cycloaddition of vinylsulfonamides with purely thermal activation and under high pressure. Using N-1-phenylethyl substituted vinylsulfonamides, enantiopure sultams were readily obtained, debenzylation of which provided the corresponding NH sultams in high yields in the case of δ-sultams.
Arkivoc 2007, ν,167-190
"Thermal and high pressure intramolecular Diels-Alder reaction of vinylsulfonamides"
V. O. Rogachev, P. Metz, Nature Protocols 2006, 1, 3076-3087.
Vinylsulfonamides with a furan, a 1,3-cyclohexadiene and an acyclic 1,3-diene moiety are synthesized via a domino elimination-amidation reaction of 2-chloroethanesulfonyl chloride. Intramolecular Diels-Alder reaction of these vinylsulfonamides with thermal (toluene, 110°C) or high pressure (dichloromethane, 13 kbar) activation provides an efficient access to a range of γ- and δ-sultams by a 2-3 day long synthetic procedure. Enantiopure sultams are readily obtained from N-1-phenylethyl substituted vinylsulfonamides.
"Verfahren zur Herstellung von (2S)- und (2R)-8-Prenylnaringenin"
P. Metz, P. Schwab, DE 10 2006 032 500.1.
"Synthesis and Molluscicidal Activity of New Cinnoline and Pyrano[2,3‑c]pyrazole Derivatives"
F. M. Abdelrazek, P. Metz, N. H. Metwally, S. F. El-Mahrouky, Arch. Pharm. Chem. Life Sci. 2006, 339, 456–460.
2-(3-Hydroxy-5,5-dimethylcyclohexylidene)malononitrile (5) undergoes an azo coupling reaction with aryldiazonium salts to afford 3-amino-2-aryl-6,6-dimethyl-8-oxo-2,6,7,8-tetrahydrocinnoline-4-carbo-nitriles 7. Upon reflux in acetic acid these compounds were acetylated to give the cinnoline derivatives 9. The pyrazolones 10a,b react with 3-furfurylidene- and 3-thienylidene-malononitrile derivatives 11a,b to afford the pyrano[2,3-c]pyrazole derivatives 13a-d. These newly synthesized compounds show generally a moderate molluscicidal activity to Biomphalaria alexandrina snails.
"Diastereoselective Epoxidation of N-Enoylsultams with Different Chiral Sultams as Auxiliaries"
S.-J. Zhang, Y.-K. Chen, H.-M. Li, W.-Y. Huang, V. Rogatchov, P. Metz, Chin. J. Chem. 2006, 24, 681–688.
Asymmetric epoxidation of N-enoylsultams incorporating a variety of chiral sultams as the chiral induction elements with UHP/TFAA has been studied. Both diastereomeric isomers of epoxides were obtained in high yield and moderate to high optical purity.
"A Concise Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides – Enantioselective Total Synthesis of the Antileukemic Sesquiterpene Lactones (-)-Eriolanin and (-)-Eriolangin"
J. Merten, A. Hennig, P. Schwab, R. Fröhlich, S. V. Tokalov, H. O. Gutzeit,
P. Metz, Eur. J. Org. Chem. 2006, 1144–1161.
Abstract: Using a sultone as the key intermediate, the first enantioselective total synthesis of the antileukemic 1,10-seco-eudesmanolides (-)-eriolanin (1) and (-)-eriolangin (2) was achieved, which also established the hitherto unknown absolute configuration of these sesquiterpene lactones. Starting from 2-bromo-1-(2-furyl)ethanone, 24 steps were required to generate the common basic structure and two additional steps in each case for completion of the natural products. The effect of 1 and 2 on the cell cycle of human leukemia (HL-60) cells was investigated by flow cytometry.
"A synthesis of novel N-sulfonylated β-amino acids"
D. Freitag, P. Metz, Tetrahedron 2006, 62, 1799–1805.
Novel N-sulfonyl β-amino acids were efficiently prepared in a seven-step synthesis starting from Boc protected methanesulfonamide and terminal epoxides. A zinc-mediated allylation of cyclic N-sulfonyl imines readily derived from these building blocks served as a key operation of this sequence.
"Stereoselective synthesis of γ- and δ-sultams by intramolecular Diels-Alder reaction of vinylsulfonamides possessing an acyclic or carbocyclic 1,3-diene moiety"
V. O. Rogachev, V. D. Filimonov, R. Fröhlich, O. Kataeva, P. Metz, Heterocycles 2006, 67, 589–595.
A range of novel γ- and enantiopure δ-sultams was prepared by intramolecular [4+2] cycloaddition of vinylsulfonamides with purely thermal activation and under high pressure.
