Hydrophobic Chitosan Derivatives for Liposome Modification O.O

Hydrophobic chitosan derivatives for liposome modification

O.O. Koloskova, U.A. Budanova, Yu.L. Sebyakin Moscow/Russia

Moscow state university of fine chemical technology named after M.V. Lomonosov, prospekt Vernadskogo 86, 119571, Moscow

Chitosan is an abundant natural polysaccharide with huge availability and potential for biomedical applications due to its biocompatibility, biodegradability, and bioactivity, but its utilization in pharmaceutical formulations has been greatly limited by its intractability. Owing to its semicrystalline nature and multiple H-bond forming groups, chitosan is insoluble in water (when pH > 6.2) and all common organic solvents. Therefore, many works are dedicated to synthesis of new chitosan derivatives to improve its properties for the applications. For example, chitosan is an attractive polymer for liposome modification to obtain a steric stabilized particles.

In this work we synthesized a chitosan derivative with residue of palmitic acid as a hydrophobic anchor (which will penetrate into liposomal bilayer and fixate chitosan on the surface). The reaction was carried out in the presence of EDC in the mixture of acetonitrile and a low-concentration solution of acetic acid. The product was purified by washing with non-polar solvents. The structure of the target compound was confirmed by 1H- NMR spectroscopy.

As a result, the derivative of chitosan have been synthesized and it can be used to create a steric barrier on the surface of liposomes.

This work was supported by the Russian Foundation for Basic Research (grant № 13- 04-00841).

Photocatalysis with Visible Light – a Sustainable Application for the Falling Film Microreactor Rehm, T. H. Mainz/DE, Löb, P. Mainz/DE Fraunhofer ICT-IMM, Carl-Zeiss-Straße 18-20, 55129 Mainz, Germany.

The utilization of visible light has become an important research field for the synthesis of fine chemicals. Several methods have been developed with pure organic or metal organic sensitizers for homogeneously photocatalysed reactions under mild reaction conditions being close to room temperature and pressure (Biological Process Win- dows).1 In conjunction with continuous-flow synthesis protocols microstructured reactors are increasingly applied as further sustainable key technology. For example, a falling film microreactor (FFMR) enables the optimized control over the dimension of the liquid phase both on generating very thin liquid films for complete illumination and excellent gas-liquid contacting.2 The synergistic approach to combine photocatalysis with visible light and microreactors for continuous-flow synthesis enables the access to a very young and promising field of synthetic organic chemistry.3 In a feasibility study the FFMR was combined with light sources of individual power and emission wavelength for performing photochemical con- versions with gas-liquid contacting. BMR1: photooxygenation of 1,5-dihydroxynaphthalene to Juglone;4 BMR2: photooxidation of p-methoxybenzyl alcohol to p-methoxybenzaldehyde.1e A commercially available cold-white LED lamp (14.2 W) and newly designed LED arrays adapted to the quartz glass win- dow of the FFMR were used for the irradiation of the reaction solution (green (3.4 W) for Rose Bengal; blue (2 W) for riboflavin tetraacetate or tetraphenylporphyrine). In case of BMR1 (#1) the photoreactor setup applied results in a strongly increased product yield, whereupon the green LED array is superior to the white light LED lamp regarding the energy efficiency. In comparison to Entry 1 the use of TPP instead of RB gives lower yield, but increases once more the energy efficiency (#2). BMR2 (#3) was successfully transferred from batch to continuous-flow mode with equal yield. Here, the use of the blue LED array gives the best energy efficiency.

Table 1: Reaction conditions and results for BMRs (tresidence ≈ 19 s, T = 20 °C, fliquid = 0.08 mL/min, fsynthetic air = 2 mL/min; ISP = 2-propanol). # Reaction Starting material Solvent Light emission of LED Type of LED Literature Sensitizer [mM] [mM] Yield [%] Efficiency [%·W-1·h-1] [%] 1 BMR1 1,5-Dihydroxy- ISP/water White Green White Green White Rose Bengal [0.5] Naphthalene [10] 9/1 92 71 1225 3944 10 (ref.4) 2 BMR1 1,5-Dihydroxy- 1,4- Blue Green Blue Green / Tetraphenylporphyrine [0.5] Naphthalene [10] Dioxane 49 <1 4642 <189 /

3 BMR2 p-Methoxy- ISP/water White Blue Green White Blue Green Blue Riboflavin tetraacetate [0.2] benzyl alcohol [2] 1/1 60 36 19 800 3411 1059 58 (ref.1e) The strongly increased yield in BMR1 and the transfer to continuous-flow mode for BMR2 give a first outlook on the potential of the falling film microreactor for photocatalytic applications. Ongoing work focuses on the development of a reactor concept to be applied to various photochemical reactions in conjunction with the highly specific adap- tation of the photocatalyst and the light source on the chemical reaction.

1 a) D. Ravelli, D. Dondi, M. Fagnoni, A. Albini, Chem. Soc. Rev. 2009, 38, 1999-2011; b) J. Xuan, W.-J. Xiao, Angew. Chem. Int. Ed. 2012, 51, 6828-6838; c) S. Füldner, R. Mild, H. Siegmund, J. Schroeder, M. Gruber, B. König, Green Chem. 2010, 12, 400-406; d) M. Neumann, S. Füldner, B. König, K. Zeitler, Angew. Chem. Int. Ed. 2011, 50, 951-954; e) H. Schmaderer, P. Hilgers, R. Lechner, B. König, Adv. Synth. Catal. 2009, 351, 163-174; f) D. Hari, P. Schroll, B. König, J. Amer. Chem. Soc. 2012, 134, 2958-2961; g) S. Protti, M. Fagnoni, Photochem. Photobiol. Sci. 2009, 8, 1499-1516; h) C. Prier, D. Rankic, D. MacMillan, Chem. Rev., 2013, 113, 5322-5363. 2 V. Hessel, S. Hardt, H. Löwe, A. Müller, G. Kolb, Chemical Micro Process Engineering 2005, Wiley-VCH, Weinheim. 3 a) E. Coyle, M. Oelgemöller, Photochem. Photobiol. Sci. 2008, 7, 1313-1322; b) M. Oelgemöller, Chem. Eng. Technol. 2012, 35, 1144-1152; c) B. Mason, K. Price, J. Steinbacher, A. Bogdan, T. McQuade, Chem. Rev. 2007, 107, 2300-2318; d) H. Lu, M. Schmidt, K. Jensen, Lab Chip, 2001, 1, 22-28; e) R. Wootton, R. Fortt, A. de Mello, Org. Proc. Res. Devel. 2002, 6, 187-189; f) Y. Matsushita, N. Ohbab, S. Kumadab, K. Sakeda, T. Suzuki, T. Ichimura, Chem. Eng. J. 2008, 135S, S303-S308; g) R. Gorges, S. Meyer, G. Kreisel, J. Photochem. Photobiol. A: Chemistry 2004, 167, 95-99. 4 O. Shvydkiv, C. Limburg, K. Nolan, M. Oelgemöller, J. Flow Chem. 2012, 2, 52-55.

Rh(III)-catalyzed Halogenations: Arenes, Alkenes and Heterocycles

N. Schröder, Münster, J. Wencel-Delord, Münster, N. Kuhl, Münster, F. Lied, Münster, F. Glorius, Münster

Nils Schröder, Organisch-Chemisches Institut, Westfälische Wilhems-Universität Münster, Corrensstraße 40, 48149 Münster, Germany

The metal-catalyzed direct functionalization of C-H bonds has emerged over the last decade as a modern and environmentally friendly tool for organic synthesis. However, the applications of this strategy to create carbon-heteroatom bonds, and, in particular, carbon-halogen bonds, are still surprisingly limited. A general method enabling the high-yielding and selective formation of most valuable and versatile (with regard to further transformations) C-Br and C-I bonds, compatible with a large scope of diverse reactants, such as arenes, alkenes and hetereocycles, is of prime synthetic value. Herein, we report our efforts and recent advances in the Rh(III)-catalyzed bromination and iodination. The halogenation of arenes was achieved with excellent efficiency and selectivity, as well as a broad scope in terms of different directing groups.[1]

DG DG [RhIIICp*] + NXS H X = Br, I X + ortho-C-H bromination and iodination + versatile (33 examples) + efficient (up to 99% yield)

The selective synthesis of Z-halo acrylamides was achieved using a similar protocol.[2]

ra id access to Z-halo acr lic amides p y + easily available via starting materials direct halogenation of vinylic C-H bonds + variable R DG R DG substitution patterns Rh(III) + Z-selective

R H NXS R X X = Br, I + valuable building blocks

In addition recent results on the selective halogenation of heterocycles are reported.

Literature:

[1] N. Schröder, J. Wencel-Delord, F. Glorius J. Am. Chem. Soc. 2012, 134, 8298- 8301. [2] N. Kuhl, N. Schröder, F. Glorius Org. Lett. 2013, 15, 3860-3863.

Asymmetric Hydrogenation of Thiophenes and Benzothiophenes Catalyzed by a Ruthenium-NHC Complex

Daniel Paul, Münster, Slawomir Urban, Münster, Bernhard Beiring, Münster, Nuria Ortega, Münster and Frank Glorius, Münster

Daniel Paul, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, [email protected]

Asymmetric hydrogenation of aromatic compounds is a straightforward method for the synthesis of chiral (hetero)cycles, which are important structural motives, especially in medicinal and biological chemistry. Several aromatics like quinolines, indoles or (benzo)furans have been hydrogenated in the past, showing excellent yields and enantioselectivities.[1] Difficulties remained in the hydrogenation of strong sigma-donating molecules like sulfur containing aromatics, which tend to poison the homogenous catalyst. Thiophenes and their (partly) reduced pendants are widely distributed in natural products. But the formation of diverse and enantiopure derivates remains challenging.[2]

The homogenous hydrogenation of unsubstituted thiophene and benzothiophene has been extensively studied in order to understand the heterogenous hydrodesulfurization-reaction (HDS). Unfortunately, just one precedence is known for substituted thiophenes and none for substituted benzothiophenes[3]

We will present an efficient and asymmetric ruthenium-N-heterocyclic carbene-catalyzed hydrogenation of substituted thiophenes and benzothiophenes, providing a new strategy for the formation of valuable enantiomerically pure tetrahydrothiophenes and 2,3- dihydrobenzothiophenes.[4]

Literature: [1] Wang, D.-S.; Chen, Q. A.; Lu, S. M.; Zhou, Y.-G. Chem. Rev. 2012, 112, 2557. [2] Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V. Chem. Rev. 2012, 112, 2129. [3] Borowski, A. F.; Sabo-Etienne, S.; Donnadieu, B.; Chaudret, B. Organometallics 2003, 22, 4803. [4] Urban, S.; Beiring, B.; Ortega, N.; Paul, D.; Glorius, F., J. Am. Chem. Soc. 2012, 134, 15241.

Oxidative Palladium(II)-Catalyzed Cross Dehydrogenative Arylation and Alkenylation of Indolines at the C-7 Position

Lin-Yu Jiao and Martin Oestreich*

Institut für Chemie, Technische Universität Berlin, Straße des 17. Juni 115, D-10623 Berlin, Germany E-mail: [email protected]

Recent years witnessed the revival of palladium-catalyzed C–H bond functionalization for the formation of C–C and C–Het bonds. Despite tremendous progress, site selectivity and mild catalytic setups remain challenging. Pioneering work by several research teams documented that oxidative palladium catalysis with the aid of a directing group provides an efficient way to address the aforementioned issues. However, methods for selective C–H bond activation of the indole core at the C-7 position are synthetically attractive but rare and usually require at least one prefunctionalized coupling partner. [1] Recently, we reported the direct installation of an aryl group at C-7 of 2,3-disubstituted indolines by using acetyl as a directing group ( I→II );[2a] NMR experiments showed that the substituent at C-2 is a crucial factor for regiocontrol. Moreover, we also disclosed alkenylation of simple indolines directed by a carbamoyl group under mild condition (I→III ). [2b] The catalytic systems were efficient, and a wide range of both coupling partners was cross-coupled in moderate to excellent yields. [3]

[1] For C-7 selective arylation, see: a) D. Kalyani, N. R. Deprez, L. V. Desai, M. S. Sanford, J. Am.

Chem. Soc. 2005 , 127 , 7330–7331 (using [Ph 2I]BF 4); b) Z. Shi, B. Li, X. Wan, J. Cheng, Z. Fang, B. Cao, C. Qin, Y. Wang, Angew. Chem. Int. Ed . 2007 ,46 , 5554–5558 (using PhB(OH) 2); c) T. Nishikata, A. R. Abela, S. Huang, B. H. Lipshutz, J. Am. Chem. Soc . 2010 , 132 , 4978–4979 (using PhB(OH) 2); for C-7 selective alkenylation, see: d) B. Urones, R. G. Arrayás, J. C. Carretero, Org. Lett. 2013 , 15 , 1120–1123 (using N-(2-pyridyl)-sulfonyl as directing group). [2] a) L.-Y. Jiao, M. Oestreich, Chem. Eur. J. 2013 , 19 , 10845–10848; b) L.-Y. Jiao, M. Oestreich, Org. Lett. 2013 , 15 , 5374–5377. [3] a) Z. Song, R. Samanta, A. P. Antonchick, Org. Lett. 2013 , 15 , 5662–5665 (Rh(III)-catalyzed alkenylation); b) S. Pan, N. Ryu, T. Shibata, Adv. Synth. Catal. 2014 , DOI: 10.1002/adsc.201300917 (Ir(I)-catalyzed alkylation); c) S. Pan, T. Wakaki, N. Ryu, T. Shibata, Chem. Asian J. 2014 , DOI: 10.1002/asia.201301733 (Ir(III)-catalyzed alkenylation).

Rapid Assessment of Protecting-Group Stability by Using a Robustness Screen

A. Rühling, Münster Germany, K. D. Collins, Münster Germany, F. Lied, Münster Germany

Frank Glorius, Westfälische Wilhelms-Universität Münster, Corrensstr. 40, 48419 Münster

In contrast to the rapid publication of scientific information, the application of new knowledge is often slow, and we believe this to be particularly true of newly developed synthetic methodologies. Consequently, methods to assess and identify robust chemical reactions are highly desirable, and would directly facilitate their application. We recently developed a simple process for assessing the likely scope and limitations of a chemical reaction beyond the idealized reaction conditions.[1],[2] Our approach is conceptually very simple, and provides complementary data to that obtained in the substrate scope: A standard reaction is undertaken in the presence of one molar equivalent of an additive for a given chemical functionality. Reactions are analysed using gas chromatography (GC), providing a quantitative assessment of the yield of the reaction, the amount of additive remaining, and thus determining the tolerance of the reaction to the given additive, and of the stability of the additive to the reaction conditions.

More recently we have extended this methodology to the important field of protecting group chemistry. When designing synthetic routes the selection of appropriate protecting groups is critical for a successful reaction concerning yield and stability of the reaction. [3] Using the Cu(OAc)2-mediated synthesis of pyrazoles, we individually assessed the stability of these protecting groups to the reaction conditions. We were also able to demonstrate multiple protecting groups can be simultaneously assessed in a single experiment, enhancing the practicability of our protocol.[4] Furthermore we validated the results using complex molecules containing protecting groups in the pyrazole synthesis, and importantly in an unrelated transformation.

Literature: [1] [2] Collins K. D.; Glorius F. Nature Chem. 2013, 5, 597. Collins K. D.; Rühling, A.; Glorius F. Nat. Protoc., accepted. [3]Suri M.; Jousseaume T.; Neumann J. J.; Glorius F. Green Chem. 2012, 14, 2193. [4]Collins K. D.; Rühling A.; Lied F; Glorius F. Chem. Eur. J., DOI: 10.1002/chem.201304508.

One-Pot Metal-free Synthesis of Sulfones from Lithium and Sodium Sulfinic Acid Salts with Diaryliodonium Salts

N. Umierski, Frankfurt/D, G. Manolikakes, Frankfurt/D

Institut für Organische Chemie und Chemische Biologie, Goethe-Universität Frankfurt, Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany

Diaryl sulfones are useful synthetic intermediates and exhibit interesting biological properties.[1] Numerous approaches for their preparation have been reported. However applicability of these methods is limited, due to their harsh reaction conditions or the use of toxic and expensive transition metals.

In the course of our investigations towards new synthetic methods for the synthesis of sulfonyl-group containing molecules, we recently developed a mild and transition metal- free synthesis of diarylsulfones starting from aryl sulfinic acids and diaryliodonium salts. The scope of this reaction is quite broad and includes the synthesis of halogen- substituted or sterically hindered diarylsulfones as well as heteroarylsulfones.[2]

Ar2 I Ar3 - O 1 X 1 2 (Het)Ar SO2Na (Het)Ar S Ar DMF, 24 h, 90 °C O 54 - 96 % yield Based on these results we were able to develop an efficient one-pot synthesis of diarylsulfones starting from readily available organolithium reagents. Reaction of the organolithium reagent with SO2 followed by a subsequent in situ trapping of the formed sulfinic acid lithium salt with a diaryliodonium reagent leads to the desired sulfones in good to excellent yields. This reaction sequence is quite general and works equally well with aryl or alkyl lithium reagents. Starting from simple unfunctionalized molecules, structurally diverse arylsulfones could be efficiently synthesized, using a deprotonation/ sulfination/arylation-sequence.[3]

Ar I Ar' - O SO2 X R Li R SO2-Li R S Ar DMF, 24 h, 90 °C O 52 - 93 % yield Literature: [1] (a) Patai, S., Rappoport, Z., Stirling, C. J. M., Eds. The Chemistry of Sulfones and Sulfoxides; Wiley: New York, 1988. (b) Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon Press: Oxford, 1993. [2] Umierski, N.; Manolikakes, G.; Org. Lett. 2013, 188. [3] Umierski, N.; Manolikakes, G.; Org. Lett. 2013, 4972.

Iron-Catalyzed Multicomponent-Synthesis of α-Amino Acid Derivatives

Juliette Halli

Dr. Georg Manolikakes, Goethe-University, Max-von-Laue-Str. 7, Frankfurt am Main

Amino acids are ubiquitous in nature and extensively use in pesticides, nutritional supplements, fertilizers, biodegradable plastics, cosmetics or pharmaceutical substances.[1,2] Because of their widespread use and biological significance the development of new efficient and sustainable methods for the synthesis of α-amino acids is of particular importance.[1,3] In the course of our research we have developed a new Iron-catalyzed multicomponent synthesis of arylglycine derivatives from simple starting materials.[4]

Fig.1: Iron-catalyzed amidoalklyation.[4]

This reaction is insensitive towards air or moisture and has a broad scope. Various amides or carbamates react with different arenes or heteroarenes and glyoxylic acid derivatives. Commercial available polymeric ethyl glyoxalate can be used directly, without prior pyrolysis and distillation. The reaction of glyoxylic acid (used as aqueous solution) furnishes directly N-protected α-amino acids. In summary, this new method provides efficient, simple and sustainable access to biological important arylglycine derivatives, using catalytic amounts of inexpensive and non-toxic Iron(III)-salts. In addition the only by-product of this reaction is water.

Literature:

[1] G. Dyker, Angew. Chem. Int. Ed. 1997, 36, 1700–1702. [2] W. Leuchtenberger, K. Huthmacher, K. Drauz, Appl. Microbiol. Biotechnol. 2005, 69, 1–8. [3] E. C. Roos, M. C. Lopez, M. A. Brook, H. Hiemstra, W. N. Speckamp, B. Kaptein, J. Kamphuis, H. E. Schoemaker, J. Org. Chem. 1993, 58, 3259–3268. [4] J. Halli, G. Manolikakes, Eur. J. Org. Chem. 2013, 2013, 7471–7475.

