Transition Metal free Regio- and Diastereoselective [2+2+2] Cycloaddition of

1,6-Enynes with Carbonyl Compounds

Vera Meyer, Aachen/D, Christoph Ascheberg, Aachen/D

Prof. Dr. M. Niggemann, RWTH Aachen University, Landoltweg 1, 52074 Aachen

[2+2+2] Cycloadditions are efficient methods to synthesize six membered carbo- and heterocycles. These intriguing reactions allow the generation of complex structures from simple starting materials and are mostly transition-metal catalyzed.[1] Some recent examples deal with gold- and rhodium catalyzed [2+2+2] cycloaddition reactions with carbonyl compounds.[2] These yield interesting products including highly substituted dihydropyranes. Due to the high expense of rhodium- and gold-catalysts and the toxicity of many transition metals, it is desirable to establish cheaper and less toxic alternatives for these reactions.

Our already well established calcium-based catalytic system[3] turned out to be very effective, so herein we report the first transition metal free [2+2+2] cycloaddition reaction of 1,6-enynes with aldehydes. Highly substituted dihydropyranes were synthesized with exceptional regio- and diastereoselectivity.

Literature: [1] For a recent review on [2+2+2] cycloadditions see: P. R. Chopade, J. Louie Adv. Synth. Catal. 2006, 348, 2307. [2] a) K. Tanaka, Y. Otake, H. Sagae, K. Noguchi, M. Hirano Angew. Chem. Int. Ed. 2008, 47, 1312; b) A. Escribano-Cuesta, V. López-Carrillo, D. Janssen, A. M. Echavarren Chem. Eur. J. 2009, 15, 5646; c) M. Schelwies, R. Moser, A. L. Dempwolff, F. Rominger, G. Helmchen Chem. Eur. J. 2009, 15, 10888. [3] For a recent review on calcium catalysis see: J.-M. Begouin, M. Niggemann Chem. Eur. J. 2013, 19, 8030.

OHR

O

O

OO DCE, RT

(5 mol%) Ca(NTf2)2/

(5 mol%) nBu4NPF6

O

R+

O

O

O

O O

R

R

40%~75% yield

1

2

2

1

Catalytic, Enantioselective Halocyclizations beyond Alkenes

Wilking, M., Münster/DE-NW

Dr. Hennecke, U., University of Münster, Corrensstraße 40, 48149 Münster, Germany

During the last few years, numerous methods for catalytic, asymmetric halocyclization reactions of alkenes have been reported.[1] Using the dimeric cinchona-alkaloid (DHQD)2PHAL as a chiral catalyst, we were able to extend the scope of such functionalizations to the first enantioselective halolactonization of alkynes.[2] Our strategy is based on desymmetrization reactions [3] of dialkynoic acids, which could be cyclized using an electrophilic halogen source such as NBS to give the corresponding bromoenol lactones with generally high enantioselectivities and very good yields (Scheme, top).

In further studies we were able to apply similar reaction conditions to achieve the first asymmetric halolactonization of allenoic acids (Scheme, bottom).[4] The concept of such transformations, their substrate scope as well as investigations on catalyst structure and activity will be presented. [1] a) S. E. Denmark, W. E. Kuester, M. T. Burk, Angew. Chem. Int. Ed. 2012, 51, 10938-10953; b) U. Hennecke, Chem. Asian J. 2012, 7, 456-465. [2] M. Wilking, C. Mück-Lichtenfeld, U. Hennecke, J. Am. Chem. Soc. 2013, 135, 8133-8136. [3] U. Hennecke, M. Wilking, Synlett 2014, accepted (doi: 10.1055/s-0033-1341160). [4] M. Wilking, C. Daniliuc, U. Hennecke, Synlett 2014, accepted.

Design and synthesis of a bis(phosphoryl)-bridged benzidine - a novel π-

conjugated push-pull system

T. Greulich, Münster/DE-NW, C.-G. Daniliuc, Münster/DE-NW

Prof. Dr. A. Studer, Westfälische Wilhelms-Universität Münster, Corrensstraße 40,

48149 Münster

The design of new electron-accepting π-conjugated frameworks is of particular

significance for the development of n-type semiconducting materials[1] and narrow-band

gap polymers.[2] These materials gain great interest and huge effort is made in order to

incorporate them as components in organic electronics, such as thin-film transistors

and photovoltaic cells. Well-established scaffolds for the design of such π-electron

systems are biphenyls. A simple and elegant way to tune the electronic properties of

complex π-systems is for example the introduction of an electron-accepting motif as a

bridging moiety, because just by substitution with electron withdrawing groups the

biphenyl framework will favour a twist conformation.

Scheme 1: Radical phosphanylation toward the doubly bridged benzidine.

Herein, we present the synthesis of a modified biphenyl, which contains not only an

electron-withdrawing but also an electron-donoring unit. Furthermore, we can show that

radical phosphanylation is an efficient tool to generate a highly strained π-system.

Literature:

[1] J. E. Anthony, A. Facchetti, M. Heeney, S. R. Marder, X. Zhan, Adv. Mater. 2010,

22, 3876-3892.

[2] A. Ajayaghosh, Chem. Soc. Rev. 2003, 32, 181-191.

Cyclizing Radical Carboiodination, Carbotelluration and Carboaminoxylation of

Aryl Amines

M. Hartmann, Münster/DE-NW

Prof. Dr. Armido Studer, University of Münster, Corrensstraße 40, 48149 Münster

Palladium-mediated radical carboiodinations of alkenes using activated alkyl iodides

are known. [1] Recently this chemistry was extended to aryl iodides. [2] However, a

quaternary C-center next to the C-I bond to prevent β-H-elimination is necessary which

outlines a major drawback of the existing Pd-catalyzed method. Herein we report a

protocol for radical carboiodination of various aryl amines. This method benefits to be

transition-metal-free and very easy to conduct. Aryl diazonium salts, in situ generated

from the corresponding aryl amines, are reacted with Bu4NI to provide the

corresponding aryl radicals which undergo 5-exo or 6-exo cyclization. I-abstraction

eventually affords the carboiodinated products in good to excellent yields (up to 99%). If

TEMPO is added, the cascade provides the cyclized carboaminoxylation products (up

to 89%). Running the reaction in the presence of PhTeTePh affords the phenyltellurated

cyclized products (up to 99%). [3] Moreover, the cyclized products can be readily

further chemically transformed by different methods.

Scheme 1: Carboiodination, Carbotelluration and Carboaminoxylation of various aryl amines.

Literature:

[1] U. Jahn, Top. Curr. Chem. 2012, 320, 363-369. [2] S. G. Newman, M. Lautens, J.

Am. Chem. Soc. 2011, 133, 1778. [3] M. Hartmann, A. Studer, Angew. Chem. Int. Ed.,

Accepted for publication.

Building Blocks for Aryl- Propargyl Foldamers: A New Class of Peptidomimetics Wünsch M., BI/DE, Klaß M., KI/DE, Fröhr T., BI/DE, Sewald N., BI/DE Matthias Wünsch, Organic and Bioorganic Chemistry OC III, Department of Chemistry, Bielefeld University, Universitätsstrasse 25, 33615 Bielefeld, Germany. Peptidomimetics have become important building blocks in the synthesis of various drugs. Because of their stability against enzymatic hydrolysis, they induce excellent properties as inhibitors when applied as a substitute for natural dipeptides in peptide-based agents. The modification of the backbone of peptides by replacing an amide by for example a hydroxyethylene group has already proven to give important bioactive compounds in drugs like Saquinavir[1] and Aliskiren.[2] A new scaffold for the substitution of an amide bond is obtained by the Sonogashira-Hagihara cross coupling reaction of a propargylamine with a halogenated aryl carboxylic acid (reaction scheme 1). Since the aromatic moiety is mutable, a variety of peptidomimetics could already be produced, including thiophene derivatives, substituted aromatics, ortho-, meta- and para- substituted benzoic acid derivatives and pyridine derivatives.

Reaction scheme 1: Synthesis of exemplary peptidomimetics.

The synthesized peptidomimetics are interesting building blocks for the development of drugs because of their expected stability against enzymatic hydrolysis and their rigid conformation. literature: [1] N. A. Roberts, J.A. Martin, D. Kinchington et al., Rational design of peptide-based HIV proteinase inhibitors, Science, 1990, 248, 358. [2] A. H. Gradman, R. E. Schmieder, R. L. Lins, J. Nussberger, Y. Chiang, M. P. Bedigian, Aliskiren, a Novel Orally Effective Renin Inhibitor, Provides Dose-Dependent Antihypertensive Efficacy and Placebo-Like Tolerability in Hypertensive Patients, Circulation, 2005, 111, 1012.

Synthesis and DNA Cleavage Activity of Bis-3-chloropiperidines

as Alkylating Agents

Zuravka, I., Giessen/DE, Göttlich, R., Giessen/DE, Roesmann, R., Giessen/DE

Pingoud, A., Giessen/DE, Wende, W., Giessen/DE,

Gatto, B., Padova/IT, Sosic A., Padova/IT

Ivonne Zuravka, Institute of Organic Chemistry, Justus-Liebig-University,

Heinrich-Buff-Ring 58, 35392 Giessen, Germany

Nitrogen mustards are an important class of bifunctional alkylating agents routinely

used in chemotherapy.[1] They react with DNA as electrophiles through the formation of

highly reactive aziridinium ion intermediates.[2] The antibiotic 593A, with potential

antitumor activity, can be considered as naturally occurring piperidine mustard

containing a unique 3-chloropiperidine ring.[3] However, the total synthesis of this

antibiotic proved to be rather challenging.[4] With the aim of designing simplified

analogues of this natural product, we developed an efficient bidirectional synthetic

route to bis-3-chloropiperidines joined by flexible, conformationally restricted, or rigid

diamine linkers (Figure 1).[5]

Figure 1. Bis-3-chloropiperidines as structurally simplified analogues of the antibiotic 593A.

The key step involves an iodide-catalyzed double cyclization of unsaturated bis-N-

chloroamines to simultaneously generate both piperidine rings. We will present the

synthesis and subsequent evaluation of a series of novel nitrogen-bridged bis-3-

chloropiperidines enabling the study of the impact of the linker structure on DNA

alkylation properties. Our studies reveal that the synthesized compounds possess DNA

alkylating abilities and induce strand cleavage, with a strong preference for guanine

residues.[5]

Literature: [1] L. H. Hurley, Nat. Rev. Cancer 2002, 2, 188–200.

[2] G. P. Warwick, Cancer Res. 1963, 23, 1315–1333.

[3] M. Slavik, Recent Results Cancer Res. 1978, 63, 282– 287.

[4] T. Fukuyama et al. J. Am. Chem. Soc. 1980, 102, 2122–2123.

[5] I. Zuravka et al. ChemMedChem 2014, doi: 10.1002/cmdc.201400034

Al - Catalyzed Redox-Neutral Insertion of Unactivated Alkynes into a σ C-C Bond

Liang Fu, Aachen/D, Helena Damsen, Aachen/D

Prof. Dr. M. Niggemann, RWTH Aachen University, Landoltweg 1, 52074 Aachen

Nitrogen-containing heterocycles are important structural components in many natural products and biologically active molecules. Especially, quinolines and their derivatives became important building blocks in organic synthesis and medicinal chemistry.[1] Therefore, the development of new, environmentally benign strategies for the synthesis of highly substituted quinoline analogues is of high importance.

Although the activation of the C-H bond has been well developed over the last a few decades, the activation and cleavage of C-C bonds remains one of the major challenges in modern synthetic chemistry.[2] Additionally, most of the C-C bond activation examples were realized by transition-metal catalysis and oxidative processes.

Herein we report transition-metal free synthesis of 1,2-dihydroquinones from benzylic alcohols as proelectrophiles with aryl-substituted alkynes via Csp2-Csp3 σ bond cleavage without any oxidants or reductants.

Literature:

[1] Kouznetsov, V.V., Vargas Mendez, L. Y., Melendez Gomez, C.M., Curr. Org. Chem. 2005, 9, 141.

[2] M. Tobisu, N. Chatani., Chem. Soc. Rev, 2008, 37, 300., H. Liu, C. Dong, Z. Zhang, P. Wu, X. Jiang., Angew. Chem. Int. Ed, 2012, 51, 12570., R. Lin, F. Chen, N. Jiao., Org. Lett, 2012, 16, 4158.

TEMPO-mediated in situ Formation and Trapping of Unstable Nitrones: Synthesis of N-carbamoyl/acyl Isoxazolines

Gini, A., Regensburg/D, Segler, M., Münster/D, García Mancheño, O., Regensburg/D

Institute for Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93053

Regensburg 4-Isoxazolines (1) are valuable heterocycles used as versatile building blocks for the preparation of biological active compounds such as α-aminoacids, aminoalcohols or alkaloids.[1] Although several methods for their synthesis have been described, the main and most used strategy to obtain the 4-isoxaline core is the 1,3-dipolar cycloaddition (1,3-DCA) between isolated stable N-alkyl and N-aryl nitrones and a dipolarophile, such as an alkene or an alkyne.[1] This leads to isoxazolines with unremovable or difficult to cleavage groups at the nitrogen in the presence of the N-O bond, which significantly limits the scope of this methodology. Thus, the use of intrinsic unstable nitrones bearing easily removable electron-withdrawing groups such as acyl or carbamoyl units is still highly desirable.[2] Herein, we present a new and convenient synthesis of N-carbamoyl and N-acyl 4-isoxalines. Based on our experience on oxidative C(sp3)-H coupling reactions with TEMPO derivatives as mild oxidants,[3] an efficient TEMPO-mediated in situ formation and trapping of unstable nitrones from benzyl hydroxylamines has been developed. Moreover, an unexpected mechanism with this nitroxide radical oxidant will also be discussed.[4]

Literature [1] T. M. V. D. Pinho e Melo, Eur. J. Org. Chem. 2010, 3363–3376. [2] (a) S. A. Hussain, A. H. Sharma, M. J. Perkins, D. J. Griller, Chem. Soc., Chem. Commun. 1979, 289-291. (b) C. Gioa, F. Fini, A. Mazzanti, L. Bernardi, A. Ricci, J. Am. Chem. Soc. 2009, 131, 9614-9615. (c) X. Guinchard, Y. Vallée, J.-N. Denis, Org. Lett. 2005, 7, 5147. [3] (a) T. Stopka, O. García Mancheño, Synthesis 2013, 45, 1602-1611. (b) H. Richter, O. García Mancheño, Org. Lett. 2011, 13, 6066-6069. (c) R. Rohlmann, O. García Mancheño, Synlett 2013, 24, 6-10. (d) H. Richter, R. Fröhlich, C. G. Daniliuc, O. García Mancheño, Angew. Chem. Int. Ed. 2012, 51, 8656-8660. [4] Manuscript in preparation.

New Diastereoselective Calcium Catalyzed Reaction

T.Stopka, Aachen/D

Prof. Dr. M. Niggemann, RWTH Aachen University, Landoltweg 1, 52074 Aachen

The design and synthesis of molecules has been massively influenced by the

development of new catalytic methods over the past decade. In this context, transition

metal catalyzed reactions have enabled so far inaccessible transformations. However,

these methods are limited by expensive and often toxic materials. Not only from a

economic but also from a ecological point of view it is highly desirable to develop

alternative processes.

To that end, calcium seems to be an ideal candidate for Lewis-acid catalysis because it

is nontoxic and is the fifth most abundant element in the earth crust.

Over recent years, our calcium-based catalytic system has proven effective in

multitudinous transformations involving π-activated alcohols and olefins with different

nucleophiles. [1] A new diastereoselective calcium-catalyzed cyclization reaction

involving cationic intermediates in the presence of different additives/ co-catalysts will

be presented.

Literature:

[1] For a recent review on calcium catalysis see: J.-M. Begouin, M. Niggemann Chem.

Eur. J. 2013, 19, 8030.

Trivalent heteroglycoclusters as mimetics for glycan diversity of the cell surface

Müller, C., Kiel/D, Lindhorst, Th. K., Kiel/D

Christian Müller, Christiana Albertina University of Kiel, Otto-Hahn-Platz 3/4, 24118 Kiel, Germany

Every eukaryotic cell is covered by a complex layer of glycoconjugates, called a cell’s ‘glycocalyx’. The width of this sweet coating expands to 100 nm and more, forming an extracellular compartment of the cell. The glycocalyx is critical in cell biology comprising molecular recognition processes in biochemical key processes and carbohydrate-protein interactions, however, its composition is extremely divers and difficult to investigate. Hence, mimetics of glycocalyx components have become important targets in the glycosciences for the investigation of carbohydrate recognition. Especially so-called cluster glycosides[1] serve as valuable tools for the investigation of processes like cell adhesion[2] and cell-cell communication. For the preparation of homo- as well as new heteroglycoclusters we have utilized orthogonally protected trifunctional non-carbohydrate core molecules (Figure 1). This type of cluster glycosides offers the possibility to test the synergetic effects of diversity and multivalency.[3] In addition, this type of molecules can be regarded as glycodendron with a functionalized focal point, offering options for further conjugation of the glycocluster, e. g. with peptides or lipids or for immobilization on different surfaces.[4]

Figure 1: Principal architecture of the targeted heteroglycoclusters.

[1] Y. M. Chabre, R. Roy, Chem. Soc. Rev. 2013, 42, 4657. [2] M. Hartmann, Th. K. Lindhorst, Eur. J. Org. Chem. 2011, 3583. [3] a) A. Patel, Th. K. Lindhorst, Carbohydr. Res. 2006, 341, 1657; b) J. L. Jiménez Blanco, C. Ortiz Mellet, J. M. García Fernández, Chem. Soc. Rev. 2013, 42, 4518. [4] a) M. J. Weissenborn et al., Chem. Commun. 2012, 48, 4444; b) J. W. Wehner, M. Hartmann, Th. K. Lindhorst, Carbohydr. Res. 2013, 371, 22; c) Th. K. Lindhorst, K. Elsner, Beilstein J. Org. Chem. 10, in press.

Enantioselective synthesis of Myrtucommulone A

Charpentier, M., Saarbrücken/D, Jauch, J., Saarbrücken/D Prof. Dr. Johann Jauch, Institut für Organische Chemie II, Universität des

Saarlandes, Campus C4.2, 66123 Saarbrücken Myrtucommulones are acyl phloroglucinol derivatives isolated from myrtle Myrtus communis[1] and from eucalyptus tree Corymbia scabrida[2]. Recently, we published our enantioselective total synthesis of Myrtucommulone A (MCA) (1) using isobutyryl phloroglucinol (2), isobutylidene syncarpic acid (3) and Lithium-Aluminium-BINOL derivatives (Figure 1).[3]

2 3 1 70% ee Figure 1. Enantioselective synthesis of Myrtucommulone A (1). We could modify the existing racemic synthesis[4] with (S)- and (R)-ALB (4) (Figure 2) to obtain the MCA (1) in almost quantitative yield and with ee values up to 70 % ee.[3] Here we wish to report the results obtained through varying the ligand, the central metal or the cation and demonstrate the specificity of (R)- and (S)-ALB (4) towards the formation of MCA (1).

OO

OO

Al

Li

(S)-4 Figure 2. Representation of (S)-ALB ((S)-4). Literature: [1] A. Rotstein, A. Lifshitz, Tetrahedron Lett. 1974, 30, 991-997. F. Cottiglia, L. Casu, M. Leonti, P. Caboni, C. Floris, B. Busonera, P. Farci, A. Ouhtit, G. Sanna,

J. Nat. Prod. 2012, 75, 225-229. [2] A. R. Carroll, J. Lamb, R. Moni, G. P. Guymer, P. I. Foster, R. J. Quinn, J. Nat. Prod. 2008, 71, 1564-1568.

F. Shaheen, M. Ahmad, S. N. Kahn, S. S. Hussain, S. Anjum, B. Tashkhodajev, K. Turgunov, Atta-Ur Rahman, Eur. J. Org. Chem. 2006, 2371-2377.

[3] M. Charpentier, M. Hans, J. Jauch, Eur. J. Org. Chem. 2013, 19, 4078-4084 [4] H. Müller, M. Paul, D. Hartmann, V. Huch, D. Blaesius, A. Koeberle, O. Werz, J. Jauch, Angew. Chemie 2010, 122, 2089-

2093.

PDMS gels as alignment media for NMR/RDC analysis of small organic molecules: synthesis and evaluation

Yu. E. Moskalenko, Darmstadt/DE, V. Bagutski, Darmstadt/DE, L. Kaltschnee, Darmstadt/DE, C. M. Thiele, Darmstadt/DE

Dr. Yulia E. Moskalenko, Technical University of Darmstadt, Alarich-Weiss-Str. 16, 64287 Darmstadt

The standard elucidation of the spatial structure of organic molecules by NMR spectroscopy is based on the analysis of 3J-couplings and on the Nuclear Overhauser Effect (NOE). Recently, a new approach based on the induction of residual dipolar couplings (RDC) in anisotropic media has become a complementary tool providing long-range structural information on configuration and conformation of a molecule [1]. Development of new alignment media compatible with common (deuterated) organic solvents is an inherent task of the RDC approach. PDMS gels are known to be chemically inert to various conditions, to not interfere with analyte signals in NMR spectra and to be compatible with non- and low-polar aprotic organic solvents [2]. However, until recently, fabrication of PDMS sticks for RDC-measurements has required such a non-conventional for a common laboratory technique as β-irradiation.

Our goal is to develop chemical synthesis of the PDMS gels suitable for NMR/RDC measurements and investigate its scope and limitations as alignment media. Thus, octamethylcyclotetrasiloxane (D4) was copolymerized with variable amounts of the cross-linker (bis-D4) in the presence of anionic catalyst [3] to give an array of gels contained 1, 2, 2.6, 3 and 4 wt.% of bis-D4. Orienting properties of these gels were characterized by measuring of the quadrupolar splitting of CDCl3 signal in 2H NMR spectra, which were in the range of 5-40 Hz depending on the cross-linker content thus offering a very low degree of alignment. Gel swelling and equilibration was visualized by 2H-NMR imaging [4]. The performance of the PDMS gels as an alignment media was evaluated in the structural analysis of β-caryophyllene.

Literature:

[1] Böttcher B., Thiele C. M. eMagRes (Ed. R. K. Harris, R. Wasylishen), John Wiley, Chichester, 2012, 1, 169. [2] Freudenberger J. C., Spiteller P., Bauer R., Kessler H., Luy B. J. Am. Chem. Soc. 2004, 126, 14690. [3] Zheng P. W., McCarthy T. J. J. Am. Chem. Soc. 2012, 134, 2024. [4] Trigo-Mouriño P., Merle C., Koos M. R. M., Luy B., Gil R. R. Chem. Europ. J. 2013, 19, 7013.

Bidirectional Gold-Catalyzed Synthesis of Polycyclic Heteroarenes

T. Schnitzer, Heidelberg, A. S. K. Hashmi, Heidelberg

Prof. Dr. A. Stephen K. Hashmi, University of Heidelberg, Im Neuenheimer Feld 270,Heidelberg

Recently, multi-component reactions became a powerful tool in the synthesis ofheterocyclic compounds. Inspired by the work of B. Kundu and colleagues whodescribed an efficient synthesis of heterocyclic urea systems via tandem metal-catalyzed cross-coupling followed by a gold-catalyzed cyclization (scheme 1) [ 1], we setout to synthesize pentacyclic heteroarenes.

Scheme 1: Previous work on palladium, copper and gold catalyzed tandem cyclization to urea compounds.

Herein we report on the synthesis of bis-dibromovinyl phenylenediamine. The resultson the study for the synthesis towards pentacyclic urea systems will be presented onthis contribution.

Scheme 2: Bidirectional synthesis of heterocyclic urea systems.

[1] S. Grupta, D. Koley, K. Ravikumar, B. Kundu, J. Org. Chem. 2013, 78, 8624-8633.

Chiral Helical Oligotriazoles: New Class of Anion Acceptor Catalysts for the

Asymmetric Dearomatization of Quinolines

Zurro, M., Regensburg/D, Asmus, S., Regensburg/D, Beckendorf, S., Münster/D, García

Mancheño, O., Regensburg/D

Institute for Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93053

Regensburg Dearomatization reactions are very important transformations as they lead directly to a variety of

functionalized rings, including heterocyclic systems. Heterocycles are moieties present in a wide

variety of natural products. Although many dearomatization methods have been developed,

enantioselective processes are still rare.[1] An interesting approach is the use of neutral H-donor

molecules as anion acceptor catalysts.[2] However, till date essentially only chiral ureas and

especially thioureas have been employed as efficient acceptors in organocatalysis. With the aim

of providing alternative structures for anion acceptor catalysis, our group has recently developed

a family of BisTriazoles and efficiently employed for the first time as H-donor organocatalysts.[3]

Herein, the catalytic activity of chiral helical oligotriazoles is described. In particular, their

outstanding performance as chloride acceptors for the organocatalyzed dearomatization of

quinolines will be presented.

Literature:

[1] Review on asymmetric dearomatizations: C. Zhuo, W. Zhang, S. You, Angew. Chem. Int. Ed.

2012, 51, 12662-12686.

[2] Recent Reviews: a) M. Mahlau, B. List, Angew. Chem. Int. Ed. 2013, 52, 518-533; b) K. Brak,

E. N. Jacobsen, Angew. Chem. Int. Ed. 2013, 52, 534-561; c) S. Beckendorf, S. Asmus, O.

García Mancheño, ChemCatChem 2012, 4, 926-936; d) Z. Zhang, P. R. Schreiner, Chem. Soc.

Rev., 2009, 38, 1187–1198.

[3] a) S. Beckendorf, S. Asmus, C. Mück-Lichtenfeld, O. García Mancheño, Chem. Eur. J.

2013,19, 1581-1585; b) S. Asmus, S. Beckendorf, M. Zurro, C. Mück-Lichtenfeld, R. Fröhlich, O.

García Mancheño, Chem. Asian J. 2014, DOI: 10.1002/asia.201402237.

Investigations towards the Total Synthesis of Socein A and Derivatives: Cyclic Peptides with High Antifungal Activities

M. R. Klos, Saarbrücken/DE , U. Kazmaier, Saarbrücken/DE

Dipl.-Chem. Manuel R. Klos, Saarland University, Campus C4 2, 66123 Saarbrücken

Soceins are natural products structurally closely related to the Microsclerodermins and Pedeins.[1] From the aforementioned peptides, they differ in the key β-amino acid in the eastern part of the macrocycle (figure 1). In the Microsclerodermin/Pedein scaffold, this polyhydroxylated building block appears in an open chain form, whereas in Socein A it exists as an oxygen containing heterocycle.

So far only one total synthesis of Microsclerodermin E has been reported.[2] Further publications deal with the assembly of fragments, especially of the unusual β-amino acids of the substance class.[3] Because of the slightly novel chemical lead in this rigid region of Socein A, we have made efforts towards its modular construction.

Figure 1: Structure, shortcut retrosynthesis and features of Socein A.

Literature:

[1] R. Müller et al., J. Am. Chem. Soc. 2013, 135, 16904. [2] D. Ma et al., Angew. Chem. 2003, 115, 5506. [3] a) T.J. Donohoe et al., Org. Lett. 2013, 15 (21), 5492; b) S.G. Davies et al., J. Org. Chem. 2013, 78, 2500.

Application of the P450 BM3 monooxygenase for the stereoselective

synthesis of substituted isocoumarines

C. Holec, Jülich/D, K. Neufeld, Jülich/D

Prof. Dr. Jörg Pietruszka, Heinrich Heine University Düsseldorf located in the Forschungszentrum Jülich, Stetternicher Forst, Bldg. 15.8, Jülich/D

The regio- and stereoselective hydroxylation of organic compounds has been extensively studied in the last decades aiming at improved access to key building blocks and fine chemicals. The application of transition metal catalysts for the selective hydroxylation of carbon-hydrogen bonds using molecular oxygen has been proven as difficult.[1] Therefore the use of enzymes as chiral catalysts offers high potential in this field. Cytochrome P450 monooxygenases are able to catalyze the insertion of an oxygen atom from molecular oxygen into activated and even non-activated carbon-hydrogen bonds of a variety of organic compounds in a regio- and stereoselective manner.[2] As a well-characterized and highly active enzyme, the monooxygenase P450 BM3 from Bacillus megaterium was modified in mutagenesis approaches to oxidize a variety of non-natural substrates.[3] Here we present our recent results regarding the stereoselective P450 BM3 catalyzed synthesis of isocoumarines as building blocks for natural product and active agent synthesis.