"Asymmetric epoxidation of N-enoylsultams with urea-hydrogen peroxide/trifluoroacetic anhydride"
S. J. Zhang, W. H. Chan, A. W. M. Lee, W. Y. Wong, V. O. Rogatchov, P. Metz, J. Chem. Res.
Epoxides are obtained in high yield and moderate to high diastereomeric purity when N-enoylsultams incorporating a variety of chiral sultams as the chiral induction elements are treated with urea-hydrogen peroxide/trifluoroacetic anhydride.
"A Sultone Route to the Antileukemic 1,10-seco-Eudesmanolides (-)-Eriolanin and (-)-Eriolangin"
J. Merten, A. Hennig, P. Metz, J. Fudan Univ. Nat. Sci. 2005, 44, 730–731.
"Eine generelle Sulton-Route zu den Pamamycin-Makrodioliden – Totalsynthese von Pamamycin-621A und Pamamycin-635B (A General Sultone Route to the Pamamycin Macrodiolides – Total Synthesis of Pamamycin-621A and Pamamycin-635B)"
P. Fischer, A. B. García Segovia, M. Gruner, P. Metz, Angew. Chem. 2005, 117, 6387–6390; Angew. Chem. Int. Ed. 2005, 44, 6231–6234.
Sultones swing again: The first total syntheses of the title antibiotics were achieved by application of sultone methodology. Since the final lactonizations with formation of the ester linkage between C1' and the oxygen substituent on C8' proceeded with complete epimerization at C2', the more readily available C2' epimeric smaller fragments could be used for streamlining the synthetic sequence.
"Synthetic and computational studies on intramolecular [2+2] sulfonyl isocyanate-olefin cycloadditions"
D. Freitag, M. Drees, S. Goutal, T. Strassner, P. Metz, Tetrahedron 2005,
Novel unsaturated sulfonyl isocyanates were prepared using a boron trichloride promoted thermal cleavage of the corresponding sulfonylcarbamates. Due to their moisture sensitivity, the isocyanates were directly converted into sulfonylureas in good yields. An intramolecular cycloaddition of the olefinic sulfonyl isocyanates to give β-lactam-sulfonamide hybrids was not observed experimentally. Investigation of this cycloaddition by DFT-calculations using the 6-31G* and 6-311+G** basis sets showed it to be endergonic.
"Synthesis of Sultams by Intramolecular Heck Reaction"
S. Merten, R. Fröhlich, O. Kataeva, P. Metz, Adv. Synth. Catal. 2005, 347, 754–758.
A novel access to α-methylene-γ-sultams via the intramolecular Heck reaction of α-bromovinylsulfonamides derived from allylic amines is reported. These heterocycles are potent Michael acceptors towards sulfur nucleophiles.
"Naringenin-type flavonoids show different estrogenic effects in mammalian and teleost test systems"
O. Zierau, J. Hamann, S. Tischer, P. Schwab, P. Metz, G. Vollmer, H. O. Gutzeit, S. Scholz, Biochem. Biophys. Res. Commun. 2005, 326, 909–916.
The estrogenic activity of several intermediary plant compounds has raised concern about possible risks of unwanted interference with endocrine regulation, but on the other hand there are potential medical benefits, in particular in treatment of menopausal symptoms or cancer. In the present study, we compare the estrogenic effects of phytoestrogens naringenin, 8-prenylnaringenin, 6-(1,1-dimethylallyl)naringenin, and the synthetic 4′-acetyl-7-prenyloxynaringenin. Two mammalian in vitro systems and a fish in vivo system were used to study the estrogenic properties with reference to genistein, 17β-estradiol or ethynylestradiol. Strong differences were observed between the mammalian in vitro and the fish in vivo test system. In the medaka sex reversal/νtg gene expression assay no estrogenic effects of the naringenin-type flavonoids were observed, while mammalian in vitro systems showed a similar and graded response to the test compounds.
"Synthesis of 18F-labelled cyclooxygenase-2 (COX-2) inhibitors via Stille reaction with 4-[18F]fluoroiodobenzene as radiotracers for positron emission tomography (PET)", F. R. Wüst, A. Höhne, P. Metz, Org. Biomol. Chem. 2005, 3, 503–507.