Allenyl Isothiocyanates – Versatile Precursors in the Synthesis of Heterocycles

F. Richter, Chemnitz/DE, K. Banert, Chemnitz/DE

M.Sc. Frank Richter, Technische Universität Chemnitz, Institute of Chemistry, Straße der Nationen 62, 09111 Chemnitz

The chemistry of allenyl isothiocyanates is well investigated. Nucleophilic addition in connection with ring closure gives rise to a wide range of substituted thiazoles. [1,2,3] In advancement, bisthiazol formation on a the same nucleophilic center occurs with additional equivalents of isothiocyanate 1. Furthermore, multi-component reactions (MCR) of allenyl isothiocyanate ( 1) were developed. Key intermediate of the basic three-component reaction (3-CR) is a zwitterionic thiazole type heterocycle 6, which itself acts as a carbon nucleophile. Several electrophiles 9 have been found to readily react and form MCR products 10 in good to high yields. β-Nitrostyrene ( 7) was shown to follow a secondary reaction pathway, giving access to highly substituted 1,3-thiazine derivatives 8.

MCRs are a very atom economic and ecological tool to build up highly complex molecules. Using nitrogen nucleophiles in this 3-CR gives a new and efficient access to 2-aminothiazoles, a substance class known for its antibacterial and inhibitor activity in prion disease. [4,5,6]

[1] K. Banert, B. J. Al-Hourani, S. Groth, K. Vrobel, Synthesis 2005 , 2920–2926. [2] B. J. Al-Hourani, K. Banert, N. Gomaa, K. Vrobel, Tetrahedron 2008 , 64 , 5590–5597. [3] B. J. Al-Hourani, K. Banert, T. Rüffer, B. Walfort, H. Lang, Heterocycles 2008 , 75 , 2667–2679. [4] J. Das, P. Chen, D. Norris, R. Padmanabha, J. Med. Chem. 2006 , 49 , 6819–6832. [5] S. Ghaemmaghami, B. C. H. May, A. R. Renslo, S. B. Prusiner, J. Virol. 2010 , 84 , 3408–3412. [6] A.Gallardo-Godoy, J. Gever, K. L. Fife, B. M. Silber, S. B. Prusiner, A. R. Renslo, J. Med. Chem. 2011 , 54 , 1010–1021. Synthesis of Carbamic acid derivatives: A proof for the existence of 4,5- dihydro-1,2,3-oxadiazole

N. Singh, Chemnitz/DE, Prof. Dr. K. Banert, Chemnitz/DE

M.Sc. N. Singh, TU Chemnitz, Str. der Nationen 62, 09111 Chemnitz

4,5-Dihydro-1,2,3-oxadiazoles of type 2 have been hypothesized to be intermediates in important transformations1 such as industrial scale preparation of ketones (by BASF) by the reaction between alkenes and nitrous oxide, etc. Various theoretical studies2,3 have been done on this molecule, but its complete characterization still eludes the scientific community. We have in our research proved its existence indirectly by the identification of its decomposition products3 viz., ethylene oxide and acetaldehyde, along with the characterization of new types of carbamic acid derivatives 3. This was achieved by studying the decomposition of suitably substituted N-nitrosoureas 1 in the presence of thallium(I) alkoxides.4 The advantage of thallium(I) alkoxides is that they are soluble in a wide range of organic solvents, and therefore the reaction can be studied at low temperature under controlled conditions.

NO NR'2 O TlOR" N O R N O N + -R"OCONR' O 2 H 1 2

i) TlOR" ii) R"OCONR'2

H OR"

OCONR'2 3

1) K. Banert, Angew. Chem. Int. Ed. 2011, 50, 6171–6174; Angew. Chem. 2011, 123, 6295–6298. 2) J. W. Lown, J. Am. Chem. Soc. 1988, 110, 5671–5675. 3) R. B. Brundrett, J. Med. Chem. 1980, 23, 1245–1247. 4) L. K. Keefer, J. Am. Chem. Soc. 1988, 110, 2800–2806. Rhodium-Catalyzed Chemo- and Regioselective Decarboxylative Addition of β-Ketoacids to Allenes: Efficient Construction of Tertiary and Quaternary Carbon Centers

Changkun Li, Freiburg/Germany, Bernhard Breit* Freiburg/Germany

Prof. Dr. Bernhard Breit, Albert-Ludwigs-Universität, Albertstrasse 21, 79104 Freiburg im Breisgau

A rhodium-catalyzed chemo- and regioselective intermolecular decarboxylative addition of β-ketoacids to terminal allenes is reported. Using a Rh(I)/ DPPF system, tertiary and quaternary carbon centers were formed with exclusively branched selectivity under mild conditions. Preliminary mechanism studies support that the carbon-carbon bond formation precedes the decarboxylation and the reaction occurs in an outer-sphere mechanism.[1]

O 2 1.0 mol% [Rh(cod)Cl] R O O 2 + 2.0 mol% DPPF R3 1 + CO2 R R3 OH DCE, rt, 5 h R1 R2 High regioselectivity Mild reaction conditions 37 examples, 55-95 % yield

Literature:

[1] C. Li, Breit, B. J. Am. Chem. Soc. 2014, 136, 862.

Atom-Economic, Regiodivergent, and Stereoselective Coupling of Imidazole Derivatives with Terminal Allenes Kun Xu, Freiburg/Germany 49, Niels Thieme, Freiburg/Germany 49, Prof. Dr. Bernhard Breit, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104 Freiburg im Breisgau Functionalization of nitrogen containing heterocycles is an important topic since these structural motifs are prevalent in natural products, agrochemicals and pharmaceuticals. Additionally, their application in ligand and catalyst design, supramolecular chemistry and nanotechnology has drawn much attention. To this end, N-allylation of heterocyclic compounds is of particular interest due to the versatility of the allylic moiety, which allows further elaboration and even straightforward syntheses towards biologically active target molecules.[1-2]

Over the past few decades, allylic substitution and allylic oxidation have been the preferred methods for the synthesis of allylic derivatives. Limitations of these approaches include the requirement of a stoichiometric amount of a leaving group or an oxidant, thus making them less attractive in terms of atom economy.[3-6]

We developed a new Rh- and Pd-catalyzed regiodivergent and stereoselective intermolecular coupling reactions of imidazole derivatives with mono-substituted allenes. Using a Rh(I)/Josiphos system, perfect regioselectivities and high enantiomeric excess were obtained, while a Pd(II)/dppf system gave linear products with high regioselectivities and high E/Z selectivities. This method permits the atom economic synthesis of valuable branched and linear allylic imidazole derivatives.[7]

Scheme 1. Coupling of Imidazole Derivatives with Terminal Allenes

Literature: [1] J. A. Joule, K. Mills, Heterocyclic Chemistry, Wiley, Chichester, 2010; chap. 32-33. [2] B. M. Trost, G. Dong, J. Am. Chem. Soc. 2006, 128, 6054-6055. [3] B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921-2943. [4] L. M. Stanley, J. F. Hartwig, J. Am. Chem. Soc. 2009, 131, 8971-8983. [5] G. Liu, S. S. Stahl, J. Am. Chem. Soc. 2007, 129, 6328- 6335. [6] B. M. Trost, Science 1991, 254, 1471-1477. [7] K. Xu, N. Thieme, B. Breit, Angew. Chem. 2014, 126, 2194-2197; Angew. Chem. Int. Ed. 2014, 53, 2162-2165.

Studies towards the Total Synthesis of Monilicine

C. Wink, Mainz/Germany, S. R. Waldvogel, Mainz/Germany

Prof. Dr. S. R. Waldvogel, Johannes Gutenberg-University, Duesbergweg 10-14, 55128 Mainz

The goal of the presented research project is the development of a total synthesis of monilicine (1, figure 1). Monilicine consists of a 5-hydroxychromenone skeleton which is annulated to a ĮȕȖį-unsaturated İ-lactone. Chloro- and bromomonilicine (2, 3, figure 1) are secondary metabolites with fungicide properties which were isolated form a mutant of the fungi Monilinia fructicola.[1,2] Consequently, a synthetic pathway to chloro- and bromomonilicine might be of interest for the crop protection.

Figure 1: Structures of Monilicine (1), Chloromonilicine (2) and Bromomonilicine (3)

Our synthetic strategy for the total synthesis of monilicine (1) includes a formation of a 2-substituted chromenone by a Baker-Venkataraman rearrangement followed by a selective iodination in position 3 of the chromenone.[3,4] To introduce further functionality in position 3 a Stille coupling and a bishydroxylation of the vinyl moiety were achieved. Finally, a synthesis route was established to form “dihydromonilicine” by macrolactonization.

[1] T. Sassa, H. Kachi, M. Nukina, J. Antibiot. 1985, 38, 439-441. [2] T. Sassa, H. Kachi, M. Nukina, J. Antibiot. 1986, 39, 164-166. [3] P. Königs, B. Rinker, G. Schnakenburg, M. Nieger, S.R. Waldvogel, Synthesis, 2011, 593-598. [4] P. Königs, L. Maus, B. Rinker, J. Rheinheimer, S.R. Waldvogel, J. Nat. Prod. 2010, 73, 2064-2066.

The Lewis Base-Catalyzed Silylation of Alcohols

P. Patschinski, H. Zipse, Department of Chemistry, LMU München, Butenandtstr. 5–13, 81377 Munich, Germany

The silylation of hydroxy groups represents one of the most important protecting group strategies in the manipulation of polyfunctional molecules. The usefulness of this reaction was demonstrated by Corey et al. in 1972 using tert-butyldimethylsilyl chloride (TBSCl, 1) in DMF as the solvent and imidazole as base and catalyst for the protection of secondary alcohols.[1] In an effort to develop more reactive and more selective catalysts for the silylation of alcohols, we have now analyzed the most relevant reaction parameters such as choice of solvent, choice of auxiliary base, reaction temperature, and the impact of substrate structure. The silylation of primary and secondary alcohols is particularly efficient in the presence of donor-substituted pyridines such as DMAP (7a), PPY (7b) or more Lewis-basic pyridines 7e – 7g (Figure 1). Imidazoles 7c and 7d are, in comparison, much less active. Furthermore, the silylation of alcohols strongly responds to the choice of solvent, and there is actually no need for added catalysts in Lewis-basic solvents such as dimethyl- formamide (DMF). Reactions are much slower in apolar organic solvents such as dichloromethane (DCM) or chloroform, even in the presence of highly active catalysts. For the purpose of preparing silyl ethers of primary and secondary alcohols with the known silyl chloride reagents, the established Corey procedure thus still provides the most rapid and economic means. However, should the selective transformation of primary over secondary alcohols be the goal, the conclusions will be somewhat different, as the reactivity difference of primary and secondary alcohols amounts to 20.3 under DMF conditions, to 51 for N-methylimidazole (7d) in CDCl3, and to 120–145 for elec- [2] tron-rich pyridines such as 7g and 7f in CDCl3.

Figure 1. Silylation of various alcohols 4a–c with TBSCl (1) and TEA (2) in CDCl3 and structures for all used catalysts 7a–g.

An auxiliary base is required to neutralize the generated acid and thus allow the reaction to proceed to full conversion. Amine bases such as triethylamine, trioctylamine, or diisopropylethylamine are effective for this purpose, but have little impact on the rate of reaction. A moderate increase of the reaction temperature is helpful to solve solubility issues for certain substrates, but will otherwise lead to only moderate rate enhancement.[2]

[1] P.G.M. Wuts, T.W. Greene Greene's Protective Groups in Organic Synthesis, 4th Ed.; John Wiley & Sons, 2006; P.J. Kocienski Protecting Groups, 3rd Ed.; Thieme: Stuttgart, 2005. ; A. Venkateswarlu, E.J. Corey J. Am. Chem. Soc. 1972, 94, 6190. [2] P. Patschinski, C. Zhang, H. Zipse, manuscript in preparation.

Heteroaryl Boronate Nucleophiles in Rhodium-catalysed 1,4-Additions

O. Sowada, Hannover/D, F. Albrecht, Hannover/D, M. M. K. Boysen, Hannover/D

Jun.-Prof. Dr. Mike M. K. Boysen, Leibniz University of Hannover Institute of Organic Chemistry, Schneiderberg 1B, 30167 Hannover, Germany

In the last decade, chiral olefin ligands have emerged as interesting stereodirecting tools for asymmetric transformations.[1] We have developed a new family of pseudo enantiomeric olefin-phosphinite hybrid ligands based on inexpensive, enantiopure monosaccharides,[2] which lead to excellent results in asymmetric rhodium(I)-catalysed 1,4-addition reactions of arylboronic acids to enones.[3]

While arylboronic acids are common substrates for 1,4-additions, their heteroaryl counterparts have scarcely been employed, as they are prone to protodeboration[4] under the reaction conditions. Our group is working towards the enlargement of the reaction scope to heteroaryl nucleophiles by employing MIDA boronates[5] and pinacolboronic esters as surrogates for unstable heteroaryl boronic acids. After optimisation of the conditions for boronic acid liberation from the stable surrogates, we obtained the addition products of several heteroarylboronic acid derivatives in high enantioselectivity.

Literature:

[1] C. Defieber, H. Grützmacher, E. M. Carreira, Angew. Chem. Int. Ed. 2008, 47, 4482. [2] a) T. Minuth, M. M. K. Boysen, Org. Lett. 2009, 11, 4212; b) H. Grugel, F. Albrecht, T. Minuth, M. M. K. Boysen, Org. Lett. 2012, 14, 3780. [3] a) T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829; b) P. Tian, H.-Q. Dong, G.-Q. Lin, ACS Catal. 2012, 2, 95. [4] E. Tyrrell, P. Brookes, Synthesis 2004, 469. [5] D. M. Knapp, E. P. Gillis, M. D. Burke, J. Am. Chem. Soc. 2009, 131, 6961.

Sythesis of side-chain modified homopolypeptides

Stefanie Hansmann1, Tobias Montag1, Christina M. Thiele1 1Clemens-Schoepf Institute for Organic Chemistry, Technische Universität Darmstadt, Alarich-Weiss-Str. 4, 64287 Darmstadt (Germany) – Email: [email protected]

To get the constitution of an analyte via NMR spectroscopy is a standard procedure, understanding the conformation or configuration in solution is more challenging. So called RDCs (residual dipolar couplings) provide complementary information to conventional NMR restraints as NOE (Nuclear Overhauser Enhancement) and dihedral [1] angles from 3J couplings.

RDCs are anisotropic NMR parameters and therefore the analyte needs to be oriented with respect to the magnetic field. This can be achieved by adding the analyte to a lyotropic liquid crystalline phase (see figure 1). The perfect alignment medium for small organic molecules is compatible with organic solvents and has a low degree of orientation. If the medium is chiral, diastereomorphous interactions lead to different orientations of enantiomers.[2] Helical homopolypeptides of high-molecular weight fulfill most of the desired properties. PBLG (poly-γ- benzyl-L-glutamate)[3] and PELG (poly-γ-ethyl-L-glutamate)[4] Figure 1: Hindered rotation of the analyte through have already been used as alignment media, but the interactions with the enantiodiscrimination observed is quite small. homopolypeptide.

The work presented deals with the rational design and synthesis of tyrosine, proline and glutamic acid based homopolypeptides as prospective lyotropic liquid crystalline phases for the NMR-RDC approach. Homopolypeptides were synthesized via ROP (ring-opening polymerisation) of high purified NCAs (N-carboxyanhydrides) by either amine initiation or via Ni-catalysis.[5] Side-chain modification of the amino acid building block should allow the compatibility with organic solvents and implementation of an additional chiral center in the side chain is proposed to increase the desired enantiodifferentiation. Impurities of the NCA lead to low molecular weights and high polydispersities of the polyamino acids. As result, due to the low aspect ratio of the rod- like polymer, a higher polymer concentration is needed to observe liquid crystallinity. Therefore the purification of the NCA via repeated recrystallization or chromatography in inert conditions is the key step to high-molecular weight polymers. Our recent results in this area are presented.

[1] B. Böttcher, C. M. Thiele, in Encyclopedia of Magnetic Resonance, John Wiley & Sons, Ltd, 2012. M. Sarfati, P. Lesot, D. Merlet, J. Courtieu, Chemical Communications 2000, 2069-2081. [2] A. Marx, V. Schmidts, C. M. Thiele, Magnetic Resonance in Chemistry 2009, 47, 734-740. [3] A. Marx, C. Thiele, Chemistry – A European Journal 2009, 15, 254-260; C. Aroulanda, V. Boucard, F. Guibé, J. Courtieu, D. Merlet, Chemistry – A European Journal 2003, 9, 4536-4539; [4] C. Aroulanda, M. Sarfati, J. Courtieu, P. Lesot, Enantiomer 2001 6, 281-287; C. M. Thiele, Journal of Organic Chemistry 2004, 69, 7403-7413. [5] N. Hadjichristidis, H. Iatrou, M. Pitsikalis, G. Sakellariou, Chemical Reviews 2009, 109, 5528–5578.

Construction of chiral building blocks for 1,3-polyol synthesis on the way to polyketidic natural products

A. Bredenkamp‡, A. Häring‡, S. Hummel‡, S. F. Kirsch*‡, M. Wegener‡, Z.-B. Zhu,

‡Bergische Universität Wuppertal, Organic Chemistry, Gaußstr. 20, 42119 Wuppertal/D,

A range of polyketidic natural products include 1,3-polyol structures.[1] The synthesis of these rather large moieties can become quite difficult and time-consuming due to the pure number of stereogenic centers to be controlled. Previous studies in our group already focused on iterative reaction cycles to form 1,3-polyol structures.[2] We now present an easy and fast access to these structures via the iterative use of chiral building blocks.

Each chain elongation using this chiral four-carbon building block generates two fully controllable stereocenters while the overall iteration only contains four steps. The number of stereoselective reactions is reduced to a minimum by using pre-installed stereocenters, and all the reactions of the iterative sequence are simple to perform and easily reproducible providing the possibility of large-scale synthesis. Exemplarily, the applicability of these method is demonstrated by the synthesis of Cryptocaryol A in only 17 steps under full control of all six stereocenters.

[1] a) S. E. Bode, M.Wolberg, M. Müller, Synthesis 2006, 557 b) A. K. Miller, D. Trauner, Synlett 2006, 2295. [2] a) J. T. Binder, S. F. Kirsch, Chem Commun. 2007, 4164 b) H. Menz, S.F. Kirsch, Org. Lett. 2009, 11, 5634 c) S. F. Kirsch, P. Klahn, H. Menz, Synthesis 2011, 3592.

A Boron Cluster as Counterion in a Silver-free Activation Method for Gold(I) Catalysts Demonstrated with a Cyclization Cascade of Allenynes

M. Wegener, Wuppertal/DE, F. Huber, Wuppertal/DE, S. F. Kirsch*, Wuppertal/DE

Bergische Universität Wuppertal, Organic Chemistry, Gaußstr. 12, 42119 Wuppertal

Complications that arise from the use of silver salts as activating reagents in gold(I) catalysis have been the subject of recent investigations. [1][2] As a result, alternative methods for the activation of gold(I) catalysts that avoid the use of silver salts are of increasing interest. [3][4] We now wish to report the successful application of an anionic boron cluster, employed in the form of its sodium salt, as a facile means for the in situ activation of gold(I) chloride complexes. The reactivity of the resulting active species is demonstrated with a cyclization cascade of 5-siloxy-1,6-allenynes, the scope of which was investigated using both cluster and silver salt activation for comparative purposes. The new method proves to be equally effective and at times superior to the activation by silver salt. In addition, the scope of the reaction is further expanded by iododemetallation experiments that lead to unexpected allylic iodides. Furthermore, in an effort to demonstrate its broad applicability, the new activation method was successfully employed on a variety of known reactions that rely on π-activation by different activated gold(I) catalysts under various conditions, including carbo- and heterocyclizations as well as intermolecular reactions.