Figure 1: Crystall structure of P450 BM3 (PDB: 1BVY) showing the heme- and

reductase-domain fused in a single polypeptide chain and its catalyzed reaction.

References: [1] E. Roduner W. Kaim, B. Sarkar, V. B. Urlacher, J. Pleiss, R. Gläser, W.-D. Einicke, G. A. Sprenger, U. Beifuß, E. Klemm, C. Liebner, H. Hieronymus, S.-F. Hsu, B. Plietker, S. Laschat, ChemCatChem, 2013, 5, 82. [2] a) R. Agudo, G. D. Roiban, M. T. Reetz, ChemBioChem. 2012, 13, 1465; b) M. W. Peters, P. Meinhold, A. Glieder, F. H. Arnold, J. Am. Chem. Soc. 2003, 125, 13442. [3] a) C. J. C. Whitehouse, S. G. Bell, L.-L. Wong, Chem. Soc. Rev. 2012, 41, 1218; b) K. Neufeld, J. Marienhagen, U. Schwaneberg, J. Pietruszka, Green Chem. 2013, 15, 2408.

New Catalyst for CF Bond Activation

N. Kordts, Oldenburg/D, T. Müller, Oldenburg/D

Prof. Dr. Thomas Müller, Carl von Ossietzky Universität Oldenburg, Carl von Ossietzky

Straße 9-11, 26129 Oldenburg (Federal Republic of Germany) The great successes of fluorine chemistry lead to numerous applications in daily life. The high stability of CF bonds gives rise to a very persistent family of substances with problems in disposal of wastes. It is a challenge to find methods for selective bond cleavage. Strong Lewis acids such as silyl cations are able to activate sp³-CF bonds.1 Silyl cationic naphthyl systems 1 und 2 were synthesized with group 14 and 16 elements in the 1,8-position and tested in CF activation reactions.

R2E ER2H

E = Si, GeR = Me, n-Bu

Ch SiMe2Ar

E = S, Se, TeAr = Ph, Mes

1 2 Using Ph3C[B(C6F5)4] we were able to synthesize the silyl cations 1 and 2 starting from their naphthyl hydrosilanes2 and naphthyl chalcogenyl hydrosilanes.3 The cations 1 are stabilized via three center two electron bonds caused by a bridging hydride between the two group 14 elements.2 The cations 2 are stabilized by an intramolecular interaction involving the chalcogen lone pair to account for the electron deficiency at the silicon atom. [1] T. Stahl, H. F. T. Klare, M. Oestreich, ACS Catal. 2013, 3, 1578 – 1587. [2] T. Müller, N. Lühmann, H. Hirao, S. Shaik, Organometallics. 2011, 30 (15), 4087 – 4096. [3] F. R. Knight, A. L. Fuller, M. Bühl, A. M. Z. Slawin, J. D. Woollins, Chem. Eur. J. 2010, 16, 7503 – 7516.

Synthesis of Argyrins and SAR Studies for Lead Optimisation

P. Engel García, Hannover/D, D. Könning, Hannover/D, M. Kalesse, Hannover/D,

Institute for Organic Chemistry, Leibniz University Hannover, 30167 Hannover and Helmholtz Center for Infection Research, 38124 Braunschweig

paloma.engel@oci.uni-hannover.de, daniel.koenning@helmholtz-hzi.de

In the quest for new targets for antitumor therapy, the proteasome and its inhibitors have been the focus of academic and industrial research. In this context, Kalesse and co-workers recently reported the stabilisation of p27 mediated through selective inhibition of the proteasome by argyrin F.[1] Due to the potential of the argyrins as drug candidates, and in order to understand the precise mode of action, an elegant solution-based synthesis of argyrins A-H and six other analogues was performed, which were then utilised in SAR studies.[2] In addition, it has been shown that argyrins inhibit bacterial protein synthesis. Argyrin B binds a novel allosteric pocket in elongation factor G (EF-G),[3] distinct from the known EF-G inhibitor antibiotic fusidic acid, revealing a new mode of protein synthesis inhibition, which represents an interesting advance in the development of new antibiotics with alternative modes of action.

In the current study, we propose both an expedient solution and solid-phase synthesis

which would allow rapid access to argyrins A-H, as well as a raft of argyrin analogues. The solid-phase strategy employs the N-acylsulfonamide safety-catch linker to allow for the assembly of the complete peptide chain from commercially available sulfamylbutyryl resins, by standard Fmoc-solid-phase peptide synthesis.[4] The derivatives produced would then undergo further SAR studies as proteasome inhibitors to complement those already performed, as well as SAR at EF-G. These studies would allow us to differentiate the original argyrin core structures into proteasome and EF-G specific inhibitors as well as elucidating which structural motifs are essential for each target. [1]S. Nickeleit et al., Cancer Cell 2008, 14, 23-35; [2]S. V. Ley, A. Priour, Eur. J. Org. Chem. 2002, 3995-4004; L. Bülow et al., ChemMedChem 2010, 5, 832-836; [3]B. Nyfeler et al., PLoS ONE 2012, 7, e42657; [4]J. A. Ellman et al., J. Am. Chem. Soc. 1996, 118, 3055-3056.

α-Hydroxyl Carbonates Prepared Catalytically in One-Pot

S. M. M. Schuler, D. Niedek, and Prof. Dr. P. R. Schreiner

Justus-Liebig University, Heinrich-Buff-Ring 58, 35392 Gießen, Germany/DE

Organic carbonates (OCs) appear in a large number of natural products (e.g., 1 and 2)[1]

and as intermediates in total syntheses.[2] Various strategies have been established for

synthesizing OCs,[1, 3] with the protocol developed by Roush et al. being common.[2a, 2c, 4]

Only a few organocatalytic variants are known[5] and we present herein a one-pot

synthesis of α-hydroxyl carbonates under ambient conditions starting from the

corresponding allyl carbamates.

In a two-step sequence carbamate[6] 3 is epoxidized with mCPBA yielding

epoxycarbamate 4, which is directly converted into carbonate 5 utilizing thiourea

catalyst[7] 6. Parameters such as the effect of the amine leaving group, reaction time, and

additives were tested to optimize the reaction conditions. This protocol enables access

to a variety of synthetically highly valuable α-hydroxyl carbonates.

[1] H. Zhang, H.-B. Liu, J.-M. Yue, Chem. Rev. 2014, 114, 883-898. [2] (a) D. A. Clark, F. De Riccardis, K. C. Nicolaou, Tetrahedron 1994, 50, 11391-11426; (b) H. Okamura,

H. Shimizu, N. Yamashita, T. Iwagawa, M. Nakatani, Tetrahedron 2003, 59, 10159-10164; (c) T. K. Trullinger, J. Qi, W. R. Roush, J. Org. Chem. 2006, 71, 6915-6922.

[3] A.-A. G. Shaikh, S. Sivaram, Chem. Rev. 1996, 96, 951-976. [4] W. R. Roush, R. J. Brown, M. DiMare, J. Org. Chem. 1983, 48, 5083-5093. [5] (a) P. U. Naik, L. Petitjean, K. Refes, M. Picquet, L. Plasseraud, Adv. Synth. Catal. 2009, 351, 1753-

1756; (b) Y.-B. Wang, Y.-M. Wang, W.-Z. Zhang, X.-B. Lu, J. Am. Chem. Soc. 2013, 135, 11996-

12003. [6] G. Peris, C. E. Jakobsche, S. J. Miller, J. Am. Chem. Soc. 2007, 129, 8710-8711. [7] (a) P. R. Schreiner, A. Wittkopp, Org. Lett. 2002, 4, 217-220; (b) Z. Zhang, K. M. Lippert, H.

Hausmann, M. Kotke, P. R. Schreiner, J. Org. Chem. 2011, 76, 9764-9776.

Dye Functionalized Mesoporous Silica Hybrids

Showing White Light Fluorescence

Markus Börgardts, Thomas J. J. Müller:

HHU Düsseldorf, Institut für Organische Chemie und Makromolekulare Chemie,

Düsseldorf, Germany

Mesoporous silica such as MCM-41 and SBA-15, exhibit a hexagonal, honeycomb-like,

ordered cylindrical pore system with high specific surface areas around 1000 m²/g.[1]

The pore diameters are in the range of 2 - 10 nm and thus of the size of organic

molecules.[2] By incorporation of fluorescent dyes inside the mesoporous silica, hybrid

materials can be obtained which show white light emission when mixed in a defined

ratio.

The covalent attachment of the dyes to the inorganic silica can be accomplished via a

triethoxysiliyl terminated linker, which is introduced to the dye via a click reaction. The

obtained mesoporous structures are characterized by nitrogen sorption analysis and

small angle X-ray scattering (SAXS). The spectroscopic behaviour of the hybrid

materials is studied by excitation and emission measurements.

References

[1] P. Cool, E. F. Vasant, O. Collart, Inorganic Chemistry in Focus II, G. Meyer, D. Naumann, L. Wesemann (Hrsg.), 2005,

319-346, Wiley, Weinheim.

[2] F. Hoffmann, M. Cornelius, J. Morell, M. Fröba, Angew. Chem. 2006, 118, 3290-3328; Angew. Chem. Int. Ed. 2006, 45,

3216-3251.

Novel One-pot Cu(I)-catalyzed Carboxylation-CuAAC Sequence

E. Schreiner, Düsseldorf/D

Prof. Dr. Thomas J. J. Müller, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1,

40225 Düsseldorf/D

Multicomponent reactions (MCR) and sequential one-pot catalytic processes possess

great importance for accessing heterocyclic compounds and pharmaceutically

interesting targets. These methodologies represent rapid accesses to highly

functionalized molecules from simple and readily available starting materials. In this

context the development of novel sequential catalytic one-pot processes recently

gained much attention. [1] The advantages over traditional multistep syntheses are

considerably shorter reaction times, resource efficiency, and reduced waste production,

warranting ecologically and economically benign processes. [2]

The copper-catalyzed carboxylation of terminal alkynes furnishes propiolic acids [3] that

can be converted into the corresponding esters by the addition of an alkylating agent.

Propargyl bromide allows for the incorporation of a terminal alkyne so that a

subsequent copper-catalyzed azide-alkyne cycloaddition (CuAAC) can be performed.

These 1,4-functionalized 1,2,3-triazoles can be synthesized in one-pot process in good

yields (Scheme 1).

Scheme 1: Sequential catalysis combining the Cu(I)-catalyzed Carboxylation and CuAAC in a one-pot fashion.

Literature

[1] a) L. M. Ambrosini, T. H. Lambert, ChemCatChem 2010, 2, 1373-1389; b) R. C. Wende, P.

R. Schreiner, Green Chem. 2012, 14, 1821-1849; [2] L. F. Tietze, Chem. Rev. 1996, 96,

115-136; [3] D. Yu, Y. Zhang, PNAS 2010, 107, 20184-20189.

Synthesis of AB4 Carbohydrate Scaffolds as Branching Units in the

Glycosciences

T.-E. Gloe, Kiel/DE, T. K. Lindhorst*, Kiel/DE Tobias-Elias Gloe (M. Sc.), Christiana Albertina University of Kiel, Otto Diels Institute of

Organic Chemistry, Otto-Hahn-Platz 4, 24118 Kiel Every cell in nature is covered by a thick layer consisting of highly complex glycoconjugates, the glycocalyx.[1] Carbohydrates as part of these glycoconjugates modulate a broad variety of processes such as signaling,[2] recognition[3] and adhesion[4] through proteins that specifically recognize and bind carbohydrates. Since single protein-carbohydrate interactions are rather weak, multivalent interactions are important for carbohydrate recognition.[5] To further investigate multivalency effects, branched and hyperbranched molecules are suitable tools. Due to their multifunctionality and conformational rigidity carbohydrates are excellent branching units for the synthesis of carbohydrate-centered glycomimetics such as dendrimers[6], glycoclusters[7] and other bioactive compounds. In this approach we report about the synthesis of AB4-type carbohydrate scaffolds that allow for substitution via different ligation methods. Each hydroxyl group is functionalized with a propylamino tether, thus allowing for further branching or direct substitution with other carbohydrate moieties via thiourea coupling or Amadori rearrangement. Different functional groups in the aglycon of the scaffold provide a variety of applications such as coupling to different surfaces, supramolecules or carbohydrate moieties (Figure 1).

Figure 1: Schematic illustration of AB4-type carbohydrate scaffolds. Hydroxyl groups are functionalized with a propylamino tether while the aglycon can be substituted with different functional groups.

Literature

[1] Dwek, R. A., Biochem Soc Trans 1995, 23 (1), 1-25. [2] Sharon, N.; Lis, H., Science 1989, 246 (4927), 227-34. [3] Sharon, N.; Lis, H., Sci Am 1993, 268 (1), 82-9. [4] Ofek, I.; Hasty, D. L.; Sharon, N., FEMS Immunology and Medical Microbiology 2003, 38 (3), 181-191. [5] Kiessling et al., Multivalency in Protein–Carbohydrate Recognition, Springer Berlin Heidelberg 2008. [6] Dubber, M.; Lindhorst, Th. K., Chem Commun 1998, 12, 1265-1266. [7] Dubber, M.; Lindhorst, Th. K., J Org Chem 2000, 65, 5275-5281.

Regioselective Enzymatic Halogenation of Substituted Tryptophan Derivatives

using the FAD-Dependent Halogenase RebH

Frese, M., Sewald, N.

Frese, M., Organic and Bioorganic Chemistry OC III, Department of Chemistry, Bielefeld University, Bielefeld, Germany. Although halogenation is a common methodology for the functionalization of organic compounds, regioselective methods to establish carbon-halide bonds are still rare. The chemical incorporation of halogen atoms is a wasteful process with a high detrimental influence on the environment. It requires harsh conditions in combination with hazardous chemicals like elementary chlorine or bromine, shows poor regioselectivity and results in the formation of unwanted byproducts that have to be removed elaborately. Since halogenated products are essential intermediates for nucleophilic substitution and metal-catalyzed cross-coupling reactions in the chemical, agrochemical and pharmaceutical industry, the development of new sustainable, environmental friendly regio- and stereoselective methods for halogenation is highly desirable. In nature, several enzymatic strategies for the selective halogenation of more than 5000 metabolites are known. The FAD-dependent tryptophan halogenase RebH originates from the biosynthetic pathway of the chlorinated antitumor agent Rebeccamycin from Lechevalieria aerocolonigenes. Notably, the enzyme is able to chlorinate and brominate L-tryptophan and its substituted derivatives only in presence of halide ions and oxygen at pH 7 and 25 °C in aqueous media at the electronically unfavored C7-(meta) position, even in presence of ortho/para-directing groups. Using this sustainable enzymatic approach, these novel halogenated products can be used as valuable intermediates for the synthesis of peptides and signaling molecules that contain chemoselective sites for functionalization. Reference Frese, M., Guzowska, P. H., Voß, H., and Sewald, N. (2014) Regioselective Enzymatic Halogenation of Substituted Tryptophan Derivatives using the FAD-Dependent Halogenase RebH. ChemCatChem 6, 1270–1276.

FADH2

FAD

HOX

NAD+

NADH

+ H+

RebH

FAD-dependent Trp-halogenase

pH 7.4, 25 °C, aqueous

Flavin reductase

NaX

X = Cl, Br

~10 Å

FAD-OOH

FAD-OH

O2

Recognition of DNA Sequences by N-Heterocyclic Polyamides

Müller, S. and Sewald, N.

Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, D-33615 Bielefeld

Natural compounds containing N-heterocyclic aromatic units such as distamycin A and netropsin bind to the minor groove of A·T-rich DNA sequences [1]. Moreover, polyamides containing the aromatic amino acids N-methylpyrrole (Py), N-methylimidazole (Im) and N-methylhydroxypyrrole (Hp) act as synthetic analogues of the natural compounds and bind to corresponding sequences. Short polyamides containing a γ-aminobutyric acid linker form so called hairpins which fit into the minor groove of the DNA double strand [1]. In order to address desired base sequences specifically, pairs of aromatic amino acids (C·G – Py/Im; G·C – Im/Py; T·A – Hp/Py; A·T – Py/Hp) have been used as molecular identifiers [1]. Due to this sequence specific binding inhibition of gene expression was found for different types of cancer [2-4]. Upregulation of transcription can be achieved in two distinct ways. On the one hand binding of a repressor can be blocked by the polyamide [5], whereas on the other hand an artificial transcription factor, containing a hairpin polyamide [6], results in activation of transcription.

En route to artificial bacterial transcription factors, photoswitchable N-heterocyclic polyamides targeting bacterial promotor sequences have been synthesized and tested with respect to DNA binding.

[1] P. B. Dervan, R. E. Bürli Curr. Opin. Struct. Biol. 1999 3 688. [2] H. Matsuda et al. Kidney Int. 2011 79 46. [3] X. Wang et al. Cancer Sci. 2010 101 759. [4] N. G. Nickols, P. B. Dervan Proc. Natl. Acad. Sci. USA 2007 104 10418. [5] L. A. Dickinson, J. W. Trauger, E. E. Baird, P. Ghazal, P. B. Dervan, J. M.

Gottesfeld Biochemistry 1999 38 10801. [6] A. K. Mapp, A. Z. Ansari, M. Ptashne, P. B. Dervan Proc. Natl. Acad. Sci. USA

2000 97 3930.

New Strageties in Halocyclization Reactions

C. Rösner., Münster/DE-NW

Dr. Ulrich Hennecke, University of Münster, Corrensstraße 40, 48149 Münster

Halocyclization reactions like iodoetherifications are important reactions for the preparation of heterocycles and often proceed under mild conditions with a high diastereoselectivity. Mechanistically, the reactions are generally believed to proceed via an halonium ion intermediate. Its opening by backside attack leads to the observed anti-addition to the double bound.[1] Although halocyclization reactions are such a powerful tool in organic synthesis, reagent controlled enantioselective variants of these reactions are rare and often limited to special cases.[2] Most approaches to catalytic enantioselective halocyclization reaction are based on nucleophilic catalysis of the formation of the halonium ion. These approaches are generally only successful for halolactonizations but not haloetherifications. Our approach is instead based on the selective opening of halonium ions in the presence of a suitable chiral counteranion. [3]

NuH NuH

+ XY

NuH NuH

XYchiral

stereochemistrydeterming step

-HY

NuH

X

Nu

Figure 1: Asymmetric halonium ion trapping.

Using a BINOL-based phosphate catalyst good yields and enantioselectivities in asymmetric haloetherifications can be achieved under practical reaction conditions. [4]

Figure 2: Asymmetric Haloetherification using a sodium phosphate catalyst. Literature: [1] A. N. French, S. Bissmire, T. Wirth Chem. Soc. Rev. 2004, 33, 354-362. [2] U. Hennecke Chem. Asian J. 2012, 7, 456-465. [3] U. Hennecke, C. H. Müller, R. Fröhlich Org. Lett. 2011, 13, 860-863. [4] C. H. Müller, C. Rösner, U. Hennecke Chem. Asian J. 2014, DOI: 10.1002/asia.201402229.

α-Aminonitriles as Versatile Building Blocks for the Synthesis of the

Bisbenzylisoquinoline Skeleton of Tubocurarine

N.Otto, Mainz/D, T. Opatz*, Mainz/D Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, D-55128

Mainz, Germany

Bisbenzylisoquinoline alkaloids exhibit diverse biological activities; an important example is tubocurarine 5, known as the arrow poison curare, which acts as a skeletal muscle relaxant by inhibiting the nicotinic acetylcholine receptor.[1]

Recently, we have shown α-aminonitriles to be useful building blocks for the modular enantioselective synthesis of dimeric benzyl tetrahydroisoquinolines.[2] Here, we report on current studies towards the synthesis of the bisbenzylisoquinoline skeleton of tubocurarine from deprotonated α-aminonitriles.

Deprotonation of α-aminonitriles 1 with KHMDS furnishes stabilized α-aminocarbanions which can be C-alkylated with benzylbromides 2 and subsequently reduced to yield the 1-benzyl 3,4-dihydroisoquinolines 3.[3] Starting from two benzyl tetrahydroisoquinoline units 3a and 3b, the seco-heterodimer 4 can be prepared by head-to-tail Ullmann coupling. Currently, we are working on the closure of the macrocyclic ring through C-O-bond forming reactions to furnish the skeleton of tubocurarine.

References:

[1] West, R. Med. Hist. 1984, 28, 391–405 [2] Werner, J.; Blank, N.; Opatz, T. J. Org. Chem. 2011, 76, 9777–9784 [3] Blank, N.; Opatz, T. Eur. J. Org. Chem. 2007, 3911–3915.

Total Synthesis of a new Alternaria Toxin

D. Kohler, Karlsruhe/D, G. Nemecek, Trostberg/D, J. Podlech, Karlsruhe/D

Prof. Dr. Joachim Podlech, Karlsruher Institut für Technologie,

Institut für Organische Chemie, Fritz-Haber-Weg 6, 76131 Karlsruhe

Alternaria spp. are common and ubiquitous molds producing toxins, which are harmful

for humans and animals. Some of the alternaria toxins are structurally unknown. We

are interested in the structure elucidation of these compounds by total synthesis.

Spectroscopical data of the synthesized products can be compared with those of

authentical natural products.

Intermediate 1 was postulated in the anabolic pathway of altenuic acid II (2), a toxin

produced by Alternaria alternata (Figure 1).[1,2]

Fig. 1: Biosynthesis of altenuic acid II from intermediate 1.

Tricarboxylic acid 1 was synthesized by oxidative cleavage of the catechol unit in

altenusin (3) (Figure 2).

Fig. 2: Sythesis of intermediate 1 by oxidative cleavage.

[1] D. Williams, R. Thomas, Tetrahedron Lett. 1973, 639 – 640.

[2] G. Nemecek, R. Thomas, H. Goesmann, C. Feldmann, J. Podlech,

Eur. J. Org Chem. 2013, 6420 – 6432.

Altertoxin I: A total synthetic strategy

D. Pfaff, Karlsruhe/D, J. Podlech, Karlsruhe/D

Prof. Dr. Joachim Podlech, Karlsruher Institut für Technologie,

Institut für Organische Chemie, Fritz-Haber-Weg 6, 76131 Karlsruhe

We are interested to develop a total synthesis of different perylenequinone-derived

Alternaria toxins like Altertoxin I (1). As a possible intermediate we use the 9,10-

phenanthrenequinone 2, which was synthesized according to a modified route

presented by Dallacker et al.[1]

OH

HOH

OH

OH

O

O

OC6H13

OC6H13

O

O

1 2

OC6H13

OC6H13

O

O

O

3

Fig.1: Altertoxin I (1), 9,10-phenanthrenequinone 2 and acetal-protected 9,10-

phenanthrenequinone 3.

Ghera et al. demonstrated that selective acetal protection of one carbonyl group in the

9,10-phenanthrenequinones is possible.[2] So we are able to modify the carbonyl

groups independently. Among the routes tested with intermediate 3 is an approach via

a Grignard addition, a Petasis olefination[3] and an HWE olefination.

[1] F. Dallacker, H. Leidig, Chem. Ber. 1979, 112, 2672 – 2679.

[2] M. Mervič, E. Ghera, J. Org. Chem. 1980, 45, 4720 – 4725.

[3] N. A. Petasis, E. I. Bzowej, J. Am. Chem. Soc. 1990, 112, 6392 – 6394.

 

The Use of α,β-Unsaturated δ-Lactones in Natural Product Synthesis

Y. Gehrke, Jülich, D, J. Pietruszka, Jülich, D

Institut für Bioorganische Chemie der Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich, Stetternicher Forst, Geb. 15.13, D-52426 Jülich, Germany

α,β-Unsaturated δ-lactones are a common feature in many natural products with pharmacological activities, such as the derivatives of brevipolides 1, bioactive 5,6-dihydro-α-pyrones from Hyptis brevipes. Recently, six derivatives of this cytotoxic compound have been isolated from plant specimens from Indonesia.1

The enantioselective synthesis of lactones has been established in our group over the last years, using a chiral boron compound 2. The ligand attached to the boron was shown to be extremely stable and therefore easily to handle. As an example, the stereoselective synthesis of rugulactone could be achieved using an allyladdition reaction with compound 2 followed by oxidation and ring closure.2

Herein we report our progress towards the synthesis of the brevipolides framework with a focus on the stereoselective formation of the lactone.

 

1. (a) Deng, Y.; Balunas, M. J.; Kim, J. A.; Lantvit, D. D.; Chin, Y. W.; Chai, H.; Sugiarso, S.; Kardono, L. B. S.; Fong, H. H. S.; Pezzuto, J. M.; Swanson, S. M.; de Blanco, E. J. C.; Kinghorn, A. D.,J. Nat. Prod. 2009, 72 1165-1169; (b) Suárez-Ortiz, G. A.; Cerda-García-Rojas, C. M.; Hernández-Rojas, A.; Pereda-Miranda, R.,J. Nat. Prod. 2013, 76 72-78.

2. (a) Böse, D.; Fernández, E.; Pietruszka, J.,J. Org. Chem. 2011, 76 3463-3469; (b) Böse, D.; Niesobski, P.; Lübcke, M.; Pietruszka, J.,J. Org. Chem. 2014, 79 4699-4703.

 

Phenylcyclopropylamines

MAO A and B Inhibitors and Precursors for 18F-Radiotracers

Bartels, K., Münster/DE, Schinor, B., Münster/DE, Haufe, G., Münster/DE

Prof. Dr. Günter Haufe, Westfälische Wilhelms-Universität, Organisch-Chemisches Institut, Corrensstr. 40, D-48149 Münster

Phenylcyclopropylamines like Tranylcypromine (trans-2-Phenylcyclo-propylamine, Parnate®, Jatrosom® N) are very prominent irreversible inhibitors of monoamine oxidases (MAO). An overexpression of MAO A is associated with the occurrence of depression due to a reduced amount of neurotransmitters like dopamine, noradrenaline, and adrenaline in the central nervous system. MAO B is connected to Alzheimer’s and Parkinson’s diseases.[1]

To increase the inhibitor efficiency several structural modifications have been studied. It is already known that the attachment of a fluorine atom to the cyclopropyl system leads to increased inhibitory activities.[2] Therefore influences of different substituents on the phenyl ring were determined.

The tranylcypromine derivatives were synthesized from the corresponding styrenes or α-fluoro styrenes, respectively. Cyclopropanation with diazo compounds gave the diastereomeric cis- and trans-cyclopropylcarboxylic esters, which were saponificated to the free carboxylic acids. CURTIUS degradation to the Boc-protected amines and deprotection with HCl resulted in the final amine hydrochlorides.

Tests against human recombinant MAO A and B revealed that introduction of electron withdrawing substituents in the aryl ring of fluorinated trans-phenylcyclopropylamines led to improved inhibitory potency against both isoenzymes. In contrast, the corresponding fluorinated cis-diastereomers exhibited an increased MAO B selectivity.[3]

Further modifications of the p-substituent on the phenyl ring led to precursors for the 18F-radiolabeling for PET investigations.

[1] M. B. Youdim, D. Edmondson, K. F. Tipton, Nature Rev. Neurosci. 2006, 7, 295. [2] S. Hruschka, T. Rosen, S. Yoshida, K. L. Kirk, R. Fröhlich, B. Wibbeling, G. Haufe, Bioorg. Med. Chem. 2008, 16, 7148. [3] B. Schinor, B. Wibbeling, G. Haufe, J. Fluorine Chem. 2013, 155, 102.