The Stille reaction with 4-[18F]fluoroiodobenzene as a novel approach for the synthesis of radiotracers for monitoring COX-2 expression by means of PET has been developed. Optimized reaction conditions were elaborated by screening of various catalyst systems and solvents. By using optimized reaction conditions 18F-labelled COX‑ inhibitors [18F]-5 and [18F]-13 could be obtained in radiochemical yields of up to 94% and 68%, respectively, based upon 4-[18F]fluoroiodobenzene.
"Synthetic studies on the pamamycin macrodiolides"
P. Metz, Top. Curr. Chem. 2005, 244, 215–249.
The pamamycins are structurally intriguing 16-membered macrodiolides displaying a wide range of interesting biological activities. A comprehensive survey of the total syntheses reported in this area so far and the various synthetic approaches to the hydroxy acid constituents of the pamamycins described to date is presented.
"Two major metabolites of 8-prenylnaringenin are estrogenic in vitro"
O. Zierau, S. Hauswald, P. Schwab, P. Metz, G. Vollmer, J. Steroid Biochem. Mol. Biol. 2004, 92, 107–110.
8-Prenylnaringenin and preparations containing 8-prenylnaringenin have been suggested for use in medicinal and cosmetic applications like hormone replacement or bust enhancement. However, the safety of application is still under considerable debate. Recently it has been shown that human liver microsomes are converting 8-prenylnaringenin to 12 metabolites, with (E)-8-(4´´-hydroxyisopentenyl)naringenin (8-PN-OH) and (E)-8-(4´´-oxoisopentenyl)naringenin (8-PN=O) being among the most abundant. Applying two independent in vitro test systems we demonstrate that these two metabolites of 8-prenylnaringenin are estrogenic in vitro. These results represent an important piece of information towards the discussion of safety of use of preparations containing 8-prenylnaringenin.
"Enantioselektive Totalsynthese der hoch oxygenierten 1,10-seco-Eudesmanolide Eriolanin und Eriolangin (Enantioselective Total Synthesis of the Highly Oxygenated 1,10-seco-Eudesmanolides Eriolanin and Eriolangin)"
J. Merten, R. Fröhlich, P. Metz, Angew. Chem. 2004, 116, 6117–6120; Angew. Chem. Int. Ed. 2004, 43,
Sultones of swing: A sultone served as the key intermediate in the first enantioselective total syntheses of the bioactive title compounds, the absolute configuration of which is now established. Starting from 2-bromo-1-(2-furyl)ethanone, 24 steps were required to generate the common basic structure, and in each case two additional steps yielded the natural products.
"Synthesis and Molluscicidal Activity of 5-Oxo-5,6,7,8-tetrahydro-4H-chromene Derivatives"
F. M. Abdelrazek, P. Metz, E. K. Farrag, Arch. Pharm. Pharm. Med. Chem. 2004, 337, 482–485.
Furfurylidenemalononitriles and thienylidenemalononitriles were treated with 1,3-cyclohexanediones to afford 2-amino-4-hetaryl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile derivatives. The molluscicidal activity of these compounds was investigated.
"Antimycobacterial activity of synthetic pamamycins"
P. Lefèvre, P. Peirs, M. Braibant, M. Fauville-Dufaux, R. Vanhoof, K. Huygen, X.-M. Wang, B. Pogell, Y. Wang, P. Fischer, P. Metz, J. Content, J. Antimicrob. Chemother. 2004, 54, 824–827.
Early studies have indicated that pamamycins, a group of macrodiolides first isolated from Streptomyces alboniger, have potent antimicrobial activity against Gram-positive bacteria, fungi and mycobacteria but not against Gram-negative bacteria. The recent availability of highly purified and reasonable quantities of several pamamycins through their total syntheses has rendered possible more extensive studies on their effects on mycobacteria. Bioluminescent strains of Mycobacterium tuberculosis, Mycobacterium bovis BCG and Mycobacterium smegmatis, expressing the luxA and luxB genes from Vibrio harveyi were used for the comparison of the antimycobacterial activity of the two synthetic macrodiolides pamamycin-607 and pamamycin-621A and a non-naturally occurring cyclic dimer of pamamycin-607, i.e. yukomycin. Pamamycin-607 was the most active of the three macrocycles and was more active against M. tuberculosis than against M. smegmatis. Twenty-five clinical isolates of M. tuberculosis were susceptible to pamamycin-607 in a narrow MIC range of 1.5-2.0 mg/L. The new assay was also validated by comparison with the BACTEC radiometric test. Rapid screening of a new class of macrocyclic antimycobacterials using bioluminescent mycobacteria identified pamamycin-607 as a potential antituberculous agent. The latter was active against clinical isolates of M. tuberculosis within a narrow MIC range of 1.5-2.0 mg/L irrespective of their resistance to isoniazid or rifampicin. Our findings warrant further investigations.