Literature:

[1] D. Wang, R. Cai, S. Sharma, J. Jirak, S. K. Thummanapelli, N. G. Akhmedov, H. Zhang, X. Liu, J. L. Petersen, X. Shi, J. Am. Chem. Soc. 2012, 134, 9012–9019. [2] A. Homs, I. Escofet, A. M. Echavarren, Org. Lett. 2013, 15, 5782–5785. [3] D. Hueber, M. Hoffmann, B. Louis, P. Pale, A. Blanc, Chem. Eur. J. 2014, 20, 3903–3907. [4] W. Fang, M. Presset, A. Guérinot, C. Bour, S. Bezzenine-Lafollée, V. Gandon, Chem. Eur. J. 2014, 20, early view.

Studies Towards the Total Synthesis of Myxovalargin

Franziska Gille, Hannover/D Prof. Dr. Andreas Kirschning, Institut für Organische Chemie and Zentrum für Biomolekulare Wirkstoffe (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover/D

Myxovalargin, the first peptide antibiotic from myxobacteria, was isolated from the Myxococcus fulvus strain Mx f65 at the Helmholtz Center of Infectious Diseases (HZI).1 At lower concentrations (MIC 0.3~5 µg/mL) Myxovalargin possesses a strong inhibitory activity against GRAM-positive bacteria by inhibition of the prokaryotic protein synthesis. In higher concentrations (MIC > 5 µg/mL) it is also active against GRAM-negative bacteria, including Pseudomonas aeruginosa.2

Myxovalargin is a linear peptide containing 14 amino acids, a carboxylic acid and an amine function. Among the amino acids, there are several unusual species like α,β- dehydrovaline, α,β-dehydroisoleucine, N-methylalanine, β-hydroxyvaline and β- tyrosine. Key steps of our total synthesis approach towards Myxovalargin are a copper-mediated cross coupling3 of an amide and vinyl iodide to install the α,β-dehydroamino acids. Additionally, the synthesis includes an amidination of primary amines4 to introduce the guanidine moieties of the arginine and the amine at the carboxy terminus. Fragment coupling relies on a peptide coupling cascade followed by saponification steps.

References:

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. 4 (a) A. Wohlrab, R. Lamer, M. S. VanNieuwenhze, J. Am. Chem. Soc. 2007, 129, 4175-4177; (b) C. W. Zapf, M. Goodman, J. Org. Chem. 2003, 68, 10092- 10097.

From trichloroethylene to highly substituted pyrroles, benzo[h]quinolines and thiazolidinones

D. E. Kaufmann, S. Kaul, V. Zapol‘skii, M. Gjikaj, D-Clausthal-Zellerfeld Prof. Dr. Dieter E. Kaufmann, Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstr. 6, D-38678 Clausthal-Zellerfeld

Based on the building block 2-nitroperchloro-1,3-butadiene, [1] it is possible to build up highly substituted heterocycles in a two-step synthesis. (Fig. 1) The stepped reactivity of the building block allows this approach. Donor-acceptor substituted pyrroles 1, persubstituted benzo[h]quinolines 2 and allylidenethiazolidiones 3[2] are accessible this way. Even small changes in the nucleophilicity and the steric bulk of the used anilines, the solvent, and the ratio of the starting materials result in the selective formation of a certain product type. [3]

Figure 1: Highly substituted heterocycles synthesized from 2-nitroperchloro-1,3-butadiene

Nitrogen-heterocycles, like 1 and 2, are biologically interesting. Additionally, thiazolidinones, like 3, are also very photosensitive.[4] The specific substitution pattern of these three heterocycles also allows a subsequent, specific modification of the functional groups.

______[1] V. A. Zapol’skii, D. E. Kaufmann, TUContact 11, 2002 , 26-29. [2] V. A. Zapol’skii, J. C. Namyslo, M. Gjikaj, D. E. Kaufmann: Chemistry of Polyhalogenated Nitro- butadienes, 14: Efficient Synthesis of Functionalized (Z)-2-Allylidene-thiazolidin-4-ones , Beilstein JOC 2014, submitted. [3] S. Kaul, master thesis 2012 , Clausthal University of Technology. [4] V. A. Zapol‘skii, J. C. Namyslo, A. E. W. Adam, D. E. Kaufmann, Heterocycles 2004 , 63 , 1281-1298.

Diaminoterephthalates – a Versatile Toolkit for Materials Science

L. Freimuth, Oldenburg/D, J. Christoffers,* Oldenburg/D

Universität Oldenburg, Carl von Ossietzky-Str. 9–11, 26111 Oldenburg

Diaminoterephthalates 2 are bearing strong fluorescence properties. They can be easily synthesized from their corresponding succinylsuccinates 1. These compounds 2 are capable of carrying up to four different residues, e.g. functional groups which enables one to use them as scaffolds for various applications in Physics, Biology or Biochemistry. The synthesis was already established in our group, as well as first applications in a Biochemistry project. [1] The unsymmetric ester-functions of compound 2 open up the possibility to address them separately and therefore install different functional groups. The installation of a carotine-residue on one end and a fullerene on the other will lead to an readily accessible so called light-harvesting-triad which will be used as a molecular model compound for solar cells (compound 3). [2] This model compound will be examined with femto-second-spectroscopy concerning photo-induced electron transfer.

OH NHR 1 2 2 CO 2R 1 CO 2R R NH 2

3 3 R O2C R O2C 1 OH R = Me, Ph NHR 1 2 C 1 R = thiol, alkyne, maleimide, etc. 2 60 R3 = alkyne, etc.

MeHN O N Me O O Me Me Me Me O NHMe

Me Me Me

[1] N. Wache, A. Scholten, T. Klüner, K. W. Koch, J. Christoffers, Eur. J. Org. Chem . 2012 , 5712–5722. [2] C. A. Rozzi, S. M. Falke, N. Spallanzani, A. Rubio, E. Molinari, D. Brida, M. Maiuri, G. Cerullo, H. Schramm, J. Christoffers, C. Linau, Nature Commun. 2013 , 1602.

Diaminoterephthalic Acid Derivatives – Fluorescent Dyes for Life Sciences

M. Wallisch, Oldenburg/D, J. Christoffers*, Oldenburg/D

Universität Oldenburg, Carl von Ossietzky-Str. 9–11, 26111 Oldenburg

Fluorescent dyes are important tools for many applications in biology. They can, for example, act as chemosensors by reacting selectively to certain ions in the cell or indicate conformational changes or the position of a functional group inside of a protein. Therefore diaminoterephthalates 2 can be used due to their strong chromaticity. These compounds can be synthesized from succinylsuccinates 1. Different functional groups, so called effector groups (e.g. X and Y), can then be attached to the dye, resulting in a versatile toolkit of many different derivatives. One example is the attachment of a maleinimide residue to the scaffold. This group can then bind to a thiol of for example a cysteine residue in a protein. Due to this, conformational changes within this protein can be detected via FRET-studies. Another possibility is the coupling of propargylamine to the dye. The resulting alkyne can be applied in a “click” reaction and therefore act as a fluorescent marker for different azides. A linker connected with all-trans retinoic acid (at-RA) could also be attached to the diaminoterephthalate scaffold via a Mitsunobu reaction. The resulting fluorescence- labeled at-RA can then be used to localize at-RA in the horizontal-cell tissue and to identify its interaction partners, leading to a better understanding of the signaling cascade associated with the process of vision.

Synthesis of Optically Active 1,2-Cyclohexanedisulfonic Acid

F. Behler, Oldenburg/D, J. Christoffers,* Oldenburg/D

Universität Oldenburg, Carl von Ossietzky-Str. 9–11, 26111 Oldenburg

Sulfonic acids have a strong potential as a new class of linkers for the use in metal organic frameworks. The superior acidity and coordination capability over carboxylic acids expands the spectrum of metal precursors used and improves the stability of their corresponding frameworks. As a new approach to chiral linkers for the synthesis of asymmetric MOFs we investigated the synthesis of trans-1,2-cyclohexanedisulfonic acid. Starting from cyclohexene, we developed a five step synthesis of enantiomerically pure (S,S)-1,2-cyclohexanedisulfonic acid. The key step of this sequence was the formation of a cyclic trithiocarbonate intermediate, which could further be directly oxidized to the corresponding racemic acid. Optical resolution with optically active 1,2-cyclohexane diamine in two additional steps led to enantiomerically pure product in good yield. First results of MOF-formation utilizing the title compound as a linker molecule are reported.

18-nor-D-homo-Androstane – Identification and Synthesis of a C19-Sterane from the Oman Salt Basin

M. Bender, Oldenburg/D, J. Rullkötter, Oldenburg/D, J. Christoffers,* Oldenburg/D

Universität Oldenburg, Carl von Ossietzky-Straße, 26111 Oldenburg, Germany

Molecular fossils are important tools in modern organic geochemistry. Their structures, distribution patterns, and reaction pathways reveal deep insight into geological history. Mass spectra provided evidence that Early Paleozoic sedimentary rocks from the

Oman Salt Basin contained three clearly separated isomers (GC) of putative C19 steranes. Since there is empirical evidence that the occurrence and isomer distribution of the unknown biomarkers correlate with the salinity of the waters during sediment formation, there is considerable interest in revealing their precise structures. The concentrations of the unknown biomarkers in the samples are too low for rigorous identification. Thus, based on the mass spectrometry data, a strategy was developed to [1] synthesize possible C19 compounds. One of them being D-homo-androstane 4.

Gaschromatogram of the admixture of 4 and the crude oil hydrocarbons containing 19a, 19b and 19c.

The synthetic plan for androstane 4 envisaged a shift of the 18-methyl group to position 17 by Wagner-Meerwein rearrangement followed by a D-ring expansion. Therefore, we started with commercially available dihydrotestosterone 1. In two steps tosylate 2 was obtained which was treated with an excess of ethyl Grignard reagent. The 18-methyl group shifted from position 13 to 17. A mixture of four tetrasubstituted olefins was obtained in 91% yield; compound 3 is assumed to be the major component (ca. 80%) of this mixture. In the following steps bearing an oxidative cleavage of the C-C-double bond, aldol condensation and reduction reactions D-homo-androstane 4 could be obtained as single isomer. Comparison of GC and MS data revealed a perfect match with the crude oil constituent 19C.

[1] M. Bender, M. Schmidtmann, J. Rullkötter, R. E. Summons, J. Christoffers, Eur. J. Org. Chem. 2013, 5934–5945.

Synthesis of Tetrasubstituted Furan Derivatives by Condensation of 1,3-Diketones with α-Hydroxy-β-oxo Esters

B. Schickmous, Oldenburg/D, J. Christoffers,* Oldenburg/D

Universität Oldenburg, Carl von Ossietzky-Str. 9–11, 26111 Oldenburg

Tetrasubstituted furan derivatives 3 were prepared by the condensation of cyclic α- hydroxy-β-oxo esters 1 with 1,3-diketones 2 via [b]-annulated 4-acyl-3-hydroxy-5- methylfuran-2-carboxylate intermediates using cerium chloride (CeCl3 · 7 H2O) as Lewis acid catalyst in acetic acid. The reaction of alicyclic compounds 1 with acetylacetone (2a) to furans 3a-c proceeded in three steps. First, cerium-catalysis led to a bicyclic dihydrofuran with an ester moiety. Saponification and subsequent acidification led to compounds 3a-c in up to 62% yield. Contrastingly, the reaction of compounds 1 with dibenzoylmethane (2b) to furans 3d-f ran as a domino reaction in one-pot fashion with up to 63% yield. Conversion of heterocyclic compounds 1 with acetylacetone (2a) led to furans 3g-i with yields up to 86% under ring-opening of the heterocycles in a retro-Mannich type reaction.

Cycloalkene Carbonitriles in Asymmetric Rhodium-Catalysed 1,4-Additions

W. J. Dziechciejewski, Hannover/D, M. M. K. Boysen, Hannover/D

Jun.-Prof. Dr. Mike M. K. Boysen, Leibniz University of Hannover Institute of Organic Chemistry, Schneiderberg 1B, 30167 Hannover, Germany

Asymmetric rhodium-catalysed 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds is an important method for creating one new stereocentre under carbon-carbon bond formation. [1] The reaction is well-documented for cyclic and acyclic enones as well as unsaturated lactones and acyclic enonates but examples for other electrophiles are scarce. Cycloalkenes with exocyclic acceptor substituents are potentially attractive electrophiles, as 1,4-addition to these substrates creates two new stereocentres in one step. Surprisingly there is few literature precedence for this transformation: up to now only nitrocycloalkenes [2] and pyrroline carboxylic esters [3] have been employed in enantioselective 1,4-additions.

Our group is interested in the development of new methods for asymmetric 1,4-addition reactions, [4] and we are currently expanding the scope of the reaction to new electrophiles with exocyclic electron-withdrawing groups: We successfully employed carbo- and heterocyclic unsaturated nitriles to synthesize 1,2-disubstituted addition products with two new stereocentres. The reaction yielded predominantly the cis- diastereomers, which were obtained in good yields and up to 96%ee. Basic epimeristion of the cis-diastereomer into the thermodynamically more stable trans- configured product can be achieved in high yield without erosion of the ee. Thus both diastereomers of the addition product can be obtained in nearly enantiomerically pure form.

Literature:

[1] a) T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829; b) P. Tian, H.-Q. Lin, ACS Catal. 2012, 2, 95. [2] T. Hayashi, T. Senda, M. Ogasawara, J. Am. Chem. Soc. 2000, 122, 10716. [3] K. M. Belyk, C. D. Beguin, M. Palucki, N. Grinberg, J. DaSilva, D. Askin, N. Yasuda, Tetrahedron Lett. 2004, 45, 3265. [4] a) T. Minuth, M. M. K. Boysen, Org. Lett. 2009, 11, 4212; b) H. Grugel, F. Albrecht, T. Minuth, M. M. K. Boysen, Org. Lett. 2012, 14, 3780.

Minimalistic Peptide- and Uracil-based Hydrogelators Kleinsmann, A. J. Tübingen/D; Nachtsheim, B. J. Tübingen/D Jun.-Prof. Dr. Boris J. Nachtsheim, Eberhard Karls Universität Tübingen, Institut für Organische Chemie, Auf der Morgenstelle 18, D-72076 Tübingen Supramolecular hydrogels have gained significant interest in material science due to a broad spectrum of possible biomedical applications such as tissue engineering and drug delivery.[1] Physical hydrogels, which contain only low molecular weight gelators (LMWG’s) held together by non-covalent interactions, show interesting thixotropic or “self-healing” properties, providing drug-loaded injectable gels for a directed and delayed drug delivery.[2] Here we want to present a well-chosen set of cyclic dipeptides (Diketopiperazines – DKP’s) as the lowest molecular weight hydrogelators based on proteinogenic amino acids.[3] The investigated DKP-hydrogels show remarkable viscoelastic properties including an impressive self-healing ability. The gelation process can be triggered by changing the pH-value, salt concentration or temperature.

In addition, we will demonstrate that combining different DKP’s in a blend provides control over the properties of the resulting hydrogel, such as pH-dependent mechanical stability, sol-gel transition temperature and morphology. We show a potential application of these simple hydrogels as tunable drug delivery systems for a variety of hydrophilic and lipophilic model substrates. Furthermore, N-((Uracil-5-yl)methyl)urea is reported as the lowest molecular weight hydrogelator comprising a nucleobase.[4] This rare example of an anion triggered urea-based LMWG is found to be the first example of a pyrimidine and urea-containing molecule which can be forced into self-assembly in aqueous solution without additional aromatic or lipophilic groups. Literature: [1] D. M. Ryan, B. L. Nilsson, Polym. Chem. 2012, 3, 18. [2] E. K. Johnson, D. J. Adams, P. J. Cameron, J. Mater. Chem. 2011, 21, 2024. [3] A. J. Kleinsmann, B. J. Nachtsheim, Chem. Commun. 2013, 49, 7818-7820. [4] A. J. Kleinsmann, N. M. Weckenmann, B. J. Nachtsheim, Chem. Eur. J. 2014, manuscript in revision.

Enantioselective Synthesis of D-α-(Uracil-5-yl)glycine Weckenmann, N. M., Tübingen/D; Nachtsheim, B. J., Tübingen/D Jun.-Prof. Dr. Boris J. Nachtsheim, Eberhard Karls Universität Tübingen, Institut für Organische Chemie, Auf der Morgenstelle 18, D-72076 Tübingen Non-natural α-amino acids have become important chiral building blocks for the synthesis of a variety of pharmaceuticals and in peptide chemistry.[1] Among these non- natural amino acids, nucleobase-containing derivatives, so called nucleo amino acids, are of increasing interest. Peptides thereof are characterized by good intrinsic cell- membrane permeability and form highly stable complexes with endogenous nucleobases and polynucleotides.[2] Here we want to present the first enantioselective synthesis of the novel non-natural nucleo amino acid D-α-(uracil-5-yl)glycine 2. Key steps of the synthesis include a Mannich-type reaction to 5-(hydroxymethyl)uracil, subsequent oxidation and a Bucherer-Bergs reaction to give racemic hydantoine 1 as key intermediate.

O O CO H O O (1) dynamic kinetic 2 resolution HN HN NH HN NH2 HN (2) deprotection O N O N O N H H O H key intermediate: D--(Uracil-5-yl)glycine (2) DL-Hydantoine (1) 88% ee

Dynamic kinetic resolution of DL-hydantoine 1 using a hydantoinase followed by deprotection finally gave the unnatural α-amino acid 2 in 88% ee.[3]

In addition to the synthesis of 2, we will discuss the incorporation of the corresponding Fmoc-protected derivative into a small model tripeptide, to proof the general use of this building block in solid phase peptide synthesis.

Literature: [1] a) J. Kamphuis, Chirality in Industry, Wiley & Sons Ltd. 1992. b) L. Wang, P. G. Schultz, Chem. Commun. 2002, 1. c) J. Xie, P. G. Schultz, Nat. Rev. Mol. Cell Biol. 2006, 10, 775. d) I. Kwon, S. I. Lim, Macromol. Chem. Phys. 2013, 214, 1295. e) N. Budisa, Curr. Opin. Biotechnol. 2013, 24, 591. [2] G. N. Roviello, E. Benedetti, C. Pedone, E. M. Bucci, Amino Acids 2010, 39, 45. [3] N. M. Weckenmann, B. J. Nachtsheim, 2014, manuscript in preparation.

5-cis-Substituierte Prolinamine – neue, privilegierte Liganden für hochgradig enantioselektive Henry-Reaktionen

F. Prause, Bayreuth/D, J. Kaldun, Bayreuth/D, D. Scharnagel, Bayreuth/D

Prof. Dr. Matthias Breuning, Universität Bayreuth, Universitätsstr. 30, 95447 Bayreuth

Während „normale“ Prolin-Derivate viele Anwendungen als chirale Liganden und Kata- lysatoren fanden, blieben 5-cis-substituierte Prolinamine des Typs 2 bislang noch völlig unbeachtet in der asymmetrischen Synthese. Wir haben erstmals ausgehend von L-Pyroglutaminsäure (1) effiziente Routen zu dieser interessanten Substanzklasse ent- wickelt, die eine Variation der Substituenten R1-R4 auf später Stufe erlauben. [1]

Das Potential der Prolinamine 2 wurde anhand von enantioselektiven Cu(II)-katalysier- ten Henry-Reaktionen studiert. [2] Nach Optimierung der Bedingungen konnte in Gegenwart des Diamins 2a bei der Umsetzung einer Vielzahl an aromatischen, hetero- aromatischen, vinylischen und aliphatischen Aldehyden mit Nitromethan die entspre- chenden β-Nitroalkohole in guten ≥90% Ausbeute und hervoragenden 99% ee erhalten werden. Damit ist das Prolinamin 2a allen anderen bekannten Liganden, wovon die besten derart hohe Enantiomerenüberschüsse nur mit wenigen ausgewählten Sub- straten liefern können, weit überlegen. [3]

Literatur:

[1] F. Prause, B. Arensmeyer, J. Kaldun, B. Wennemann, B. Fröhlich, D. Scharnagel, M. Breuning, Manuskript in Vorbereitung. [2] D. Scharnagel, F. Prause, J. Kaldun, R. Haase, M. Breuning, Manuskript in Vorbereitung. [3] Aktuelle Beispiele (a) A. Das, R. I. Kureshy, K. J. Prathap, M. K. Choudhary, G. V. S. Rao, N. H. Khan, S. H. R. Abdi, H. C. Bajaj, Appl. Catal. A, 2013, 459, 97; (b) T. Deng, C. Cai, J. Fluorine Chem., 2013, 156, 183; (c) R. Ćwiek, P. Niedziejko, Z. Kałuża, J. Org. Chem., 2014, 79, 1222.