Reactions of 1-Azido-1-halo Compounds

K. Weigand, Chemnitz/DE, K. Banert, Chemnitz/DE

Dipl.-Chem. Kevin Weigand, Technische Universität Chemnitz, Institute of Chemistry, Straße der Nationen 62, 09111 Chemnitz

The previous attempts towards the synthesis of geminal 1-azido-1-halo compounds 3 from 1 were unsucccesful because the first substitution step of 1 is very slow relative to the succeeding process 3 � 4, leading to 4 as the exclusive product. However, we synthesised azidohalomethane (X = Br, Cl) for the first time from tris(azidomethyl)-amine and hydrogen chloride or hydrogen bromide. [1]

The convenient access to different title compound 3 by treating α-azido alcohols 2 [2] with PX3 enables consecutive reactions, for example, nucleophilic substitution or HX elimination, to establish new functionalized azides. Furthermore, photolysis and [4+2] or [2+2] cycloadditions [3] are possible successive reactions of the vinyl azides.

R N3

X

R N3

SCN

R N3

N3

N3 SCN

KOtBu

X N3

R N

X

N

N

34b,c

7

5a,b,c

8a,b,c,d,e

a) R = CCl3

b) R = CO2Et

c) R = CH2Cl

d) R = CH3

e) R = CH2CH3

f) R = HKOtBu

N3 N3

9

N3

Cl

6

+

R N3

OH

2

PX3

X = Cl, Br

N3

R X

X

1

R = CH2ClR = CH2Cl

X = Cl, Br

X = Cl, Br

[1] K. Banert, Y.-H. Joo, T. Rüffer, B. Walfort, H. Lang, Tetrahedron Lett. 2010, 51, 2880–2882.

[2] K. Banert, C. Berndt, S. Firdous, M. Hagedorn, Y.-H. Joo, T. Rüffer, H. Lang, Angew. Chem. 2010, 122, 10404−10407; Angew. Chem. Int. Ed. 2010, 49, 10206–10209.

[3] K. Banert, Chem. Ber., 1989, 122, 123−128.

Pd(II)‐Catalyzed, Enantioselective Three-Component Synthesis of -Substituted Amine Derivatives from Sulfonamides, Aldehydes and Boronic Acids

T. Beisel, Frankfurt am Main/D, G. Manolikakes, Frankfurt am Main/D

Tamara Beisel, Goethe-Universität Frankfurt am Main, Max-von-Laue-Str. 7, 60438

Frankfurt am Main/D

-Substituted nitrogen functions are present in a variety of bioactive molecules with wide-ranging biological properties. [1] One of the most used methods for the synthesis of these interesting structural motifs is the nucleophilic addition to carbon-nitrogen double bonds, such as imines. Simple N-alkylimines and N-arylimines show a limited reactivity and do not react with weak nucleophiles. The introduction of electron-withdrawing groups on the nitrogen atom can render the azomethine carbon considerably more electrophilic. These reactive imine derivatives, such as N-sulfonylimines or N-acylimines, can add to a wide variety of different nucleophiles. [2] One example is the Pd-catalyzed addition of arylboronic acids to N-tosylimines. [3] However, these 2-component reactions require the synthesis of reactive imine species or suitable precursors prior to the addition reaction.

A general efficient and enantioslective 3-component synthesis of -substituted amines without the need of preformed imine derivatives would be of great interest. In the course of our studies towards novel multicomponent reactions, our group developed a Pd(II)-catalyzed, enantioselective 3-component reaction based on the addition of boronic acids to in situ generated N-sulfonylimines. [4] This method allows an

efficient and practical synthesis of -substituted amine derivatives from readily available sulfonamides, aldehydes and boronic acids. The scope of this reaction is quite broad and good to excellent yields and enantioselectivities are obtained. Crucial for the development of this new reaction, was the identification of a suitable catalyst system, based on a Pd2+-salt and a chiral bi(oxazoline) ligand.

References: [1] a) Chemistry and Biochemistry of the Amino Acids Barrett, G. C., Ed.; Chapman and

Hall: London, 1985. b) A. E. Taggi, A. M. Hafez, T. Lectka, Acc. Chem. Res. 2003, 36,

10 and references therein. [2] a) W. N. Speckamp, M. J. Moolenaar, Tetrahedron 2000,

56, 3817; b) M. Petrini, E. Torregiani, Synthesis 2007, 2, 159; c) A. Yazici, S. G. Pyne,

Synthesis 2009, 3, 339. [3] a) Q. Zhang, J. Chen, M. Liu, H. Wu, J. Cheng, C. Qin, W.

Su, J. Ding, Synlett 2008, 6, 935; b) H. Dai, x. Lu, Tetrahedron Lett. 2009, 50, 3478. [4]

T. Beisel, G. Manolikakes, manuscript in preparation.

Synthesis and Application of 2Z, 4E-Diene Ethyl Esters

S. Audörsch, Dr. O. Kunz, Prof. Dr. B. Schmidt

University of Potsdam, Karl-Liebknecht-Straße 24/25, 14476 Golm

2Z, 4E-Diene esters are an attractive motif for synthetic chemists due to their

occurrence in natural products such as Dictyostatin[1a] or Macrolactine A[1b].

Furthermore, they can serve as a valuable building block for the introduction of

conjugated Z, E-Dienes[2] which would otherwise be hardly accessible. Common

approaches for the synthesis of 2Z, 4E-Diene esters include (i) the Still-Gennari

protocol for the Horner-Wadsworth-Emmons reaction[3], (ii) Palladium- or Copper-

catalyzed Stille coupling reactions[4] or (iii) transition metal-catalyzed ring closing

metathesis (RCM) of macrocycles[5]. However, these methods are either not absolutely

selective or suffer from demanding substrates. In this context, tethered RCM represents

an attractive alternative[6]. Besides easily accessible substrates, further

transformations are also possible, depending on the tether employed.

We herein report a selective one-pot synthesis of 2Z, 4E-diene ethyl esters from easily

accessible butenoates. The reaction proceeds via ruthenium catalyzed RCM followed

by a base induced ring opening sequence and esterification of the carboxylate

intermediate with the Meerwein’s salt Et3OBF4. Only 2Z, 4E configurated diene ethyl

esters are obtained, in moderate to good yields. Applications of these esters include

the Kowalski ester homologation, asymmetric Sharpless dihydroxylation and the

transformation into the corresponding Z,E-alkynes, which can be used in the synthesis

of natural occurring polyacetylenes.

[1] a) Brückner et al. Angew. Chem., Int. Ed. 2004, 43, 4634-4637; b) Carreira et al. Angew. Chem. Int. Ed. 1998, 37, 1261-1263. [2] Cossy et al. Chem. Eur. J. 2012, 18, 11788-11797. [3]

Still, W. C; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408. [4] Duchêne et al. Synthesis 1996, 82–86. [5] Grubbs et al. J. Am. Chem. Soc. 1992, 114, 5426-5427; Hanson et al. Org. Lett. 2005, 7, 3375-3378; [6] Ramachary et al. Eur. J. Org. Chem. 2011, 3514-3522; Schmidt et al. Eur. J. Org. Chem. 2012, 1008-1018; Schmidt et al. Kunz, O. Org. Lett. 2013, 15, 4470–4473.

Development of a Myxovalargin Library

Maik Siebke, Hannover/D, Franziska Gille, Hannover/D, Andreas Kirschning, Hannover/D, Institut für Organische Chemie and Zentrum für Biomelekulare Wirkstoffe

(BMWZ), Schneiderberg 1b, Hannover/D

The peptidic natural product Myxovalargin was isolated from the Myxococcus fulvus strain Mx f65 at the Helmholtz Center for Inflectional Diseases (HZI) [1]. The linear peptide shows antibiotic activity against GRAM-positive bacteria through the inhibition of prokaryotic protein synthesis [2].

The peptide contains 14 amino acids with 3-methylbutyric acid at its N-terminus and an agmatine residue at the C-terminus. Other interesting structural features are two α,β-dehydro valine, α,β-dehydro isoleucine and 3-hydroxy-D-valine residues. Their biosynthesis and relevance for the bioactivity is not fully understood yet.

Our approach for the development of a myxovalargin library is based on the permutation of the substitution pattern of those dehydro amino acids and 3-hydroxy-D-valine.

We therefore plan to utilize a solid phase approach for the rapid access of large peptide fragments and copper mediated coupling reactions to install the α,β-dehydroamino acids [3].

[1] H. Irschik, K. Gerth, T. Kemmer, H. Steinmetz, H. Reichenbach, J. Antibiot. 1983, 36, 6-12.

[2] H. Irschik, H. Reichenbach, J. Antibiot 1985, 38, 1237-1245.

[3] T. Kuranaga, Y. Sesoko, K. Sakata, N. Maeda, A. Hayata, M. Inoue, J. Am. Chem. Soc. 2013, 135, 5467-5474.

Synthesis and application of 4-trifluoromethylsulfonyloxy-7-

diethylaminocoumarin as a fluorescent label

Doroshenko T., Saarbrücken/DE

Prof. Dr. Uli Kazmaier, Institute of Organic Chemistry, Saarland University Geb. C 4.2, 3. OG, D-66123 Saarbrücken

Besides isolation, structure estimation and total synthesis of natural products in modern research the knowledge of the molecular targets and mechanisms of the reactions taking place is of a central interest. It is important to estimate the exact site of an action of a drug and all other possible targets in the cell, which may lead to possible side effects. Fluorescence microscopy allows by fluorescent labelling of biomolecules the observation and recording of the course of molecular or cellular processes.[1,2] 7-dialkylamino coumarins are very popular based on their low pH dependence and excellent fluorescence quantum yield. The goal of the presented work was to develop a new fluorescence label and study its application.

On the scheme is given the synthesis of 4-trifluoromethylsulfonyloxy-7-diethylamino-coumarin and its coupling reactions, which proceeded with good yields.

Labelling of amino acids and peptides via Sonogashira coupling reaction with 4-trifluoromethylsulfonyloxy-7-diethylaminocoumarin also proceeded with good yields. Literature [1] Böttcher, T., Pitscheider, M. and Sieber, Stephan A. Natural Products and Their Biological Targets: Proteomic and Metabolomic Labeling Strategies . Angew. Chem. Int. Ed., 49: 2680–2698, 2010; [2] J. R. Lakowicz, Principles of Fluorescence Spectroscopy, Vol. 3, Springer Verlag, 2006.

Calcium-Catalyzed Ring Expansion of Cyclopropanols

F. Gou,F. Capitta ,S. Schröder, Aachen/D

Prof. Dr. M. Niggemann, RWTH Aachen University, Landoltweg 1, 52074 Aachen

Substituted cyclobutanes, and in particular substituted cyclobutanones, constitute valuable building blocks for organic synthesis because of the rich chemistry allowed for by their intrinsic ring strain. Furthermore, they are found as motifs in numerous natural and biologically active molecules.1 In view of the importance of cyclobutanones, the development of new synthetic methodologies for their construction is still very much desired.

Inspired by previous results showing the ability of our calcium catalyst to activate

alcohols for various transformations,2 we envisaged to use Ca(NTf2)2 / Bu4NPF6 as a

catalyst system in a ring expansion reaction leading to substituted cyclobutanones from

alkynyl cyclopropanols (Scheme 1).

Scheme 1

Herein we present our results for the calcium-catalyzed tandem addition/ring expansion reaction from alkynyl cyclopropanols and substituted secondary alcohols.

Literature:

[1] a) Iwasawa, N.; Matsuo, T.; Iwamoto, M.; Ikeno, T. J. Am.. Chem. Soc. 1998, 120,

3903. b) Markham, J. P.; Staben, S. T.; Toste F. D. J. Am. Chem. Soc. 2005, 127,

9708. c) Trost, B. M.; Xie, J.; Maulide, N. J. Am. Chem. Soc. 2008, 130, 17258.

[2] J.-M. Begouin, M. Niggemann Chem. Eur. J. 2013, 19, 8030.

Phage selection of photoswitchable peptide ligands

S. Bellotto, Lausanne/CH, Giessen/DE, S. Chen, Lausanne/CH, I. Rentero Rebollo, Lausanne/CH, C. Heinis, Lausanne/CH, H.A. Wegner, Giessen/DE

Silvia Bellotto, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne

Justus-Liebig-Universität, Heinrich-Buff-Ring 58, D-35392 Giessen

Photoswitchable ligands represent a potent tool to control and investigate biological

processes in a spatial and temporal fashion.[1-2] The rational design of such ligand is not

trivial and as of now they are available only for a limited number of targets. Their main

shortcomings are low affinity and small change in binding affinity between the cis and trans

conformation.[3-4] Thus, we have developed a robust strategy for in vitro generation of

high-affinity light-activatable peptide ligands to potentially any target. Random phage-

encoded peptides were cyclized with an azobenzene linker 3,3'-bis(sulfonato)-4,4'-

bis(bromoacetamido) azobenzene (BSBBA), irradiated with UV-light in situ and panned

against streptavidin, used as model target. After only two rounds of selection, strong

consensus sequences were found and the peptides presented high affinity when cyclized

with BSBBA. The binding of peptides isolated from two consensus sequences could be

modulated upon UV-light irradiation. The cis exhibited a binding affinity up to 3-fold higher

than the trans conformer.[5]

[1] Beharry A. A., Woolley G. A. Chem. Soc. Rev. 2011, 40, 4422.

[2] Renner C., Kusebauch U., Löweneck M., Milbradt A.G., Moroder L., J. Petide Res.

2005, 65, 4.

[3] Liu M., Tada S., Ito M., Abe H., Ito Y., Chem. Commun. 2012, 48, 11871.

[4] Ulysse L.G Jr., Chmielewski J., Chem. Biol. Drug. Des. 2006, 67,127.

[5] Bellotto S., Chen S., Rentero Rebollo I., Wegner A.H., Heinis C., J. Am. Chem. Soc., 2014, 136, 5880.

Studies towards the Total Synthesis of Integramycin

J. Trenner, Braunschweig/DE, E. Prusov, Braunschweig/DE, W. Collisi,

Braunschweig/DE, M. Kalesse, Hannover/DE

Johanna Trenner, Helmholtz Centre for Infection research, Inhoffenstraße 7, D-38124 Braunschweig

To fight the HI-virus, usual drug targets for inhibition are the reverse transcriptase and the protease. For the inhibition of the third enzyme, integrase, up to date only three compounds are used clinically, of which none is a natural product [1]. In 2002, the natural product polyketide integramycin was isolated from Actinoplanes sp. and found to inhibit HIV-1 integrase coupled and strand transfer reaction with IC50 values of 3 and 4 µM, respectively [2]. The structure of integramycin contains an octohydronaphthalene connected to a 5-hydroxy-3-acyl tetramic acid and an aryl spiroketal unit. Several partial syntheses for the spiroketal unit [3] and the octahydronaphthalen core [4] are known, but up to date no method for the preparation of the highly oxidized tetramic acid or a total synthesis was published. Our aim is to find an enolate oxidation method to introduce the 5-hydroxy moiety into the tetramic acid. Further we plan to construct the octahydronaphthalene core via a sequence of Wittig reaction, Julia-Kocienski olefination, asymmetric aldol and Horner-Wadsworth-Emmons reaction followed by an intramolecular Diels-Alder reaction. [1] K. Shimura et al., J. Virol. 2008, 82, 764-774. [2] S.B. Singh et al., Org. Lett. 2002, 4, 1123-1126. [3] L. Wang, P.E. Floreancig, Org. Lett. 2004, 6, 569-572; H. Sun, J.R. Abbott, W.R. Roush, Org. Lett. 2011, 13, 2734-2737;E. Prusov, Beilstein J.Org. Chem. 2013, 9, 2446-2450. [4] T.A. Dineen, W.R. Roush, Org. Lett. 2005, 7, 1355-1358.

Identification of novel biologically active spirangien derivatives from Sorangium

cellulosum and target search of Spirangien A

N. Bruns, Braunschweig/DE, W. Collisi, Braunschweig/DE, B. Hinkelmann,

Braunschweig/DE, M. Kalesse, Hannover/DE

Nicole Bruns, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124

Braunschweig (Germany), Leibniz University Hannover, Schneiderberg 1B, 30167

Hannover (Germany)

Natural products constitute important lead structures for drug development. Especially the myxobacteria of the genus Sorangium have proved in the last few years to be extremely versatile producers of secondary metabolites with various biological activities. [1,2] In 2005, a novel group of antifungal and highly cytotoxic compounds named Spirangien

A and B were isolated from culture extracts of epothilone-producing Sorangium

cellulosum strain So ce90. [3]

Based on the potential of spirangiens as drug lead structures due to their high

cytotoxicity, a large scale fermentation of Sorangium cellulosum was analyzed for

derivatives of spirangiens that were tested in cytotoxicity assays for several cancer cell

lines. The 11 novel derivatives, isolated by different extraction and purification steps

and elucidated by nuclear magnetic resonance spectroscopy (NMR) and mass

spectroscopy, show very good cytotoxic activities against L929 mouse fibroblast cell

line in nanogram range.

In further investigations of searching the specific target for Spirangien A, the Ras

GTPase-activating-like protein (IQGAP1), that acts as a node for many signaling

pathways implicated in cancer progression, is suspected to be a possible target. [4]

Literature:

[1] D. J. Newman, G. M. Cragg, J. Nat. Prod. 2012, 75, 311-335. [2] H. Reichenbach,

G. Höfle, Biotech. Adv. 1993, 11, 219-277. [3] J. Niggemann, N. Bedorf, U. Flörke, H.

Steinmetz, K. Gerth, H. Reichenbach, G. Höfle, Eur. J. Org. Chem 2005, 23, 5013-

5018. [4] M. W. Briggs, D. B. Sacks, EMBO Rep. 2003, 4, 571-574.

Domino Bidentate Lewis Acid Catalyzed Inverse Electron-Demand Diels-Alder Reaction - Investigation on a Unique Consecutive [1,5] Nitrogen Shift

L. Schweighauser, Gießen/D, S. Götz, Basel/CH, S. N. Kessler, Basel/CH, H. A.

Wegner,* Gießen/D

Justus-Liebig-University Gießen, Heinrich-Buff-Ring 58, 35392 Gießen

In the past years our group established the inverse electron-demand Diels-Alder reaction (IEDDA) of phthalazines with different dienophiles catalyzed by a bidentate Lewis acid as an efficient tool to synthesize ortho-substituted aromatics. [1] These reactions were proposed to proceed over highly reactive quinodimethane intermediates. Remarkably, these intermediates could also be exploited for consecutive transformation to produce cyclopropanes [2] or bicyclic systems. [3] Herein we present a new Domino IEDDA rearrangement reaction of phthalazine and its substituted analogues with in situ generated enamine substrates. The inverse electron-demand Diels-Alder reaction was followed by an unusual sigmatropic [1,5] nitrogen shift leading to a wide range of different dihydronaphthalenes in good yields. Such products could be possible precursors for the synthesis of benzo[c]phenanthridine alkaloid derivatives. [4] Domino-type reaction cascades address the main challenge of organic synthesis, the development of transformations that allow access to molecules in an efficient and selective way.

Literature: [1] S. N. Kessler, H. A. Wegner, Org. Lett. 2010, 12, 4062. [2] S. N. Kessler, M. Neuburger, H. A. Wegner, J. Am. Chem. Soc. 2012, 134, 17885. [3] L. Schweighauser, I. Bodoky, S. N. Kessler, D. Häussinger, H. A. Wegner, Synthesis 2012, 44, 2195. [4] a) H. Miyoji, Y. Shuji, A. Masami, M. Chisato, Chem. Lett. 1986, 739. b) P. Lv, K. Huang, L. Xie, X. Xu, Org. Biomol. Chem. 2011, 9, 3133.

NN

N

HO

NH

+

N

BB

cat.:

-N2

[1,5] shift

Dehydroannulene-linked Porphyrin/C60-Molecular Wires with Pendant Metal Fragment Binding Groups

T. Trieschmann, Kassel/DE, J.-U. Holzhauer, Kassel/DE,R. Faust,* Kassel/DE

Prof. Dr. Rüdiger Faust, University of Kassel, Heinrich-Plett-Straße 40, D-34132 Kassel

Light-induced energy and electron transfer are fundamental processes in the design of components suitable for energy conversion. At the molecular level, donor-bridge-acceptor (D-B-A) architectures have emerged as promising candidates for electroluminescent devices or the phototunable wiring in molecular transistors. [1] These molecular dyads frequently feature porphyrins and fullerenes as the corresponding starting and endpoints of redistributed electron density. The bridge element between these points often derives from the rigid π-circuit of phenylethynyl motives. [2]

We wish to add to this field by the design of a bifurcated D-B-A molecular wire with a pendant dehydroannulene suitable for metal fragment coordination. Photoexcitation of a metal fragment complexed to the binding site will affect the electron density in the dehydroannulene [3] and hence in the conjugation path along the molecular wire.

We will present here first steps towards the realisation of structure 1 starting from a porphyrin functionalised with ethynyltolanyl subunits as depicted in 2.

References:

[1] M. Wielopolski, G. d. M. Rojas, C. van der Pol, L. Brinkhaus, G. Katsukis, M. R. Bryce, T. Clark, D. M. Guldi, ACS Nano 2010, 4, 6449-6462.

[2] S. A. Vail, P. J. Krawczuk, D. M. Guldi, A. Palkar, L. Echegoyen, J. P. C. Tome, M. A. Fazio, D. I. Schuster, Chem. Eur. J. 2005, 11, 3375-3388.

[3] E. L. Spitler, C. A. Johnson, M. M. Haley, Chem. Rev. 2006, 106, 5344-5386.

Visible Light Driven Water Oxidation at Soft Interfaces

M. Hansen, Regensburg/D, B. König, Regensburg/D

Malte Hansen, University of Regensburg, Universitätsstr. 31, 93053 Regensburg

Photochemical water splitting by artificial photosynthesis is one of the great scientific

challenges of our time. The overall water splitting process consists two half reactions,

where the oxidation is considered to be the “bottle neck” due to the four electron

transfer steps and the reactive oxygen species involved. [1]

Figure 1: Self-assembly of functionalized vesicles (left), schematic mechanism (right)

A typical photochemical water oxidation system consists of two components: A light

harvesting photosensitizer and a water oxidation catalyst. Homogeneous systems

with these as separated entities provide facile synthesis, and allow different

combinations and ratios of the redox partners, but suffer from diffusion controlled

electron transfer. Hence huge effort has been spent on the tedious synthesis of

covalently connected assemblies, to enhance the electron transfer and make it

diffusion independent. In biology, photosynthetic compounds are bound to

phospholipid membranes. The two dimensional arrangement in the bilayer increases

the local concentration and brings the catalytic subunits in close proximity compared

to homogeneous solution. This facilitates the electron transfer and improves the

catalytic activity.

By co-embedding amphiphilic derivatives of ruthenium bipyridyl photosensitizers and

ruthenium based water oxidation catalysts into small unilamellar phospholipid vesicle

membranes photochemical water oxidation was achieved. The clustering and phase

separation in these metallolipid-functionalized membranes enables photocatalytic

water oxidation at very low overall catalyst concentrations while still allowing the easy

variation of combinations, ratios and concentrations of the redox partners.[2]

[1] N. S. Lewis, D. G. Nocera, PNAS 2006, 103, 15729-15735. [2] M. Hansen, F. Li, L. Sun, B. König, Chem. Sci. 2014.

Fluorinated phosphodiesterase 10A inhibitors with a potential use as 18F-labeled

imaging agents

S. Wagner, Leipzig/DE, M. ScheunemannLeipzig/DE, U. Egerland, Radebeul/DE,

N. Hoefgen, Radebeul/DE, P. Brust, Leipzig/DE

Sally Wagner, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, 04318 Leipzig

Phosphodiesterases (PDEs) are a class of enzymes heavily involved in cellular

signaling by inactivating the second messenger cAMP and cGMP. So far, 11 different

PDE families are known, of which one, the dual substrate enzyme PDE10A is

abundantly expressed in a particular brain region, the striatum. Since it is thought to be

involved in the pathomechanism of schizophrenia, PDE10A inhibition represents a

novel approach in the treatment of this disease. In-vivo imaging via positron emission

tomography (PET) of PDE10A would allow investigating the enzyme and its expression

in neuropathological processes.

Recently, 1-arylimidazo[1,5a]quinoxalines have been reported as potent and selective

PDE10A inhibitors.1 Considering the potential use of these inhibitors as 18F-labeled

imaging agents fluorinated PDE10A inhibitors based on 1-arylimidazo[1,5a]quinoxaline

as lead structure have been synthesized.

The imidazo[1,5a]quinoxaline key structure was synthesized from 2,6-difluoroaniline

over 7 steps in an total yield of 8%. Using the palladium catalyzed Suzuki-coupling

different substituted 2-fluoropyridine boronic acids could be linked to brominated

imidazo[1,5a]quinoxalines. This divergent step allows a quick and easy variation.

Moreover 2-fluoropyridines could be introduced at two positions of the aromatic system.

The inhibitory potency of these compounds was tested towards human, recombinant

PDE10A and other PDE families. All inhibitors showed a high affinity for PDE10A with

moderate to good selectivity versus other PDEs.

Currently the most selective inhibitor is under further investigation to be developed as

PET tracer.

[1] Malamas et. al. J. Med. Chem. 2011,54, 7621-7638.

Gold-Catalyzed Generation of Naphtylcarbenoids and their Applications

Tobias Lauterbach and A. Stephen K. Hashmi*

Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg,

Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)

e-mail: hashmi@hashmi.de

One of the fundamental reactions in the field of gold catalysis is the generation of gold

carbenoids via 1,2 acyl migration of propargylic acetates. Based on the easy

accessibility of the starting materials combined with the diverse reactivity of the

carbenoid centre many useful organic transformations following this reactivity principle

have been developed. A valuable expansion of this methodology is introduced if a

second pendant alkyne is offered in appropriate distance. A transfer of the carbenoid

over this alkyne is possible and further transformations with the so formed vinyl gold

carbenoids are feasible.[1]

In the case of R2 = H intermolecular trapping of the transferred carbene with alkenes is

also possible.[2] The complex products obtained by this approach are not easily

accessible by classical routes or require the use of toxic and expensive starting

materials.

Literature:

[1] T. Lauterbach, S. Gatzweiler, P. Nösel, M. Rudolph, F. Rominger, A. S. K. Hashmi, Adv. Synth. Catal. 2013, 355, 2481-2487

[2] T. Lauterbach, M. Ganschow, M. W. Hussong, M. Rudolph, F. Rominger, A. S. K. Hashmi, Adv. Synth. Catal. 2014, 356, 680-686

Prospecting for novel anti-plasmodial compounds from endophytic fungi isolated from Oncostemum botroyides (Myrsinaceae)

A. A. Razakarivony, Bielefeld/DE, C. Michalek, Bielefeld/DE, E. Langer, Kassel/DE, B. Lenta, Bielefeld/DE, P. J. Rosenthal California/USA, B. V. Razanamahefa, Antananarivo/MG, D. R. Razafimahefa, Antananarivo/MG, B. Andriamihaja, Antananarivo/MG, N. Sewald, Bielefeld/DE

Organic and Bioorganic Chemistry, Bielefeld University, Universitätstrasse 25, 33615 – Bielefeld, Deutschland

Endophytes are found omnipresent in all plants species and are a promising novel source of potentially useful secondary metabolites exhibiting a variety of biological activities. [1] On the other hand, more extensive medical research needs to be carried out, e.g. to find appropriate and efficient drugs to treat parasitic protozoan infectious diseases such as malaria which is responsible for 627,000 cases of death in 2012. [2] Research into new anti-malarial molecules are top priority. Our approach is driven by the isolation and characterization of natural products from an endophytic fungus Paecilomyces sp. isolated from plant Oncostemum botryoides which is used in traditional medicine in Madagascar. The structures of the isolated compounds were determined using spectroscopic and spectrometric analyses and the compounds were tested in vitro for their antiplasmodial activity against Plasmodium falciparum chloroquine-resistant strain W2 and for their cytotoxic activity against human cervix carcinoma cell line KB-3-1.