"Uterine effects of the phytoestrogen 6-(1,1-dimethylallyl)naringenin in rats"
O. Zierau, R.-B. Thomae, S. Tischer, P. Schwab, P. Metz, G. Vollmer, Planta Med. 2004, 70, 590–593.
Phytoestrogens are discussed as candidate substances to treat symptoms related to estrogen deficiency. In in vitro experiments the naturally occurring flavonoid 6-(1,1-dimethylallyl)naringenin (6-DMAN) emerged as one of the most potent phytoestrogenic substances. 6-DMAN is not as well characterized as other flavonoids (8-prenylnaringenin) or isoflavones (genistein). We tested 6-DMAN for the first time in vivo, in a dose-dependent three-day uterotrophic assay in ovariectomized Wistar rats, using 6-DMAN at three different concentrations (1.5 mg/kg; 7.5 mg/kg and 15 mg/kg BW/d). Estradiol (E2; 10 mg/kg BW/d) and the carrier castor oil were used as positive and negative controls. 6-DMAN did not have any effect on uterine wet weight, while the positive control E2 did. In contrast, 6-DMAN stimulated uterine mRNA expression of estrogen responsive genes in ovariectomized rats. Estrogen receptor a and b mRNA was expressed in the uterus. They mediate the expression of genes with an estrogen responsive element in the promoter, e.g., complement C3 and the progesterone receptor. Therefore, we analyzed the expression of the above-mentioned genes in threee different concentrations. 6-DMAN up-regulated progesterone receptor and particularly complement C3 mRNA expression however, less pronounced than E2. In conclusion, we demonstrated for the first time estrogenic activities of 6-DMAN in vivo. Surprisingly, although 6-DMAN regulated estrogen responsive gene expression, there was no uterine wet weight gain. These findings make 6-DMAN a very interesting candidate substance for further characterization, as it potentially represents a naturally occurring selective estrogen receptor modulator.
"Ring Closing Metathesis in the Synthesis of Sultones and Sultams"
S. Karsch, D. Freitag, P. Schwab, P. Metz, Synthesis 2004, 1696-1712 (Feature Article).
Unsaturated sultones with normal, medium and large ring sizes were efficiently synthesized by ring closing metathesis (RCM) of sulfonates. The resulting α,β-unsaturated sultones act as dienophiles in intermolecular Diels-Alder reactions. A first cyclic sulfate formation through RCM has been discovered, and a rapid access to β-lactams fused to a sultam moiety of variable ring size was developed from inexpensive, commercially available starting materials using RCM as the key operation. An efficient RCM of 4-vinylazetidin-2-ones to give 1-aza-bicyclo[4.2.0]oct-4-en-8-ones is also described.
"A concise synthesis of β-lactam-sulfonamide hybrids"
D. Freitag, P. Schwab, P. Metz, Tetrahedron Lett. 2004, 45, 3589–3592.
Using ring closing metathesis (RCM) as the key operation, a rapid access to β-lactams fused to a sultam moiety of variable ring-size was developed from low-cost, commercially available starting materials. An efficient RCM of 4-vinyl-azetidin-2-ones to give 1-aza-bicyclo[4.2.0]oct-4-en-8-ones is also reported.