The Earths Critical Zone: Understanding the Subsurface Hydro-Geo-Chemistry Using Metabolomic Profiling* N. Ueberschaar†, V.-N. Roth‡, V. Schwab-Lavric‡, G. Gleixner‡, G. Pohnert† *: Collaborative research center 1076: „AquaDiva: Understanding the Links Between Surface and Subsurface Biogeosphere“; †: Friedrich Schiller University Jena, Institute for Inorganic and Analytical Chemistry, Lessingstr. 8, 07743 Jena; ‡: Max Planck Institute for Biogeochemistry, Hans-Knoell-Str. 10, 07745 Jena The world’s freshwater resources are consisting of 69% ice. More usable for human beings is the groundwater which compose 30% of the earth’s freshwater.[1] During the last century, an extensive knowledge about the migration and transformation of environmental pollutants has been accumulated. Yet a little is known about the fate and behavior of organic substances naturally occurring in the aqueous phase of our environment. Our work aims towards the identification of biological signatures and their transformations during their passage through the Earth´s Critical Zone (CZ). We profile the naturally existing metabolic signatures and additionally deal with the transformation of specific compound classes (e.g. carbohydrates, aromatic metabolites, amino acids and organic acids) to investigate specific (a)biotic processes that determine the fate of biomarkers through the passage. We will focus on the inventory of organic molecules in the aqueous phase using a general screening approach by metabolomic profiling[2-3] and high resolution profiling of molecular structures in natural organic matter (NOM), focusing on the identification of signals and their changes due to biological processes using state of the art metabolomic software tools.[4].

Figure: General Scheme of the Hainich site and strategy for environmental mimic and sampling strategy. A: Cut through the surface of the Hainich CZ including the basic model for water flow, metabolisation and sampling. B: Environmental mimetic laboratory experiments using soil extract as input signal and isolated bacteria as biotransformants. C: Workup of aqueous samples using SPE and LCMSn experiments for chemoinformatic metabolimic analysis tools.

[1] H. Perlman, Vol. 2014, The USGS Water Science School, 2014. [2] J. Gillard, J. Frenkel, V. Devos, K. Sabbe, C. Paul, M. Rempt, D. Inze, G. Pohnert, M. Vuylsteke, W. Vyverman, Angew. Chem. Int. Ed. 2013, 52, 854-857. [3] G. M. Nylund, F. Weinberger, M. Rempt, G. Pohnert, PloS one 2011, 6, 29359. [4] R. Tautenhahn, G. J. Patti, D. Rinehart, G. Siuzdak, Anal. Chem. 2012, 84, 5035-5039.

New paths for generation of cyanoform

Madhu Chityala, 09111 Chemnitz

Prof. Dr. Klaus Banert, Technische Universität Chemnitz,

Straße der Nationen 62, 09111 Chemnitz

Cyanoform (2) is one of the strongest acids with pKa ≈ –5, and lot of efforts put forward by many people since more than a century were futile in isolation and characterisation of either cyanoform (2) or its aci-tautomer dicyanoketenimine (3).[1] Here, we tried to find the existence of either 2 or 3 by deep temperature photolysis and thermolysis of the azide 4. Azide 4 can be synthesized in three steps as reported in literature.[2] Deep temperature photolysis of azide 4, initially lead to the azirine 5 at –80 oC, and on warming to room temperature, azirine 5 is converted into the very reactive cyanoform (2) and underwent nucleophilic addition with another molecule of 5 to generate the aziridine 6. On the other hand, thermal reactions of azide 4 with epoxides (e.g., 7), azirines (e.g., 10) and aziridines (e.g., 12) produced ring extended products with push– pull[3] substituted C=C bond. The formation of the ring extended products (e.g., 9) can be explained by the reaction of the short-lived intermediate 2/3, produced from 4, with 7 through the intermediate 8. Reaction of azide 4 with α,β-unsaturated carbonyl compounds (e.g., 14) also indicate the generation of cyanoform (2).

References: [1] D. Šišak, L. B. McCusker, A. Buckl, G. Wuitschik, Y. L. Wu, W. B. Schweizer, J. D. Dunitz, Chem. Eur. J. 2010, 16, 7224–7230. [2] H. Schubert, M. Regitz, Synthesis 1982, 149–151. [3] E. Kleinpeter, S. Klod, W. D. Rudorf J. Org. Chem. 2004, 69, 4317–4329.

The C–H Activation/1,3-Diyne Strategy: Highly Selective Direct Synthesis of Diverse bis-Heterocycles via RhIII-Catalysis

T. Gensch, Münster/DE, D.-G. Yu, Münster/DE, F. de Azambuja, Münster/DE, F. Glorius, Münster/DE

Tobias Gensch, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster

Adjacent bis-heterocycles are an important structural motif in natural products and ligands for transition metals. A versatile and modular approach for the synthesis of a range of highly substituted adjacent bis-heterocycles has been developed exploiting the reactivity and selectivity of 1,3-diynes in RhodiumIII-catalyzed C–H activation, forming four strategic bonds. [1] This C–H activation/1,3-diyne strategy overcame challenges of selectivity (chemo-, regioselectivity, as well as mono-/di-annulation) and has been used in the construction of seven kinds of adjacent bis-heterocycles. Product patterns ranging from fully symmetrical bis-heterocycles to ones with different core structures and substituents are accessible through the choice of substrates.

Literature:

[1] Yu, D.-G.; de Azambuja, F.; Gensch, T.; Daniluc, C. G.; Glorius, F., Angew. Chem. Int. Ed. 2014, 10.1002/anie.201403782.

Palladium-catalyzed Synthesis of Sterically Congested Triarylamines Riedmüller, S. Tübingen/D; Nachtsheim, B. J. Tübingen/D Jun.-Prof. Dr. Boris J. Nachtsheim, Eberhard Karls Universität Tübingen, Institut für Organische Chemie, Auf der Morgenstelle 18, D-72076 Tübingen The Pd-catalyzed construction of C-N bonds from aryl halides and amines (Buchwald- Hartwig reaction) has become a powerful tool in academia[1] and industry[2] for the synthesis of triarylamines, which are important structural core motifs in a variety of pharmaceuticals and natural products. Furthermore, triarylamines are widely found as organic components in organic light emitting diodes (OLEDs).[3] Even though, the developments in this field made substantial progress, available synthetic procedures for the synthesis of sterically highly demanding triarylamines are rare. Here, we wish to present an improved Buchwald-Hartwig amination procedure that enables the generation of such highly sterically demanding tertiary amines which show an improved stability in OLED devices (a).[4]

Furthermore, we will present a novel palladium-catalyzed synthesis of N-aryl and N- alkyl-substituted carbazoles utilizing stable and easy obtainable cyclic iodonium salts as precursors (b).[5]

Literature: [1] D. S. Surry, S. L. Buchwald, Angew. Chem. 2008, 120, 6438-6461. [2] a) S. L. Buchwald, C. Mauger, G. Mignani, U. Scholz, Adv. Synth. Catal. 2006, 348, 23-39; b) B. Schlummer, U. Scholz, Adv. Synth. Catal. 2004, 346, 1599-1626. [3] Y. Shirota, J. Mater. Chem. 2000, 10, 1-25. [4] a) S. Riedmüller, O. Kaufhold, H. Spreitzer, B. J. Nachtsheim, Eur. J. Org. Chem. 2014, 1391-1394; b) O. Kaufhold, H. Spreitzer, S. Riedmüller, WO 2013/068075 A1, 2013. [5] S. Riedmüller, B. J. Nachtsheim, Beilstein J. Org. Chem. 2013, 9, 1202-1209. Dual Metal and Photoredox Catalysis

Fabry, D.C., Aachen/D, Zoller, J., Aachen/D, Raja, S., Aachen/D and Rueping, M., Aachen/D

Prof. Dr. Magnus Rueping Institute of Organic Chemistry, Landoltweg 1, 52074 Aachen.

In recent years, photoredox catalysis became a powerful tool in the field of organic synthesis. Initially emerging from transformations concerning activations of tertiary amines, alkyl halides or olefins, photoredox catalysis has spread nowadays over a broad field of different substrates, activation modes, and reaction partners.[1] As many groups could illustrate, photoredox catalysis is also highly suitable in terms of dual catalysis since the in situ, photoredox-activated substrate can be intercepted by Copper-activated alkynes,[2] Palladium-activated diazonium-[3] or iodonium salts[4] or Gold-activated olefins.[5] Ambitious to find even more applications for photoredox catalysis beyond existing reactivities, we envisioned the combination of photoredox and rhodium catalysis in C- H activations.[6]

hν

O Rh Ru O R R2 N 2 N R1 + E R R3 1 R3

21 examples 47-96% yield

Literature: [1] (a) C. K. Prier, D. A. Rankic, D. W. C. Macmillan, Chem. Rev. 2013, 113, 5322– 5363; (b) J. Hu, J. Wang, T. H. Nguyen, N. Zheng, Beilstein J. Org. Chem. 2013, 9, 1977–2001 (c) L. Shi, W. Xia, Chem. Soc. Rev. 2012, 41, 7687–7697; (d) J. M. R. Narayanam, C. R. J. Stephenson, Chem. Soc. Rev. 2010, 40, 102–113. [2] M. Rueping, R. M. Koenigs, K. Poscharny, D. C. Fabry, D. Leonori, C. Vila, Chem. Eur. J. 2012, 18, 5170–5174. [3] D. Kalyani, K. B. McMurtrey, S. R. Neufeldt, M. S. Sanford, J. Am. Chem. Soc. 2011, 133, 18566–18569. [4] S. R. Neufeldt, M. S. Sanford, Adv. Synth. Catal. 2012, 354, 3517–3522. [5] B. Sahoo, M. N. Hopkinson, F. Glorius, J. Am. Chem. Soc. 2013, 135, 5505–5508. [6] D. C. Fabry, J. Zoller, S. Raja, M. Rueping, Angew. Chem., doi: 10.1002/ange.201400560.

Alkynyliodonium Salt Mediated Alkynylation of Azlactones: Fast Access to Cα-Tetrasubstituted α-Amino Acid Derivatives Finkbeiner, P. Tübingen/D, Nachtsheim, B. J. Tübingen/D Jun.-Prof. Dr. Boris J. Nachtsheim, Eberhard Karls Universität Tübingen, Institut für Organische Chemie, Auf der Morgenstelle 18, D-72076 Tübingen Quaternary α-amino acids are important building blocks for short peptides and peptidomimetics as they are able to rigidify their three-dimensional structure and show enhanced pharmacokinetics.[1] Recent efforts towards electrophilic alkylations, benzylations, allylations and propargylations allowed the stereoselective construction of Cα-tetrasubstituted amino acids from cyclic or acyclic amino acid synthons.[2] Despite this plethora of synthetic methods, fast and reliable methods to construct quaternary β,γ- alkynyl α-amino acids are still rare, although alkyne functionalized amino acids turned out to be particularly useful for the site specific functionalization of proteins.

R3 N N R2 N 3 R1 R N3 HN CO2Me R2 Bz R2 R1 R2 I H TsO R2 Ar [H] N 1 NaOMe R1 R H 1 O Bz R Base N N CO Me Ph O O quant. 2 H HN CO2 (R2 = Ph, O Azlactone Ph ,-alkynyl Bz Me nBu, SiR3) amino acid up to 97% Ar Pd Ar-X R1

HN CO2Me Bz

Herein we want to present an operationally simple and highly effective protocol for the direct electrophilic alkynylation of azlactones (oxazol-5(4H)-ones) as nucleophilic amino acid synthons.[3] By using alkynyl(phenyl)iodonium salts as stable and nontoxic alkyne transfer reagents highly desirable β,γ-alkynylated oxazol-5(4H)-ones can be prepared in remarkably short reaction times and excellent yields of up to 97%. Moreover, the synthetic utility of these quaternary amino acids could be demonstrated by ring-opening, cycloaddition, reduction and Palladium-mediated cross-coupling.

Literature: [1] P. Maity, B. König, Peptide Sci. 2008, 90, 8. [2] V. A. Soloshonok, A. E. Sorochinsky, Synthesis 2010, 2319. [3] P. Finkbeiner, N. M. Weckenmann, B. J. Nachtsheim, Org. Lett. 2014, 16, 1326. Combined Metal and Photoredox Catalysis for the Synthesis of Indoles

Ronge, M. A., Aachen/D, Zoller, J., Aachen/D, Fabry, D.C., Aachen/D and Rueping, M., Aachen/D

Prof. Dr. Magnus Rueping

Institute of Organic Chemistry, Landoltweg 1, 52074 Aachen. The indole motif is one of the most common structural components found in many bioactive compounds and natural products. Thus, it has been the target of various methodology developments.[1] The Fujiwara-Moritani reaction represents an efficient way to accomplish the required C-H functionalization[2]. However, a major drawback is the inevitable reoxidation of the metal-H species that is formed after reductive elimination of the product. Therefore, often stoichiometric amounts of external metal- based oxidants such as copper or silver salts are required.[3] Recently, we were able to demonstrate that the catalyst regeneration in rhodium catalyzed processes can be achieved by means of photoredox catalysis [4]. Based on previous achievements in the area of CH-functionalization and light mediated transformations we have now been able to develop an intramolecular cyclization of aromatic enamides by employing a combined metal and potoredox catalyzed procedure.

hν

M PS

H N N H H

Literature: [1] G. W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075; W. Gul, M. T. Hamann, Life Sci. 2005, 78, 442–453; L. Shen, M. Zhang, Y. Wu, Y. Qin, Angew. Chem. Int. Ed. 2007, 47, 3618–3621; D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 16474–16475; T. Vlaar, E. Ruijter, R. V. A. Orru, Adv. Synth. Catal. 2011, 353, 809–841. [2] A. D. Kong, X. L. Han, X. Y. Lu, Org. Lett. 2006, 8, 1339–1342.[3] C. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem. Res. 2001; 34, 633-639; Y. Fujiwara, C. Jia, Pure Appl. Chem. 2001, 73, 319–324; N. P. Grimster, C. Gauntlett, C. R. A. Godfrey, M. J. Gaunt, Angew. Chem. Int. Ed. 2005, 117, 3185–3189; T. Nishikata, B. H. Lipshutz, Org. Lett. 2010, 12, 1972–1975; J. Wencel-Delord, T. Dröge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40, 4740–4761. [4] D. C. Fabry, J. Zoller, S. Raja, M. Rueping, Angew. Chem. 2014, doi:0.1002/ ange.201400560. Synthesis of New 1,2-Diaryl-4-methylpyrrolidines via a Hydroaminoalkylation- Hydroamination-Sequence

Preuß, T., Oldenburg/D, Doye, S., Oldenburg/D Prof. Dr. Sven Doye, Carl von Ossietzky Universität Oldenburg, Carl-von-Ossietzky-Straße 9-11, 26111 Oldenburg (Germany)

Since the discovery of the transition metal-catalyzed hydroaminoalkylation of alkenes,[1] many catalysts have been identified which favor the formation of the branched hydroaminoalkylation products and in many cases, these branched products are formed exclusively or in significantly larger amounts than the corresponding linear [2] products. Although a similar behavior was observed with the catalyst Ind2TiMe2, it is remarkable that with this catalyst, it was possible for the first time to use 1,3-butadienes as substrates.[3] We now show that the obtained 2-methylbut-3-en-1-ylanilines which still contain a C−C double bond easily undergo HI-catalyzed cyclization reactions to form 1,2-diaryl-substituted 4-methyl-pyrrolidines. These rarely described products can be of pharmaceutical interest, because simple methyl groups can multiply physiological effects of certain molecules.[4]

The reactions are performed in the presence of 10 mol-% HI at 150 °C in toluene or n- hexane under an inert atmosphere and the diastereoselectivity can be controlled by the reaction time. While the formation of the trans-product is preferred after 12 h, the cis- product represents the thermodynamic product which dominates after more than 36 h with almost unchanged overall yield. Although a variety of substituents on both phenyl rings is tolerated in this intramolecular hydroamination reaction, the efficiency of the entire two-step sequence remains limited by the restrictions of the initial hydroaminoalkylation reaction.

[1] Review: P. W. Roesky, Angew. Chem. 2009, 121, 4988-4991; Angew. Chem. Int. Ed. 2009, 48, 4892-4894. [2] R. Kubiak, I. Prochnow, S. Doye, Angew. Chem. 2010, 122, 2683-2686; Angew. Chem. Int. Ed. 2010, 49, 2626-2629. [3] T. Preuß, W. Saak, S. Doye, Chem. Eur. J. 2013, 19, 3833-3837. [4] H. Schönherr, T. Cernak, Angew. Chem. 2013, 125, 12480-12492; Angew. Chem. Int. Ed. 2013, 52, 12256-12267.

Strongly underestimated dispersion energy in supramolecular complexes G. Haberhauer*, S. Woitschetzki, Essen/GER Prof. Dr. G. Haberhauer, University of Duisburg-Essen, Universitätsstr.7, 45117 Essen

Noncovalent interactions play a pivotal role in molecular recognition. These interactions can be subdivided into hydrogen bonds, cation- interactions, ion pair interactions and London dispersion forces. The latter are considered to be weak molecular interactions and increase with the size of the interacting moieties. Here we show that even the small chloroform molecule forms a very stable complex with a modified marine cyclopeptide. By means of high-level quantum chemical calculations, the size of the dispersive interactions is calculated; the dispersion energy (approximately 40 kcal mol-1) is approximately as high as if the four outer atoms of the guest form four strong hydrogen bonds with the host.[1]

Figure 1: Molecular structures of the complexes

CHCl3∙4 (left) and CHCl3@cyclopeptide (right) was optimized using M05-2X/6-31G*,cc-pVTZ. Most hydrogen atoms are omitted for clarity.

However, these findings raised the question why the new complex of chloroform and the examined cyclopeptide shows a two orders of magnitude higher binding constants than the very similar cryptophanes by A. Collet et al.[2] Cryptophanes, composed of two bowl- shaped cyclotriveratrylene subunits linked by three aliphatic linker groups, are prototypal organic host molecules which bind reversibly neutral small guest compounds via London forces. The binding constants for these complexes are usually measured in tetrachloroethane and are in the range of 102-103 M-1. Here we show that tetrachloroethane is – in contrast to the scientific consensus – enclosed by the cryptophane-E cavity. By means of NMR spectroscopy we show that the binding constant for CHCl3@cryptophane-E is in larger solvents two orders of magnitudes higher than the one measured before. Ab initio calculations reveal that attractive dispersion energy is responsible for high binding constants and for the formation of imploded cryptophanes which seem to be more stable than cryptophanes with empty cavities.[3]

Figure 2: Molecular structures of CHCl3 (left), C2H2Cl4 (middle) and C6H4Cl2 (right) with cryptophane-E optimized using M05-2X/6-31G*,cc-pVTZ.

References: [1] G. Haberhauer, Á. Pintér, S. Woitschetzki, Nat. Commun. 2013, 4, 2945; [2] J. Gabard, A. Collet, J. Chem. Soc., Chem. Commun. 1981, 1137-1139; [3] G. Haberhauer, S. Woitschetzki, H. Bandmann, Nat. Commun. 2014, 5, 3542.