[1] Barbara Schulz et al.,Mycological Research, 2002, 106 (9), 996-1004

[2] WHO Global Malaria Programme, World Malaria Report 2013

Syntheses of Carolacton Derivatives as highly potent Biofilm Inhibitors

J. Ammermann, Hannover/D; P. Premnath, Braunschweig/D; M. Reck,

Braunschweig/D; T. Schmidt, Hannover/D; M. Stiesch, Hannover/D; N. Stumpp, Hannover/D; I. Wagner-Döbler, Braunschweig/D, A. Kirschning*, Hannover/D

Institut für Organische Chemie und Zentrum für Biomolekulare Wirkstoffe (BMWZ),

Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover Carolacton (1) is a secondary metabolite first isolated in 1998 from myxobacterium Sorangium cellulosum strain So ce960.[1] Initial biological tests showed antibiotic activity against E. coli strain tolC bacteria as well as moderate antifungal activity.[2] However, the most remarkable biological property of Carolacton is its unique ability to inhibit biofilms of the caries- and endocarditis-associated bacterium Streptococcus mutans at nanomolar concentrations.[3] Since bacterial biofilms are inherently resistant to extreme pH and temperature as well as antimicrobial agents, biofilm-associated infections have become a major concern in clinical treatment. Thus, the synthesis of natural products and derivatives with novel modes of action is a promising approach to inhibition and treatment of biofilms.

X O OMe O

OH

OH

OH

O

macrolactonization/macrolactamization

asymmetric Negishi coupling

Nozaki-Hiyama-Kishi reaction

Marshall reaction

Duthaler-Hafner-aldol reaction1 X=O2 X=NH

Ley aldol reaction

Breit substitution

Figure 1: Retrosynthetic key dissections of Carolacton (1) and the corresponding lactam (2). Recently, we published the first total synthesis of Carolacton (1) that is based on several key dissections depicted in Figure 1.[4] Here we present our recent results towards the syntheses of highly active Carolacton derivatives towards structure-activity relationship analysis. With respect to higher chemical and physiological stability we also pursue the synthesis of lactam derivative 2. Literature: [1] G. Höfle, Scientific Annual Report of the GBF , 1998, p. 101. [2] H. Irschik, R. Jansen, K. Gerth, J. Antibiot. 1987, 40, 7-13. [3] B. Kunze, M. Reck, A. Dötsch, A. Lemme, D. Schummer, H. Irschik, H. Steinmetz,

I. Wagner-Döbler, BMC Microbiology 2010, 10, 199. [4] T. Schmidt, A. Kirschning, Angew. Chem. Int. Ed. 2012, 51, 1063-1066.

Functionalized Vesicles for Photochemical Water Reduction

S. Troppmann, Regensburg/D, B. König, Regensburg/D

Stefan Troppmann, University of Regensburg, Universitätsstr. 31, 93053 Regensburg

The conversion of sunlight energy into chemical energy by means of photocatalytic water splitting into hydrogen and oxygen is a promising approach towards a sustainable energy supply. In the field of artificial photosynthesis the two half-reactions water reduction and water oxidation are investigated separately using a suitable combination of a photosensitizer and a catalyst.[1] The incorporation of amphiphilic photosensitizers and water reduction catalysts into vesicles leads to functionalized membranes for photocatalytic hydrogen production mimicking the membrane-embedded photosystem in nature. The two dimensional distribution of the embedded subunits results in patch formation and promotes the necessary electron transfer.[2]

Figure 1. Self-assembled membranes with amphiphilic redox active subunits for photocatalytic hydrogen production.

By co-embedding of a modified ruthenium photosensitizer and an amphiphilic H2-evolving cobalt catalyst into unilamellar vesicles, photochemical hydrogen production in aqueous solution at the lipid water interface could be observed. The catalytic activity of the functionalized vesicles was optimized and a dependence on the nature of the phospholipid used for membrane preparation was found. The phase transition temperature of the phospholipid has an influence on the mobility and arrangement of the artificial amphiphiles in the membrane and determines the performance of the proton reduction system.

[1] E. S. Andreiadis, M. Chavarot-Kerlidou, M. Fontecave, V. Artero,Photochemistry and Photobiology 2011, 87, 946-964.

[2] B. Gruber, B. König, Chemistry – A European Journal 2013, 19, 438-448.

N-(trifluoromethylthio)phthalimide – a new shelf-stable reagent for

trifluoromethylthiolations

Roman Pluta, Pavlo Nikolaienko and Prof. Dr. Magnus Rueping*

Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen (Germany), e-mail: magnus.rueping@rwth-aachen.de

Compounds bearing fluoroalkylated groups have received increased attention due to their unusual biological and therapeutic properties. Fluorinated substituents have been part of blockbuster drugs and highly effective agrochemicals.[1] Among the enormous range of fluorinated compounds known to date, those containing perfluorinated alkylsulfenyl groups are valuable for pharmaceutical and agrochemical industry. These compounds possess unique and important physical, chemical and biological properties compared to the parent non-fluorinated compounds. Development of methods for direct insertion of these groups are gaining increasing attention in academic research.[2]

We report a new air- and moisture-stable electrophilic trifluoromethylthiolating reagent and its application in copper-catalysed electrophilic trifluoromethylthiolation of carbon nucleophiles, such as boronic acids and terminal alkynes.[3]

We also applied this reagent in the synthesis of trifluoromethanesulfenamides and fluorinated disulfides. These compounds belong to a new interesting class of organic molecules and might possess remarkable properties for medicinal chemistry.

Literature: 1. a) R. Filler, Y. Kobayashi, L. M. Yugapolskii, Organofluorine Compounds in Medicinal Chemistry

and Biomedical Applications 1993, Elsevier, Amsterdam; b) A. Becker, Inventory of industrial fluoro–biochemicals 1996, Eyrolles, Paris; c) T. Yamazaki, T. Taguchi, I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology 2009, Wiley–Blackwell, Chichester.

2. a) A. Ferry, T. Billard, B. R. Langlois, E. Bacqué, J. Org. Chem. 2008, 73, 9362-9365; b) A. Ferry, T. Billard, B. R. Langlois, E. Bacqué, Angew. Chem. Int. Ed. 2009, 48, 8551-8555; c) F. Baert, J. Colomb, T. Billard, Angew. Chem. Int. Ed. 2012, 51, 10382-10385; d) X. Shao, X. Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem. Int. Ed. 2013, 52, 3457–3460; e) S. Alazet, L. Zimmer, T, Billard, Angew. Chem. Int. Ed. 2013, 52, 10814–10817; f) X. Q. Wang, T. Yang, X. Cheng, Q. Shen, Angew. Chem. Int. Ed. 2013, 52, 12860-12864; g) S. Azalet, K. Ollivier, T. Billard, Beilstein J. Org. Chem. 2013, 9, 2354-2357.

3. R. Pluta, P. Nikolaienko, M. Rueping, Angew. Chem. Int. Ed. 2014, 53, 1650-1653.

Evolution of Siderophore Pathways in Human Pathogenic Bacteria

J. Franke, K. Ishida, C. Hertweck, Jena/DE

Jakob Franke, Leibniz Institute for Natural Product Research and Infection Biology, Hans

Knoell Institute, Beutenbergstr. 11a, 07745 Jena

Siderophores, small molecules required for providing the essential trace element iron,

have been in the focus of natural product research for over 20 years, as they are often

important virulence factors. Bacteria from the genus Burkholderia, known for several

human pathogenic species, employ the hydroxamate-type siderophores ornibactin and

malleobactin. While the structure of the former one has been elucidated already in 1993,[1]

we could show only recently that malleobactin is a close analog featuring an unusual

aliphatic nitro group.[2] However, the evolutionary connection between the corresponding

biosynthetic gene clusters had not been examined.

 

We successfully manipulated the biosynthetic machinery of malleobactin to produce

ornibactin instead.[3] Not only is this the first targeted morphing of a non-ribosomal peptide

biosynthetic pathway, it also gives insight into the evolutionary mechanisms that lie behind

both virulence factors.

[1] H. Stephan, S. Freund, W. Beck, G. Jung, J.-M. Meyer, G. Winkelmann, Biometals 1993, 6, 93–100.

[2] J. Franke, K. Ishida, M. Ishida-Ito, C. Hertweck, Angew. Chem. Int. Ed. 2013, 52, 8271–8275.

[3] J. Franke, K. Ishida, C. Hertweck, J. Am. Chem. Soc. 2014, 136, 5599–5602.

Total Synthesis of the Biphenyl Alkaloid (−)-Lythranidine

K. Gebauer, Mülheim a. d. R./DE

Prof. Alois Fürstner, Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,

45470 Mülheim a. d. R.

Lythranidine (1) is a cylcophane alkaloid which was isolated in 1967 by Fujita and co-workers from the Japanese plant Lythrum anceps Makino together with two related natural products. [1] Although fairly detailed physico-chemical studies have been carried out, it has only once been target of a completely unselective racemic total synthesis. [2]

Scheme 1: Retrosynthetic analysis of lythranidine (1)

We envisioned that that a RCAM approach could be strongly beneficial in the synthesis of the natural product lythranidine (1). As outlined in our retrosynthetic analysis, cross coupling of 4 and 5 followed by RCAM would afford a 19-membered ring containing a propargylic alcohol, which we hoped to selectively convert to the corresponding enone 3 by a redox isomerization. A subsequent transannular aza-Michael reaction would afford the 2,6-trans-piperidine ring. This triad of reactions represents the key transformations in this synthesis.

Herein, the first enantioselective total synthesis of lythranidine (1) is presented. It features a longest linear sequence of 15 steps and an overall yield of approximately 5 %. [3]

[1] E. Fujita, K. Fuji, K. Bessho, A. Sumi, S. Nakamura Tetrahedron Lett. 1967, 46, 4595-4600. [2] K. Fuji, K. Ichikawa, E. Fujita Tetrahedron Lett. 1979, 4, 361-364. [3] K. Gebauer, A. Fürstner Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201402550

Selective Double-Bond Isomerization of Terminal 1,3,7-Dienes towards Single Skipped 2,4,7-Trienes and its Application in the Synthesis of Urushiol

Schmidt, A., Marburg/D and Hilt, G., Marburg/D

Prof. Dr. Gerhard Hilt, Philipps-Universität Marburg, Hans-Meerwein-Str., 35032 Marburg

Recently, we reported the stereoselective cobalt-catalysed isomerization of the E/Z-mixtures of 1,3-dienes 1 to the 2Z,4E-isomers 2.[1] Remarkably, a further isomerization of the double bonds to corresponding 3,5-dienes 3 was not observed (Scheme 1).

Scheme 1: Cobalt-catalysed isomerization of terminal 1,3-dienes to 2Z,4E-isomers 2.

We were able to apply the isomerization reaction as the key step in the synthesis of the natural product urushiol 4,[2] a main component of the (non-polymerized) East Asian lacquer (japanese: urushi),[3] which has been used in East Asia for thousands of years for the decoration and preservation of wooden materials.[4]

Figure 1. Structure of 4, the main component of urushiol.[3c]

The challenge was to synthesize the 1,3-diene subunit 5 with an additional Z-double bond in position 7 and to isomerise 5 to the sensitive skipped 2Z,4E,7Z-triene subunit in the side chain of Urushiol.

Scheme 2: Cobalt-catalysed isomerization of terminal 1,3-diene to a 2Z,4E,7Z-triene.

The synthesis of the O-protected urushiol could be accomplished highly selective, in a good yield and in only seven steps.

Literature:

[1] F. Pünner, A. Schmidt, G. Hilt, Angew. Chem. Int. Ed. 2012, 51, 1270. [2] a) O. Vogl, J. Polym. Sci. A 2000, 38, 4327, and references therein; b) Y. Yamauchi, R. Oshima, J. Kumanotani, J. Chromatography 1982, 243, 71; c) S. Billets, M. D. Craig, M. D. Corbett, J. F. Vickery, Phytochem. 1976, 15, 533. [3] a) R. Lu, T. Yoshida, T. Miyakoshi, Polymer Rev. 2013, 53, 153; b) H. S. Kim, J. H. Yeum, S. W. Choi, J. Y. Lee, I. W. Cheong, Prog. Org. Coatings 2009, 65, 341; c) J. Kumanotani, Prog. Org. Coatings 1995, 26, 163. [4] A. Schmidt, G. Hilt Chem. Asian J. 2014, accepted.

From Diradicals to Cyclic Dialkoxyamines as Precursors for Ring Polymers

S. Eusterwiemann, Münster/D, T. Makino, Nagoya/JP, R. Kakuya, Nagoya/JP

Prof. A. Studer, Organisch Chemisches Institut, Westfälische Wilhelms-Universität,

Corrensstrasse 40, 48149 Münster (Germany) Prof. M. M. Matsushita, Prof. K. Awaga, Department of Chemistry & Research Center for Materials Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602 (Japan)

We present a new approach for the design of ring polymers. In contrast to conventional

methods, where the construction of cyclic structures was achieved either by a ring closing

reaction[1] or ring-expansion metathesis,[2] this approach utilizes cyclic dialkoxyamines as

initiators for nitroxide mediated radical polymerization (NMRP) to form polystyrene rings.

Starting with TEMPO diradicals, different cyclic dialkoxyamines were synthesized,

characterized and investigated as initiators in the polymerization of styrene.

O

N

O

O

N

O

O

N

O

O

N

O

nn

O

N

O

O

N

O

2n

TEMPO diradical cyclic dialkoxyamine ring polymer

In future works we hope to establish a route to cyclic polymers without an alkoxyamine unit

via elimination of the diradical, which should possess interesting physical properties.

References:

[1] J. Xu, J. Ye, S. Liu, Macromolecules 2007, 40, 9103.

[2] C. W. Bielawski, D. Benitez, R. H. Grubbs, Science 2002, 297, 2041.

Novel T3P® mediated condensation reaction of alcohols with secondary amines

L. Levi, Düsseldorf/D

Prof. Dr. Thomas J. J. Müller, Heinrich-Heine-Universität Düsseldorf, Universitätsstr.1,

40225 Düsseldorf/D

After the first studies executed by Wissman et al. on n-propylphosphonic acid

anhydride (T3P®) as a condensation reagent, this substance received considerable

interest in organic synthesis, due to its coupling, dehydrating and catalytic properties

which are already active under very mild conditions. [1]

Nucleophilic substitutions are conventional methods for the exchange of functional

groups or the introduction of new fragments to a given scaffold. The investigation of this

process with respect to its potentials and limits has always been of interest. [2]

The activation of a carbon atom for a nucleophilic substitution at the oxidation state of

an alcohol with T3P® without any other reagents allows for a fast and straightforward

method to synthesize diverse tertiary amines. Due to its broad functional group

tolerance and the easy work up of water-soluble byproducts, this peculiar anhydride

allows access to interesting systems in good yields.

+ (hetero)aryl OHT3P®

1,4-dioxane (hetero)aryl

NN

R2R1

H

R2R1

R1 = Aryl, AlkylR2 = Aryl, Alkyl

Scheme 1: T3P® mediated condensation reaction of alcohols with secondary amines.

Literature

[1] a) H. Wissmann, H.-J. Kleiner, Angew. Chem. Int. Ed. Engl. 1980, 19, 133-134; b)

Basavaprabhu, T. M. Vishwanatha, N. R. Panguluri, V. V. Sureshbabu, Synthesis 2013,

45, 1569-1601; [2] a) A. Baeza, C. Nájera, Synthesis 2014, 46, 25-34; b) R. Kumar, E.

V. Van der Eycken, Chem. Soc. Rev. 2013, 42, 1121-1146.

In vitro Studies of Polyketide Synthase Ketoreductases for Chemoenzymatic Total Synthesis of Polyketide Fragments

M. Schröder, Hannover/D, H. Geise, Hannover/D, F. Hahn, Hannover/D

Institute of Organic Chemistry and Center for Biomolecular Drug Research (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, D-30167 Hannover, Germany

In our contribution we present our investigations on the biocatalytic applicability of

ketoreductase (KR) domains for the chemoenzymatic synthesis of complex polyketide natural

products and their derivatives.

Reduced polyketides are important natural products with diverse structures and a broad range

of biological activities.[1]

Their backbones are biosynthesised by multi-modular type I

polyketide synthases (PKS I), which account for a large part of their overall complexity. The

basic logic of polyketide assembly consists of stepwise elongation by Claisen-like

condensations and subsequent processing of the formed -keto-thioester by KR, dehydratase

(DH) and enoyl reductase (ER) domains. Although the principle genetics of PKS I systems

are now well understood, the enzymology is still under intense investigation.[1]

Scheme 1: Enzymatic, stereospecific reduction of -keto-thioesters by KR.

KR domains are responsible for the intermediate reduction of a -keto-thioester to a

-hydroxy-thioester. They are categorised according to the configuration of their products,

which can also be predicted from their amino acid sequence. As up to two stereocentres are

formed during this step and a prominent motif of reduced polyketides is obtained, KR

domains are attractive tools for a broad biocatalytic application.

Previous work showed their applicability on simple diketide substrates.[2]

We expand this

study by synthesising and assaying a library of more complex β-keto-thioesters to learn about

KR substrate specificity. With the results from these assays in hand, we will apply several KR

domains in the total synthesis of complex polyketides and optimise their properties by

structure-guided enzyme engineering.

[1] J. Staunton, K. J. Weissman, Nat. Prod. Rep., 2001, 18, 380-416. [2] S. K. Piasecki, C. A. Taylor,

J. F. Detelich, J. Liu, J. Zheng, A. Komsoukaniants, D. R. Siegel, A. T. Keatinge-Clay, Chem. Bio., 2011, 18,

1331-1340.

Synthetic Approach of a Novel Regioselective Azide Alkyne Cycloaddition with

BODIPY Derivatives and its Application in the Bioorthogonal Labeling of a

Proteins

M. Albrecht, Saarbrücken/D, A. Lippach, Saarbrücken/D, P. Wiater, Saarbrücken/ D,

M. Exner, Berlin/D, M. Springborg, Saarbrücken/D, N. Budisa, Berlin/D,

G. Wenz, Saarbrücken/D

Dr. Marcel Albrecht, Saarland University, Organic Macromolecular Chemistry, Campus

C 4.2, 66123 Saarbrücken, Germany

The development of new synthetic strategies for selective bond formation reactions is

one of the most challenging tasks in the field of organic chemistry. Especially, the

copper catalyzed click chemistry approach provides fundamental advantages

compared to other synthetic techniques as it allows a regioselective and economic

combination of two reaction partners with high conversion rates under mild reaction

conditions. But nevertheless, based on the high toxicity of the heavy atom catalyst this

method suffers from significant drawbacks preventing their application in biological

systems. Based on these considerations the development of novel metal-free

approaches is essential for a convenient use, e.g. in labeling processes of proteins.

Herein, we report a new copper-free Click Chemistry approach which was investigated

using model reactions of acetylene substituted BODIPY derivatives with benzyl azide.

Interestingly, our results reveal an unexpected high 1,4-product selectivity which was

additionally analyzed by kinetic measurements and computational methods (DFT-

calculations).

Furthermore, the site-specific incorporation of a novel alkyne-BODIPY into the

congener of recombinant barstar (ψ-b*) decorated with azide functionality (i.e. made by

the replacement of the N-terminal methionine of ψ-b* with azidohomoalanine was

performed (Scheme 1)). After conjugation reaction, the resulting BODIPY-ψ-b*

exhibited the expected fluorescence profile with remarkable blue shift.

Scheme 1: Graphic representation of bioorthogonal conjugation of acetylene substituted BODIPY to barstar with azidohomoalanine.

Electron as a Catalyst – Synthesis via Base-Promoted Homolytic Aromatic

Substitution

D. Leifert, Münster/DE-NW

Prof. Dr. Armido Studer, University of Münster, Corrensstraße 40, 48149 Münster C–C-bond formation is of great importance in organic chemistry. Especially the coupling of two prefunctionalized substrates is well explored. [1] To achieve a higher atom economy, CDCs (Cross-Dehydrogenative Couplings) are gaining importance because prefunctionalization is not necessary in these cases. [2] Due to this advantage we herein present an efficient method to synthesize 6-aroylated phenanthridines from 2-isocyanobiphenyls and benzaldehydes via CDC. In a green chemistry approach we used a low amount of an iron catalyst (0.4 mol%) and tBuOOH as a cheap oxidant. [3] Reactions are suggested to occur via Base-Promoted Homolytic Aromatic Substitution (BHAS). [4]

Figure 1: Synthesis of 6-aroylated phenanthridines. Literature: [1] F. Diederich, P. J. Stang Eds., Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH: New York, 1998. [2] C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215–1292. [3] D. Leifert, C. G. Daniliuc, A. Studer, Org. Lett. 2013, 15, 6286-6289. [4] a) A. Studer, D. P. Curran, Angew. Chem. Int. Ed. 2011, 50, 5018–5022; b) S. Wertz, D. Leifert, A. Studer, Org. Lett. 2013, 15, 928-931.

Living Alternating Polymerization via Nitroxide Mediated Polymerization (NMP) and Subsequent Orthogonal Functionalization

M. Tesch, Münster/DE-NW, J.A.M. Hepperle, Münster/DE-NW, M. Letzel,

Münster/DE-NW

Prof. Dr. Armido Studer, University of Münster, Corrensstraße 40, D-48149 Münster Sequence control is one of the greatest challenges in modern polymer science. Recently, great advances have been achieved in the field of radical polymerization along these lines.[1] It is well known that proper tuning of the electronics of two different monomer units allows them to be polymerized in an alternating mode. However, controlled alternating copolymerization using living radical polymerization is still not well established.[2] We herein present a novel approach that comprises alternating nitroxide mediated radical polymerization (NMP) of two electronically distinct monomers 1 and 2 which bear functionalities in their side chains that are chemically orthogonally addressable. A single type of alternating polymer 3 can then be further functionalized via sequential orthogonal polymer analogous reactions such as amidation and thiol-ene click chemistry to give various alternating polymers 4 in a combinatorial approach.[3]

Literature: [1] a) N. Badi, J.-F. Lutz, Chem. Rev. 2009, 38, 3383; b) S. Pfeifer, J.-F.-Lutz, J. Am. Chem. Soc. 2007, 129, 9542; c) N. Baradel, S. Fort, S. Halila, N. Badi, J.-F. Lutz, Angew. Chem. Int. Ed. 2013, 52, 2335; [2] a) D. Benoit, C. J. Hawker, E. E. Huang, Z. Lin, T. P. Russell, Macromolecules 2000, 33, 1505; b) B. Kırcı, J.-F. Lutz, K. Matyjaszewski, Macromolecules 2002, 35, 2448-2451; c) E. Mishima, S. Yamago, J. Polym. Sci., Part A: Polym. Chem. 2012, 50, 2254; [3] M. Tesch, J.A.M. Hepperle, M. Letzel, A. Studer, submitted.

Synthesis of new Cross-linkable Monomers for Applications in Polymer-based Organic Light-Emitting Diodes

L. Schnellbächer, M. Reggelin* Clemens Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiß-Straße 4, D-64287 Darmstadt, E-Mail: ls@punk.oc.chemie.tu-darmstadt.de

Poly(p-phenylene) and its derivatives belong to a group of semiconducting polymers, which are in the focus of interest because of their high potential as blue emitters in organic light-emitting diodes (OLEDs).[1] Problems associated with polymers processed in solution are possible aggregation,[2] the bathochromic shift in emission due to chemical defects,[3] as well as dissolution and intermixing of interfaces between adjacent layers during spin-coating. [4] To overcome these problems, we envisioned syntheses of new mixed, cross-linkable, indenofluorene-based monomers of type 1, accessible from ester 4 and aryl bromide 5 via indenofluorene 2.

Here we present our synthetic approach to indenofluorene-based monomers of type 1 from commercially available starting materials.

References:

[1] A. Kraft, A. C. Grimsdale, A. B. Holmes, Angew. Chem. Int. Ed. 1998, 37, 402-428. [2] S. Setayesh, A. C. Grimsdale, T. Weil, V. Enkelmann, K. Müllen, F. Meghdadi, E. J. W. List, G.

Leising, J. Am. Chem. Soc. 2001, 123, 946-953.

[3] E. J. W. List, R. Guentner, P. S. d. Freitas, U. Scherf, Adv. Mat. 2002, 14, 374-378. [4] a) A. Köhnen, N. Riegel, J. H.-W. M. Kremer, H. Lademann, D. C. Müller, K. Meerholz, Adv. Mat.

2009, 21, 879-884; b) O. Nuyken, S. Jungermann, V. Wiederhirn, E. Bacher, K. Meerholz, Monatsh. Chem. 2006, 137, 811-824.

The Synthesis of NMDA-Receptor Antagonists

Damsen, H., Aachen/D, Niggemann, M., Aachen/D

Institute for Organic Chemistry, RWTH Aachen, Landoltweg 1, 52074 Aachen

The N-methyl-D-aspartate (NMDA) receptors are members of a family of excitatory ionotropic glutamate receptors, which play an important role in several neurological processes such as learning and memory. Overactivation of the NMDA receptor leads to a high intracellular Ca2+ concentration inducing a number of neurotoxic effects and neurological diseases such as epilepsy, Parkinson’s and Alzheimer’s diseases. Controlling the cellular intake of Ca2+ with NMDA receptor agonists and antagonists is therefore of great interest. Known NMDA receptor antagonists contain the tetrahydro-3-benzazepine scaffold, hence these compounds are interesting lead molecules for the treatment of neurodegenerative diseases.[1]

R3

NR4

R2

R1

N

R2R4

R3 R1

- H2O

OH

We have developed a new method for the stereoselective synthesis of differently substituted tetrahydro-3-benzazepines, including a calcium-catalyzed Friedel-Crafts cyclization[2] as a key step.

N

R2R4

R3 R1

different amino acids

post cyclization derivatizationR3

O

H

NH2

R2HO

O

different aldehydes

different metal organicreagents

R4MgX, R4Li

calcium catalyzedFriedel-Crafts cyclization

In addition, the synthetic route towards the cyclization precursor allows for a variation of every substituent in the lead molecule by a simple adaption of reagents, leaving the general synthetic route unchanged. Starting from simple amino acids we synthesized tetrahydro-3-benzazepines with novel substitution patterns in only six steps.

Literature:

[1] C. Wang, J Drug Metab Toxicol, 2013, 4:3.

[2] M. Niggemann, M. Meel Angew. Chem. Int. Ed. 2010, 49, 3684-3687.

Cyclotheonamaide-based Inhibitors of the human β-tryptase

A.-K. Drewel, Bielefeld/D, N. Schaschke, Bielefeld/D, C. P. Sommerhoff, München/D

A.-K. Drewel, Universität Bielefeld, Universitätsstraße 25, 33615 Bielefeld/D

β-Tryptase is a serine protease with trypsin-like activity which is expressed in mast cells. It is well accepted that this protease, which is released during an allergic reaction, affects the modulation of bronchial tone, airway inflammation and tissue remodeling, which are the hallmarks of asthma. Thus, the inhibition of β-tryptase is expected to be a promising novel approach for the treatment of allergic asthma.[1]

Based on the cyclotheonamide E4 (1) as scaffold, the potent and selective inhibitor 2 was developed. For this, the skeletal structure of the natural product was modified in different positions. The exchange to -aminohexanoic acid in P3-Position leads to an improved inhibitory profile.[2] In addition, the S1-ligand was changed from (S)-3-amino-6-guandino-2-oxo-hexanoic acid to 3hPhe(3-H2N-CH2) for shifting the binding mode from a covalent to a fully reversible one.[3] Further modifications are the replacement of proline with pipecolic acid and of the vinylogous tyrosine with a triazole unit.

Figure 1: Structures of cyclotheonamide E4 (1) and inhibitor 2.