"Toxicity and Cell Cycle Effects of Synthetic 8-Prenylnaringenin and Derivatives in Human Cells"
S. V. Tokalov, Y. Henker, P. Schwab, P. Metz, H. O. Gutzeit, Pharmacology 2004, 71, 46–56.
The estrogenic flavanone rac-8-prenylnaringenin (8-PN) and 3 derivatives (rac-7-(O-prenyl)naringenin-4´-acetate (7-O-PN), rac-5-(O-prenyl)naringenin-4´,7-diacetate (5-O-PN), and rac-6-(1,1-dimethylallyl)naringenin (6-DMAN)) were prepared by chemical synthesis and analysed with respect to their toxicity and possible cell cycle effects in human acute myeloid leukemia (HL-60) cells. With the exception of 5-O-PN all other naringenins showed only weak toxic effects at concentrations below 50 μM. A cell cycle analysis over several cell generations up to 4 days was carried out using the fluorescent dye carboxyfluorescein diacetate N-succinimidyl ester (CFSE) followed by propidium iodide (PI) staining at the end of the experiment. The well studied flavone quercetin was included in the analysis as reference substance. All flavonoids affected cell proliferation but the extent and the resulting changes of the proliferation pattern was specific for each substance. In contrast to the radical scavinging activity of quercetin the tested flavanones showed no anti-oxidative properties using several different test systems. Similarly, the mitochondrial membrane potential (ΔΨm) was hardly effected by these compounds while both menadione and quercetin strongly reduced the potential after 1h treatment. The reported chemical modification of interesting lead substances (like the strongly estrogenic 8-PN) presents a promising approach to modulate the properties of a relevant substance in a pharmacologically desirable way. The low toxicity and weak cytostatic properties of the tested naringenin derivatives is encouraging for further studies on known naringenin target molecules.
"Metabolism of 8-prenylnaringenin, a potent phytoestrogen from hops (Humulus lupulus), by human liver microsomes"
D. Nikolic, Y. Li, L. R. Chadwick, S. Grubjesic, P. Schwab, P. Metz, R. B. van Breemen, Drug Metab. Dispos. 2004, 32, 272–279.
The female flowers of hops are used throughout the world as a flavoring agent for beer. Recently, there has been increasing interest in the potential estrogenic properties of hop extracts. Among the possible estrogenic compounds in hops, 8-prenylnaringenin is perhaps most significant due to its high in vitro potency exceeding that of other known phytoestrogens. Since data regarding the pharmacokinetic properties of this compound are lacking, we investigated the in vitro metabolism of 8-prenylnaringenin by human liver microsomes. A total of 12 metabolites were identified, and biotransformation occurred on the prenyl group and the flavanone skeleton. The major site of oxidation was on the terminal methyl groups, and of the two possible isomers, the trans isomer was more abundant. The double bond on the prenyl group was also oxidized to an epoxide that was opened by intramolecular reaction with the neighboring hydroxyl group. On the flavanone skeleton, the major site of oxidation was at 3' position on the B ring. Other metabolites included oxidation at carbon-3 as well as desaturation of the C ring to produce 8-prenylapigenin. An unusual hydroxy quinone product formed by ipso hydroxylation of the B ring of 8-prenylnaringenin was also detected. This product was probably an intermediate for the B ring cleavage product, 8-prenylchromone.
"Regulation of Gene Expression by 8-Prenylnaringenin in Uterus and Liver of Wistar rats"
P. Diel, R. B. Thomae, A. Caldarelli, O. Zierau, S. Kolba, S. Schmidt, P. Schwab, P. Metz, G. Vollmer, Planta Med. 2004, 70, 39–44.
The potential estrogenic activity of 8-prenylnaringenin has been investigated using several in vitro test systems. 8‑Prenylnaringenin is a natural secondary product of the female blossoms of hops. The aim of the present study was to characterize 8‑prenylnarengenin for its estrogenic effects in vivo. A three day uterotrophic assay was carried out on ovariectomized young female rats. A single dose of 8-prenylnaringenin (10 mg/day/kg body mass) was administered s.c. 17β-Estradiol (0.03 mg/day/kg body mass; s.c. administration) was used as a positive control. Uterine wet weight, endometrial and vaginal epithelial height were determined by histological methods. Gene expression in uterus and in liver was assessed using realtime RT-PCR. Both estradiol and 8-prenylnaringenin significantly stimulated uterine wet weight accompanied by a proliferative response. The three day treatment resulted in a statistically significant increase of the uterine epithelial height as well as of the vaginal epithelial height, the latter being the more sensitive parameter. In the uterus of ovariectomized animals estrogen receptor-α and clusterin gene expression were down regulated following treatment with estradiol, whereas expression of complement C3 was up-regulated. In response to treatment with 8-prenylnaringenin the same gene expression pattern was detectable, but less pronounced. The levels of estrogen receptor-α mRNA in rat liver were very low and therefore could not be quantitatively assessed. Like in the uterine tissue, estradiol down regulated clusterin expression. The response to 8- prenylnarengenin was weaker but still significant. Conversely, 8‑prenylnarengenin was found to be more potent than estradiol in inducing expression of IGFBP-1. In summary, the multiparametric assessment of the estrogenic activity of 8-prenylnaringenin provides overwhelming evidence that 8-prenylnaringenin has largely to be regarded as a pure estrogen agonist and is therefore a questionable candidate molecule for hormone replacement therapy.