Facile Syntheses of Quinazolinone-Derivatives

S. Oschatza,b, X.-F. Wua, P. Langera,b a) Leibniz-Institut für Katalyse e.V. an der Universität Rostock, A.-Einstein-Str. 29a, 18059 Rostock, Germany b) Universität Rostock, Institut für Chemie, A.-Einstein-Str. 3a, 18059 Rostock, Germany

Quinazonlinones represent an important class of alkaloids with a range of biological activities, e.g. Methaqualone, and a crucial building block for the synthesis of natural compounds such as tryptanthrin or fumiquinazoline A[1].

Pd(OAc)2 BuPad Mo CO ( )6 O DBU r CN B DMF CN UHP + O NH

R NH2 N N R' R H R' R R'

21 Examples, 21 - 82 % 4 Examples, 25 - 76 %

O O O K3PO4 CN H O + 2 NH TBHP NH

NH2 N N R R' R H R' R R' 18 Examples, 14 - 80 % 1 Example, 60 %

Figure 1. Reaction overview to obtain quinazolinones from 2-aminobenzonitriles

In this work, new convenient and economically friendly methods to synthesize quinazolinones from 2-aminobenzonitriles are presented. A brief overview is given in Figure 1. First, we realized the 1-pot-2-step Pd-catalyzed aminocarbonylation with [2] subsequent rearrangement to obtain 2-aryl-quinazolin-4(3H)-ones, using Mo(CO)6 as alternative CO-source[3]. Furthermore, a procedure to give 2-aryl-1,2-dihydro- quinazolin-4(3H)-ones from 2-aminobenzonitriles and aldehydes has been developed[4]. The reaction uses only water as solvent and K3PO4 as base. Subsequent in-vitro transformation to obtain the oxidized quinazolin-4(3H)-ones has been established as well.

Literature:

[1] L. He, H. Li, J. Chen, X.-F. Wu, RSC Adv. 2014, 4, 12065 – 12077. [2] a) X.-F. Wu, S. Oschatz, M. Sharif, A. Flader,L. Krey, M. Beller, P. Langer, Adv. Synth. Catal. 2013, 18, 3581 – 3585. b) L. R. Odell, F. Russo, M. Larhed, Synlett, 2012, 23, 685 – 698. [3] X.-F. Wu, S. Oschatz, M. Sharif, M. Beller, P. Langer, Tetrahedron 2014, 1, 23 – 29. [4] X.-F. Wu, S. Oschatz, A. Block, A. Spannenberg, P. Langer, Org. Biomol. Chem. 2014, 12, 1865 – 1870.

Supramolecular lyotropic liquid cristalline phases as alignment media

M. Leyendecker, N.-C. Meyer, C. M. Thiele

Clemens-Schöpf Institut für Organische Chemie, Technische Universität Darmstadt, Alarich-Weiss-Str. 4, 64287 Darmstadt (Germany), Email: [email protected]

Benzene-1,3,5-tricarboxyamides (BTAs) are known to self-assembe into rod like and helical supramolecules.[1] These stiff aggregates act as mesogenes to form liquid crystalline phases. Thermotropic and lyotropic (in water) liquid crystalline behavior of BTAs have been reported.[2,3] Aggregates of achiral substituted BTAs form racemic mixtures of (M)- and (P)-helices. Introduction of enantiopure side chains leads to helices with only one handedness.[4]

Determining the conformation or relative configuration of Figure 1: Helical small organic molecules is not always accessible by mesogene formed by classic NMR-spectroscopy via ³J couplings or NOE data. If self-assembly of BTAs this is the case NMR-spectroscopy in weak orienting media gives access to residual dipolar couplings (RDCs) which offer complementary information. RDCs provide angular and distance information with respect to the external magnetic field. To achieve anisotropic conditions lyotropic liquid crystalline phases (LLCs) are used as so called alignment media. For anisotropic NMR-spectroscopy of small organic molecules the LLCs should be compatible with organic solvents and introduce only a low degree of orientation.[5] By using chiral media, the chiral information can be transferred to the analyte. Enantiomers interact differently with chiral alignment media and can therefore be differentiated.[6]

In this work several BTAs were synthesized and tested for their LLC behavior. We could show that BTAs with achiral, aliphatic side chains and asymmetrically substituted BTAs with achiral and chiral, aliphatic side chains form LLCs in organic solvents. To investigate the capability of BTA-LLCs as alignment media, analytes were added to the phases. By fitting the obtained RDCs to structure proposals, the structures of the analytes could be confirmed. This demonstrates BTA-LLCs can be used as alignment media for organic compounds.

[1] S. Cantekin, T. de Greef, A. Palmans, Chem. Soc. Rev. 2012, 41, 6125–6137. [2] Y. Matsunaga, N. Miyajima, Y. Nakayasu, Bull. Chem. Soc. Jpn. 1988, 61, 207. [3] D. Wang, Y. Huang, J. Li, Chem. Eur. J. 2013, 19, 685–690. [4] M. Smulders, A. Schenning, E. Meijer, J. Am. Chem. Soc. 2008, 130, 606-611. [5] B. Böttcher, C. M. Thiele, eMagRes 2012, 1, 169-180. [6] M. Sarfati, P. Lesot, D. Merlet, J. Courtien, Chem. Comm. 2000, 21, 2069-2081.

Studies towards the synthesis of disciformycin

M. Wolling, Hannover/DE

Prof. Dr. A. Kirschning, Leibniz University of Hannover, Schneiderberg 1B, 30167 Hannover

The glycosylated, 12-membered macrocyclic, polyketide disciformycin shows antibiotic activity against several methicillin-resistant S. aureus (MRSA) strains. However, disciformycin is also active against mammalian cells [1]. These circum- stances make this polyketide an important synthetic target for achieving the following goals:

a) The total synthesis of this natural product and the proof of its stereochemistry. b) The preparation of new derivatives with improved biological profile.

The key steps of our synthesis of disciformycin include a YAMAGUCHI esterification, an EVANS aldol reaction and a vinylogous MUKAIYAMA aldol reaction [2].

The poster will discuss the structure elucidation, the biological properties and our synthetic efforts towards disciformycin.

Literature:

[1] Unpublished results by R. Müller et. al. (Saarbrücken). [2] I. Paterson, E. A. Anderson, S. M. Dalby, J. Ho Lim, P. Maltas, O. Loiseleur, J. Genovino, C. Moessner, Org. Biomol. Chem. 2012 , 10 , 5861; M. Yamaoka, A. Nakazaki, S. Kobayashi, Tetrahedron Letters 2010 , 51 , 287-289; J. Willwacher, N. Kausch-Busies, A. Fürstner, Angew. Chem. Int. Ed. 2012 , 51 , 12041–12046; P. Wipf, S. Lim, Angew. Chem. Int. Ed. Engl. 1993 , 32 , 1068-1071.

A Three-Component [3+2]-Cycloannulation Process for the Rapid and Stereoselective Synthesis of Complex N-Heterocycles

C. Schneider, Leipzig/DE, M. Boomhoff, Leipzig/DE, R. Ukis, Leipzig/DE

Prof. Dr. Christoph Schneider, University of Leipzig, Johannisallee 29, D-04103 Leipzig

The rapid assembly of novel complex heterocycles is a highly actual research topic in terms of the diversity oriented synthesis and delivers diverse compound libraries and ideally more valuable information in biological screenings.[1] Recently, we established a novel Lewis acid-catalyzed, stepwise [3+2]-cycloannulation process of bis- silyldienediolate 1, aldehydes, and 2-aminophenols which furnished tetrahydropyrrolo[2,1-b]benzoxazoles directly and with excellent diastereoselectivity.[2] In this process 1 adds to the in situ generated imine in a vinylogous Mannich reaction to generate an intermediate silyl enol ether which is hydrolyzed into the corresponding -keto ester which then spontaneously cyclizes into the final benzoxazole.

We have now expanded the scope of this reaction to include amines containing different nucleophilic elements in their scaffolds, namely anthranilic acid and anthranilic amide derivatives. Using these modified substrates novel highly interesting heterocyclic scaffolds like pyrrolobenzoxazinones 2 and pyrroloquinazolinones 3 were accessible.

An adjusted procedure was developed using Sm(OTf)3 as Lewis acid catalyst in the initial vinylogous Mannich reaction and the Brønsted acid DNBSA to hydrolyze the silyl enol ether and to obtain the heterocyclic products in very good yields and selectivities, respectively. The substrate scope was very broad in both cases tolerating various substitutents in the aldehyde and amino components, respectively, and leading to more than 30 different products. Hence, this methodology provides a wide range of complex heterocyclic structures starting from simple precursors and forms four new -bonds and two chiral centers in a single process.

Literature: [1] for example, see: a) S. L. Schreiber, Science 2000, 287, 1964; b) M. D. Burke, S. L. Schreiber, Angew. Chem. Int. Ed. 2004, 43, 46; c) S. L. Schreiber, Nature 2009, 457, 153. [2] M. Boomhoff, C. Schneider, Chem. Eur. J. 2012, 18, 4185. The Brønsted-Acid-Catalyzed, Enantioselective Aza-Diels-Alder Reaction for the Direct Synthesis of Chiral Piperidones

C. Schneider, Leipzig/DE, C. Weilbeer, Leipzig/DE Prof. Dr. Christoph Schneider, University of Leipzig, Johannisallee 29, 04301 Leipzig

Asymmetric hetero-Diels-Alder reactions are one of the most direct and powerful methods towards the synthesis of enantiomerically pure oxygen and nitrogen heterocycles.[1] Specifically, the aza-Diels-Alder reaction of electronrich dienes and imines has become a valuable synthetic tool to furnish important precursors for the synthesis of nitrogen-containing heterocycles, in particular alkaloids.[2] In previous studies we have shown that chiral phosphoric acids can effectively catalyze vinylogous Mannich reactions of acyclic silyl dienolates furnishing δ-amino-α,β- unsaturated carboxylic esters with excellent regio-, enantio-, and diastereoselectivities.[3] We have discovered that the typical Mannich reaction pathway can be largely turned into a cycloaddition if the vinylketene silyl acetale 3 is substituted with a β-alkyl group. The 2-piperidones 4 were formed in high yields and typically good to excellent enantioselectivities. The Mannich products were obtained only in minor amounts additionally.

PMP

NH2 O 2 O 2 R OTBS 5 mol% cat. 5 PMP O O N + 2 vinylogous P + O OH R1 H Mannich Products OEt up to 82% 2 R1 R 1 3 up to >99% ee 4

1 2 R =Ar, Het-Ar, Alkyl R = Me, Et, nBu cat. 5

The 2-piperidones were further converted into more highly substituted piperidines. Hydrogenation of the unsaturated piperidone 6 furnished the corresponding lactam in excellent yield and diastereoselectivity. For the synthesis of 2,4,6-trisubstituted piperidines 8 a cerium(III)-chloride mediated addition of Grignard reagents (pathway a) to the lactam moiety was used. 3,4,6-trisubstituted piperidones 9 were synthesized by enolate alkylation (pathway b) in good yields and as single trans-stereoisomers. R2

PMP 2 N R = Et, Pr, Hex up to 74% a) Me O O 8 PMP Hydrogenation PMP Et N N O 95%, d.r. > 25:1 Me Me PMP R3 b) N R3 = Me, Et, Bn Et 6 Et 7 up to 89% Me

Et 9 [1] L. F. Tietze, Tropics in Current Chemistry 1997, 189, 1; H. Waldmann, Synthesis 1993, 6, 535; [2] A. Whiting, Advanced Asymmetric Synthesis 1996, 126; G. Dagousset, M. Benohoud, C. Lalli, G. Masson, Chem. Soc. Rev. 2013, 42, 902;[3] M. Sickert, C. Schneider, Angew. Chem. 2008, 120, 3687; Angew. Chem. Int. Ed. 2008, 120, 3631; D. S. Giera, M. Sickert, C. Schneider, Org. Lett. 2008, 10, 4259; M. Sickert, F. Abels, M. Lang, J. Sieler, C. Birkemeyer, C. Schneider, Chem. Eur. J. 2010, 16, 2806; F. Abels, C. Schneider, Synthesis 2011, 4050; F. Abels, C. Lindemann, E. Koch, C. Schneider, Org. Lett. 2012, 14, 5972.

A General Strategy for the Catalytic, Highly Enantio- and Diastereoselective Synthesis of Indolizidine-based Alkaloids

C. Schneider, Leipzig/DE, C. Lindemann, Leipzig/DE, F. Abels, Leipzig/DE Prof. Dr. Christoph Schneider, University of Leipzig, Johannisallee 29, D-04103 Leipzig

Indolizidine-based alkaloids (IBAs) are important core structures in several natural products and are commonly found in skin glands of poison frogs. Some of them display interesting biological activities, especially by blocking nicotinic receptors.[1] We have developed a novel route to synthesize these IBAs in a highly flexible and stereoselective manner. The key step of this procedure was a three-component, organocatalytic vinylogous Mukaiyama-Mannich reaction to provide butyrolactams in high diastereo- and enantioselectivities.[2]

The butyrolactams were subsequently converted within few steps into the corresponding substituted indolizidinones. Organometallic addition then delivered the 5-substituents with full stereochemical control from the substrate. Other IBAs could be obtained after methylation in the 6-position or by synthesis of the ,-unsaturated lactam. By using this synthetic strategy we were able to obtain 13 indolizidine-based natural products.[3]

[1] J. W. Daly, T. F. Spande, H. M. Garraffo, J. Nat. Prod. 2005, 68, 1556-1575; [2] M. Sickert, C. Schneider, Angew. Chem. Int. Ed. 2008, 47, 3631-3634; M. Sickert, F. Abels, M. Lang, J. Sieler, C. Birkemeyer, C. Schneider, Chem. Eur. J. 2010, 16, 2806-2818; F. Abels, C. Schneider, Synthesis 2011, 24, 4050-4058; [3] F. Abels, C. Lindemann, E. Koch, C. Schneider, Org. Lett. 2012, 14, 5972-5975; F. Abels, C. Lindemann, C. Schneider, Chem. Eur. J. 2014, 20, 1964-1979.

The Rapid, Modular and Stereoselective Synthesis of Pyrroloquinolines

C. Schneider, Leipzig/DE, J. Appun, Leipzig/DE, M. Boomhoff, Leipzig/DE, A. K. Yadav, Leipzig/DE

Prof. Dr. Christoph Schneider, University of Leipzig, Johannisallee 29, D-04103 Leipzig

The rapid assembly of complex and diverse molecules is one of the fundamentals for constant progress in medicinal chemistry and chemical biology.[1] In this context our group developed a novel 1,2-dinucleophile [2] which sequentially engages two imines in a double Mannich-Friedel-Crafts cyclization process to generate complex hexahydropyrrolo[3,2-c]quinolines in a one-pot operation. This methodology provides a rapid, highly modular and flexible access toward a wide range of products and forms up to six new σ-bonds and four chiral centers.

In more than 50 examples including aromatic, heteroaromatic and aliphatic imines this process has been shown to be extremely broad in scope. Furthermore, this methodology provides single diastereomers in preparatively useful amounts upon chromatographic purification. The diastereoselectivity may even be inverted by adjustment of the reaction conditions and the nature of the imines.

Literature: [1] E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew. Chem. 2011, 123, 6358– 6371. S. L. Schreiber, Nature 2009, 457, 153–154. [2] M. Boomhoff, C. Schneider, Chem. Eur. J. 2012, 18, 4185–4189.

Brønsted Acid-Catalyzed, Conjugate Addition of β-Dicarbonyls toward in situ Generated Ortho-Quinomethides - Enantioselective Synthesis of 4-Aryl-4H- Chromenes C. Schneider, Leipzig/DE, O. El-Sepelgy, Leipzig/DE, S. Haseloff, Leipzig/DE, S. Kumar Alamsetti, Leipzig/DE Prof. Dr. Christoph Schneider, Institut für Organische Chemie, Universität Leipzig

Johannisallee 29, 04103 Leipzig (Germany)

Ortho-quinomethides represent highly reactive intermediates in organic chemistry and have been employed in particular toward the synthesis of chromanes which belongs to the privileged classes in the field of natural products as well as in the area of pharmacologically active compounds.[1] Most of the previous synthetic strategies for the assembly of 4H-chromenes lead to racemic products[2] and only very few enantioselective protocols have been developed which were limited in scope.[3] We describe herein the first Brønsted acid-catalyzed, highly enantioselective, conjugate addition of β-dicarbonyls toward in situ generated ortho-quinomethides furnishing upon dehydrative cyclization 4-aryl-4H-chromenes in excellent yields and enantioselectivities.[4]

We employed ortho-hydroxybenzhydryl alcohols 1 as precursors which upon treatment with the chiral phosphoric acid gave rise to hydrogen-bonded ortho-quinomethides. Those were reacted with acylic 2 as well as cyclic β-dicarbonyls 5 to furnish the desired 4-aryl-4H-chromenes 3 and 6. [1] E. E. Schweizer, O. Meeder-Nycz in Chromenes, Chromanes, Chromones (Ed. G. P. Ellis), Wiley-Interscience, New York, 1977; [2] Review: H. C. Shen, Tetrahedron 2009, 65, 3931-3952; [3] T. Nishikata, Y. Yamamoto, N. Miyaura, Adv. Synth. Cat. 2007, 349, 1759-1764. [4] O. El-Selpelgy, S. Haseloff, S. K. Alamsetti, C. Schneider, Angew. Chem. 2014, 126, in press.

Synthesis of Marine Natural Product Derivatives for Photoaffinity Labeling

Jan Hendrik Lang, Braunschweig/D, Thomas Lindel, Braunschweig/D

Jan Hendrik Lang, M. Sc., TU Braunschweig, Institute of Organic Chemistry, Hagenring 30, 38106 Braunschweig

Marine natural products are interesting for academia and industry. Many of these molecules possess significant bioactivities and currently, seven compounds are in clinical use.[1] Our research focuses on synthesizing natural product derivatives with a photo- reactive group which may be used for photoaffinity labeling (PAL) experiments. In PAL, the photoanalog is mixed with its target protein and, after UV irradiation, generates a reactive species which binds covalently. Purification and analysis of the protein-photoanalog complex can lead to valuable insights into structure-activity relationships (SAR).[2]

Jasplakinolide A (1) has been thoroughly studied due to its cytotoxicity in the low nano- molar range as well as high bioactivities against various organisms.[3] Seragamide A and pipestelide A are two recently discovered molecules of the “jasplakinolide class”, each being a cyclic depsipeptide consisting of tripeptide and tetraketide sections.[4,5] We aim at synthesizing these compounds and photo-derivatives e. g. with a diazirine group and conduct PAL experiments with the target protein actin. A similar approach is pursued for hemiasterlin (2), a marine tripeptide with a unique tetramethylated tryptophan moiety.[6]

[1] W. H. Gerwick, B. S. Moore, Chem. Biol. 2012, 19, 85-98. [2] L. Dubinsky, B. P. Krom, M. M. Meijler, Bioorg. Med. Chem. 2012, 20, 554-570. [3] T. M. Zabriskie, J. A. Klocke, C. M. Ireland, A. H. Marcus, T. F. Molinski, D. J. Faulkner, C. Xu, J. C. Clardy, JACS 1986, 108, 3124-3125. [4] C. Tanaka, J. Tanaka, R. F. Bolland, G. Marriott, T. Higa, Tetrahedron 2006, 62, 3536-3542. [5] Sorres, M.-T. Martin, S. Petek, H. Levaique, T. Cresteil, S. Ramos, O. Thoison, C. Debitus, A. Al-Mourabit, J. Nat. Prod. 2012, 75, 759- 763. [6] R. Talpir, Y. Benayahu, Y. Kashman, Tetrahedron Lett. 1994, 35, 4453-4456.