To improve the inhibitory profile of our lead structure 2, we have tested different P1’-residues to address the S1’-pocket more effectively. The synthesis and the inhibitory profile of these novel β-tryptase inhibitors will be presented.

References:

[1] C. P. Sommerhoff, N. Schaschke, Curr. Pharm. Design 2007, 13, 313. [2] N. Schaschke, C. P. Sommerhoff, Chem. Med. Chem. 2010, 5, 367. [3] D. Janke, C. P. Sommerhoff, N. Schaschke, Bioorg. Med. Chem. 2011, 19, 7236.

3,10-Difunctionalized Dibenz[a,h]anthracenes as Monomers for Step-Ladder-Type PPP Polymers T. Wiesner, M. Reggelin*, Technical University Darmstadt, Clemens-Schöpf-Institute for Organic- and Biochemistry, Alarich Weiss-Straße 4, 64287 Darmstadt, Germany. PPP-type semiconducting polymers play an important role as blue fluorescent materials in OLEDs.[1] In the past, Polyfluorenes and Polyindenofluorenes have proved to be useful for these applications. In contrast to these thoroughly investigated structures, higher polycyclic aromatic hydrocarbons are seldom used in semiconducting polymers as emitting material due to their challenging synthesis.[1] In our group we envisioned a synthesis of functionalized higher acenes as monomers in polymerisation reactions leading to step-ladder-type-PPP materials. 2009 Swager et al.[2] described a stair-step-structured copolymer containing dibenz[a,h]anthracene-subunits, though to the best of our knowledge a linear polymer based on 3,10-difunctionalized dibenz[a,h]anthracenes has not yet been published. Here we present our initial results on the synthesis of a 3,10-dibromobenz[a,h]anthracenes 1. Though as key-step a PtCl2-catalysed cycloisomerisation[3] of the terphenyl 2 could not be accomplished, a base-mediated cyclisation as described by Burton et al.[4] turned out to be successful.

[1] a) A. Kraft, A. C. Grimsdale, A. B. Holmes, Angew. Chem., Int. Ed. 1998, 37,

402-428; b) X. Guo, M. Baumgarten, K. Müllen, Prog. Polym. Sci. 2013, 38, 1832-1908.

[2] J. M. W. Chan, S. E. Kooi, T. M. Swager, Macromolecules 2010, 43, 2789-2793. [3] A. Fürstner, V. Mamane, J. Org. Chem. 2002, 67, 6264-6267. [4] Y. Wang, D. J. Burton, Org. Lett. 2006, 8, 5295-5298.

Flow Generated Sequential Complexity: Biomimetic Syntheses of

Borrerine-Derived Alkaloids and Unnatural Derivatives Thereof

Kamptmann, S. B., Cambridge/GB, Ley, S. V.*, Cambridge/GB

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom, sbk31@cam.ac.uk

The bisindole alkaloids borreverine (3) and isoborreverine (1) were first isolated from Borreria verticillata in 1973.1 In 1978 it was shown that the two molecules can be directly derived from the dimerisation of the naturally occuring indole alkaloid borrerine (10).2 Since then a number of structurally related bisindole alkaloids proposed to be biosynthesised from borrerine (10) have been reported. Borrerine-derived alkaloids have been seen to exhibit significant antimalarial activity, notably in chloroquine-resistant strains of Plasmodium falciparum.3 Although some bisindole compounds have been successfully synthesised to date – either by classical or biomimetic syntheses - these syntheses often suffer from low yields or require extensive purification processes to separate complex product mixtures.4

NH

NR

Me

N

NR

Me

H

R = H: isoborreverine (1)R = Me: dimethylisoborreverine (2)

NH

NR1

Me

N

R2

NR1

Me

R1 = H, R2 = α-Me: flinderole A (5)R1 = Me, R2 = α-Me: flinderole B (6)R1 = H, R2 = β-Me: desmethylflinderole (7)R1 = Me, R2 = β-Me: flinderole C (8)

NH

NR

Me

NH

HH

NMe

R = H: borreverine (3)R = Me: auricularine (4)

NH

OH

NH

HH

NMe

spermacoceine (9)

NH

NMe

borrerine (10)

One goal of the flow reactor program in the Ley group is to conduct synthesis more akin to the way a cell produces a compound rather than in typical round-bottom flasks, hence to exploit biomimetic pathways. By taking the advantages of flow-chemical methods we aim to overcome the aforementioned downfalls in the batch syntheses of bisindoles, namely the need for time consuming and expensive purification steps, and to control the synthetic outcome. Our progress towards the biomimetic syntheses of the mentioned bisindole compounds as well as towards the syntheses of unnatural homo- and heterodimeric bisindole compounds in flow will be presented. [1] a) J. L. Pousset, J. Kerharo, G. Maynart, A. Cavé, R. Goutarel, Phytochemistry 1973, 12, 2308-2310; b) J. L.

Pousset, A. Cavé, A. Chiaroni, C. Riche, J. Chem. Soc., Chem. Commun. 1977, 261-262. [2] F. Tillequin, M. Koch, J. Chem. Soc., Chem. Commun. 1978, 826-828. [3] L. S. Fernandez, M. F. Jobling, K. T. Andrew, V. M. Avery, Phytother. Res. 2008, 22, 1409–1412; L. S. Fernan-

dez, M. S. Buchanan, A. R. Carroll, Y. J. Feng, R. J. Quinn, V. M. Avery, Org. Lett. 2009, 11, 329-332; L. S. Fer-nandez, M. L. Sykes, K. T. Andrew, V. M. Avery, Int. J. Antimicrob. Agents 2010, 36, 275-279.

[4] a) D. H. Dethe, R. D. Erande, A. Ranjan, J. Am. Chem. Soc. 2011, 133, 2864-2867; b) R. M. Zeldin, F. D. Toste, Chem. Sci. 2011, 2, 1706-1709; c) R. Vallakati, J. A. May, J. Am. Chem. Soc. 2012, 34, 6936-6939; d) R. Valla-kati, J. A. May, Synlett 2012, 23, 2577-2581; e) D. H. Dethe, R. D. Erande, A. Ranjan, J. Org. Chem. 2013, 78, 10106-10120; f) R. Vallakati, J. P. Smuts, D. W. Armstrong, J. A. May, Tetrahedron Lett. 2013, 54, 5892-5894; g) D. H. Dethe, R. D. Erande, B. D. Dherange, Org. Lett. 2014, 16, 2764-2767.

Dynamic Behavior of a Monohaptoallylpalladium Species investigated by Resid-ual Dipolar Couplings (RDCs) and NOE/Exchange NMR-Spectroscopy

V. Bagutski, Darmstadt/DE, V. Schmidts, Darmstadt/DE, L.-G. Xie, Vienna/AT, D. Audi-sio, Mülheim/DE, L. Wolf, Mülheim/DE, K. Hofmann, Darmstadt/DE, C. Wirtz, Mül-heim/DE, W. Thiel, Mülheim/DE, N. Maulide, Vienna/AT, C. M. Thiele, Darmstadt/DE.

Dr. Volker Schmidts, Technische Universität Darmstadt, Alarich-Weiss-Str. 4, D-64287 Darmstadt.

The understanding and improvement if catalytic transformations crucially relies on characterization of the catalytically active species and other intermediates in the cata-lytic cycle. We chose to investigate the reaction pathways of the recently introduced Pd-catalyzed diastereodivergent asymmetric allylic alkylation on cyclobutene sub-strates,[1,2] using a combination of XRD-, NMR- and DFT-methods. Previous studies identified a η1-allyl palladium complex as the key species.[3] Using an amide-stabilized cyclobutene substrate and a monodentate R-MONOPHOS ligand, we were able to iso-late and characterize a fairly stable intermediate (1) of this reaction.[4]

The intermediate crystallizes in a single form (1a). However in solution, two sets of sig-nals are observed, indicating suprafacial allylic migration of the Pd-fragment across the cyclobutene ring, leading to diastereomeric complexes 1a and 1b. This assignment is supported by NOE spectra, showing exchange peaks of resonances from 1a, when se-lectively irradiating a resonance of 1b, and vice versa. By introducing the mixture of 1a and 1b into an alignment medium (chemically cross-linked PDMS-gel), we were able to measure eight RDCs per diastereoisomer, allowing the calculation of an order tensor and validation of calculated structure models for both species.

DFT calculations of the thermochemistry of the transition states involved in the η1→η3→η1 interconversion is in accordance with the experimental exchange rates as determined by NMR. In addition, the calculated geometries show the thermodynamic importance of the internal coordination of the amide carbonyl to the palladium. This chelation and the steric repulsion of the MONOPHOS ligand are the main reasons for the relatively high stability of the monohaptoallylpaladium complex.

The observation of the internal coordination and the facile isomerization of the interme-diate species could be of importance not only to the catalytic behavior of Pd-catalyzed allylic alkylation but also to a better understanding of transformations dealing with direct C-H activation of unreactive positions.

[1] M. Luparia et al., Angew. Chem. Int. Ed. 2011, 50, 12631-12635. [2] D. Audisio et al., Angew. Chem. Int. Ed. 2012, 51, 7314-7317. [3] D. Audisio et al., Angew. Chem. Int. Ed. 2013, 52, 6313-6316. [4] L.-G. Xie et al., manuscript in preparation.

Synthesis and Evaluation of fluorinated analogues of S1P Receptor Subtype

Specific Antagonists for PET

Prasad, V. P., Münster/DE, Wagner, S., Münster/DE, Schäfers, M., Münster/DE, Haufe,

G., Münster/DE

Prof. Dr. Günter Haufe, Westfälische Wilhelms-Universität, Organisch-Chemisches

Institut, Corrensstr. 40, D-48149 Münster

Sphingosine-1-phosphate (S1P) [1,2] is a bioactive lysophospholipid mediator that

is mainly released from activated platelets. A wide variety of biological cellular

responses to S1P have been ascribed to the presence of five S1P subtype receptors

(S1PR1-5), that belong to the family of G protein-coupled receptors. Among the five

known high-affinity receptors, the S1P1 receptor is expressed by many cell types,

including endothelial and cardiac cells. Although the receptor activation has been

studied using various agonists, there are not many suitable antagonists available. At

present there are no tools available to visualise the S1P receptors in vivo.

A couple of years ago, Sanna et al.[3] reported a S1P1 inhibitor molecule (R)-3-

amino-4-(3-hexylphenyl-amino)-4-oxobutylphosphonic acid (Lead compound), which

has been used in in vivo experiments to provide insights into the role of S1P/S1PR1

signalling. We have synthesized several fluorinated analogues of W146 and tested

their activities as antagonists for S1PR1 receptors. Most of the fluorinated analogues

found to be active in the in vitro assay. Radiolabelling of the most active fluorinated

analogue was achieved and the resulted tracer was tested for in vivo imaging of S1P

receptors using PET.

[1] H. Rosen, E. J. Goetzl, Nat. Rev. Immunol.2005, 5 560-570.[2] H. Rosen, P. J.

Gonzalez-Cabrera, M. G. Sanna, S. Brown, Ann. Rev. Biochem. 2009, 78, 743-768. [3]

M. G. Sanna, S. Wang, P. J. Gonzalez-Cabrera, A. Don, D. Masolais, M. P. Matheu, S.

H. Wei, I. Parker, E. J. Jo, W.-C. Cheng, M. D. Kahalan, W. Wong, H. Rosen, Nature

Chem. Biol. 2006, 2, 434-441.

A New Strategy for the Synthesis of Fluorinated Statin Analogues

Berlemann, H., Münster/DE, Kondratov, I. S., Kiev/UA, Haufe, G., Münster/DE,

Prof. Dr. Günter Haufe, Westfälische-Wilhelms-Universität, Organisch-Chemisches-

Institut, Corrensstraße 40, D-48149 Münster

Statins belong to an important class of drugs for the treatment of hypercholesterolemia

due to their ability to inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)

reductase. Fluvastatin, Atorvastatin, Rosuvastatin and Pitavastatin are the most well-

known compounds from this family. The main structural feature of statins is the

presence of the 3-hydroxy-valerolactone moiety playing the crucial role in binding [1].

While plenty of statins and their analogues (including some fluorine containing

compounds) were widely investigated, little attention was paid to analogues, which

contain fluorine in the lactone fragment [2], although the introduction of fluorine or

fluorine-containing substituents into the lactone moiety can change or even improve

this activity.

Here we present a new strategy for the synthesis of statin analogues 4, containing a

trifluoromethyl group in 3-position of the lactone ring. The synthesis starts from the

trifluoroacetoacetate 1, which is transformed to compound 2 by allylation similarly to a

known protocol [3]. Now an olefin cross metathesis reaction with allylic acetates of type

3 can take place. After saponification and ring closure, the lactone 4 can be obtained.

This strategy enables the synthesis of new fluorinated statin analogues.

Literature: [1] F. Bennett, D. W. Knight, G. Fenton, Tetrahedron Lett. 1988, 29, 4865-4868., [2] X. Wang, X. Fang, H. Xiao, Y. Yin, H. Xia, F. Wu, J. Fluorine Chem. 2012, 133, 178-183. [3] A. Rivkin, F. Yoshimura, A. E. Gabarda, Y. S. Cho, T.-C. Chou, H. Dong, S. J. Danishefsky J. Am. Chem. Soc. 2004, 126, 10913–10922.

New Synthetic Approach Towards Aspergillide A-C via Intramolecular Heck-Reaction Starting from Chiral Pool Materials

Petersen, M. H., Potsdam/D, Schmidt, B.*, Potsdam/D

*Prof. Dr. Bernd Schmidt, University of Potsdam, Karl-Liebknecht-Straße 24-25,

D-14476 Golm, Germany, e-mail: bernd.schmidt@uni-potsdam.de

Since the isolation of Aspergillides A - C (6) in 2008 by Kusumi et. al1 from the marine-derived fungus Aspergillus ostianus strain 01F313 many groups have started with the research on various total synthesis. Due to its interesting chemical composition and biological activity new pathways to the 14 membered lactone and the included tetrahydropyrane-core are still being investigated.

d

Fig 1: Overview to our approach of the total synthesis of Aspergillide A - C

Dienediol 1 and ent-1 are well known starting materials which are easily synthesized from the chiral pool. Fragment A contains the tetrahydropyrane-core which is formed by a ring closing metathesis-isomerisation-sequence developed in our group2. After coupling 2 and 4 which is synthesized from 3 in five steps and includes a cross metathesis step, the 14 membered lactone will be formed by an intramolecular Heck-reaction to obtain 6.

1 Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.; Ooi, T.; Kusumi,T. Org. Lett. 2008, 10, 225-228. 2 Schmidt, B. Eur. J. Org. Chem. 2003, 816-819.

Synthesis of -Benzylated ,-Unsaturated Lactams via Palladium Catalyzed

MATSUDA-HECK-Reaction of Arene Diazonium Tetrafluoroborates and

-Methylene--Valerolactame

Wolfa, F.; Schmidta, Prof. Dr. B.

a University of Potsdam, Karl-Liebknecht-Straße 24/25, 14476 Potsdam-OT Golm

The palladium catalyzed Matsuda-Heck-Reaction of arene diazonium salts is a

powerful synthetic tool for the coupling of olefins and aryl compounds. Mild reaction

conditions such as low catalyst loading, ambient temperature and fast reaction times

support this fact[1].

After developing a highly efficient protocol for the Pd-mediated synthesis of -

benzylated ,-pentenolides[2], we successfully used this method in the preparation of

-benzylated ,-unsaturated lactams, starting from arene diazonium

tetrafluoroborates and N-proctected--methylene--valerolactame. A set of different

substituted products could be obtained under mild reaction conditions (5 mol%

Pd(OAc)2, room temperature, no inert gas atmosphere necessary) as a single

regioisomer in moderate to excellent yield. The required starting materials are easily

accessible from the corresponding acetanilides[3] and from ethyl nipecotate,

respectively.

The received structure presented below is an integral part of many biological active

molecules, which inhibit receptors[4] or decrease the specific cell adhesion[5].

Literature:

[1] J. G. Taylor, A. V. Moro, C. R. D. Correia, Eur. J. Org. Chem. 2011, 1423-1428, and

the references therein. [2] B. Schmidt, F. Wolf, manuscript in preparation. [3] B.

Schmidt, R. Berger, F. Hölter, Org. Biomol. Chem 2010, 8, 1406-1414; B. Schmidt, F.

Hölter, R. Berger, Adv. Synth. Catal. 2010, 352, 2463-2473. [4] US2006/142312 A1,

Flamme, C. M. 2006. [5] US2003199692 A1, Biedinger, R. J., 2003.

A Bidentate Lewis Acid Catalysed Inverse Electron-Demand Diels-Alder Reaction

of Diazines with Arynes

S. Ahles, Giessen/D, H. A. Wegner, Giessen/D

Justus-Liebig Universität Giessen, Heinrich-Buff-Ring 58, 35392 Giessen

The inverse electron-demand Diels-Alder (IEDDA) reaction of phthalazines with different dienophiles catalysed by a bidentate Lewis acid was investigated to great success in our group. However, the scope of the reaction was mostly concentrated on dienophiles such as furanes[1], dioxolanes[2] or enamines[3]. Herein we present an investigation to widen the range of this process to arynes. The presented reaction will enable a novel synthetic access to acenes and graphene nanoribbons, which are promising building blocks for molecular electronics. [4,5]

Literature: [1] S. N. Kessler, M. Neuburger, H. A. Wegner, J. Am. Chem. Soc., 2012, 134, 17885. [2] S. N. Kessler, H. A. Wegner, Org. Lett. 2010, 12, 4062. [3] L. Schweighauser, I. Bodoky, S. N. Kessler, D. Häussinger, H. A. Wegner, Synthesis, 2012, 44, 2195. [4] J. E. Anthony, Angew. Chem. Int. Ed. 2008, 47, 452. [5] L. Chen, Y. Hernandez, X. Feng, K. Müllen, Angew. Chem. Int. Ed. 2012, 51, 7640.

A Fluorescent Rainbow: Recent Developments Concerning 4-Hydroxy-1,3-thiazoles

S. H. Habenicht, Jena/DE, D. Weiß, Jena/DE, R. Beckert, Jena/DE

Prof. Dr. Rainer Beckert, Friedrich-Schiller-University Jena, Institute of Organic and

Macromolecular Chemistry, Humboldtstr. 10, 07743 Jena

4-Hydroxy-1,3-thiazoles and their derivatives have been intensively studied during the

last few years, as they represent a new class of functional chromophores/fluorophores

[1]. In addition, they form the substructure of several natural products and were chosen

by nature as part of the chemical compound responsible for the dual luminescence of

the firefly (lampyridae). The remarkable spectroscopic properties of this heterocycle

and its easy functionalization allow the development of a variety of novel applications.

4-Hydroxy-1,3-thiazoles have also been used as novel ligands for metal complexes,

emitting polymers, DSSCs, solvatochromic dyes, and sensors [2].

A series of rather bulky red emissive 4-alkoxythiazole based dyes has been

synthesized previously [2c], proving that their emission can be shifted far beyond

green. For many applications however, molecule size plays an important role and

sterically demanding molecules may not reach their point of destination.

Our new fluorescent dyes are featured by emissions in the blue, turquoise, green,

yellow, orange and even red range of the visible light spectrum, furthermore being

relatively small in size in contrast to various existing fluorescent dyes.

Literature:

[1] a) E. Täuscher, Synthesis 2010, 1603; b) E. Täuscher, Tetrahedron Lett. 2011, 52, 2292. [2] a) R. Menzel, Eur. J. Org. Chem. 2012, 5231; b) R. Menzel, Macromol. Chem. Phys. 2011, 212, 840; c) R. Menzel, Dyes & Pigments 2012, 94, 512; d) A. Schade, Asian J. Org. Chem. 2013, 2, 441; e) L. K. Calderón–Ortiz, Eur. J. Org. Chem. 2012, 2535.

Studies on correlations between static and kinetic acidities

of complex Lewis acids

G. Hilt, Marburg/D, M. Oestreich, Berlin/D, P. R. Schreiner, Gießen/D, A. R. Nödling, Marburg/D, K. Müther, Berlin/D, V.H.G. Rohde, Berlin/D, G. Jakab, Gießen/D

Prof. Dr. G. Hilt, Philipps-Universität Marburg, Hans-Meerwein-Str., 35032 Marburg

Relationships between quantified acidities of Lewis acids and their catalytic activities or selectivities in organic reactions are useful as guides for future catalyst design. Pivotal studies of our group revealed good correlations between NMR-spectroscopically quantified Lewis acidities and catalytic activities of simple metal halides.[1]

Scheme 1: Excerpt of the qualitative correlation between 2H-NMR-spectroscopically quantified Lewis

acidities and catalytic activities in a Povarov reaction, obtained for several metal halide Lewis acids.[1]

Recently we focused on non-trivial Lewis acids used in modern organic synthesis. By studying a series of highly reactive silylium ions we wanted to elaborate on the general possibility of quantifying the acidity of these potent Lewis acids. Also targeted was the

predictive power of 29Si shifts, which are seen as measure of strength of silicon Lewis acids.[2] In contrast, we also investigated rather weakly Lewis acidic thioureas, which are an important class of hydrogen-bonding catalysts. Since these are known to activate carbonyl groups in a similar fashion to common Lewis acids, we set out to probe possible correlations between their quantified Lewis acidities and catalytic activities.[3,4]

Scheme 2: Examples of modern, complex Lewis acids investigated in recent quantification studies.

Literature:

[1] G. Hilt, F. Pünner, J. Möbus, V. Naseri, M. A. Bohn, Eur. J. Org. Chem. 2011, 30, 5962. [2] A. R. Nödling, K. Müther, V. Rohde, G. Hilt, M. Oestreich, Organometallics 2014, 33, 302. [3] A. Wittkopp, P. R. Schreiner, Chem. Eur. J. 2003, 9, 407. [4] A. R. Nödling, G. Jakab, P. R. Schreiner, G. Hilt, unpublished results.

Novel Fluorinated Aminophosphonic Acid Derivatives as Potential Matrix Metalloproteinase Inhibitors

Beutel, B., Münster/DE, Daniliuc, C., Münster/DE, Riemann, B., Münster/DE, Schäfers,

M., Münster/DE, Vidyadharan, R., Münster/DE, Waller, M., Münster/DE, Haufe, G.,

Münster/DE

Prof. Dr. Günter Haufe, Westfälische-Wilhelms-Universität, Organisch-Chemisches-

Institut, Corrensstraße 40, D-48149 Münster

The matrix metalloproteinases (MMP) – a group of endopeptidases located in the space between cells – are heavily involved in early stages of inflammatory diseases and hence are attractive targets for molecular imaging by positron emission tomography (PET) [1]. Continuing our research efforts on fluorinated MMP inhibitors and PET tracers [2] we focused our attention to the synthesis of phosphonic acid derivatives analogous to compound 1 [3]. In a diversity oriented synthesis we made use of fluorinated building blocks to synthesize potential inhibitors bearing various substituted biphenyl moieties (e.g. 2 and 3) and investigated their potencies against MMP-2 and MMP-9 in vitro.

In previous investigations we found that due to fluorine protein interactions [3] both enantiomers of MMP inhibitors based on fluorinated α-amino hydroxamic acids are almost equally potent. To investigate whether this holds true for fluorinated analogues we developed a 12 step asymmetric synthesis towards the two enantiomeric inhibitors (R)-4 and (S)-4 similar to a pathway published for non-fluorinated analogues [4].

[1] D. Hartung, M. Schäfers, S. Fujimoto, B. Levkau, N. Narula, K. Kopka, R. Virmani, C. Reutelingsperger, L. Hofstra, F. D. Kolodgie, A. Petrov, J. Narula, Eur. J. Nucl. Med. Mol. Imaging 2007, 34, 1–8. [2] M. Behrends, S. Wagner, K. Kopka, O. Schober, M. Schäfers S. Kumbhar, M. Waller, G. Haufe, to be submitted. [3] M. Schudok, W. Schwab, G. Zoller, E. Bartnik, F. Büttner, K.-U. Weithmann, 2001, US 6235727. [4] G. Pochetti, E. Gavuzzo, C. Campestre, M. Agamennone, P. Tortorella, V. Consalvi, C. Gallina, O. Hiller, H. Tschesche, P. A. Tucker, F. Mazza, J. Med. Chem. 2006, 49, 923–931.

XR

SNH

O O

P(O)OH2

1 X = CH, R = OMe2 X = N, R = F

3 X = CH, R = OCH2CH2F

MeO

SNH

O O

P(O)(OH)2

(R)-/(S)-4

F

4

Novel One-Pot Three-Component Synthesis of Merocyanines

J. Papadopoulos, Düsseldorf/D

Prof. Dr. Thomas J. J. Müller, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1,

40225 Düsseldorf/D

Multi-component reactions (MCRs) allow for fast and efficient syntheses for a variety of

substance classes. Due to many advantages over conventional methods they received

an increased interest in academia and industry. [1]

Functional π-electron systems such as merocyanines find important applications in

science and technology, for example in use as bulk heterojunction (BHJ) and dye-

sensitized solar cells (DSSC). [2]

A novel consecutive one-pot three-component synthesis consisting of

hydrobromination, Sonogashira-coupling and Michael-addition opens an access to new

types of merocyanines in good yields.

Scheme 1: Novel one-pot three-component synthesis of merocyanines.

Literature

[1] D.M. D’Souza, T.J.J. Müller, Chem. Soc. Rev. 2007, 36, 1095-1108. [2] a) N.M.

Kronenberg, V.Steinmann, H. Bürckstümmer, J. Hwang, D. Hertel, F. Würthner,

K.Meerholz, Adv. Mater. 2010, 22, 4193-4197. b) K. Sayama, K. Hara, N. Mori, M.

Satsuki, S. Suga, S. Tsukagoshi, Y. Abe, H. Sugihara, H. Arakawa, Chem. Comm.

2000, 1173-1174.

Electrochemical Reactions of 1,4-dienes

Röse, P., Marburg/D, Hilt G., Marburg D

Prof. Dr. Gerhard Hilt, Philipps-Universität Marburg, Hans Meerwein-Str., 35032

Marburg

The cobalt-catalyzed 1,4-hydrovinylation of hydroxy functionalized terminal alkenes

with 1,3-diens leads to a variety of 1,4-dienes. Depending on the alkene and diene

used a broad range of high functionalized 1,4-dienes are accessible.[1,2]

Scheme 1: Cobalt catalyzed 1,4-hydrovinylation for the synthesis of hydroxyl functionalized

1,4-dienes.

The 1,4-dienes can be converted in highly functionalized tetrahydrofuran and pyran

derivatives under electrochemical conditions using reactive cations generated by

direct or indirect electrolysis. Thereby, the tetrahydrofuran and pyran derivatives can

be synthesized in good regio- and diasterioselectivities. Moreover, the introduction of

a functional group during the electrochemical reaction enables further chemical

transformations.[3]

Scheme 2: Electrochemical Synthesis of high functionalized tetrahydrofuran and pyran

derivatives.

Literature:

[1] G. Hilt, F. du Mesnil, S. Lüers, Angew. Chem. Int. Ed. 2001, 40, 387-389.

[2] G. Hilt, M. Danz, J. Treutwein, Org. Lett. 2009, 11, 3322-3325.

[3] P. Röse, S. Emge, G. Hilt, unpublished results.

New fluorescent probes for phosphate based on dipyrrolylmethanes

Müller, C. Chemnitz/Germany D-09111, Kataev, E. A. Chemnitz/Germany D-09111

Christoph Müller, Technische Universität Chemnitz, Fakultät für Naturwissenschaften,

Institut für Chemie, Straße der Nationen 62, D-09111 Chemnitz

In our early work we demonstrated the phosphate binding ability of 5,5’-substituted

dipyrrolylmethanes with guanidinum functionalities.[1] Now we like to present our

preliminary results on the development of fluorescent phosphate probes based on turn-

on fluorescence systems of Huston et al. This group was able to detect oxoanions in

aqueous solution at pH = 6.[2] Combining their approach on detection of oxoanions with

our structures optimized on phosphate recognition,[1] we develop fluorescent probes for

phosphate detection in aqueous solution at physiological pH value. Our key structures

are substituted dipyrrolylmethanes, which provide hydrogen bonding donors in suitable

geometrical arrangement for recognition and binding of tetrahedral phosphate ions.