"Enantioselective Formal Synthesis of Eleuthesides"
N. Ritter, P. Metz, Synlett, 2003, 2422–2424.
An intramolecular Diels–Alder reaction of an enantiopure 3,5-hexadienyl acrylate and a chemoselective epimerization constitute the key steps of a highly stereoselective synthesis of a triol, whose conversion to eleutherobin, eleuthosides A and B and sarcodictyins A and B is known.
Antiandrogenic activity of the phytoestrogens naringenin, 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin"
O. Zierau, C. Morrissey, R. W. G. Watson,P. Schwab, S. Kolba, P. Metz, G. Vollmer, Planta Med. 2003, 69, 856–585.
Naturally occurring naringenin derivatives, known for their estrogenic activity, were tested in two independent (anti-)androgen screening assays. Using a yeast-based androgen receptor assay relatively strong antiandrogen activities were demonstrated for 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin, while the parent compound naringenin did not show recognizable antiandrogen activity. In an androgen receptor activity assay based on the analysis of prostate specific antigen (PSA) concentrations in the supernatants of treated PC3(AR)2 cells the antiandrogenic activity of 6-(1,1-dimethylallyl)naringenin was detected at concentrations of 10-5 M. 8-Prenylnaringenin or naringenin have no detectable antiandrogenic effect. In summary, for the first time we provide evidence of the antiandrogenic activity of 6-DMA-N in two independent model systems. In conclusion, we demonstrated the ability of prenylated naringenins not only to act via the estrogen receptor but also through the androgen receptor.
"A symmetry-based approach to the heterobicyclic core of the zaragozic acids – model studies in the C2-symmetric series"
A. Bierstedt, J. Roels, J. Zhang, Y. Wang, R. Fröhlich, P. Metz, Tetrahedron Lett. 2003, 44, 7867–7870.
A conceptually novel access to models for the title structures has been achieved by rapid enantioselective construction of polyhydroxy diketones in a two-directional or convergent fashion and group-selective intramolecular acetalization.
"Estrogenic activity of the phytoestrogens naringenin, 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin"
O. Zierau, S. Gester, P. Schwab, P. Metz, S. Kolba, M. Wulf, G. Vollmer, Planta Med. 2002, 68, 449–451
Naturally occurring, chemically synthesized naringenin derivatives were tested on their estrogenic activity in two independent estrogen screening assays. In the yeast based estrogen receptor assay strong estrogenic activities could be demonstrated for 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin, while the parent compound naringenin did not show recognizable estrogenic activity. In MVLN cells, a bioluminescent MCF-7-derived cell line, the estrogenic activity of 8-prenylnaringenin and 6-(1,1-dimethylallyl)naringenin could be verified. Naringenin showed estrogenic activity but only at a concentration of 10 M. The estrogenic effects are mediated by the ER, because the antiestrogen 4-hydroxytamoxifen inhibited these activities. In conclusion, chemical synthesis is an appropriate tool to produce larger quantities of naturally occurring bioactive compounds. Our assays provided further evidence for the high estrogenic activity of 8-prenylnaringenin and demonstrated for the first time a reasonable high estrogenic activity of 6-(1,1-dimethylallyl)naringenin.
"Amino analogs of actic acids – synthesis and lactamization"
H. Bernsmann, Y. Wang, R. Fröhlich, P. Metz, Tetrahedron 2002, 58, 4451–4457.
Novel THF-amino acids were efficiently synthesized from actic acid methyl esters. The conformational restriction imposed by the 2,5-cis disubstituted tetrahydrofuran moiety is apparent from their facile cyclization to give medium-sized lactams.
"Preparation of enantiopure sultams by intramolecular Diels-Alder reaction of furan-containing vinylsulfonamides"
V. O. Rogatchov, H. Bernsmann, P. Schwab, R. Fröhlich, B. Wibbeling, P. Metz, Tetrahedron Lett. 2002, 43, 4753–4756.
Enantiomerically pure δ- and γ-sultams have been prepared by intramolecular [4+2] cycloaddition of N-1-phenylethyl substituted vinylsulfonamides with purely thermal activation and under high pressure. An optimized procedure for reductive debenzylation of the resultant δ-sultams is also reported.