Towards embedding diazirines into terpenes

Tina Bohlmann, Braunschweig/D, Thomas Lindel, Braunschweig/D

Tina Bohlmann, M. Sc., TU Braunschweig, Institute of Organic Chemistry, Hagenring 30, 38106 Braunschweig

Functionalizing biologically active compounds with photoactivatable units has, in principle, been established since 1969.[1,2] Several photoactivatable groups have been described and primarily used in organic synthesis. They differ in size, chemical properties, photolability and form different reactive species upon irradiation, e. g., nitrenes, radicals, or carbenes. Photoaffinity labeling (PAL) aims at identifying a target enzyme of a bioactive natural product. However, with regard to terpenes only a few examples for PAL have been published. Distefano et al. have synthesized farnesyl pyrophosphates, which are labeled by azides 1[3] or diphenyl ketones 2[4] for detecting the corresponding target enzymes. Until now there is no example of diazirine-functionalized terpenes.

We try to synthesize farnesyl-based photoactivatable terpenes 3 by installing diazirine units, which would have the advantage of moderate size. Ideally, these compounds would be convertible into photolabeled complex terpenoids by enzymatic cyclization.

[1] C. A. Converse, F. F. Richards, Biochemistry 1969, 8, 11, 4431-4436. [2] G. W. Fleet, R. R. Porter, J. R. Knowles, Nature 1969, 224, 5218, 511-512. [3] A. J. DeGraw, C. Palsuledesai, J. D. Ochocki, J. K. Dozier, S. Lenevich, M. Rashidian, M. D. Distefano, Chem. Biol. Drug. Des. 2010, 76, 460-471. [4] O. Henry, F. Lopez- Gallego, S. A. Agger, C. Schmidt-Dannert, S. Sen, D. Shintani, K. Cornish, M. D. Distefano, Bioorg. Med. Chem. 2009, 17, 13, 4797-4805.

Concise, Stereodivergent and highly Stereoselective Synthesis of cis- and trans 2- substituted 3-Piperidinols - Development of a Phosphite-driven Cyclodehydration

P. H. Huy,1* J. Westphal,2 A. M. P. Koskinen3*

1. Saarland University, Organic Chemistry, Mailbox 151150, D-66041 Saarbrücken; 2. University of Cologne, Department of Chemistry, Organic Chemistry, Greinstrasse 4, D-50939 Cologne; 3. Aalto University, School of Chemical Technology, Laboratory of Organic Chemistry, Kemistintie 1, Fi-00076 Espoo. *Email: Ari M. P. Koskinen - [email protected]; Peter H. Huy - [email protected]

The 2-substitued 3-hydroxy piperidine scaffold of the general structure B (as a type of an 1,2- amino alcohol A) can be found in numerous natural products and other bioactive compounds.[1] Selected examples are the non-peptidic human neurokinin-1 (NK1) substance P receptor antagonist L-733,060, 3-hydroxy pipecolic acids, which serve as (conformationally restricted) substitutes of proline and serine and have been incorporated into diverse bioactive peptidomimetics, and the iminosugar swainsonine, which is a new potential chemotherapeutic agent.

In this context, a concise (5-6 steps), stereodivergent, highly diastereoselective (dr up to >19:1 for both stereoisomers) and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3- piperidinols 3 was developed.[2] This sequence allowed the efficient synthesis of the NK-1 inhibitor L-733,060 in 8 steps. Additionally, a cyclodehydration (2cis-3) realizing simple triethyl phosphite as a substitute for triphenyl phosphine was established. Here the stoichiometric oxidized P(V)-byproduct (triethyl phosphate) is easily removed during the work up through saponification overcoming separation difficulties usually associated to triphenyl phosphine oxide.

Literature [1] Selected reviews: (a) Karjalainen, O. K.; Koskinen, A. M. P. Org. Biomol. Chem. 2012, 10, 4311– 4326. (b) Wijdeven, M. A.; Willemsen, J.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2010, 2831–2844. [2] (a) P. H. Huy, A. M. P. Koskinen, Org. Lett. 2013, 15, 5178-5181; (b) P. H. Huy, J. Westphal, A. M. P. Koskinen, Beilstein J. Org. Chem. 2014, 10, 369-383.

Unsymmetrical Bodipy-Porphyrazine Conjugates with Panchromatic Light Harvesting and Tripodal Surface Anchoring Groups

Engelhardt, V., Kassel/D, Faust, R., Kassel/D

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

Phthalocyanines - or more general porphyrazines - have great potential for the effective use in dye-sensitized solar cells (DSSC) due to their high molar absorption coefficients, controllable redox potentials and semiconducting properties.[1] Nevertheless the use of porphyrazines in technical DSSCs is still limited by low efficiencies. Phthalocyanines with good solubility and little aggregation tendencies are continuously being developed to overcome these limitations.[2] In particular, unsymmetrically substituted phthalocyanines with electronic push-pull character are promising candidates.[2]

In an effort to close the typical optical gap between the B- and the Q-band absorptions of the porphyrazines, we previously reported the preparation of porphyrazines that are peripherally substituted by eight complementary absorbing BODIPYs. In addition to the almost panchromatic absorption profile of these hybrids, the chromophores feature a donor-bridge-acceptor structure with pronounced light-induced energy transfer properties.[3] In continuation of this work we have now developed an unsymmetrical porphyrazine with peripheral BODIPYs and two tripodal anchoring groups for the covalent attachment to semiconductor surfaces. At the centre of the synthesis lies a porphyrazine that allows for the unsymmetrical functionalization of the prefabricated core via Pd-catalyzed CC-cross coupling reactions. Synthesis, photophysical properties and surface binding modes will be discussed.

F F F R' R' F Light harvesting antenna B N N B N N

R' R' Br Br R' R R OH OH F N R R OH 1. F B OH N N OH N R N N OH R Br I N N R' N N N N N N N N Semiconductor N Zn N N Zn N N N N N N binding site N N N N N Br I R' R' R R F N N OH N N N 2. B F N F B OH N F N R R OH R R R' Br Br R'

R' R' N N B N N B F R' R' F Literature: F F

[1] M. Grätzel, J. Photochem. Photobiol. 2003, 4, 145. [2] (a) I. Radivojevic, A. Varotto, C. Farley, C. M. Drain, Energy Environ. Sci. 2010, 3, 1897; (b) M. V. Martinez-Diaz, G. de la Torre, T. Torres, Chem. Commun. 2010, 46, 7090; (c) M. G. Walter, A. B. Rudine, C. C. Wamser, J. Porphyrins Phthalocyanines 2010, 14, 759. [3] Y. Rio, W. Seitz, A. Gouloumis, P. Vázquez, Jonathan L. Sessler, Dirk M. Guldi, T. Torres, Chem. Eur. J. 2010, 16, 1929. Controlling Binding Site Geometries to Oxidic Nanoparticles with Polyphenyl-Substituted Porphyrazines

R. Münnich, Kassel/D, A. Winzenburg, Kassel/D, R. Faust, Kassel/D

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

Organic/inorganic hybrid materials derived from porphyrazines (Pz) and oxidic semi- conductors like TiO2 are of interest for a broad range of applications, among them solar energy conversion and photocatalysis.[1-2] The functionality and efficiency of these hybrid materials are intimately coupled to the relative binding geometry between Pz and the oxide surface and hence a definite control over the parameters governing the interaction is of general interest. We have shown recently that peripheral poly- phenylation of dibenzoquinoxalino-Pz is a conceivable way for shielding the photo- physically active core from environmental impact.[3] We are now developing this concept further and introduce anchoring groups to oxidic nanoparticles in a regio- specific manner around the dendritic polyphenyl shell embedding the Pz. With regiochemical variations of the anchoring group positions we will be able to control the relative binding angle and the distance between the Pz core and the oxide surface. Synthetically, this project develops along two independent routes. One route delivers a functionalized Pz with regiochemically constrained anchoring groups on all four quandrants of the Pz. A second one will lead to unsymmetrically functionalized [3+1]-Pz featuring only one quadrant with substituents enabling Pz-attachment to oxidic surfaces. Shown below are representative target structures highlighting our concept. We will discuss details of their syntheses along with preliminary photophysical properties of the Pz derivatives.

HO OH HO OH HO OH

HO OH OH HO OH OH HO OH OH

NN NN

N N N N N N N N N N N Zn N N Zn N N N N N N N N N N N

NN NN

HO OH OH HO OH OH HO OH OH

- Anchoring Groups HO OH HO OH OH OH - Dibenzoquinoxalino-Pz Core Literature: - Polyphenyl Shell

[1] M. K. Nazeeruddin, R. Humphry-Baker, M. Grätzel, D. Wohrle, G. Schnurpfeil, G. Schneider, A. Hirth, N. Trombach, J. Porphyrins and Phthalocyanines 1999, 3, 230. [2] A. E. H. Machado, M. D. França, V. Velani, G. A. Magnino, H. M. M. Velani, F. S. Freitas, P. S. M. Jr., C. Sattler, M. Schmücker, Int. J. Photoenergy 2008, 2008, 12. [3] P. Löser, A. Winzenburg, R. Faust, Chem. Commun. 2013, 49, 9413.

A new approach of chiral catalysts for asymmetric reactions G. Haberhauer*, C. Füten, Essen/GER Prof. Dr. G. Haberhauer, University of Duisburg-Essen, Universitätsstr.7, 45117 Essen

Catalysts are essential compounds in various chemical reactions. There is a wide variety of catalysts, which can solve different kind of problems. The use of catalysts often leads to higher yields or enables a reaction for the first time. In the last couple of years asymmetric catalysts became a more interesting research area. For some applications a specific chirality of a molecule is a key problem. In that case an asymmetric catalyst can play a pivotal role. There are many examples like BINOL [1] systems or chiral BrØnsted acids, which show good results in certain reactions.

Here we describe a catalytic system which consists of an achiral unit and a C2- symmetric cyclic peptide scaffold (Figure 1). The achiral unit consists of the catalytic active part and two variable aromatic rests. The cyclic peptide scaffold (based on amino acids and heterocyclic compounds) contains the chiral information and predetermines the chirality of the previously achiral unit. This delivers a novel chiral catalyst system for enantioselective synthesis.

Figure 1: A shows the well-known (R)-BINOL and B an example of the newly designed asymmetric catalysts.

With one synthetic step the two hydroxy groups can be modified into a phosphoric acid or phosphoramidate. Additional they can be used as ligands for metal catalyzed asymmetric synthesis.[2] This leads to a wide variety of possible reactions for this designable catalytic system.

References: [1] M. Terada, Chem. Commun. 2008, 4097-4112; [2] F. Zhou, J. Guo, J. Liu, K. Ding, S. Yu, Q. Cai, J. Am. Chem. Soc. 2012, 134, 14326-14329.

Hypervalent Iodine Mediated Oxidative Nitration of Electron Deficient Arenes

Kloeckner, U., Tübingen/D, Nachtsheim, B. J., Tübingen/D

Jun.-Prof. Dr. Boris J. Nachtsheim, Eberhard Karls Universität Tübingen, Institut für Organische Chemie, Auf der Morgenstelle 18, D-72076 Tübingen

Nitroarenes are versatile structural motifs due to their importance as precursors for the synthesis of pharmaceuticals, dyes, explosives, plastics and other industrial products.[1] The classical nitration method requires harsh and strong acidic reaction conditions such as concentrated nitric acid or a mixture of nitric acid and sulphuric acid.[2] As an alternative, oxidative radical nitrations evolved using tert-butyl nitrite (TBN) as nitrating reagent.[3] However, despite its versatility, TBN is potential hazardous due to its known highly exothermic decomposition at elevated temperatures.

Here we want to present a novel oxidative and acid-free method for the nitration of N- arylsulphonamides under very mild reaction conditions. By using a combination of sodium nitrite as a cheap and easy to handle nitro-source and the hypervalent iodine reagent (Bis(trifluoroacetoxy)iodo)benzene (PIFA) as a stoichiometric oxidant, the desired mononitrated aryl sulphonamides were isolated in up to 87% yield. Furthermore, dinitration can be easily achieved by increasing the stoichiometery of the oxidant and the nitrite salt.

F3C O O CF3 HN Ms 1.2 eq PIFA HN Ms I 1.2 eq NaNO2 O O R R NO2 MeCN, rt up to 87% PIFA

· mild reaction conditions · acid-free · high functional group tolerance

To the best of our knowledge, this is the first example of a hypervalent iodine mediated oxidative nitration of aromatic compounds.[4] Beside an intensive discussion of the substrate scope, further studies for a deeper understanding of the underlying reaction mechanism will be presented.

Literature: [1] N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, 2001 [2] R. M. a. S. C. N. G. A. Olah, in Nitration Metthods and Mechanisms, VCH Publishing, 2002. [3] (a) S. Manna, S. Jana, T. Saboo, A. Maji, D. Maiti, Chem. Commun. 2013, 49, 5286-5288. (b) S. Maity, T. Naveen, U. Sharma, D. Maiti, Org. Lett. 2013, 15, 3384-3387. (c) B. Kilpatrick, M. Heller, S. Arns, Chem. Commun. 2013, 49, 514- 516. [4] U. Kloeckner, B. J. Nachtsheim, manuscript in preparation.

Organocatalytic Route to Arylidene & Alkylidene Succinates

M.-L. Schirmer, Rostock/DE, S. Adomeit, Rostock/DE, M. Hoffmann, Rostock/DE, T. Werner*, Rostock/DE

Dr. Thomas Werner, Rostock/DE, Leibniz-Institut für Katalyse e.V., Albert-Einstein-Str. 29a, 18059 Rostock

Arylidene and alkylidene succinates contain a double bond as well as two carboxylic acid ester groups. Due to this functionality they are important building blocks and precursors in natural and pharmaceutical product synthesis.[1] One possibility for their preparation is the Heck reaction of an aryl halide and an itaconate (method A).[2] Another common method is the transformation of an aldehyde with dimethyl maleate (method B) [1a, 3] or maleic anhydride (method C) [3b] in the presence of stoichiometric amounts of phosphines. The conversion with dimethyl succinat is also described (method D).[4] Therefor a two-step sequence including a Stobbe condensation followed by re-esterification is necessary.

The existing synthetic routes are connected with drawbacks such as the utilization of expensive transition metal catalysts, stoichiometric amounts of phosphine reagents, strongly basic conditions or subsequent reaction steps. We developed an alternative organocatalytic and base free route. The conversion of benzaldehyde and diethyl maleate was employed as a model system. An inexpensive and commercial available phosphine served as catalyst and a silane as suitable reducing agent. The synthesis of about 20 derivatives in up to 95% yield with a high E selectivity as well as a feasible mechanism will be presented.

Literatur:

[1] (a) V. Bilenko, H. Jiao, A. Spannenberg, C. Fischer, H. Reinke, J. Kösters, I. Komarov, A. Börner, Eur. J. Org. Chem. 2007, 5, 758–767; (b) U. A. Kshirsagar, N. P. Argade, Synthesis 2011, 1804–1808. [2] L. Botella, C. Nájera, J. Org. Chem. 2005, 70, 4360–4369. [3] (a) S. W. McCombie, C. A. Luchaco, Tetrahedron Lett. 1997, 38, 5775–5776; (b) H. Jiang, W. Wang, W. Liu, C. Qiao, Chin. J. Chem. 2010, 28, 263–268. [4] J. M. Miguel del Corral, M. Gordaliza, M. A. Castro, M. A. Salinero, J. M. Dorado, A. S. Feliciano, Synthesis 2000, 154–164.

Peripherally fluorinated Porphyrazines for modification of photocatalytically active TiO2-nanoparticles

P. Löser, Kassel/DE, R. Faust, Kassel/DE

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

Photocatalysis based on UV-active titanium dioxide (TiO2) is a promising technique for passive air purification. After UV-excitation the semiconductor TiO2 generates reactive - oxygen species like •O2 and •OH which decompose organic and inorganic material oxi- datively.[1] However, in areas of low UV-exposure (interior spaces, north facades) photocatalysis based on pure TiO2 is ineffective. In order to address this problem, efforts [2] have been made to modify TiO2 with organic antenna dyes. Porphyrazines (Pz) are particularly attractive in this regard because of their high intensity absorptions in the 1 [3] visible and their ability to generate singlet oxygen ( O2) when irradiated with red light. In principle, therefore, hybrid materials based on TiO2 and Pz should function by what we call dual pathway photocatalysis using light from the UV to the red end of the visible. A point of concern in the design of TiO2/dye-hybrids is the fact that the photocatalytically generated oxygen-species may impact the lifetimes of the Pz molecules on the titania surface.[2] We have therefore designed an unsymmetrical [3+1]-Zn-Pz in which three quadrants bear pentafluorophenyl-substituents to enhance the stability towards autophotooxida- tion. The fourth quadrant features two anchoring groups ensuring an orthogonal bond- ing to the TiO2-surface. We present here the synthesis of the fluorinated [3+1]-Pz as well as the preparation of an unfluorinated model compound. First results with respect to the photophysical and photocatalytic properties of the Pz as well as their resistance towards photooxidation will be discussed.

REFERENCES [1] a) M. Kaneko, I. Okura, Photocatalysis: science and technology, Springer, Berlin, 2002; b) M. R. Hoffmann, S. T. Martin, W. Choi, D. W. Bahnemann, Chem. Rev. 1995, 95, 69. [2] D. Chatterjee, S. Dasgupta, J. Photochem. Photobiol. C: Photochem. Rev. 2005, 6, 186. [3] M. C. DeRosa, R. J. Crutchley, Coord. Chem. Rev. 2002, 233-234, 351.

π-Conjugated Rigid Rods with Pendant Diazafluorene Binding Sites J.-U. Holzhauer, Kassel/DE, R. Faust, Kassel/DE

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

Highly conjugated architectures with metal binding sites are of great interest at the interface between synthetic and physical organic chemistry. In this context, the photoinduced interactions between metal fragments and acetylenic macrocycles[1] open a wide field of possible applications such as molecular wires[2], storage devices[3] or photo- chemically active compounds for artificial photosynthesis[4].

1 n=1 2 n=2 N N N N Our ongoing research on the development of new motives for molecular wires focuses on π-conjugated architectures such as dehydroannulenes with pendant diazafluorene units as metal-binding sites. The target structures 1 and 2 with different bridge-length between two dehydroannulene fragments serve as model compounds for photoswitchable organic wires. This design allows photoinduced charge transfer from coordinated metal fragments to the conjugated π-system. We will present the realisation of such structures starting with the synthesis of precursors 3 and 4.

TMS TMS

R R

TMS 3 n=1 TMS R= C(p-Tol) 4 n=2 3 Literature:

[1] M. M. Haley, Chem. Rev. 2006, 106, 5344-5386. [2] S.-X. Liu, Y. Fu, T. Wandlowski, J. Am. Chem. Soc. 2012, 134, 19425-19431. [3] J. S. Lindsey, D. F. Bocian, Acc. Chem. Res. 2011, 44, 638-650. [4] J.-C. Chambron, J.-P. Sauvage, J. Chem. Soc., Perkin Trans. 1 2002, 1226-1231.

An Unexpected Ring Expansion via [1,4]-Sigmatropic Rearrangement of Nitrile Stabilized Ammonium Ylides. Synthesis of Dibenzo[c,f]azonines.