Functionalized naphthalimides are used for turn-on fluorescence response of the anion

binding event caused by suppression of the PET.

(Principle of our intended fluorescent probes for phosphate detection)

[1] E. A. Kataev, C. Müller, G. V. Kolesnikov, V. N. Khrustalev; Eur. J. Org. Chem.

2014, 2747. [2] M. E. Huston, E. U. Akkaya, A. W. Czarnik; J. Am. Chem. Soc. 1989,

111, 8735.

Synthesis and structural assignment of Annonaceae Acetogenins from the seeds of Asimina triloba

van Kempen, J., Münster/DE, Haufe, G., Münster/DE, Schimanski, H., Münter/DE

Prof. Dr. G. Haufe, Westfälische-Wilhelms-Universität, Organisch-Chemisches Institut, Corrensstraße 40, 48149 Münster

Among other properties Annonaceous Acetogenins are known for their cytotoxic activity against different types of cancer cells. In 1998 WOO, KIM and MCLAUGHLIN isolated two novel Annonaceous Acetogenins from the seeds of Asimina triloba. The one with the structure shown below was named Asitrilobin A. Its structure has not been elucidated but reduced to either a threo-cis-erythro or an erythro-cis-threo configured core unit, while the configuration at C-10 is not known.[1]

Based on earlier research in our group on the total synthesis of Acetogenins we are planning to synthesize both of the proposed structures of Asitrilobin A and to assign the configuration of the natural product. We started from commercially available cis,trans,trans-Cyclododeca-1,5,9-triene (5) and converted it into bislactone 2 via a procedure developed in our group.[2] Bislactone 2 is a racemic mixture and can serve as a building block for the enantiomers of the threo-cis-erythro and also the erythro-cis-threo configured core unit as possible structure fragments for Asitrilobin A. The aliphatic chain on the left of the structure can be attached by WITTIG-reaction. The

aliphatic spacer moiety and the -butyrolactone moiety can be provided by the

bromoalcohol 3 and -butyrolactone building block 4; both are literature known compounds.[3,4]

Literature:

[1] M. H. Woo, D. H. Kim, J. L. McLaughlin, Phytochemistry 1999, 50, 1033-1040. [2] H. Schimanski, Dissertation, Münster, 2001. [3] S. Jiang, Z.-H. Liu, G. Sheng, B.-B. Zeng, X.-G. Cheng, Y.-L. Wu, Z.-J. Yao, J. Org. Chem. 2002, 67, 3404-3408. [4] S. Hallouis, C. Saluzzo and R. Amouroux, Synth. Commun. 2000, 30, 313-324.

Towards the synthesis of alkynyl vinyl ethers

T. Gauger, Braunschweig/DE.

Prof. Dr. S. Schulz, Braunschweig/DE.

Institut für Organische Chemie, Hagenring 30, 38106 Braunschweig.

Because of the rising resistance against known antibiotics, new agents and

compounds are needed to address this issue. During a screening program at the

Helmholtz Center for Infection diseases, an unusual fatty acid, Maracin (1), has

shown promising activity against certain bacteria.[1] Unfortunately, the

biotechnological fermentation yields only very low amounts, so a synthetic approach

might be promising. Nevertheless, the unusual alkynyl vinyl ether motif makes such a

synthesis most challenging, because almost nothing of the chemistry of this structural

motif is known.

 

First attempts to synthesize ethinyl vinyl ethers failed, probably due to the chemical

instability of this uncommon structural motif. For this reason several model

compounds of Maracin lacking ether the ethinyl- or vinyl group directly connected to

the ether function shall be synthesized and their chemical properties analyzed. The

new insights into compounds of this class gained from the synthesized model

compounds may then be used to design a synthetic route for the total synthesis of

Maracin. The progress made towards construction of aliphatic alkynyl vinyl ethers will

be presented on the poster.

Literature:

[1] M. Herrmann, B. Böhlendorf, H. Irschik, H. Reichenbach, G. Höfle, Angew. Chem.

1998, 110, 1313-1315.

Investigation of the conformational space of a Diarylethene derivative using residual dipolar couplings MF, Maic Fredersdorf, 64287 Darmstadt/ Germany RG, Robert Göstl, 12489 Berlin/ Germany AK, Andreas Kolmer, 64287 Darmstadt/ Germany PM, Peter Monecke, 65926 Frankfurt am Main/ Germany SH, Stefan Hecht, 12489 Berlin/ Germany CMT, Christina M. Thiele, 64287 Darmstadt/ Germany Clemens-Schöpf-Institute for Organic Chemistry and Biochemistry Technische Universität Darmstadt Alarich-Weiss-Strasse 16 64287 Darmstadt/ Germany Diarylethenes (DAEs) are a prominent member of photochromic molecules which can exist in a ring-open and a ring-closed form. The switching between both isomers is induced by UV and VIS light, respectively.[1] It is proposed that the efficiency of the switching depends on the population of the parallel (p) and anti-parallel (a-p) conformation of the ring-open form. Only the a-p conformation leads to the ring-closed form during the photocyclization process. We have chosen one modified DAE derivative, synthesized by the Hecht group, oriented the sample in a weak alignment medium (our new cross-linked PBLG gel)[2] and started investigating the conformational space by residual dipolar couplings (RDCs) and NOE. In addition to (CLIP)-HSQC[3] for one bond carbon-proton couplings, the heteronuclear long-range HETLOC[4] and the 1,1-ADEQUATE[5] experiment for coupled carbon pairs are used to obtain a total of 8 RDCs. Using these RDCs in combination with force-field optimized structure proposals in the software hotFCHT[6] we have identified an (a-p) conformer ensemble which showed a very good accordance between the experimental and theoretical data. This result was supported by NOE-distance measurements.[7][8] [1] a) R. Göstl, B. Kobin, L. Grubert, M. Pätzel, S. Hecht, Chem. Eur. J. 2012, 18,

14282-14285. b) M. Irie, Chemical Reviews 2000, 100, 1685–1716. [2] T. Montag, C. M. Thiele, Chem. Eur. J., 2013, 19, 2271-2274 [3] A. Enthart, J.C. Freudenberger, J. Furrer, H. Kessler, B. Luy, J. Magn. Reson.,

2008, 192, 314-322 [4] M. Kurz, P. Schmieder, H. Kessler, Angew. Chem., Int. Ed., 1991, 30, 1329-1331 [5] C. M. Thiele, W. Bermel, Magn. Reson. Chem., 2007, 45, 889-894 [6] V. Schmidts:http://tuprints.ulb.tudarmstadt.de/3568/1/Diss_vsz_final_tuprints.pdf [7] S. Macura, R. R. Ernst. Mol. Phys. 1980, 41, 95–117 [8] D. Neuhaus, M. P. Williamson, The Nuclear Overhauser Effect in Structural and

Conformational Analysis, Wiley, Chichester, 2000

Sc(III) mediated regioselective functionalization of 3-hydroxypyridines for nosiheptide synthesis

K. P. Wojtas1, Jena/D; Dr. J.-Y. Lu2, Dortmund/D; D. Krahn2, Dortmund/D;

Prof. Dr. H.-D. Arndt1

1Friedrich-Schiller-Universität, IOMC, Humboldt Str. 10, D-07743 Jena.

2MPI of Molecular Physiol., Dep. Chem. Biol., Otto-Hahn-Str. 11, D-44227 Dortmund.

Beside their ubiquitous presence in non- and natural products, carboxylic acid esters serve both as key intermediates and/or protecting group in organic transformations.1 Access to synthetically and biologically more useful molecules can be facilitated by post modification via transesterification2, ester-amide exchange3 and saponification. The conventional modification conditions suffer from harsh reaction conditions and the use of stoichiometric amounts of activating reagents in step wise manipulations, what makes this kind of procedures generally expensive and wasteful.3a In this regard, transition metal mediated or catalyzed transesterification and ester-amide exchange attract growing interest.2-4

We developed a Sc(OTf)3 catalyzed regioselective hydrolysis, transesterification and ester-amide exchange of unactivated highly substituted pyridine methyl esters under neutral conditions without any additives. More interestingly, lower temperature (60°C) is sufficient to give excellent yields. The regioselective functionalization has a wide substituents tolerance ([hetero]aryl, alkyl and amino acid) in case of ester-amide exchange. Initial mechanistic studies revealed that the multi-functionalization is directed by the 3-hydroxy moiety and Sc(OTf)3 catalyzed. Furthermore, applications of this method in the synthesis of advanced building blocks for nosiheptid5 will be presented.

Literature:

[1] Otera, J. Esterification, Wiley-VCH, Weinheim, 2003. [2] (a) Otera, J. Chem. Rev. 1993, 93, 1449. (b) Grasa, G. A.; Singh, R.; Nolan, S. P. Synthesis 2004, 971. (c) Hatano, M.; Ishihara, K. Chem. Commun. 2013, 49, 1983. (d) Hayashi, Y.; Santoro, S.; Azuma, Y.; Himo, F.; Ohshima, T.; Mashima, K. J. Am. Chem. Soc. 2013, 135, 6192. [3] (a) Allen, C. L.; Williams J. M. J. Chem. Soc. Rev. 2011, 40, 3405. (b) Ohshima, T.; Hayashi,Y.; Agura, K.; Fujii, Y.; Yoshiyama, A.; Mashima, K. Chem. Commun. 2012, 48, 5434. (c) Lundberg, H.; Tinnis, F.; Adolfsson, H. Chem. Eur. J. 2012, 18, 3822. [4](a) Kobayashi, S. Eur. J. Org. Chem. 1999, 15. (b) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W. L. Chem. Rev. 2002, 102, 2227. [5] (a) J.-Y. Lu, M. Riedrich, M. Mikyna, H.-D. Arndt Angew. Chem. 2009, 121, 8281–8284; (b) J.-Y. Lu, M. Riedrich, K. P. Wojtas, H.-D. Arndt, Synthesis 2013, 45, 1300-1311.

Anion receptors based on halogen bonding with halo-1,2,3-triazoliums

Tepper, R., Jena/D, Schulze, B., Jena/D, Jäger, M., Jena/D, Friebe, C., Jena/D, Scharf, D., Jena/D, Görls, H., Jena/D, Schubert, U. S., Jena/D

Tepper, R., Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstraße 10, 07743, Germany

The ubiquity of anions in biological and chemical processes rendered the design of selective anion binding sites into a constantly growing field of interest. In this context, the potential of (charge-assisted) hydrogen bonds as well as of halogen bonds for anion recognition were intensively studied and offered a broad range of potential applications, including e.g. organocatalysis.[1] In particular, the high preference for a bond angle (E–X…Y) close to 180° in case of halogen bonds offers the possibility to create strong and highly selective binding sites.[2,3]

In order to establish C–H / X bonds, the sufficient polarization of the respective bond is essential. The nitrogen-rich 1,2,3-triazole and triazolium systems are highly polarized and, thus, offering strong (charge-assisted) hydrogen / halogen bonds. Moreover, the triazole moiety can be readily generated and functionalized via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC).[4]

For a better understanding of the properties of halogen bonds, namely the dependency of the interaction strength on the polarizability of the covalently bound halogen X as well as on the bond angle (E–X…Y) to the anion Y, a systematic study of modified anion receptors is presented (Figure 1). For this purpose, the influence of different halogen-bond-donor atoms X, electron-withdrawing groups E, and linker groups R on a bidentate complexation is investigated. To quantify the impact of the different moieties on the halogen bond, comprehensive NMR studies supported by isothermal titration calorimetry (ITC) were performed with different halides and oxo-anions.[5]

Literature: [1] Zhang, Z., Schreiner, P. R., Chem. Soc. Rev. 2009, 38, 1187. [2] Beale, T. M., Chudzinski, M. G., Sarwar, M. G., Taylor, M. S., Chem. Soc. Rev. 2013, 42, 1667. [3] Priimagi, A., Cavallo, G., Metrangolo, P., Resnati, G., Acc. Chem. Res. 2013, 46, 2686. [4] Schulze, B., Schubert, U. S., Chem. Soc. Rev. 2014, 43, 2522. [5] Tepper, R., Schulze, B., Jäger, M., Friebe, C., Scharf, D., Görls, H., Schubert, U. S., 2014, in preparation.

Figure 1: Overview of modified moieties in the receptor.

Synthesis and evaluation of 1,3,4-oxadiazole derivatives with an additional

α,βα,βα,βα,β-unsaturated carbonyl unit

A. Rasras, Regensburg/D, G. Sergeev, Braunschweig/D, M. Brönstrup,

Braunschweig/D, S. Amslinger, Regensburg/D

PD Dr. Sabine Amslinger, Institut für Organische Chemie, Universität Regensburg,

Universitätsstr. 31, 93053 Regensburg

1,3,4-Oxadiazole derivatives have been extensively studied due to their wide spectrum

of biological activities such as anti-inflammatory,[1] anticancer,[2] antibacterial, antifungal

and antiproliferative activity.[3] On the other hand, α,β-unsaturated carbonyl compounds,

which are abundant in edible plants, also display a wide variety of biological activities

including anti-inflammatory, antioxidant, antibacterial, anticancer and antimalarial

properties.[4] Since we could successfully apply the enone unit to modulate biological

activity,[5] we introduced the α,β-unsaturated carbonyl moiety onto the oxadiazole ring.

In this work, a series of new 1,3,4-oxadiazole derivatives with an additional α,β-unsatu-

rated carbonyl system in positions 3 and 2 (Figure 1) was prepared using mild

conditions and a short reaction sequence. The synthesized compounds were tested

against bacteria and fungi as well as for antiproliferative and anti-inflammatory activity.

Additionally, a kinetic assay was used to evaluate the reactivity of the products as

potential electrophiles.

Literature:

[1] M. Burbuliene, V. Jakubkiene, G. Mekuskiene, E. Udrenaite, R. Smicius, P.

Vainilavicius, ll Farmaco 2004, 59, 767-774. [2] A. Aboraia, H. Abdel-Rahman, N.

Mahfouz, M. EL-Gendy, Bioorg. Med. Chem. 2006, 14, 1236-1246. [3] A. Singh, V.

Sahu, D. Yadav, IJPSR 2011, 2, 135-147. [4] S. Amslinger, ChemMedChem 2010, 5,

351-356. [5] N. Al-Rifai, H. Rücker, S. Amslinger, Chem. Eur. J. 2013, 19, 15384-15395.

Synthesis of solution-processable, crosslinkable mixed indenofluorenes as small molecules for multi-layered semiconducting devices

M. Hempe, Darmstadt/DE, M. Reggelin*, Darmstadt/DE

Prof. Dr. M. Reggelin, Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss Straße 4, 64287 Darmstadt, Germany

Due to their generally poor film-forming properties, small molecule-based organic semiconducting materials are mostly processed by vacuum deposition techniques to build up high performance „multi-layer“ devices. Nonetheless, a procession of these materials by low cost solution-based methods like inkjet-printing or spincoating is highly wanted. To build small molecule-based “multi-layer” architectures which are cast from solution it is necessary to depose high-quality films of each layer, which must not be affected by the deposition of a subsequent layer. One way to meet this requirement is the use of crosslinkable moieties which allow to form insoluble films before depositing additional layers. In this respect, the use of oxetanes which can be crosslinked through photoinitiated cationic ring-opening polymerization (CROP)[1] is of great interest. Up to now, their use as crosslinking units has been impressively demonstrated in the field of hole-transport and triplett-emitting materials.[2-4] To investigate new solution-processable emitting materials, the motif of 6,12-dihydroindeno[1,2-b]fluorenes (IFs) is of high potential. IFs are known to be highly efficient blue light-emitting materials and their tetra-alkylated, as well as tetra-arylated derivatives are widely spread amongst both, polymeric and small molecule-based organic semiconducting materials.[5-7] However due to synthetic complexity, mixed substituted (pairwise alkylated and arylated) indenofluorenes (MIFs) are still rare in scientific literature.[8] In this work, we present the synthesis of a series of solution-processable, crosslinkable MIF-based small molecules for the potential application in multi-layered semiconducting devices. The crosslinkable oxetane moiety is separated by alkylspacers of variable length and attached in a geminal (molecule centered), as well as in a terminal fashion. The influence of these different substitution patterns on the film forming properties and crosslinking behavior is investigated.

[1] J.-P. Fouassier, Photoinitiation, Photopolymerization and Photocuring: Fundamentals and Applications, 1 ed., Hanser, München, 1995.

[2] M. S. Bayerl, T. Braig, O. Nuyken, D. C. Müller, M. Groß, K. Meerholz, Macromolecular Rapid Communications 1999, 20, 224-228.

[3] G. Liaptsis, K. Meerholz, Advanced Functional Materials 2013, 23, 359-365. [4] G. Liaptsis, D. Hertel, K. Meerholz, Angew. Chem. Int. Ed. 2013, 52, 9563-9567. [5] S. Setayesh, D. Marsitzky, K. Müllen, Macromolecules 2000, 33, 2016-2020. [6] J. Jacob, J. Zhang, A. C. Grimsdale, K. Müllen, M. Gaal, E. J. W. List,

Macromolecules 2003, 36, 8240-8245. [7] D. Thirion, J. l. Rault-Berthelot, L. Vignau, C. Poriel, Org. Lett. 2011, 13, 4418-

4421. [8] H. Kim, N. Schulte, G. Zhou, K. Müllen, F. Laquai, Adv. Mater. 2011, 23, 894-

897.

1,3-Dipolar cycloaddition of acetylenedicarboxylates at cyclooctyne

S. Bochmann, Chemnitz/DE, K. Banert, Chemnitz/DE

M. Sc. Sandra Bochmann, Chemnitz, University of Technology, Institute of Chemistry, Straße der Nationen 62, 09111 Chemnitz.

Dimethyl acetylenedicarboxylate (DMAD) 1 is an electron-deficient alkyne with great synthetic potential.[1] During long-time storage or heating, DMAD forms the tetrameric product 4.[2] At first, DMAD reacts with another molecule of DMAD via 1,3-dipolar cycloaddition to the carbene intermediate 2, which adds a third molecule of DMAD and yields the cyclopropene 3. Through Diels−Alder cycloaddition of a fourth DMAD-molecule to 3, product 4 is formed.[3] Coincidentally, we found that the reaction of DMAD with cyclooctyne results in an analogous polycyclic product 6.[4] Corresponding to the reaction of DMAD with itself, a carbene intermediate 5 is postulated. This intermediate 5 could be quenched, for example, by methanol to give 7.[5] To find out whether similar compounds also yield a polycyclic product, purchasable substances like acetylenedicarboxylic acid, di-tert-butyl acetylenedicarboxylate or bis(trimethylsilyl) acetylenedicarboxylate 8 were treated with cyclooctyne. It was found out that the reaction of the first two compounds with cyclooctyne did not result in a product. Only the reaction with 8, was successful to yield the retro-Brook-product 9.

[1] C. G. Neochoritis, T. Zarganes-Tzitzikas, J. Stephanidou-Stephanatou, Synthesis 2014, 537−585.[2] J. C. Kauer, H. E. Simmons, J. Org. Chem. 1968, 33, 2720−2726.[3] E. LeGoff, R. B. LaCount, Tetrahedron Lett. 1967, 2333−2335.[4] F. Taubert, Bachelor Thesis, TU Chemnitz, 2013.[5] O. Plefka, Dissertation, TU Chemnitz, 2011.

Isolation and Derivatization of Nosiheptide, a Thiopeptide Antibiotic

T. Winkler, Jena/D, O. Makarewicz, Jena/D and H.-D. Arndt, Jena/D

Prof. Dr. Hans-Dieter Arndt, Friedrich Schiller University Jena,

IOMC, Humboldtstr. 10, 07743 Jena/D

Nosiheptide is a natural product first isolated from Streptomyces actuosus in the 1960s

and belongs to the thiopeptide antibiotics, a class of highly modified, sulfur-rich peptide

antibiotics. [1, 2] Despite very high antibacterial activity in vitro against gram-positive

bacteria, no applications in human therapy have appeared so far, potentially as a result

of poor physicochemical properties such as aqueous solubility and stability. [3]

We have developed a high yielding isolation procedure starting from a commercially

available mixture containing about 1% of the target molecule which is used as feed

additive in farm animals. Isolation was achieved by extraction and purification steps

and led to a slightly yellowish solid with high purity. The gram-scale isolation of

nosiheptide enables us to use it as starting material for semi-synthetic derivatization

and novel analogues were characterized. The antimicrobial activity of the compounds

against several pathogenic strains was determined as minimum inhibitory concentration

(MIC). The obtained values demonstrate a very high activity in vitro against Gram-

positive bacteria and the potential for a promising scaffold for drug development.

Structure of nosiheptide

Literature:

[1] F. Benazet, M. Cartier, J. Florent, C. Godard, G. Jung et al., Experientia 1980, 36,

414. [2] M. C. Bagley, J. W. Dale, E. A. Merritt, X. Xiong, Chem. Rev. 2005, 105, 685.

[3] N. M. Haste, W. Thienphrapa, D. N. Tran, S. Loesgen, P. Sun et al., J. Antibiot.

2012, 65, 593.

New Applications for Enoate Reductases in Organic Synthesis´

E. Rüthlein, Jülich, D, T. Classen, Jülich, D, J. Pietruszka, Jülich, D

Institut für Bioorganische Chemie der Heinrich-Heine-Universität Düsseldorf im

Forschungszentrum Jülich, Stetternicher Forst, Geb. 15.13, D-52426 Jülich

Due to the increasing demand of optically pure compounds in various industries there is an on-going interest in quick and highly selective methods of asymmetric synthesis.[1] Biocatalysts are of special interest here as they exhibit exquisite enantio-, regio-, and chemoselectivity and are generally regarded as a more environmentally benign approach compared to chemical variants. Thus biocatalysts have over the last ten years become increasingly important for the synthesis of optically active compounds in laboratory as well as industrial applications.[2]

Figure 1: Enoate reductase catalysed trans-hydrogenation of activated alkenes

A class of enzymes that is of particular interest in organic synthesis are enoate reductases [EC 1.3.1.x]. These reduce C=C double bonds producing up to two new stereogenic centres within one reaction step. The reaction follows a trans-pathway producing the stereocomplementary compounds compared to most chemically catalysed C=C hydrogenations As in addition to that a broad range of activated alkenes can act as substrates various applications of enoate reductases in asymmetric synthesis are possible.[3] We present our recent results in asymmetric organic synthesis utilizing the enoate reductase YqjM.[4] [1] M. Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Keßeler, R. Stürmer, T.

Zelinski, Angew. Chem. Int. Ed. 2004, 43, 788-824. [2] U. T. Bornscheuer, G. W. Huisman, R. J. Kazlauskas, S. Lutz, J. C. Moore,

K. Robins, Nature 2012, 485, 185-194. [3] a) C. Stueckler, N. J. Mueller, C. K. Winkler, S. M. Glueck, K. Gruber, G.

Steinkellner, K. Faber, Dalton Trans. 2010, 39, 8472-8476; b) M. Korpak, J. Pietruszka, Adv. Synth. Catal. 2011, 353, 1420-1424; c) J. Pietruszka, M. Schölzel, Adv. Synth. Catal. 2012, 354, 751-756; d) J. F. Chaparro-Riggers, T. A. Rogers, E. Vazquez-Figueroa, K. M. Polizzi, A. S. Bommarius, Adv. Synth. Catal. 2007, 349, 1521-1531.

[4] K. Kitzing, T. B. Fitzpatrick, C. Wilken, J. Sawa, G. P. Bourenkov, P. Macheroux, T. Clausen, J. Biol. Chem. 2005, 280, 27904-27913.

Unexpected Influence of London Dispersion on a Diels-Alder Reaction

J. Philipp Wagner, Christian Kühn, Andrey A. Fokin* and Peter R. Schreiner*

Justus-Liebig University, Heinrich-Buff-Ring 58, 35392 Giessen/DE

The Diels-Alder reaction of aryne 1 and furan 2c is the key step in the synthesis of

chiral [2]helicene 4 yielding the apparently more crowded 3a with both 1-adamantyl

substituents on the same side as the main product (Scheme (a)).[1] This remarkable

regiochemistry contradicts the view that large hydrocarbon moieties repel each other

and rather suggests attraction due to London dispersion.[2] To probe this hypothesis,

we performed the analogous Diels-Alder reaction with the even bulkier 4-diamantyl

substituent (d) on both reaction partners and indeed found comparable selectivity. To

unveil the role of dispersion we carried out a systematic computational study with

substituents of different sizes (Me, tBu, Ad, Dia; Scheme (b)) comparing the popular

B3LYP hybrid density functional lacking dispersion to its dispersion-corrected

version.[3] Strikingly, without dispersion there is a high selectivity for the products cis-

6 while upon inclusion of dispersion the trans-6 structures become more favorable

kinetically for the smaller substituents; this fact can be traced back to dispersive

attraction of ortho hydrogens and substituents in the transition states.

[1] Aikawa, H.; Takahira, Y.; Yamaguchi, M. Chem. Commun. 2011, 47, 1479-1481.

[2] Grimme, S.; Huenerbein, R.; Ehrlich, S. ChemPhysChem 2011, 12, 1258-1261.

[3] Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104-

154119.

Selective bond activation in lignin model substrates

Dr. T. den Hartog, Aachen/DE, T. vom Stein, Aachen/DE, A. M. L. Hell, Aachen/DE, Dr. J. Buendia, Aachen/DE, Dr. S. Stoychev, Aachen/DE, J. Mottweiler, Aachen/DE,

Prof. Dr. J. Klankermayer,* Aachen/DE, Prof. Dr. C. Bolm, Aachen/DE, and Prof. Dr. W. Leitner,* Aachen/DE, Institut für Technische und Makromolekulare Chemie, RWTH Aachen University, Worringerweg 1, 53074 Aachen, Germany

New selective methods for the breakdown of the ligninic part of lignocellulose are essential for the viability of biorefineries. An approach to identify catalysts for the selective fragmentation of bonds in lignin is the study of model systems. Since the beta-O-4-linkage is the most present in lignin, the corresponding substrate 1 is the model substrate of choice. We have developed Ru-catalyzed methods for the selective C-O and C-C bond cleavage in 1. Here, we will report studies on the scope and the mechanism of these transformations.

O

OH

OH

1R R

OH

R

O

OH

O

R R

H

redox neutral .C-O bond cleavage.

[Ru]-cat

redox neutral.C-C bond cleavage.

[Ru]-cat

+

+

OH

O

R

N-Trifluoromethylthiophthalimide: A Stable Electrophilic SCF3 Reagent and its Application in the Catalytic Asymmetric Trifluoromethylsulfenylation

Xiangqian Liu, Teerawut Bootwicha, Roman Pluta, Iuliana Atodiresei, and Magnus Rueping*

Institute of Organic Chemistry, RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) E-mail: magnus.rueping@rwth-aachen.de

Over the years, much attention has been devoted to the development of efficient methods for the stereoselective introduction of fluorinated moieties into organic molecules because of their ability to significantly change the physical and chemical properties of the parent compounds.1, 2 Among various established fluoroalkyl groups, the trifluoromethanesulfenyl group (SCF3) is of current interest because of its remarkable properties, in particular its high stability and electronegativity, which can be useful in the rational modification of drug candidates. There has only been few reports on the use of electrophilic trifluoromethylsulfenylation reagents for the formation of C-SCF3 bonds,3, 4 with the formation of C(sp3)-SCF3 bonds scarcely investigated. We now report a highly enantioselective cinchona alkaloid catalyzed trifluoromethylsulfenylation of β-ketoesters5 and 3-aryl oxindoles with N-trifluoromethylthiophthalimide as an electrophilic SCF3 source.

cat.quinidine

O

CO2R1

H

N

O

O

SCF3

n+R

O

SCF3

CO2R1nR

cat.quinine

O

CO2R1

SCF3nRup to 96% ee 17 examples

up to 99% ee

NBoc

O

Ar

+ N

O

O

SCF3

cat.(DHQD)2Pyr

NBoc

O

Ar SCF3

18 examplesup to 95% ee

R R

References:

1. a) Selective Fluorination in Organic and Bioorganic Chemistry (Ed.: J. T. Welch), ACS Symposium Series, Washington, 1991; b) V. A. Soloshonok, Enantiocontrolled Synthesis of Fluoro-Organic Compounds: Stereochemical Challenges and Biomedical Targets, Wiley, New York, 1999; c) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applications,Wiley-VCH,Weinheim, 2004; d) D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308-319.