"Enantioselective Synthesis of the Molluscicidal Furanosesquiterpene Lactones Ricciocarpin A and Ricciocarpin B via Ring Closing Metathesis"
C. Held, R. Fröhlich, P. Metz, Adv. Synth. Catal. 2002, 344, 720–727.
Using two catalytic ring closing metatheses as the key events, a short, completely diastereoselective and highly enantioselective access to the molluscicidal sesquiterpenoids ricciocarpin A and ricciocarpin B was achieved. The hitherto unknown absolute configuration of these natural products was unambiguously established.
"Synthesis of Sultones by Ring Closing Metathesis"
S. Karsch, P. Schwab, P. Metz, Synlett 2002, 2019–2022.
Unsaturated sultones with normal, medium and large ring sizes were efficiently synthesized by ring closing metathesis of sulfonates. The required substrates were readily derived from alkenols and olefinic sulfonyl chlorides.
"An Efficient Synthesis of the Potent Phytoestrogens 8-Prenylnaringenin and 6-(1,1-Dimethylallyl)naringenin by Europium(III)-Catalyzed Claisen Rearrangement"
S. Gester, P. Metz, O. Zierau, G. Vollmer, Tetrahedron 2001, 57, 1015–1018.
Starting from commercially available naringenin (3), the flavanoids 8-prenylnaringenin (1) and 6-(1,1-dimethylallyl)naringenin (2) have been prepared in racemic form using prenyl ether 5 as a general intermediate. While a domino Claisen-Cope rearrangement of 5 was the key step in the synthesis of 1, the cytotoxic compound 2 was additionally secured via a europium(III)-catalyzed Claisen rearrangement of 5 at low temperature. Both 1 and 2 display strong estrogenic activities.
"Oxidation of α,ω-Diols using the Dess-Martin Periodinane"
J. Roels, P. Metz, Synlett 2001, 789–790.
Depending on the length of the carbon tether, α,ω -diols either afford cyclic acetoxy acetals or dialdehydes upon treatment with the Dess-Martin periodinane.
"A shortcut to the smaller fragment of pamamycin-607"
H. Bernsmann, M. Gruner, R. Fröhlich, P. Metz, Tetrahedron Lett. 2001, 42, 5377–5380.
Starting from a key intermediate for the synthesis of the larger hydroxy acid constituent of pamamycin-607 (1), an efficient three-step route to the methyl ester of the smaller fragment of 1 involving a Yamaguchi lactonization with concomitant C(2) epimerization was developed. Alternatively, the methyl ester of the smaller hydroxy acid portion of 1 was prepared by direct C(2) epimerization.
"A rapid and general access to 3-arylpiperidines"
I. K. Büchner, P. Metz, Tetrahedron Lett. 2001, 42, 5381–5383.
A short and efficient synthetic sequence to produce a wide variety of 3-arylpiperidines from three simple building blocks is described. Key step is a palladium catalyzed arylation of cyclopentene.
"Synthesis of Highly Substituted Methylenecyclohexenes Using New Domino Reactions with Sultones"
B. Plietker, D. Seng, R. Fröhlich, P. Metz, Eur. J. Org. Chem. 2001, 3669–3676.
New methods for the synthetic elaboration of sultones with concomitant desulfurization have been developed. Alkylation of sultones with (iodomethyl)trimethylsilane followed by treatment of the resultant silyl compound with tetrabutylammonium fluoride gave rise to sulfur-free methylenecyclohexenes. In a more straightforward fashion, highly substituted compounds of the latter type were readily accessible by alkylation of α-metallated allylic sultones prepared either by deprotonation, radical cyclization/transmetallation, or conjugate 1,6-addition with (iodomethyl)magnesium chloride in a one-pot transformation. An advanced intermediate for the synthesis of several 1,10-seco-eudesmanolides was rapidly constructed using such a protocol.
"Total synthesis of pamamycin-607"
Y. Wang, H. Bernsmann, M. Gruner, P. Metz, Tetrahedron Lett. 2001, 42, 7801–7804.
The macrodiolide antibiotic pamamycin-607 has been synthesized by coupling of the two hydroxy acid constituents using the Yamaguchi method. While the final lactonization with formation of the ester linkage between C(1) and the C(8') oxygen proceeded with complete C(2) epimerization, the alternative ring closure involving the carboxylic acid of the smaller fragment and the hydroxyl group of the larger fragment yielded the target molecule.