Orejarena-Pacheco, J. C., Mainz/D, Opatz, T.*, Mainz/D Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, D-55128 Mainz, Germany

Dibenzo[c,f]azonines represent a poorly investigated class of nine-membered N- heterocycles, which possess a promising potential as CNS stimulants, anti- inflammatory drugs and modulators of NO synthase.1-3 Herein, we report a novel and broadly applicable method for the preparation of 6,7,8,13-tetrahydro-5H- dibenzo[c,f]azonines starting from 1,2,3,4-tetrahydroisoquinolines.4,5 To the best of our knowledge, this represents the first direct ring expansion of ammonium ylides via [1,4]- sigmatropic rearrangement as well as the first efficient protocol for the preparation of dibenzo[c,f]azonines from simple starting materials.6

-Aminonitriles 3 were readily available via Knoevenagel-Bucherer-type Strecker reaction of aldehydes 2 and 1,2,3,4-tetrahydroisoquinolines 1. Quaternization with alkyl triflates affords the respective 1,2,3,4-tetrahydroisoquinolinium salts 4. Deprotonation of these salts leads to the corresponding nitrile stabilized ammonium ylides, which undergo [1,4]-sigmatropic rearrangement at ambient temperature furnishing 6-alkyl- 6,7,8,13-tetrahydro-5H-dibenzo[c,f]azonine-5-carbonitriles 5.

References: [1] Houlihan, W. J.; Manning, R. E. US Patent 3642777A. 1970. [2] Houlihan, W. J.; Manning, R. E. US Patent 3498988A. 1972. [3] Nallet, J. P.; Megard, A. L.; Dreux, J. FR Patent 2745812A1. 1997. [4] Orejarena Pacheco, J. C.; Opatz, T. J. Org. Chem. 2014. Accepted manuscript, DOI: 10.1021/jo500749x. [5] Lahm, G.; Orejarena Pacheco, J. C.; Opatz, T. Synlett. 2014. Under Review. [6] Jonczyk, A.; Lipiak, D. J. Org. Chem. 1991, 56, 6933.

A Formal Total Synthesis of (–)-Morphine from an ɑ-Aminonitrile

Geffe M., Mainz/D, Opatz T.*, Mainz/D Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, D-55128 Mainz, Germany

Morphine, the major constituent of the opium poppy latex, has been used for medical purposes as early as in 3000 B.C. by the Sumerians in Mesopotamia.[1] Even today it is still one of the most common and most effective analgesic drug and showed a strong influence on mankind, both in a positive and negative sense. Even 60 years after the first total synthesis by Gates there is still a continuing interest in the academic community to devise new routes which lead to an enantiopure product and are suitable for large-scale production. Although many asymmetric approaches have been reported, only the Rice synthesis of the racemic material fulfills the last criteria to an acceptable extent.[2] Here, we report on a catalytic asymmetric synthesis of the morphinan skeleton from a deprotonated ɑ-aminonitrile.

The deprotonation of 1 under controlled conditions furnishes a stabilized ɑ-aminocarbanion which is C-alkylated by 2 to yield a 1-benzyl 3,4-dihydroisoquinoline after spontaneous dehydrocyanation. Asymmetric reduction of the imine by Noyori´s transfer hydrogenation gives the desired (R)-configurated compound 3 in up to 95% enantiomeric excess.[3] Along the lines of the Beyerman route,[4] this material can converted to morphinan 4 by methoxycabonylation, Birch reduction and Grewe cyclization. Closure of the ether-bridge, removal of the remaining phenol by a triflylation/detriflylation sequence and simultaneously reduction of the ketone and the carbamate furnishes dihydrocodeine 5 which completes the formal total synthesis of (–)-morphine.

References: [1] Zezula, J., Hudlicky, T., Synlett 2005, No. 3, 388–405. [2] Rinner, U., Hudlicky, T., Top Curr Chem 2012, 309, 33-66. [3] Meuzelaar, G.J., van Vliet, M.C.A., Maat, L., Sheldon, R.A., Eur. J. Org. Chem. 1999, 2315-2321. [4] Beyerman, H.C. et al., Recl. Trav. Chim. Pays-Bas 1978, 95, 127-130.

Total Synthesis of Cyclonerodiol

Langhanki J., Mainz/D, Erkel G., Kaiserslautern/D, Opatz T.*, Mainz/D

Prof. Dr. Till Opatz, Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, D-55128 Mainz, Germany

Cyclonerodiol is a cyclopentanoid sesquiterpene which was first described by Nozoe et al. in 1970.[1] They isolated it from the strain of Trichothesium roseum, a mould fungus that can be found worldwide on decaying crops. Furthermore, cyclonerodiol was detected over the years in several other fungi, for instance in Fusarium[2,3], Epichloë[4] or Algicolorus species.[5,6]

The complete stereostructure of cyclonerodiol was reported in 1990 by Laurent et al..[3] It has anti-inflammatory activities and elicits a wide range of other biological effects.[4,7]

The regioselective epoxidation of the terminal double bond in Linalool (1) and the subsequent radical cyclisation with Cp2TiCl leads to the cyclic product 2. Conversion of the primary alcohol to a methyl xanthogenate and a following Barton-McCombie reaction furnishes the deoxygenated product. C=C–bond cleavage via Lemieux- Johnson oxidation yields ketone 3, the reaction with homoprenyllithium gives cyclonerodiol, along with its C2’ epimer in a 10:1 ratio. The natural product could be purified by preparative HPLC.

Literature: [1] S. Nozoe, M. Goi, N. Morisaki, Tetrahedron Lett. 1970, 11, 1293–1296. [2] J. R. Hanson, P. B. Hitchcock, R. Nyfeler, J. Chem. Soc., Perkin Trans. 1 1975, 1586–1590. [3] D. Laurent, N. Goasdoue, F. Kohler, F. Pellegrin, N. Platzer, Magn. Reson. Chem. 1990, 28, 662–664. [4] Q. Yue, C. J. Miller, J. F. White, M. D. Richardson, J. Agric. Food Chem. 2000, 48, 4687–4692. [5] X. Li, M. K. Kim, U. Lee, S.-K. Kim, J. S. Kang, H. D. Choi, B. W. Son, Chem. Pharm. Bull. 2005, 53, 453–455. [6] X. Li, D. Zhang, U. Lee, X. Li, J. Cheng, W. Zhu, J. H. Jung, H. D. Choi, B. W. Son, J. Nat. Prod. 2007, 70, 307–309. [7] Q. Huang, Y. Tezuka, Y. Hatanaka, T. Kikuchi, A. Nishi, K. Tubaki, Chem. Pharm. Bull. 1995, 43, 1035–1038.

Microwave-Assisted Catalytic Wittig Reaction

S. Adomeit, Rostock/DE, M. Hoffmann, Rostock/DE, T. Werner*, Rostock/DE

Dr. Thomas Werner, Leibniz-Institut für Katalyse e.V. Albert-Einstein-Str. 29a, 18059 Rostock

The carbonyl olefination by Wittig reaction is one of the most important transformations in organic chemistry. This method has been employed in the synthesis of numerous natural and pharmaceutical products. [1] Thereby a phosphorus ylide reacts with an aldehyde to the desired alkene by releasing stoichiometric amounts of triphenyl- phosphine oxide which are usually regarded as waste products. First catalytic attempts of this reaction were reported with triphenylarsine [2] and dibutyltelluride. [3] However, the high toxicity of these catalysts is obviously a disadvantage. Recently, the first metal- free catalytic conversion was carried out by means of a cyclic phosphine oxide. [4] Based on our general interest in the use of organophosphorus compounds as organic catalysts our effort was to develop a catalytic Wittig reaction with commercially available and inexpensive phosphine oxides. [5] The conversion of benzaldehyde with -bromo methyl acetate to methyl phenylpropenoate served as a model reaction. Several phosphines und phosphine oxides were tested as catalysts under various conditions in the presence of silanes as in situ reducing agents. Furthermore, organic as well as inorganic bases were also employed.

After optimization of the reaction conditions several aldehydes were converted with alkyl halides containing electron withdrawing groups in the presence of Bu3PO as the pre-catalyst. Additionally microwave irradiation was successfully applied as an energy source. 19 aromatic, heteroaromatic and also aliphatic aldehydes were converted with various halides into alkenes in yields of 45–88% and with high E/Z-selectivities of up to 99:1. A reliable mechanistic proposal will be presented.

Literature: [1] (a) A. Saklani, S. K. Kutty, Drug Discovery Today 2008, 13, 161–171; (b) K. K.-C. Liu, J. Li, S. Sakya, Mini-Rev. Med. Chem. 2004, 4, 1105–1125. [2] P. Cao, C.-Y. Li, Y.- B. Kang, Z. Xie, X.-L. Sun, Y. Tang, J. Org. Chem. 2007, 72, 6628–6630. [3] Z.-Z. Huang, S. Ye, W. Xia, Y. Tang, Chem. Commun. 2001, 1384–1385. [4] C. J. O'Brien, J. L. Tellez, Z. S. Nixon, L. J. Kang, A. L. Carter, S. R. Kunkel, K. C. Przeworski, G. A. Chass, Angew. Chem. 2009, 121, 6968–6971; Angew. Chem., Int. Ed. 2009, 48, 6836– 6839. [5] T. Werner, Adv. Synth. Catal. 2009, 351, 1469–1481.

Combination of Aqueous Reaction Media with Inductive Heating for Rapid Phase Transfer Reactions

J. Hartwig

Prof. Dr. A. Kirschning, Leibniz Universität Hannover, Schneiderberg 1B, D-30167 Hannover, Germany

The application of water in organic synthesis results in a variety of advantages. E.g. cost issues, safety and environmental concerns raised the interest to use water in industrial processes.[1] Unique reactivity of organic compounds or acceleration of reaction rates resulted in a comeback of water in organic synthesis.[2] The suspension of conventional organic solvents in water under subcritical conditions (high temperature, high pressure) removes the phase boundary and allows handling of such mixtures in micro fluidic reactors with high mass transfer. In combination with inductive heating problems, such as low solubility and rapid heating, can be solved while avoiding the disadvantages of cosolvents.[3] Furthermore the application of water allows better handling of polar molecules and salts in a continuous setup. Pressure stable reactors that are inductively heated were used for rapid phase transfer reactions with high mass transfer.

With a resistant and reliable system in hand the synthesis of Iloperidone under flow conditions with water as reaction media was investigated to show the applicability on a commercialized product.

[1] a) F. M. Kerton, R. Marriott, Alternative Solvents for Green Chemistry RSC, Croydon, 2013; b) U. M. Lindstrom, Chem. Rev. 2002, 102, 2751; c) P.A. Grieco, Organic Synthesis in Water, Blackie, London, 1998. [2] S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B. Sharpless, Angew. Chem. Int. Ed. 2005, 44, 3275-3279. [3] P. E. Savage, S. Gopalan, T. I. Mizan, C. J. Martino, E. E. Brock, AlChE 1995, 41, 1723-1778. Titanium(III)-Catalyzed Reductive Coupling of Heterocyclic Enones with Michael-Acceptors Bichovski, P., Freiburg/D, Streuff, J., Freiburg/D Dr. Jan Streuff, Albert-Ludwigs-Universität Freiburg, Institut für Organische Chemie Albertstraße 21, 79104 Freiburg, Germany

The synthesis of molecules containing 1,2-, 1,4- and 1,6-functionalities by C-C bond formation is still a challenging task for organic chemists. The reductive ‘‘umpolung’’[1], a process that enables the connection of similarly polarized coupling partners by single-electron transfer, is one available helpful method to avoid this problem. In 2011 we reported the development of a titanium(III)-catalyzed cross coupling between enones and acrylonitriles.[2] The scope of the reaction was demonstrated on a number of substrates varying both, the enone and the acrylonitrile partner. We then further explored this reaction and found that this method can be also applied to different heterocyclic enones such as coumarines, quinolinones and chromones resulting in direct β-alkylation of these compunds. The corresponding products were obtained in moderate to high yields and diastereoselectivities. Moreover, we were able to combine this alkylation reaction with a second titanium(III)-catalyzed ketonitrile cyclisation yielding bridged α-hydroxyketones in diastereoselective fassion. [3]

Literature: [1] a) D. Seebach, Angew. Chem. Int. Ed. Engl. 1979, 18, 239; b) J. Streuff, Synthesis 2013, 281; [2] J. Streuff, Chem. Eur. J. 2011, 17, 5507; [3] P. Bichovski, J. Streuff, unpublished results.

The First Total Synthesis of Guttiferone A

F. Horeischi, Stuttgart/ DE, B. Plietker,* Stuttgart/ DE

Bernd Plietker, Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany

Polyprenylated polycyclic acylphloroglucines (PPAPs) are natural products that are mostly isolated from the Clusiaceae family. Because of their wide range of biological properties the class of PPAPs has caught a lot of attention from a pharmacological point of view. An interesting member of these natural occurring polyisoprenylated benzophenones is guttiferone A, which is an active ingredient of different Garcinia species, i.e. Garcinia livingstonei , and shows cytotoxic activity in vitro and anti-tumor activity in rodent models. [1-2]

Scheme 1: Retrosynthesis The interesting biological activities and the challenging diastereoselective introduction of the C-6-side chain represent the major sources of inspiration for us to tackle the total synthesis of endo -type B PPAPs [3] possessing an additional stereocenter at C-6. Herein we describe a straightforward access to guttiferone A and epi-guttiferone A, in which full control of stereoselectivity is achieved via conformational control.[4]

References [1] G. L. Pardo-Andreu, Y. Nunez-Figueredo, V. G. Tudella, O. Cuesta-Rubio, F. P. Rodrigues, C. R. Pestana, S. A. Uyemura, M. Leopoldinio, L. C. Alberici, C. Curti, Toxicology and Applied Pharmacology 2011 , 3, 282-289. [2] L. Monzote, O. Cuesta-Rubio, A. Matheeussen, T. Van Assche, L. Maes, P. Cos, Phytotherapy Research 2011 , 3, 458-462. [3] (a) N. Biber, K. Möws, B. Plietker, Nature Chemistry 2011 , 3, 938. (b) K. Lindermayr, B. Plietker, Angew. Chem . 2013 , 52 , 12183. [4] F. Horeischi, N. Biber, B. Plietker, J. Am. Chem. Soc . 2014 , 136 , 4026.

Ru-catalyzed chemoselective reduction with water as H2-surrogate

S. Scholz, Stuttgart/DE, T. Schabel, Stuttgart/DE, B. Plietker*, Stuttgart/ DE

Bernd Plietker, Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany

The chemoselective reduction of alkyne, ketones, or nitro groups using (Ph3P)3RuCl2 as an inexpensive catalyst and Zn/water as a stoichiometric reductant was reported by our group. Depending on the nature of the additive and the temperature, good chemoselectivities were observed allowing, e.g., for the selective reduction of a nitro group in the presence of a ketone or an alkyne.[1]

Scheme 1: Additive and temperature dependent chemoselective reduction [1]

The reported catalysis led to the idea of using water not only as hydrogen source but also as solvent, facilitating the separation of products from the catalyst and therefore the possible recycling of the catalyst. Hydrogenation reactions in aqueous media with water-soluble Ruthenium and Rhodium catalysts are widely employed, using e.g. molecular hydrogen or sodium formate as hydrogen source.[2-4] We could show, that the mentioned system (scheme 1) based on water as hydrogen source and zinc as stoichiometric reductant could so far partly be transferred to aqueous media, using a water soluble Ru-TPPTS catalyst.

References [1] T. Schabel, C. Belger, B. Plietker, Org. Lett. 2013, Vol. 15, No. 11, 2858–2861. [2] K. Nuithitikul, M. Winterbottom, Catalysis Today 2007, 128, 74–79. [3] M. Hemandez, P. Kalck, Joumal of Molecular Catalysis A: Chemical 1997, 116 131–146. [4] D. J. Darensbourg, N. W. Stafford, F. Joó, J. H. Reibenspies, Journal of Organometallic Chemistry 1995, 488, 99–108.

A mild hydrosulfenylation of olefins using a defined NHC-ligated Fe-sulfur- complex under neutral conditions

Isabel Alt, Stuttgart/DE, Philipp Rohse, Stuttgart/DE, and Bernd Plietker*, Stuttgart/DE

Bernd Plietker, Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany

The development of catalytic methods for a selective formation of C-S-bonds represents a major challenge in organometallic catalysis. Within the past years the field of catalytic sulfenylations has faced an almost explosive development and within the portfolio of C-S-bond forming processes the 1,4-addition of thiols to α,β-unsaturated ketones or aldehydes occupies an important place.[1]

Scheme 1: 1,4-addition of thiols to α,β-unsaturated ketones or aldehydes.[2]

Herein we report defined Fe-NHC-mercapto complexes are highly active in the direct catalytic 1,4-addition of aromatic and aliphatic thiols to olefins. For olfactoric reasons and the oxidation sensitivity of thiols we finally set out to develop an odorless alternative.[2]

References

[1] T. Kondo, T. Mitsudo, Chem. Rev. 2000, 100, 3205. [2] a) I. Alt, Master thesis, 2013. b) I. Alt, P. Rohse, B. Plietker, ACS Catal. 2013, 3, 3002.

Synthesis of mono- and bifunctional azobenzene glycoconjugates for photosensitive crosslinking of bioactive proteins

Müller, A., Kiel/D, Chandrasekaran, V., Kiel/D, Sönnichsen, F. S., Kiel/D, Lindhorst, Th. K.*, Kiel/D

Christiana Albertina University of Kiel, Otto Diels Institute of Organic Chemistry, Otto-Hahn-Platz 4, 24098 Kiel, Germany Kiel

Proteins are essential for living organism as they play an important role in many biological processes. For instance some organisms that live in subzero regions, e.g. fish, funghi, bacteria, plants, and insects express antifreeze proteins (AFP) to protect themselves against death by freezing.[1] In order to investigate, influence and control antifreeze activity, it has become our goal to switch their bioactivity by conjugation with light-sensitive glycoconjugates. For this approach we designed different photochromic linker molecules based on glycoazobenzene derivatives owing to their photochromic properties on the one hand and on their biocompatibility on the other.[2,3] A photoswitchable AFP can be realized by linking the photoswitchable glycoconjugate to specific amino acids of the protein, thus facilitating photocontrol of functional folding. We report on the synthesis of new mono- and bifunctional azobenzene conjugates as depicted in Figure 1 with the “variable” region represented by a pyranose ring in most cases. The synthesized derivatives vary in their functional groups which enables the coupling to the peptide using different ligation methods.

Figure 1. The photochromic unit can be crosslinked to the peptide via different ligation methods e. g. (A) copper free thiol-ene reaction (B) or in a nucleophilic substitution reaction.

[1] P. L. Davies, B. D. Sykes, Curr Opin Struct Biol 1997, 7, 828-834. [2] M. Hartmann, H. Papavlassopoulos, V. Chandrasekaran, C. Grabosch, F. Beiroth, T. K. Lindhorst, C. Röhl, FEBS Lett. 2012, 586, 1459-1465. [3] V. Chandrasekaran, K. Kolbe, F. Beiroth, T. K. Lindhorst, Beilstein J. Org. Chem. 2013, 9, 223-233. New electron-rich Fe-H Complexes for “Hydrogen on Demand”

S.Rommel , Stuttgart/ DE, B. Plietker*, Stuttgart/ DE

Susanne Rommel, Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany

With regard to the recent developments in hydrogen storage, the ultrafast generation of pure hydrogen gas („Hydrogen on Demand“) have attracted considerable interest. Particularly for applications in which varying amounts of energy are required at defined timely events (i.e. automotive industry) this technology is relevant.

Herein we present a series of new defined iron hydride complexes and their application in the fast dehydrogenative silylation of methanol. All complexes and their electronic properties were investigated by spectroscopical and quantumchemical means. Their potential in the ultrafast generation of hydrogen was tested and FeHdppp was found to generate hydrogen gas with a TOF of 600000 h -1.

References

1) S. Rommel, L. Hettmanczyk, J. E. M. N. Klein, B. Plietker, Chem. As. J. , accepted; DOI: 10.1002/asia.201402142. 2.) W. Sattler, G. Parkin, J. Am. Chem Soc. 2012 , 134 , 17462-17465. 3) U. Eberle, M. Felderhoff, F. Schüth, Angew. Chem. Int. Ed. 2009 , 48 , 6608-6630.