2. a) C. Bobbio, V. Gouverneur, Org. Biomol. Chem. 2006, 4, 2065-2075; b) D. Cahard, X. Xu, S. Couve-Bonnaire, X. Pannecoucke, Chem. Soc. Rev. 2010, 39, 558 568; c) S. Lectard, Y. Hamashima, M. Sodeoka, Adv. Synth. Catal. 2010, 352, 2708-2732; d) T. Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473, 470-477.

3. a) A. Ferry, T. Billard, B. R. Langlois, E. Bacqué, J. Org. Chem. 2008, 73, 9362-9365; b) A. Ferry, T. Billard, B. R. Langlois, E. Bacqué, Angew. Chem. Int. Ed. 2009, 48, 8551-8555.

4. a) X. Shao, X. Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem. Int. Ed. 2013, 52, 3457-3460; b) X. Wang, T. Yang, Q. Shen, Angew. Chem. Int. Ed. 2013, 52, 12860-12864.

5. T. Bootwicha, X. Liu, R. Pluta, I. Atodiresei, M. Rueping, Angew. Chem. Int. Ed. 2013, 52, 12856-12859.

Cross-linked polyphenylacetylenes as alignment media

K. Wolf, Darmstadt/DE, M. Reggelin, Darmstadt/DE

Prof. Dr. Michael Reggelin, Technische Universität Darmstadt, Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Alarich-Weiss-Straße 4, 64287 Darmstadt

The determination of the absolute configuration of (small) organic molecules by NMR spectroscopy in solution is an application of increasing interest.[1] Residual dipolar couplings (RDCs), containing distance as well as angle information, provide the opportunity to determine conformational and configurational information of chiral analytes. To obtain RDCs it is necessary is to partially orient the analyte molecules in the magnetic field. The two most common techniques to do so are stretched polymer gels (SAG – strain induced alignment in a gel) or lyotropic liquid crystalline phases (LLC-phase). For the investigation of chiral, non-racemic analytes, a chiral alignment medium, such as a uniformly helical polymer is required in addition. The number of alignment media compatible to common organic solvents is still rather small.[2] Therefore, we started our research for new chiral alignment media and found LLC-phases of helically chiral amino acid-based poly(phenylacetylenes) to be very auspicious for our intention. [3] The main drawback of such LLC-phases is the need for minimum mesogen-concentration to receive the lyotropic crystalline state. Anisotropic NMR parameters like RDCs show linear dependence on the mesogen-concentration. Therefore the degree of orientation is a main aspect in the development of alignment media. In contrast to LLCs, polymer gels provide the ability to tune the orientation degree of alignment media over a much broader range by diversifying parameters like degree of crosslinking, temperature, solvent etc. Herein we would like to describe the application of chiral polymer gels derived from the promising poly(phenylacetylenes) already used in LLC-phase studies.[3] The (co)-polymers were linked by addition of a difunctionalised cross-linkers or alternatively, by initators if the monomer bears already polymerisable groups like styrene in compatible solvents. After the gel preparation, the obtained polymer sticks were anisotropically swollen in a standard NMR tube, and used for the measurement of RDCs.

[1] C. M. Thiele, Eur. J. Org. Chem. 2008, 2008, 5673-5685. [2] G. Kummerlöwe, B. Luy, in Annu. Rep. NMR Spectrosc., Vol. Volume 68 (Ed.: A. W.

Graham), Academic Press, 2009, pp. 193-232. [3] aA. Krupp, M. Reggelin, Magn. Reson. Chem. 2012, 50 Suppl 1, S45-52; bN.-C. Meyer,

A. Krupp, V. Schmidts, C. M. Thiele, M. Reggelin, Angew. Chem. 2012, 124, 8459-8463.

Synthesis of Monomers for New Semiconducting Polymers

S. Urrego Riveros, Kiel/24118, A. C. J. Heinrich, Kiel/24118

Prof. Dr. Anne Staubitz, University of Kiel, Otto-Hahn-Platz 3, 24118 Kiel

Cross-coupling reactions are very efficient for the formation of new carbon-carbon bonds.1 For such reactions, it is well established that the order of reactivity of the electrophilic coupling partner decreases for the leaving groups I>OTf>Br>>Cl.2 This has already been used to great advantage for the development of electrophile selective cross-coupling. In our group, we developed a both nucleophile and electrophile selective cross-coupling reaction an aromatic substrates in overall very good yields (Scheme 1, R = H).3

Scheme1. General concept of the highly selective coupling reactions. The resulting products of these reactions can be polymerized by using a transition metal catalyst. These highly conjugated polymers may be used as semiconductor in electronic devices. When we first polymerized one of the monomers (R = H on the nucleophile, R = Hex on the electrophile), we found that the resulting polymer was insoluble. To improve the solubility, we developed a dinucleophile where, in addition to tin and a boronic ester, and hexyl chain in 3-position was introduced. By using this nucleophile, performing the selective coupling reaction, we obtain monomers that give soluble polymers in the type of P3HT.

Literature:

[1] F. Diederich, A. d. Meijere, Metal-Catalyzed cross-Coupling Reactions; 2nd ed., Wiley-VCH, Weinheim, 2004. [2] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457. [3] A. C. J. Heinrich, B. Thiedemann, P. J. Gates, A. Staubitz, Org. Lett. 2013, 15, 4666.

Phenyl Hydrazine as Initiator for Direct Arene C-H Arylation via Base Promoted

Homolytic Aromatic Substitution

A. Dewanji, Münster/DE-NW, S. Murarka, Münster/DE-NW

Prof. Dr. Armido Studer, University of Münster, Corrensstraße 40, 48149 Münster Prof. Dr. D. P. Curran, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA

Biaryl is a very important structural motif occuring in numerous natural products, pharmaceuticals, agrochemicals and functional materials. [1] One of the most often applied approach is the transition metal catalyzed biaryl coupling between an aryl halide (Ar1-X) and an organometallic reagent (Ar2-M) or unactivated arene which suffers from the formation of hazardous metal waste. [2] Recently, radical chemistry emerged as a convenient alternative to the mainstream developments involving transition metals. The base promoted homolytic aromatic substitution (BHAS) with aryl radicals and radical anions as intermediates utilizes diamine ligand as additive and tert-butoxide as base. [3] In a proposed mechanism, the tert-butoxide serves as the radical initiator. [4] Herein we wish to introduce phenyl hydrazine as an efficient and simpler initiator along with potassium tert-butoxide as base for the direct arylation of arenes by aryl halides. [5] Literature: [1] J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359. [2] a) A. de Meijere, F. Diedrich, Metal-catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH: Weinheim, 2004. b) G. P. McGlacken, L. M. Bateman Chem. Soc. Rev. 2009, 38, 2447. [3] E. Shirakawa, K.-i. Itoh, T. Higashino, T. Hayashi, J. Am. Chem. Soc. 2010, 132, 15537. [4] A. Studer, D. P. Curran, Angew. Chem. Int. Ed. 2011, 50, 5018. [5] A. Dewanji, S. Murarka, D.P. Curran, A. Studer, Org. Lett. 2013, 15, 6102.

Nickel-Catalyzed C–H Alkylations: Direct Secondary Alkylations and Trifluoroethylations of Arenes

Lackner, S., Song, W., Ackermann, L.*, Göttingen, D.

Georg-August-Universität Göttingen, Institut für Organische und Biomolekulare Chemie, Tammannstr. 2, D-37077 Göttingen

C–H activation has proven to be an increasingly important tool for step-economic organic synthesis.[1] Despite significant advances, C–H functionalizations with alkyl halides continue to be scarce.[2] Due to the facile β-hydride elimination and the difficult oxidative addition, secondary C–H alkylations are largely limited to recently developed ruthenium-[3] and cobalt-catalyzed C–H transformations.[4] Otherwise unreactive C–H bonds were recently shown to be activated through bidentate auxiliaries, as, among others, illustrated by Daugulis and Chatani.[ 5,6]

Here, we present a robust nickel(II) catalyst for expedient secondary alkylations of arenes and indoles with both alkyl bromides and chlorides via chelation assistance.[7]

The catalytic system proved to be applicable to a variety of substituted arenes, as well as various alkyl halides. Mechanistic studies indicated a reversible C–H bond metalation. Additionally, the kinetic C–H acidity appeared to be of importance for the C–H bond metalation. Furthermore, we report on an unprecedented C–H trifluoroethylation of arenes. Literature: [1] Reviews: Collins, K.; Glorius, F. Nat. Chem. 2013, 5, 597–601.; Ackermann, L. Chem. Rev. 2011, 111, 1315–1345. [2] A review: Ackermann, L. Chem. Comm. 2010, 46, 4866–4877. [3] Hofmann, N.; Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877–5884. [4] a) Punji, B.; Song, W.; Shevchenko, G. A.; Ackermann, L. Chem. Eur. J. 2013, 19, 10605–10610.; b) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 9279–9282. [5] Zaitsev, V.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154–13155. [6] Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726–11743. [7] Song, W.; Lackner, S.; Ackermann, L. Angew. Chem. Int. Ed. 2013, 53, 2477–2480.

Synthesis and Investigation of Innovative Photoaffinity Labelling Probes

S. Chiha, Jena/D; Dr. C. Ronco, Jena/D; A. Guether, Jena/D and H.-D. Arndt, Jena/D

Prof. Dr. H.-D. Arndt, Friedrich-Schiller-Universität,Humboldtstr. 10, D-07743 Jena/D.

α, β- unsaturated amino acids biosynthetically originate from dehydration of cysteine, serine and threonine residues.1 Although called nonproteinogenic, these amino acids are found in an increasing number of natural products, including peptide antibiotics, components of the bacterial peptidoglycane, several enzymes and free radical scavengers.2 Despite their structural specificity, which often confers more rigidity to peptide backbones,3 dehydroamino acids also differ from the so-called proteinogenic amino acids, in that their side chain displays electrophilic properties, allowing site specific alkylation reactions.4 Here, the reactivity of dehydroalanine residues present on the natural thiopeptide compound thiostrepton (TS) was exploited to introduce a diazirine-based photoreactive group via a sulfa-Michael addition, enabling the synthesis of a TS photoaffinity-labelling probe (TS-PAL). In addition to the photoreactive group (PG), the designed probe carries an accessory terminal alkyne, allowing copper-assisted Huisgen cycloaddition (Click) with azide-bearing tags. Finally, an aryl-sulfonamide linkage was introduced as a cleavable connector5

between the PG and TS for easier identification of target proteins via analytical biochemical methods.

Literature:

[1] C. J. Pearce, K. L. Jr. Rinehart, J. Am. Chem. Soc., 1979, 101, 5069; [2] P. D. Cotter, C. Hill and R. P. Ross, Current Protein and Peptide Science, 2005, 6, 61-75; L. Poope and J. Rétey, Angew. Chem. Int. Ed., 2005, 44, 3668-3688; [3] D. E. Palmer, C. Pattaroni, K. Nunami, R. K. Chadha, M. Goodman et al., J. Am. Chem. Soc., 1992, 114, 5634-5642; [4] G. N. Moll, A. Kuipers, R. Rink, Antonie van Leeuwenhoek, 2010, 97, 319-333; S. Schoof, G. Pradel, M. N. Aminake, B. Ellinger, S. Baumann et al., Angew. Chem. Int. Ed., 2010, 49, 3317 –3321; [5] N. B. Bongo, T. Tomohiro, Y. Hatanaka, Bioorg. Med. Chem. Lett., 2009, 19, 80–82.

 

 

Tribenzotriquinacenes Bearing Three Peripheral Pentaphenylphenyl Groups in C3- and C1-Symmetrical Orientation: Steric Crowding at a Bowl-Shaped Core

D. Kuck, Bielefeld/DE, E. U. Mughal, Bielefeld/DE, B. Neumann, Bielefeld/DE,

H.-G. Stammler, Bielefeld/DE

Prof. Dr. Dietmar Kuck, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld

Aiming at the synthesis of three-dimensionally distorted graphene cuttings, we have studied the access to tribenzotriquinacenes (TBTQ’s) bearing three pentaphenylphenyl residues at the molecular periphery. Conceptually, the C3-symmetrical isomer 3 appeared to be of particular interest, as suggested recently in a simpler case [1].

 

TBTQ derivatives bearing suitable functionalities in a C3-symmetrical pattern at the peripheral positions (1) are highly promising bowl-shaped building blocks, but their synthesis is cumbersome as they are formed together with their C1-isomers (2) [2]. Here, we report on the first synthesis of TBTQ derivatives bearing three peripheral phenylethynyl residues. While the C3- and C1-symmetrical triformyl, triethynyl and triiodo derivatives were found to be inseparable by chromatography, the corresponding C3- and C1-tri-(phenylethynyl)tribenzotriquinacenes proved to be separable. Individual threefold cyclocondensation of these TBTQ-based tris-tolanes with tetracyclone gave the highly crowded tris-pentaphenylphenyl derivatives 3 and 4 in good yields. In turn, however, all attempts to generate a completely closed graphene-like periphery about the TBTQ core by multiple cyclodehydrogenation of 3 have failed so far. Literature: [1] E. U. Mughal, D. Kuck, Chem. Commun. 2012, 48, 8880. [2] T. Wang, Y.-F. Zhang, Q.-Q. Hou, W.-R. Xu, X.-P. Cao, H.-F. Chow, D. Kuck, J. Org. Chem. 2013, 78, 1062.

Synthesis of a Tsetse Fly Attractant from Cashew Nutshell Liquid via

Isomerising Metathesis

P. E. Podsiadly, Kaiserslautern/ D, S. Baader, Kaiserslautern/ D

Prof. Dr. L. J. Gooßen, TU Kaiserslautern, Erwin-Schrödinger-Straße 54, 67663 Kaiserslautern.

Isomerising functionalizations are valuable tools for the valorization of renewables.[1] In this context, we recently introduced the concept of isomerising metathesis. Combinations of the highly active isomerization catalyst [Pd(µ-Br)tBu3P]2 with state-of-the-art Ru-based olefin metathesis catalysts were found to convert oleic acids into industrially useful blends of olefins, mono- and dicarboxylates.[2] A related approach was successfully applied also in the selective transformation of naturally occurring allylarenes (e.g. eugenol, methyl eugenol, safrol) into the corresponding styrenes.[3]

Cashew Nut Shell Liquid (CNSL) is obtained as a by-product of cashew nut processing (450.000 t/a) and consists mainly of m-alkenylphenols and salicylic acid derivatives such as anacardic acid.[4]

 

We have now developed a concise synthesis of the tsetse-fly attractants 3-ethyl- and 3-propylphenol from CNS based on an isomerising metathesis process. Anacardic acid was first converted into 3-(non-8-enyl)phenol via ethenolysis and decarboxylation. The alkenyl side chain was shortened via isomerising ethenolysis into propylene or ethylene groups, which were hydrogenated in situ. This way, the target product could be obtained in high yields along with valuable short chain olefins as the only by-products.[5]

 

Literature: [1] A. Behr, A. J. Vorholt, K. A. Ostrowski, T. Seidensticker, Green Chem. 2014, 16, 982. [2] (a) D. M. Ohlmann, N. Tschauder, J.-P. Stockis, K. Gooßen, M. Dierker, L. J. Gooßen, J. Am. Chem. Soc. 2012, 134, 13716; (b) L. J. Gooßen, D. M. Ohlmann, M. Dierker, WO 2012143067, 2012; (c) P. Mamone, M. F. Grünberg, A. Fromm, B. A. Khan, L. J. Gooßen, Org. Lett. 2012, 14, 3716. [3] S. Baader, D. M. Ohlmann, L. J. Gooßen, Chem. Eur. J. 2013, 19, 9807. [4] A. Velmurugan, M. Loganathan, World Acad, Sci. Eng. Technol. 2011, 5, 738. [5] S. Baader, P. E. Podsiadly, D. J. Cole-Hamilton, L. J. Gooßen, manuscript in preparation.

Metal-free C–H arylations of peptides containing indoles

Bauer, M., Zhu, Y., Ackermann, L.*, Göttingen, D.

Georg-August-Universität Göttingen, Institut für Organische und Biomolekulare Chemie, Tammannstr. 2, D-37077 Göttingen

The functionalization of bioactive small molecules and synthetic biopolymers bears great potential for the direct labeling of specific structural motifs and is, for instance, attractive for the site-selective protein modification.[1] Besides strategies reliying on prefunctionalization,[2] direct C–H arylations of indoles were identified as a useful strategy. In recent years, metal-free arylations with hypervalent iodine(III) compounds have been developed.[3]

Herein, we present a robust metal-free direct C–H arylation of peptides containing indoles with diaryliodonium salts.[4] The reaction system proved applicable to various arylating reagents, including halogen-containing motifs. The peptides were functionalized exclusively at the terminal indole in moderate to excellent yields without racemization. A hexapeptide was arylated with excellent site- and chemo-selectivity. Additionally, the reaction did not require inert reaction conditions, but efficiently proceeded under an atmosphere of air.

Literature:

[1] Reviews : a) Witus, L. S. ; Francis, M. B. Acc. Chem. Res. 2011, 44, 774–783. b) Chalker, J. M. ; Bernardes, G. J. L. ; Davis, B. G. Acc. Chem. Res. 2011, 44, 730–741. [2] A recent example: Gao, Z.; Gouverneur, V.; Davis, B. G. J. Am. Chem. Soc. 2013, 135, 13612–13615. [3] A review: Merrit, E. A.; Olofsson, B. Angew. Chem. Int. Ed. 2009, 48, 9052–9070. [4] Zhu, Y.; Bauer, M.; Ploog, J.; Ackermann, L. submitted for publication.

C–H and C–C Functionalizations of Carboxylates

Patrizia Mamone, Christian Matheis, Dmitry Katayev, Prof. Dr. Lukas J. Gooßen, Kaiserslautern/D

TU Kaiserslautern, Erwin-Schrödinger-Straße 54, 67663 Kaiserslautern

Combining directed C–H functionalizations with decarboxylative processes has opened up new opportunities for C–C and C–heteroatom bond-forming reactions. [1] They ideally complement ipso-functionalizations of arenes such as decarboxylative arylations or Chan-Evans-Lam couplings of aromatic carboxylates. [2] In the presence of a Ag/Cu bimetallic catalyst system, the carboxylate groups direct C–H functionalizing alkoxylations into their ortho-position. Once the new C–O bond is formed, the carboxylate group itself is tracelessly removed via protodecarboxylation. [3] As a result, the arene substitution pattern is altered in a defined way, i.e. meta-substituted carboxylates are converted into para-substituted alkoxyarenes and vice versa. The same catalyst also promotes an oxidative dehydrogenative coupling between donor-functionalized arenes and alcohols. [4] These ortho-C–H alkoxylations provide novel synthetic entries to the important aryl ether moiety.

OH

O

H

FG

OR

O-cat

O

FG

OR

H

FG-CO2

OR

H

FG-CO2

O

O

R

OFG

-CO2

H

R

OFG O

O

R

FGO

O

RCO2

HH

Me

FG

Cu/Ag catO2, Si(OR)4

ipso-alkoxylation ortho-alkoxylation/decarboxylation

(RCO)2O

Rh cat(RCO)2O

Cu/Ag catO2, B(OR)3

ortho-acylation/decarboxylation ortho-acylation/acylalization/elimination A similar ortho-substitution/protodecarboxylation sequence was also shown in catalytic C-H acylations of benzoic acids. [5] [Rh(cod)Cl]2 directs the acylation of benzoic acids with anhydrides into the ortho-position, a selectivity that is orthogonal to Friedel-Crafts processes. In combination with an optional protodecarboxylation or an acylalization / elimination, this opens up further opportunities for selective arene functionalization. Literature: [1] a) N. Rodríguez, L. J. Gooßen, Chem. Soc. Rev. 2011, 40, 5030; b) W. I. Dzik, P. P. Lange, L. J. Gooßen, Chem. Sci. 2012, 3, 2671-2678. [2] a) B. Song, T. Knauber, L. J. Gooßen, Angew. Chem. Int. Ed. 2013, 52, 2954-2958; b) S. Bhadra, W. I. Dzik, L. J. Gooßen, J. Am. Chem. Soc. 2012, 134, 9938. [3] S. Bhadra, W. I. Dzik, L. J. Goossen, Angew. Chem. Int. Ed. 2013, 52, 2959-2962. [4] S. Bhadra, C. Matheis, D. Katayev, L. J. Gooßen, Angew. Chem. Int. Ed. 2013, 52, 9279-9283. [5] P. Mamone, G. Danoun, L. J. Gooßen, Angew. Chem. Int. Ed. 2013, 52, 6704-6708.

Formation of Supramolecular Layers in the Solid State Structure of Electronically

Deactivated Bisphenols

A. U. Augustin, Freiberg/DE, F. Katzsch, Freiberg/DE, T. Gruber*, Freiberg/DE

Dr. T. Gruber*, Technische Universität Bergakademie Freiberg, Leipziger Str. 29,

09599 Freiberg/DE; Email: Tobias.Gruber@chemie.tu-freiberg.de

For decades, bisphenols have been well-known educts for the production of a wide

range of polymers1. Furthermore, they have been studied due to their biological activity,

e.g. their estrogenic2 or antibacterial effects3, with the bioavailability being directly

connected to their molecular conformation in solution and in solid state4. Nevertheless,

in this presentation we focus on the supramolecular properties of bisphenols discussing

the X-ray structure and packing behavior of two electronically deactivated specimens (1

and 2). By way of interest, both rather simple compounds form inclusion compounds

with DMSO resulting in interesting sheet-like structures. The molecular ABAB layers

are only connected via weak C-H···O-contacts leading to anisotropic supramolecular

interactions in the overall packing. These findings promise utile macroscopic properties

and auspicious applications within materials chemistry.

1 H.-G. Franck, Industrial Aromatic Chemistry: Raw Materials, Processes, Products, Springer,

Heidelberg, 1988; H. Zhang, H. Wu, Q. Tang, Reguxing Shuzhi 1996, 11, 43-45. 2 Y. Hashimoto, M. Nakamura, Dent. Mater. J. 2000, 19, 245-262.

3 H. J. Florestano, M. E. Bahler, J. Am. Pharm. Assoc. 1946, 42, 576-578.

4 T. Gruber, R. Nestler, W. Seichter, P. Bombicz, J. Mol. Struct. 2014, 1056, 319-325.

Selenium-Catalyzed Oxidative Allylic and Vinylic Amination of Unactivated

Alkenes

A. Breder, Göttingen/D, J. Trenner, Braunschweig/D, C. Depken, Göttingen/D, T. J. Weber, Göttingen/D

Dr. Alexander Breder, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen/D

The catalytic oxidative functionalization of simple, unpolarized alkenes is one of the central areas of research within modern organic chemistry. In the recent past there has been an increasing number of efforts directed toward the development of novel strategies for the oxidative amination of carbon-carbon multiple bonds.[1] The paramount importance of such transformations is reflected in the plethora of aminated natural and anthropogenic compounds with medicinally and agrochemically relevant reactivity profiles. Until today, however, the majority of catalytic variants of the aforementioned transformations involve the use of expensive transition metals, such as palladium.[1,2] Although most of these methods are characterized by a broad applicability and atom-economy, yet there remains a dearth of more cost-efficient but equipotent metal-free alternatives.[3]

In this context, parts of our current research program focus on the development of new metal-free protocols for the stereo- and chemoselective nitrogenation of unactivated olefins. For this purpose, we became particularly interested in the employment of chalcogen compounds as potent, redox active organocatalysts.[4] Central mechanistic aspect for our endeavors towards the design of new synthetic methods is the Lewis-base-facilitated activation of precursors to formal electrophiles such as halenium-[5] or nitrenium ions. Certain sulfur and selenium compounds can efficiently stabilize this type of reactive intermediates, which is key to their controlled conversion with simple olefins. The protocols developed in our group constitute the basis for the implementation of this catalysis concept into sustainable and in part stereoselective syntheses of biologically relevant natural and artificial products.

References

1. A. Breder, Synlett 2014, 25, 899. 2. For selected seminal examples, see: a) L. S. Hegedus, G. F. Allen, J. J. Bozell, E.

L. Waterman, J. Am. Chem. Soc. 1978, 100, 5800; b) S. R. Fix, J. L. Brice, S. S. Stahl, Angew. Chem. Int. Ed. 2002, 41, 164.

3. For representative examples of iodine(III)-mediated aminations of alkenes, see: a) C. Röben, J. A. Souto, Y. González, A. Lishchynskyi, K. Muñiz, Angew. Chem., Int. Ed. 2011, 50, 9478; b) J. A. Souto, D. Zian, K. Muñiz, J. Am. Chem. Soc. 2012, 134, 7242; c) J. Souto, Y. González. A. Iglesias, D. Zian, A. Lishchynskyi, K. Muñiz, Chem. Asian J. 2012, 7, 1103.

4. J. Trenner, C. Depken, T. J. Weber, A. Breder, Angew. Chem. Int. Ed. 2013, 52, 8953.

5. a) S. E. Denmark, W. E. Kuester, M. T. Burk, Angew. Chem., Int. Ed. 2012, 51, 10938; b) S. R. Mellegaard-Waetzig, C. Wang, J. A. Tunge, Tetrahedron 2006, 62, 7191.

Quercetagetin Analogues as JNK1 Inhibitors

J. Hierold, L. F. Tietze*, Göttingen/GER and R. Huber, Martinsried/GER

Dr. Judith Hierold, Institute for Organic and Biomolecular Chemistry, University of Göttingen, Tammannstr. 2, 37077 Göttingen, Germany

Among other activites, the natural product quercetagetin (1) is a potent inhibitor of JNK1 (C-jun N-terminal kinases), protein kinases which have been linked to diseases such as cancer, type II diabetes and obesity. The high affinity of the flavonol to JNK1 originates from a variety of stabilising hydrogen bonds between the enzymes amino acids and the phenolic hydroxyl groups of 1. Crystal structure analysis shows that quercetagetin occupies the ATP binding pocket of the enzyme (see figure). A water molecule embedded next to the 3’,4’-dihydroxyphenyl moiety of quercetagetin additionally stabilises the

enzyme-substrate-complex. In an attempt to further increase the selectivity and activity of quercetagetin as JNK1-inhibitor, analogues have been targeted that replace the embedded water molecule with appropriate substituents on the natural product backbone. The synthesis of these derivatives, i.e. 2, as well as initial studies detailing their biological activities are presented.

O

O

OHOH

HO

HOOH

OH

Quercetagetin (1)

O

O

OH

HO

OHOH

Targeted Analogues (2)

2'3'

HO

R

OH

Literature: [1] S. Baek, N. J. Kang, G. M. Popowicz, M. Arciniega, S. K. Jung, S. Byun, N. R. Song Y.-S. Heo, B. Y. Kim, H. J. Lee, T. A. Holak, M. Augustin, A. M. Bode, R. Huber, Z. Dong, K. W. Lee, J. Mol. Biol. 2013, 425, 411-423.