"Enzymatic kinetic resolution of 1-(3'-furyl)-3-buten-1-ol and 2-(2'-furyl)-propan-1-ol"
A. Bierstedt, J. Stölting, R. Fröhlich, P. Metz, Tetrahedron: Asymmetry 2001, 12, 3399–3407.
The enzymatic kinetic resolution of the racemic alcohols 1-(3'-furyl)-3-buten-1-ol (rac-1) and 2-(2'-furyl)-propan-1-ol (rac-2) was investigated by screening a range of lipases and esterases for enantioselective transacylation, as well as for enantioselective hydrolysis. For both alcohols, lipase catalyzed hydrolysis of the derived racemic acetate gave the best results for accessing the desired (S) enantiomers. In case of the secondary alcohol rac-1, ASL turned out to be the optimum enzyme, whereas PPL was superior in case of the primary alcohol rac-2. Additionally, an alternative access to (S)-2via Oppolzer's camphor sultam methodology is described.
"Chemoselective Oxidative Debenzylation of N,N-Dibenzylamines"
B. Hungerhoff, S. S. Samanta, J. Roels, P. Metz, Synlett 2000, 77–79.
Tertiary amines incorporating two N-benzyl substituents are readily mono-debenzylated with CAN or DDQ. An N,N-dibenzyl derivative of a dienylamine with a homoallylic C-N bond is smoothly deblocked by DDQ as well, whereas CAN leads to fragmentation in this case.
"High Pressure Intramolecular Diels-Alder Reactions of Vinylsulfonates and Vinylsulfonamides", B. Plietker, D. Seng; R. Fröhlich, P. Metz, Tetrahedron 2000, 56, 873–879.
Acceleration of the intramolecular Diels-Alder reaction of vinylsulfonic esters and amides bearing acyclic and carbocyclic 1,3-diene moieties by application of high pressure leads to excellent yields of sultones and sultams, respectively, at ambient temperature. The influence of pressure on the stereoselectivity of these processes has been investigated.
"Toward the Synthesis of Pamamycin-607"
H. Bernsmann, B. Hungerhoff, R. Fechner, R. Fröhlich, P. Metz, Tetrahedron Lett. 2000, 41, 1721–1724.
Using sultone chemistry, a short and highly enantioselective synthesis of an advanced precursor for the larger hydroxy acid moiety and of the complete smaller hydroxy acid portion of the macrodiolide antibiotic pamamycin-607 has been accomplished.
"A Sultone Approach to the C(1)-C(18) Moiety of Pamamycin-607"
H. Bernsmann, R. Fröhlich, P. Metz, Tetrahedron Lett. 2000, 41, 4347-4351.
A highly advanced enantiomerically pure C(1)-C(18) precursor of the larger fragment of the macrodiolide pamamycin-607 has been synthesized. The stereotriad C(7)-C(9) between the two heterocyclic rings of the target was generated using a diastereoselective hydroboration controlled by minimization of allylic 1,3-strain.
"Enantioselective Synthesis of the Larger Fragment of Pamamycin-607"
H. Bernsmann, M. Gruner, P. Metz, Tetrahedron Lett. 2000, 41, 7629–7633.
The enantiomerically pure methyl ester of the complete larger hydroxyacid (C(1)-C(18)) of the macrodiolide antibiotic pamamycin-607 has been synthesized using a general sultone route to actic acids and analogs. The requisite N,N-dimethylamino moiety was introduced by Mitsunobu inversion with hydrazoic acid followed by a reaction cascade involving hydrogenation and double reductive methylation.
"Resolution of Methyl Nonactate"
Y. Wang, P. Metz, Tetrahedron: Asymmetry 2000, 11, 3995–3999.
A straightforward resolution of racemic methyl nonactate has been achieved by chromatographic separation of the corresponding D-mandelates followed by chemoselective hydrolysis of the mandelate ester function. Baker's yeast reduction of the ketone derived from racemic methyl nonactate proceeded with high enantioselectivity to give (+)-8-epi-methyl nonactate and (-)-methyl nonactate as alternative building blocks for macrotetrolide synthesis but was less efficient for the production of the latter compound.