'Traceless' Tracing of Proteins – High-Affinity Protein Labeling by Trans-Splicing

M. Braner1, R. Wieneke1, R. Tampé1

1Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Max-von-Laue-Str. 9,

60438 Frankfurt/M., Germany

Protein modifications with synthetic fluorescent probes or other chemical entities

provide valuable insights into protein functions, dynamics, and interaction. One major

challenge is the site-specific labeling of proteins for in vivo studies. Besides strategies

for noncovalent labeling, different chemoselective and semisynthetic techniques such

as intein-mediated protein splicing were involved. In protein trans-splicing, the intein

domain is split into two fragments (IntN and

IntC), which form a complex and reconstitute

the active intein. It allows the chemoselective

ligation of a synthetic peptide with a

recombinant protein at the N or C terminus.

The moderate affinity between IntN and IntC

imposes no limit for in vitro approaches, but it

bears some limitations for in vivo applications.

We used the characterized Ssp DnaB M86

intein [1] to develop a split intein system guided

by the very small high-affinity trisNTA/His-tag

interaction pair [2, 3] to increase the affinity by

several orders of magnitude.

A library of different IntN-fragments modified by

trisNTA as well as His6- tagged IntC-constructs

was generated to trigger the splicing reaction.

This small lock-and-key element increases the

affinity for the IntN-fragments 50-fold. Based on

the high-affinity interaction, we observed

protein trans-splicing at nanomolar concentrations. In addition, we used Microscale

Thermophoresis as a powerful method for studying the interaction between the split

inteins. The combination of intein and high-affinity interaction pair is as a potent and

generally applicable tool for protein modifications in vivo. The splice product formation

in the nanomolar range will open a broad spectrum of cellular applications.

Literature:

[1] Appleby et al. J. Biol. Chem. 2009, 284, 6194-6199.

[2] Lata et al. JACS 2006,128, 2365-2372.

[3] Labòria et al. Angew. Chem. Int. Ed. 2013, 52, 848-853.

-D-Mannose Based Glycodendrimers as Multivalent Inhibitors

of the Type 1 Fimbriae Mediated Bacterial Adhesion

O. Sereda, Kiel/DE, Th. K. Lindhorst, Kiel/DE

Dr. Oksana Sereda, Christiana Albertina University of Kiel,

Otto Diels Institute of Organic Chemistry, Otto-Hahn-Platz 4, D-24098, Kiel, Germany.

Cell adhesion plays one of the most important roles in biological processes, e.g. cell-

cell recognition in immunological response and fertility, as well as in inflammation and

metastasis. Moreover, the adhesion of uropathogenic Escherichia coli to the bladder

epithelium enables colonisation and growth of the pathogenic bacteria and facilitates

the development of the infection. This adhesion results from the interaction of the

carbohydrate specific FimH adhesin domain of the type 1 fimbriae in E. coli with

-D-mannose oligosaccharides from the glycocalyx of the host epithelium cells.[1]

Previous studies have shown that multivalent ligands can efficiently inhibit bacterial

adhesion mediated by FimH lectin. Nevertheless, the multivalent effects that were

observed, need to be further investigated, in order to verify the existence of feasible

allosteric binding sites on FimH adhesin.[2]

-D-Mannosides with an aromatic aglycon are among the most potent inhibitors of the

type 1 fimbriae mediated bacterial adhesion so far.[3] This mannoside scaffold was

chosen for the preparation of S-methyl thiouronium salts. A key step in our synthetic

methodology was the reaction of an S-methyl thiouronium salt with a terminal amino

group of a linker that provided a multivalent glycodendrimer containing a trisubstituted

guanidine moiety. The obtained ligands were further investigated in bacterial inhibition

assay with GFP-expressing E. coli.

Literature:

[1] For review see: a) Th. K. Lindhorst. Ligands for FimH. In: Synthesis and Biological

Applications of Glycoconjugates. Eds.: O. Renaudet, N. Spinelli, Bentham eBooks, 2011,

12-35. b) M. Hartmann, Th. K. Lindhorst, Eur. J. Org. Chem. 2011, 3583-3609.

[2] a) C. Heidecke, Th. K. Lindhorst, Chem. Eur. J. 2007, 13, 9056-9067. b) M. Dubber, O.

Sperling, Th. K. Lindhorst, Org. Biomol. Chem. 2006, 4, 3901-3912. c) Th.K.Lindhorst, K.

Bruegge, A. Fuchs, O. Sperling, Beilstein J. Org. Chem. 2010, 6, 801–809.

[3] O. Sperling, A. Fuchs, Th. K. Lindhorst, Org. Biomol. Chem. 2006, 4, 3913-3922.

Diversity-oriented synthesis of macrocyclic scaffolds using a multi-dimensional

build/couple/pair (B/C/P) strategy

Feilin Nie, Cambridge/UK CB2 1EW

Prof. Dr. David R. Spring, Department of Chemistry, University of Cambridge,

Cambridge, CB2 1EW, UK.

Diversity-oriented synthesis (DOS) represents a strategy for the efficient generation of

a collection of molecules which exhibit a high level of structural diversity.[1] The

build/couple/pair (B/C/P) strategy is a commonly used strategy to maximise diversity in

compound libraries. The classic procedure including: i) synthesis of different building

blocks containing orthogonal functionalities in the build phase, and ii) coupling of

different building blocks to give pairing precursors in the couple phase, and iii) pairing

reactions are carried out in order to generate final compounds in the pair phase.[2] We

further developed this classic strategy, whereby a set of distinct coupling reactions

were applied in the couple phase (multi-dimensional coupling) instead of one sole

reaction (one-dimensional coupling). This strategy has been successfully applied in the

DOS of a non-peptidic macrocycle library.[3]

The work here describes the further development of this strategy using three

approaches: i) in the couple phase, the conversion of a primary branching point to a

secondary branching point from where a second round of branching was employed;

and ii) using a build/couple/couple/pair (B/C/C/P) strategy to synthesise larger

macrocycles with various linking motifs within one macrocycle; and iii) in the pair phase,

diverse macrocyclisation methods were explored for multi-dimensional pairing.

Illustrative macrocycles of the DOS library are shown in Figure 1.

Figure 1: Illustrative macrocycles of the DOS library.

Literature:

[1] C. J. O' Connor, H. S. G. Beckmann, D. R. Spring, Chem. Soc. Rev. 2012, 41,

4444-4456. [2] T. E. Nielsen, S. L. Schreiber, Angew. Chem. Int. Ed. 2008, 47, 48-56.

[3] H. S. G. Beckmann, F. Nie, C. E. Hagerman, H. Johansson, Y. S. Tan, D. Wilcke, D.

R. Spring, Nature Chem. 2013, 5, 861-867.

Shedding Light on Brønsted acid Catalysis – a Photocyclization–Reduction Reaction for the Asymmetric Synthesis of

Tetrahydroquinolines from Aminochalcones in Batch and Flow

Hsuan-Hung Liao,Aachen/49, Chien-Chi Hsiao, Aachen/49, Erli Sugiono,Aachen/49

Prof.Dr. Magnus Rueping, RWTH Aachen University Landoltweg 1, 52074 Aachen 1,2,3,4-Tetrahydroquinolines represent an important class of compounds. The tetrahydroquinoline moiety is present in a large number of biologically active natural products and many tetrahydroquinoline derivatives exhibit a wide spectrum of biological activities.1 Furthermore, Optically active tetrahydroquinolines are also important synthetic intermediates for the pharmaceutical and agrochemical industries. Among the numerous methods available for the asymmetric construction of tetrahydroquinolines, the enantioselective hydrogenation of substituted quinolines represents one of the most efficient and straightforward routes to access this class of compounds.2 The development of improved protocols which combine different activation and catalytic principles for the one-pot multi-step synthesis of optically active compounds from easily available starting materials has attracted considerable attention in recent years.3 However, the use of dual catalytic methods, which combines photochemistry and asymmetric Brønsted acid catalysis, is rare.4 We now report a new asymmetric photocyclization–reduction cascade employing readily available aminochalcones has been developed .5 The reaction sequence has been achieved by unifying photochemistry and asymmetric Brønsted acid catalysis and involves photocyclization followed by Brønsted acid catalyzed enantioselective hydrogenation in batch and flow with excellent enantioselectivities.

Literature 1. (a) J. G. Keay, in Comprehensive Organic Synthesis, ed. B. M. Trost and I.

Fleming, Pergamon, Oxford, 1991, vol. 8, p. 579; (b) A. R. Katritzky, S. Rachwal and B. Rachwal, Tetrahedron, 1996, 52, 15031–15070; (c) D. H. Barton, K. Nakanishi and O. M. Cohn, Comprehensive Natural Products Chemistry, Elsevier, Oxford, 1999, vol. 1–9; (d) V. Sridharan, P. A. Suryavanshi and J. C. Men endez, Chem. Rev., 2011, 111, 7157–7259.

2. M. Rueping, A. P. Antonchick and T. Theissmann, Angew. Chem., Int. Ed., 2006, 45, 3683–3686

3. L. F. Tietze, Chem. Rev., 1996, 96, 115–136; (b) L. F. Tietze, G. Brasche and K. M. Gericke, Photochemically Induced Domino Processes, Domino Reactions in Organic Synthesis, Wiley-VCH, 2006, p. 337.

4. C.-C. Hsiao, H.-H. Liao, E. Sugiono, I. Atodiresei, M. Rueping, Chem. Eur. J. 2013, 19, 9775–9779

5. H.-H. Liao, C.-C. Hsiao, E. Sugiono, M. Rueping, Chem. Commun. 2013, 49, 7953–7955

New Synthetic Route to Nitroxide Brushes

D. Matuschek, P. Drücker, H.-J. Galla, A. Studer

Org. Chem. Inst. Westf. Wilhelms-Universität Münster

Corrensstr. 40, 48143 Münster

Nitroxides have become versatile building blocks for magnetic materials, electronic and optoelectronic

devices.[1-3]

Especially, the application of nitroxide polymers in organic radical batteries is of

importance. First studies reveal that nitroxide polymer brushes are promising materials for thin-film

cathodes in organic radical batteries. However, an efficient synthetic strategy for preparation of

nitroxide brushes is missing.[4,5]

We present a new efficient method for the preparation of nitroxide brushes via ATRP and aerobic

cleavage of the C-NO bond to release the nitroxide on silica surfaces.[6]

These nitroxide coated

surfaces could be electrochemically switched from a hydrophilic to a hydrophobic state.

Additionally, we present a catalytic system based on the nitroxide brushes or nitroxide monolayers for

the aerobic oxidation of benzyl alcohol to benzaldehyde.

Figure: Nitroxide-functionalized polymer brushes and application in aerobic oxidation catalysis.

References:

[1] C. Chatgilialougu, A. Studer, Encyclopedia of Radicals in Chemistry, Biology and Materials, Wiley,

Chichester, 2012.

[2] F. Kato, A. Kikuchi, T. Okuyama, K. Oyaizu, H. Nishide, Angew. Chem. Int. Ed., 2012, 51, 10177.

[3] H. Nishide, S. Iwasa, Y.-J. Pu, T. Suga, K. Nakahara, M. Satoh, Electrochim. Acta, 2004, 50, 827.

[4] M.-K. Hung , Y.-H. Wang , C.-H. Lin , H.-C. Lin, J.-T. Lee, J. Mater. Chem. , 2012, 22, 1570.

[5] Y.-H. Wang, M.-K. Hung, C.-H. Lin , H.-C. Lin, J.-T. Lee, Chem. Com. , 2011, 47, 1249.

[6] F. Behrends, H. Wagner, A. Studer, H. Eckert, Macromolecules, 2013, 46, 2553.

New Bacterial Sphingolipid Derivatives – Isolation from Natural Sources, Functional

Analysis and Structure Elucidation by Total Synthesis

Christine Beemelmanns,[1]

Alexandra Cantley,[2]

Arielle Woznica,[3]

Nicole King,[3]

and Jon

Clardy[2]

[1] Chemical Biology of Microbe-Host Interactions, Leibniz Institute for Natural Product

Research and Infection Biology e.V., Hans-Knöll-Institute (HKI), Beutenbergstrasse 11a,

07745 Jena

[2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical

School, Longwood Ave. 240, 02115 Boston, USA

[3] Department of Molecular and Cell Biology, UC Berkeley, Berkeley, CA 94720, USA.

All known animal and plant species are associated with microbial communities, which often

influence the development, metabolism, and evolution of the eukaryotic host. However,

until now little is known about the molecular mechanisms and signaling molecules involved

in this inter-kingdom interplay.

We are currently studying several members of the Bacteroidetes phylum, which are known

to have sphingolipid-rich membranes and other unusual amino-acid containing lipids.

Sphingolipids are important signaling molecules in eukaryotes and play key roles in inducing

morphogenesis, apoptosis or modulating the host immune response. In our model system

A. machipongonensis, a member of the Bacteroidetes phylum, induces multicelluar

morphogenesis in one of the closest living relatives of animals, the choanoflagellate

Salpingoeca rosetta, which is known to have both solitary and colonial life stages.[1] The

transition between both cell morphologies of S. rosetta is induced by chemical signals

derived from the prey bacterium A. machipongonensis.[2] Based on bio-assay guided

fractionations we were able to identify a set of sulfonolipids (sphingolipid derivatives) which

are both necessary and sufficient to robustly induce the morphological changes. The relative

structures of the chemical mediators were elucidated, and the activity confirmed by a robust

bioassay. Currently, we are synthesizing the natural sphingolipid derivatives as well as

derivatives to determine the absolute configuration, to analyze the structure-activity

relationship, and to characterize the receptors of these highly potent molecules.[3]

Unraveling the mechanism of the simple single-cell to multiple-cell transition in the

described model system will provide an unparalleled insight into the origins of animal

development.

[1] a) Dayel, M. J.; Alegado, R. A.; Fairclough, S. R.; Levin, T. C.; Nichols, S. A.; McDonald, K.;

King, N. Dev. Biol. 2011, 357, 73; b) Fairclough, S. R.; Dayel, M. J.; King, N. Curr. Biol. 2010,

20, R875.

[2] Alegado, R. A.; Grabenstatter, J. D.; Zuzow, R.; Morris, A.; Huang, S. Y.; Summons, R. E.;

King, N. Int. J. Syst. Evol. Microbiol. 2012, 63, 163; b) Alegado, R. A.; Ferriera, S.; Nusbaum,

C.; Young, S. K.; Zeng, Q.; Imamovic, A.; Fairclough, S. R.; King, N. J. Bacteriol. 2011, 193,

1485.

[3] a) Alegado, R. A.; Brown, L. W.; Cao, S.; Dermenjian, R. K.; Zuzow, R.; Fairclough, S. R.;

Clardy, J.; King, N. eLife 2012, 1, e00013; b) Beemelmanns, C.; Woznica, A.; Alegado, R. A.;

King, N.; Clardy, J. submitted 2014.

Synthesis and testing of the first azobenzene mannobioside as photoswitchable ligand for the bacterial lectin FimH

V. Chandrasekaran, Kiel/Germany, K. Kolbe, Kiel/Germany, F. Beiroth, Kiel/Germany,

T. K. Lindhorst, Kiel/Germany.

Otto Diels Institute for Organic Chemistry, Christiana Albertina University of Kiel, 24098 Kiel, Germany

Conformational changes are important in many biological events, such as in the vision

process, in receptor signalling and/or among others. Recently, it has become our goal

to investigate the role of conformational control within the molecular recognition

processes occurring at the glycosylated cell surfaces. [1] The glycocalyx of eukaryotic

cells are involved in many essential biological process like cell-cell communication, cell

signalling and cell adhesion. [2] It has been evident that spatial distribution and relative

orientation of carbohydrate ligands on the cell surface plays a key role in their biological

functions. [3] To understand the importance of conformational control of

glycoconjugates in biological events, we have designed and synthesised photo-

switchable azobenzene glycosides as functional glycomimetics. [4]

Azobenzene derivatives are well suited for biological applications as they show very

good photochemical stability. [5] The E/Z isomerizaiton of the azobenzene moiety

considerably changes the relative spatial orientation of the carbohydrate head groups.

Switching of azobenzene glycosides from trans to cis configuration can be achieved by

irradiation at 365 nm, whereas back-isomerization occurs at 440 nm or be thermal

equilibration. We will report synthesis, photochemical properties as well as biological

applications in the context of type 1 fimbriae-mediated bacterial adhesion. [6]

Literature: [1] A. J. Petrescu, M. R. Wormald, R. A. Dwek, Curr. Opin. Struct. Biol. 2006, 16, 600-607. [2] P. Crocker, J. C. Paulson, A. Varki, Nat. Rev. Immunol. 2007, 7, 255-266. [3] O. Srinivas, N. Mitra, A. Surolia, N. Jayaraman, Glycobiology. 2005, 15, 861-873. [4] V. Chandrasekaran, T. K. Lindhorst, Chem. Commun. 2012, 48, 7519-7521. [5] R. H. Kramer, D. L. Fortin, D. Trauner, Curr. Opin. Neurobiol. 2009, 19, 544-552. [6] V. Chandrasekaran, K. Kolbe, F. Beiroth, T. K. Lindhorst, Beilstein J. Org. Chem. 2013, 9, 223-233.

Toward a General Model for Designing Thiourea Organocatalysts

Hon Man Yau and Peter R. Schreiner

Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany

honman.yau@org.chemie.uni-giessen.de

Thiourea organocatalysis has garnered much attention and research efforts in the last decade and many highly-enantioselective reactions catalysed by thioureas have been developed since then.1 While there are examples of detailed mechanistic studies for enantioselective thiourea-catalysed reactions in the literature, they are highly specific and are not readily generalised to other reactions and/or thiourea catalysts.2

The equilibrium acidities (pKa) of thioureas represent a common measurable quantity between different thiourea catalysts3,4 and has structure-activity-enantioselectivity relationships have been demonstrated for a series of Michael addition reactions.9 Here we report our efforts, through mechanistic studies on distinctly different types of reactions, in understanding the thiourea class of organocatalysts using pKa as a general descriptor.

1. Hof, K.; Lippert, K. M.; Schreiner, P. R. In Science of Synthesis Asymmetric Organocatalysis 2: Brønsted Base and Acid Catalysts, And Additional Topics; Maruoka, K.; List, B., Eds.; Thieme, 2012; pp. 297–412.

2. Hamza, A.; Schubert, G.; Soós, T.; Papai, I. J. Am. Chem. Soc. 2006, 128, 13151; Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413; Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 15872; Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 15358; Lin, S.; Jacobsen, E. Nat. Chem. 2012, 4, 9286; Zhang, Y.; Sheets, M. R.; Raja, E. K.; Boblak, K. N.; Klumpp, D. A. J. Am. Chem. Soc. 2011, 133, 8467.

3. Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner, P. R. Org. Lett. 2012, 14, 1724.

4. Li, X.; Deng, H.; Zhang, B.; Li, J.; Zhang, L.; Luo, S.; Cheng, J.-P. Chem. Eur. J. 2010, 16, 450.

Synthesis and Structural Studies of Helical Imidazole-Based Oligomers

G. Haberhauer*, A. Adam, Essen/GER Prof. Dr. G. Haberhauer, University of Duisburg-Essen, Universitätsstr.7, 45117 Essen

Foldamers are of particular importance for molecular recognition process, in host-guest chemistry, as well as for molecular self-organization. The folded well-defined secondary structure can be adopt by polar and nonpolar noncovalent intramoleculary interactions including hydrogen bond, π-stacking and solvophobic interactions.[1-3] Here we describe the synthesis and structural analysis of the first imidazole-based foldamer. The secondary structure is stabilized by strong intramolecular hydrogen bonds of the amide-groups.

CD spectra show from a chain length of four imidazole units increasing cotton-effects, which are attributable to the formation of the secondary structure. The helix remains stable upon the addition of protic solvents such as methanol. It has been observed that sterically bulky groups, which are attached close to the terminal chiral unit increase the stability of the helix. Upon formation of the folded structure, the 1H NMR signals of the amide protons are broadened and shifted downfield due to hydrogen bonds. NMR and CD-temperature investigations have shown that the secondary structure is broken at high temperatures (e.g., at 70 °C in the decamer). Furthermore, the helical structure could be switched from the folded to the unfolded structure by addition of copper(II)triflate or cyclam, respectively.

References: [1] (a) S. H. Gellman, Acc. Chem. Res. 1998, 31, 173; (b) D. J. Hill, M. J. Mio, R. B. Prince, T. S.

Hughes, J. S. Moore, Chem. Rev. 2001, 101, 3893; (c) S. Hecht, I. Huc, Eds., Foldamers: Structure Properties and Applications, Wiley-VCH: Weinheim, 2007; (d) G. Guichard, I. Huc, Chem. Commun. 2011, 47, 5933;

[2] J.-m. Suk, D. A Kim, K.-S. Jeong, Org. Lett. 2012, 14, 5018; [3] (a) T. A. Martinek, F. Fülöp, Chem. Soc. Rev. 2012, 41, 687; (b) P. G. Vasudev, S. Chatterjee, N.

Shamala, P. Balaram, Chem. Rev. 2011, 111, 657.

Figure 1: Folding by intramolecular hydrogen bonds in imidazole-containing peptides.

Figure 2: Side and top views of the crystal structure of phenanthroline-imidazole peptide.

Ruthenium-Catalyzed Synthesis of Isochromenes

via Hydroxyl-Assited C–H Activation

Nakanowatari, S., Ackermann, L.*, Göttingen, D.

Georg-August-Universität Göttingen, Institut für Organische und Biomolekulare Chemie, Tammannstr. 2, D-37077 Göttingen

Isochromene derivatives are an important class of molecules, because they are found in a variety of biologically active compounds.[1] The most robust and atom-economical method to synthesize isochromene skeletons[2] would involve coupling of alkynes with benzyl alcohols via C–H activation, as was demonstrated by Miura and Satoh and co-workers by rhodium catalysis.[3] Due to the weak coordinating ability, hydroxyl-assisted C–H activation is challenging and was limited so far only to rhodium[3] and palladium[4] catalysts.

Based on our studies on economically favorable ruthenium-catalyzed C–H bond activation/annulation reactions,[5] we found that a cationic ruthenium(II) complex allowed efficient oxidative C–H bond functionalization with benzyl alcohols.[6] The catalytic process proceeded efficiently under an atmosphere of ambient air with a catalytic amount of oxidant. The reaction showed broad substrate scope with both

alkyne and -disubstitued benzyl alcohols, giving variously decorated isochromene derivatives in high yields. Furthermore, we found that the catalytic system was also

applicable to -dimethylallyl alcohol. Mechanistic studies were indicative of a kinetically relevant C–H metalation. Literature: [1] A review: Gao, J.-M.; Yang, S.-X.; Qin, J-C.; Chem. Rev. 2013, 113, 4755–4811. [2] A review: Larghi, E. L.; Kaufmann, T. S. Eur. J. Org. Chem. 2011, 5195–5231. [3] Morimoto, K.; Hirano, K.; Satoh,T.; Miura, M; J. Org. Chem. 2011, 76, 9548–9551. [4] a) Lu, Y.; Leow, D.; Wang, X.; Engle, K. M.; Yu, J.-Q. Chem. Sci. 2011, 2, 967–971; b) Wang, X; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 12203–12205; c) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 5916–5921. [5] A review: Ackermann, L. Acc. Chem. Res. 2014, 47, 281–295 [6] Nakanowatari, S.; Ackermann, L. Chem. Eur. J. 2014, 20, 5409–5413.

Oligoprolines as Scaffolds for Tumor Targeting with Hybrid Bombesin Analogues

Stefanie Dobitz and Helma Wennemers* Laboratory of Organic Chemistry, ETH Zurich, Vladimir–Prelog-Weg 3, CH-8093 Zurich, Switzerland

In recent years, oligoprolines have emerged as an attractive example of a molecular scaffold suitable for controlling the spatial arrangement of various compounds in medicine and material sciences.[1] In aqueous environments oligoprolines adopt the well-defined polyproline II (PPII) helix already at chain lengths as short as six residues.[2] Within this left-handed secondary structure every third proline residue is stacked on top of each other in a distance of approximately 1 nm (Scheme 1).[2] Incorporation of 4-azidoproline (4-Azp) residues into this helix provides reactive sites located in desired distances from each other that can easily be functionalized by Cu(I)-catalyzed Huisgen’s 1,3-dipolar cycloaddition (click reaction) with terminal alkynes or through Staudinger reduction followed by acylation.[3]

Scheme 1: Oligoproline with 4-azidoproline (4-Azp) residues in every repeating position.[3]

Previous studies within our group showed that hybrid ligands consisting of an oligoproline scaffold equipped with a bombesin-based agonist and antagonist as recognition motives exhibit extraordinary tumor uptake properties in prostate carcinoma.[4] The hybrid ligands showed significantly higher tumor uptake in vitro and in vivo compared to not only monovalent but also divalent controls. Notably, the defined distance between the recognition motives proved to be important for high, specific, and long lasting tumor uptakes. Based on these initial findings we are now designing modified oligoproline-based ligands to achieve yet higher tumor uptakes and a deeper understanding of how the uptake is accomplished on the molecular and cellular level. References [1] a) W. S. Aldridge, B. J. Hornstein, S. Serron, D. M. Dattelbaum, J. R. Schoonover, T. J. Meyer, J. Org. Chem., 2006, 71, 5186. b) K. M. Bonger, V. V. Kapoerchan, G. M. Grotenbreg, C. J. van Koppen, C. M. Timmers, G. A. van der Marela, H. S. Overkleeft, Org. Biomol. Chem., 2010, 8, 1881. c) C. C. G. Scully, V. Rai, G. Poda, S. Zaretsky, D. C. Burns, R. S. Houliston, T. Lou, A. K. Yudin, Chem. Eur. J., 2012, 18, 15612. [2] a) F. Rabanal, L. M. Pons, E. Giralt, Biopolymers, 1993, 33,1019. b) S. Kakinoki, Y. Hirano, M. Oka, Polym. Bull., 2005, 53, 109. [3] a) M. Kuemin, L.-S. Sonntag, H. Wennemers, J. Am. Chem. Soc., 2007, 129, 466. b) R. S. Erdmann, M. Kuemin, H. Wennemers, Chimia, 2009, 64, 19. c) Y. A. Nagel, M. Kuemin, H. Wennemers, Chimia, 2011, 65, 264. d) G. Upert, F. Bouillère, H. Wennemers, Angew. Chem. Int. Ed., 2012, 51, 4231. [4] C. Kroll, R. Mansi, F. Braun, S. Dobitz, H. R. Maecke, H. Wennemers, J. Am. Chem. Soc., 2013, 135, 16793.

Revealing the Truth – Accurate temperature monitoring in microwave synthesis

Andrea Härter, Alexander Stadler

Anton Paar GmbH, 73760 Ostfildern, Deutschland, e-mail: andrea.haerter@anton-paar.com

Within 25 years microwave synthesis has matured and stepped into several application fields in

chemistry. However, during many years of nobody cared about accurate parameter monitoring

which causes troubles when trying to transfer methods to different microwave instruments.

Nowadays it is well known that temperature measurement is the most crucial issue in microwave

synthesis, and that it is important to understand and correctly interpret the results especially when

scaling up reactions is an issue [1].

Additionally, if sufficient agitation cannot be ensured, temperature gradients will occur and a

representative reaction temperature cannot be obtained (see Figure1). Therefore, if unexpected

results occur in some cases it is advisable to use a camera in order to check the efficiency of

agitation in microwave reactions.

Herein we present examples and solutions to ensure accurate parameter monitoring to enhance

the reliability and reproducibility of microwave-assisted reactions.

Figure 1. Simultaneous temperature measurement by IR and an immersing fiber optic probe in a

polymerization reaction reveals the temperature gradient between vessel wall and reaction mixture if stirring

is stopped due to increased viscosity of the mixture [2].

[1] C. O. Kappe, Chem. Soc. Rev. 2013, 42, 4977

[2] S. Hayden, M. Damm, C. O. Kappe, Macromol. Chem. Phys. 2013, 214, 423