Synthesis of a macrolide library of putative pheromones used by the Madagascan frog Mantidactylus betsileanus

P. S. Peram, Braunschweig/DE., Prof. Dr. M. Vences, Braunschweig/DE., Prof. Dr. S. Schulz, Braunschweig/DE. Institut für Organische Chemie, Hagenring 30, 38106 Braunschweig.

Anuran amphibians (frogs) use mostly acoustic, visual, and tactile signals for their communication. However, it is known that frogs and other amphibians also use pheromones by dissolving them or dispersing them on water surface for communication. These compounds were chemically characterized in few cases as peptides or proteins. Besides these non-volatile compounds, frogs produce volatile pheromonal compounds, currently under investigation by our group. One area of research is chemical composition of volatile pheromonal compounds from femoral glands of mantellid frogs, a species rich family from Madagascar [1].

The femoral glands of Mantidactylus betsileanus were excised and extracted with dichloromethane. The extracts were analyzed by GC-MS. Macrolides and fatty acid ethyl esters are the major compounds that were found. Interestingly, few unknown compounds with the mass 212 with different mass spectra were present. Moreover, these isomers are likely the positional isomers of methyl-11-dodecanolide based on our experience of fragmentations with macrolides of lower molecular mass [1, 2]. Fatty acid biosynthesis allows us to propose 5 isomers as likely candidates of the possible macrolides, which are shown below.

Currently, a synthetic library of macrolides is synthesized to prove all the structural proposals. The synthetic schemes are designed in such a way that the possible shortest path is heading to the final products. The detailed results will be presented on the poster.

References:

[1]. D. Poth, K. C. Wollenberg, M. Vences, S. Schulz, Angew. Chem. Int. Ed., 2012 , 51 , 2187. [2]. D. Poth, P. S. Peram, M. Vences, S. Schulz, J. Nat. Prod., 2013 , 76 , 1548.

Iron-catalysed ring-opening reactions of vinylepoxides

Berenice Heid , Stuttgart/ DE, B. Plietker*, Stuttgart/ DE

Bernd Plietker, Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany

Due to their versatile reactivity vinylepoxides are often used as lead compounds in natural product synthesis and in the synthesis of biological active compounds [1] . The transition metal catalysed allylic substitution is a well known method to perform regio-, chemo- and enantioselective C-C- or C-X-bonds under mild conditions to obtain new synthetically interesting substrates out of the compounds named above. Among others the Palladium catalysed allylic substitution using chiral ligands is known for its good [2,3] regioselectivity . With regard to this we initiated a study using Bu 4N[Fe(CO) 3(NO)] as nucleophilic catalyst in the regioselective ring-opening reaction of vinylepoxides using different pronucleophiles. In earlier studies we already showed that non-chiral ligands affect the regioselectivity of nucleophilic substitution reactions [4]. O CO R R´ CO CO [Fe]-II -II O [Fe]-II [Fe] R´ R´ R´ Nu-H R R´ R R R II- [Fe] O O O

Nu [Fe]-II

[Fe]-II R´ R OH

Nu Nu R´ R´ R R OH OH Scheme 1: General mechanism for the Iron catalysed allylic substitution of vinylepoxides

Our intention is to investigate the influence of non-chiral ligands in combination with the Iron-catalyst respective to the regioselectivity for the reaction shown above. Of further interest is the limitation for the reaction using different vinylepoxide derivatives [5].

References [1] a) Yaragorla, S.; Muthyala, R.; Tetrahedron Lett. 2010 ; 51 ; 467 – 470; b) Afarinkia, K.; Bahar, A.; Tetrahedron: Asymmetry 2005 ; 16 ; 1239 – 1245. [2] a)Tsuji, J.; Palladium Reagents and Catalysts – Innovations in Organic Synthesis ,Wiley, Okayama, 1995 .; b) Trost, B. M.; Crawley, M. L.; Chem. Rev. 2003 ; 103 ; 2921. [3] Trost, B. M.; Jiang, C.; J. Am. Chem. Soc. 2001 ; 123 ; 12907 – 12908. [4] a) Jatsch, A.; Möws, K.; Dieskau, A.; Plietker, B; Angew. Chem. Int. Ed. 2008 ; 47 ; 198; b) Holzwarth, M.; Dieskau, A.; Tabassam, M.; Plietker, B.; Angew. Chem. 2009 ; 48 ; 7251 – 7255 c) Dieskau, A.; Holzwarth, M.; Plietker , B.; J. Am. Chem. Soc. 2012 ; 134 , 5048−5051. [5] B. Heid, Diploma Thesis, 2012 .

Switching Bacterial Adhesion - Ligand-Driven Modification of FimH

F. Beiroth, Kiel/Germany

Prof. Dr. Thisbe. K. Lindhorst, Christian Albrechts University, Otto-Hahn-Platz 3-4, 24118 Kiel

Many biological processes like cell recognition or cellular adhesion rely on specific receptor-ligand interactions. In molecular recognition processes that occur on the surface of eukaryotic cells, complex oligosaccharides of the glycocalyx are frequently involved, which are recognized by specific carbohydrate-binding proteins, called lectins. Our recent research has been focused on carbohydrate-mediated bacterial adhesion which is enabled by adhesive protein appendages projecting from the bacterial surface, called fimbriae.[1] For the adhesion of Escherichia coli bacteria so- called type 1 fimbriae are of particular importance as major virulence factors. Type 1 fimbriae are terminated by a lectin called FimH, which is specific for α-D-mannosides. As FimH is critical in bacterial adhesion, we have planned photochemical blocking of its carbohydrate-binding site to control adhesion of bacterial cells. This new approach comprises ligand-driven modify- cation of FimH using a DMAP- functionalized mannoside and an azobenzene thioester.[2] The mechanism of this approach is detailed in Figure 1. First, the DMAP glycoconjugate is in- cubated with the lectin for complexation of the sugar within Figure 1: Concept of the ligand-driven photoreversible the carbohydrate binding site of modification of FimH. FimH (CRD). Then, the azobenzene thioester is added to allow reaction of DMAP and thioester moiety to form a higly reactive intermediate that is in place to couple to a protein surface nucleophile in close proximity. This reaction sequence should allow installation of an azobenzene moiety at the entrance of the FimH carbohydrate binding site. This should leave the entrance of the binding site open for sugar complexation, once the azobenzene unit is in its trans conformation; however, after irradiation to effect trans →cis isomerization of the azobenzene N=N double bond, the cis -configured should close the binding site by steric hindrance. This process is reversible and should allow for photochemical control of FimH-mediated bacterial adhesion. Different DMAP sugar and azobenzene thioester derivatives with varied steric properties have been synthesized to be tested with FimH. Mass spectrometric analysis will be paired with biological assaying.

Literature : [1] M. Hartmann et al., Eur. J. Org. Chem. 2011, 3583-3609. [2] Y. Koshi et al., J. Am. Chem. Soc. 2008, 130, 245-251.[3] V. Chandrasekaran et al., Beilstein J. Org. Chem. 2013, 9, 223–233. Synthesis and Application of Water Soluble N-Heterocyclic Carbene Gold Complexes

K. Belger, Dortmund/D

Prof. Dr. Norbert Krause, TU Dortmund, Otto-Hahn-Str. 6, 44227 Dortmund

In 1991, the first „free“ N-heterocyclic carbene was isolated by Arduengo.[1] Since then, the interest in NHC transition metal complexes increased rapidly due to their strong σ-donating properties and their broad variation range in steric features, which allow an excellent stabilization of the metal center and an enhancement of their catalytic activity.[2,3]

Scheme 1. Recycling of water soluble catalyst by extraction.

In our investigations, water soluble, ammonium salt tagged NHC gold complexes were synthesized.[4] These catalysts can be reused due to their property to be insoluble in organic solvents. Hence, they remain in the aqueous phase, while the desired product can be removed easily by extraction.

Literature:

[1] A. J. Arduengo III, R. L. Harlow, M. Kline, J. Am. Chem. Soc . 1991 , 113 , 361. [2] S. Díez-González, N. Marion, S. P. Nolan, Chem. Rev. 2009, 109, 3612–3676. [3] S. P. Nolan, Acc. Chem. Res . 2011 , 44 , 91. [4] K. Belger, N. Krause, submitted 2014 .

Synthesis of Carbohydrate-Containing NHC-Gold-Complexes

Wiegand, A., Dortmund/D-44227

Prof. Dr. Norbert Krause, University of Technology, Otto-Hahn-Str. 6, 44227 Dortmund.

Since their first isolation by Arduengo in 1991, N-heterocyclic carbenes have gained great importance in transition metal catalysis. [1] Due to their strong σ-donating and their poor π-accepting properties, NHCs are an alternative to phosphine ligands. [2] In addition, carbohydrates are the most abundant biomolecules on earth and play an important role in many biological processes. They are commercially available and exhibit a great structural variety. [3] Moreover, the high water solubility of carbohydrates makes them attractive as ligands in catalysis. [4] The combination of N-heterocyclic carbenes and carbohydrates leads to highly reactive, water soluble ligands. Herein, we report the synthesis of carbohydrate attached NHC-gold-complexes.

Scheme 1: Synthesis of carbohydrate attached NHC-gold-complexes.

Literature: [1] A. J. Arduengo, R. L. Harlow, M. Kline, J. Am. Chem. Soc. 1991 , 113 , 361. [2] W. A. Herrmann, Angew. Chem. Int. Ed. 2002 , 41 , 1290. [3] F. Tewes, A. Schlecker, K. Harms, F. Glorius, J. Organomet. Chem. 2007 , 692 , 4593. [4] T. Nishioka, T. Shibata, I. Kinoshita, Organometallics 2007 , 26 , 1126. Synthesis of Optically Active Crinine-type Alkaloid Precursors S. Bernhard, Mainz/DE Prof. Dr. Udo Nubbemeyer, Johannes Gutenberg-University, Duesbergweg 10-14, 55128 Mainz

During the last decades Amaryllidaceae alkaloids (e.g. Lycorine, Galanthamine) have attracted the interest of chemists as target structures because of their various physiological effects such as antitumor, antiviral, acetylcholinesterase inhibition, immune-stimulatory and antimalarial activites.[1] In particular the focus of the research is on a total synthesis of the very potent Crinamine. The challenging structure of the Crinamine displays four chiral centers including a quaternary carbon atom and a pentacyclic bridged ring phenanthroline system. In this connection an “ex-chiral-pool”-synthesis from L-serine and Piperonyl alcohol to build-up the precursor lactone was developed (Fig. 1). The olefin geometry of the lactone is adjusted by an acyclic Horner-reaction of a Serine derivative and a subsequent intramolecular Heck coupling ring closure. The diastereoselective formation of the quaternary carbon center is topic of the current investigation, a radical cyclisation should be employed to generate the rigid bridged structure using the asymmetric induction of the adjacent stereogenic center.[2]

O OH O Reductive Amination N-Alkylation Piperonyl alcohol 12 steps O HO O N O N + O O O OH 5 % yield Heck-Reaction O OMe OH Horner-Reaction H2N O L-Serine Precursor Lactone Crinamine

Fig.1: Synthesis of the precursor lactone based on L-Serine and Piperonyl alcohol as starting materials

Literature: [1] Zhong, J. Nat. Prod. Rep. 2003, 20, 6, 606-614. [2] Bösche, U. Methoden zur diastereoselektiven Darstellung quartärer Kohlenstoff- zentren zur Synthese von Amaryllidaceae-Alkaloiden, Dissertation, Freie Universität Berlin, 1998. A Novel Approach towards Equisetin Analog Syntheses

L. Hoffmann, Mainz/ DE, Prof. Dr. Udo Nubbemeyer, Johannes Gutenberg-University, Duesbergweg 10-14, 55128 Mainz

Setines are natural products consisting of a decaline system connected to 3- acyltetramic acids. Analysing the decaline cores of such natural products, trans fused systems are found bearing one double bond, two or three methyl groups and an additional mostly unsaturated side chain. Furthermore equisetine and some congeners are characterized by an N-methyl tetramic acid moiety. Most of the setine natural products display various interesting biological activities, e. g., antibacterial activities against gram-positive multi-drug-resistant bacteria are reported for CJ21,058 isolated and characterized in 2002 by Sugie et al.[1] Focusing on a flexible access to generate the natural products and potentially interesting analogs, a convergent synthesis has been started. Suitably protected N-Methylserine A can be obtained from L-serine via a few steps. Then, a condensation enables to build-up the N-methyl tetramic acid building block B as the first key intermediate. An ex-chiral pool sequence starting from β-citronellene delivered the unsaturated ester C via ozonolysis and Horner reactions. Then, a Wittig olefination using ylide D delivered the unsaturated triene E derived unsaturated ester F as an E/Z-mixture. Ester and Tetramic acid have to be coupled by means of an ester condensation. A final intramolecular Diels-Alder-Reaction should serve as the key step to complete the setine synthesis.

PGO NH NHMe 2 N O HO OH PGO OR

L-serine O A O B O

+ PPh3

1 MeO C O R R1 2 D R2 R2

Me CO2Me C E

HO Me PGO Me N N

1 2 HO O R = Me, R = H: HO O equisetine O 1 O R R1

2 2 R F R Literature: [1] Sugie, Y.; Inagaki, S.; Kato, Y. et. al. J. Antibiot. 2002, 55, 25-29. For an Equisetine Synthesis see: S. V. Ley et al. Org. Lett. 2000, 2, 3611 – 3614. Studies towards Stereoselective Syntheses of Lipoxin B4 analogs

A. Nava, Mainz/ DE, Prof. Dr. Udo Nubbemeyer, Johannes Gutenberg-University, Duesbergweg 10-14, 55128 Mainz

Lipoxines A and B are known as highly active eicosanoids terminating inflammation processes. The high biologic activity is combined with a very short half life in organism preventing any drug like use of such compounds. Therefore, the synthesis of more stable and still active analogs is a challenge in total synthesis Lipoxin B4. The Z/E-isomerisation of the 8,9 double bond causes a complete loss of the biological activity of original Lipoxin B4. The introduction of a CH2 group between C6 and C11 of the tetraene moiety should suppress any isomerization by maintaining the conjugated double bond system. Such a target molecule requires the development of a convergent total synthesis. The suitably protected dihydroxyaldehyde A can be obtained from hexenol B in analogy to literature procedures. Cycloheptatriene C is acylated twice according a strategy developed by E. Vogel. An enantioselective reduction of the ketone D delivered the defined configured OH group. Introduction of suitable protecting groups and the sulfone moiety should complete the synthesis of the second building block E. Then, a trans selective Julia-Kocienski olefination should allow coupling of both building blocks to complete assembling of the carbon backbone. Final deprotection steps should allow generating the target Lipoxin B4 analog.

N N CO2Me N N SO2 Ph 5 OMe 5 OMe C D O O E OPG O

OPG OH O A B OPG HO OH HO OH 11 11 9 9

8 5 OH 8 5 OH 6 6 LXB LXB -analog 4 OH O 4 OH O

Literature: E. Vogel et al. Angew. Chem. 1980, 92, 43 – 45; K. C. Nicolaou, S. E. Webber, Stereocontrolled Total Synthesis of Lipoxins B, Synthesis,1986, 453-461; A. Duymaz, Synthese von optisch aktivem 9,14-Methylen-Lipoxin A4, Dissertation, Universität Mainz, 2007. Stereoselective Synthesis of Virginiae Butanolid A

Brüggemann, Mainz/ DE, Prof. Dr. U. Nubbemeyer, Johannes Gutenberg-University, Duesbergweg 10-14, 55128 Mainz

Streptomyces species are gram-positive filamentous bacteria that are well known for producing a vast variety of bioactive compounds, including more than 70% of commercially important antibiotics. Previous studies have shown that antibiotic production and/or morphological differentiation in some Streptomyces species is controlled by low-molecular-weight compounds called ´´γ-butyrolactone autoregulators´´. Among these γ-butyrolactones so far identified, virginiae butanolide A plays an important role in Streptomyces virginiae.[1]

O 8 steps OBn OH N 1 2

F O OBn OBn OH N

3 O O 5 O

The stereoselective total synthesis of Virginiae Butanolid A 5 using a zwitterionic Aza-Claisen rearrangement as a key step to introduce two of the stereogenic centres is the aim of the present project. Starting from 5-methyl-carboxylic-acid 1 the allyl amine 2 was generated using an eight step sequence. Then, the Aza-Claisen rearrangement enabled to react the allyl amine 2 and an acid fluoride 3 to form the amide 4 with high simple diastereoselectivity and high 1,2-asymmetric induction. In this connection, the stereogenic centre in 2 caused the passing of a single chair-like transition state within the rearrangement. In combination with a defined Z-enolate geometry a single diastereomer was obtained in very high yields within the key step of the synthesis.[2] The formation of the lactone core structure is topic of current investigations.

Literature:

[1] Fiero F.; Martin J.F.; Kerala, India.; Research Signpost. 2002, 99 – 119. [2] Nubbemeyer U.; J. Org. Chem. 1996, 61, 3677 – 3686.

Synthesis and biological evaluation of ripostatin analogues. Evgeny V. Prusov, Braunschweig/D, W. Tang, Braunschweig/D, S. Liu, Piscataway/USA, D. Degen, Piscataway/USA, R. H. Ebright, Piscataway/USA Dr. Evgeny V. Prusov, Helmholtz-Zentrum für Infektionsforschung, Inhoffenstr. 7, 38124 Braunschweig Ripostatins are the macrocyclic lactones which act as the RNA-polymerase inhibitors by binding, to the so called “Switch region”.[1] We became highly interested in ripostatins and developed a modular and convergent approach to the structural architecture of ripostatins A and B (Figure 1).[2,3] In our synthesis we utilized a sequence consisting of the double Stille cross-coupling reaction and a ring-closing metathesis to overcome the problems associated with the isomerization of sensible “skipped triene” motif of ripostatins.

Figure 1. General synthetic approach to the molecular architecture of ripostatins. With a working strategy in hands, we produced a series of structurally modified analogues of ripostatins with modifications in the lactone core (Figure 2). Biological evaluation of analogues provided the first SAR-data and revealed the directions for the further optimization of these promising leads.

Figure 2. Structural analogs produced for SAR-studies of ripostatins. [1] Ebright et al, Cell 2008, 135, 295–307. [2] W. Tang, E. V. Prusov, Angew. Chem. Int. Ed. 2012, 51, 3401–3404; Angew. Chem., 2012, 124, 3457–3460. [3] W. Tang, E. V. Prusov, Org. Lett., 2012, 14, 4690–4693.

Synthesis of Carbonated Oleo Chemicals

C. Wulf, Rostock/D, N. Tenhumberg, Rostock/D, B. Schäffner, Marl/D, T. Werner* Rostock/D

Dr. Thomas Werner, Leibniz Institut für Katalyse e.V., 18059 Rostock; Creavis Technologies and Innovation, Evonik Industries, 45772 Marl

The global climate change is closely connected to the emission of anthropogenic greenhouse gases. The by far largest part of this emission is accounted to carbon dioxide (CO2). Besides the reduction of CO2 output the use of CO2 as synthetic building block is the central point of the overall CO2 management strategy. [1] Hence, the utilization of CO2 as C1-building block in organic synthesis and industrial processes has recently been given great interest and is widely studied in current research. [2] However, the challenge utilizing carbon dioxide is its thermodynamic stability and high oxidation state which requires high energy starting materials. In this context the 100% atom economical reaction between CO2 and epoxides yielding the corresponding cyclic carbonates is an attractive reaction. [3]

Oleochemical carbonates have interesting properties and can be used as polymer precursors, lubricants or plasticizers. Some catalyst such as tetra-n-butylammonium bromide and polyoxometalates are known for the carbonation of epoxidised oleo chemicals. [4,5] By combination of an organocatalyst and various cocatalyst we developed a new catalyst system which is comparably more active than the known ones. [6] Utilizing this catalysts system, both mono- and diepoxidized oleo compounds were converted into the corresponding carbonates in high yields under comparatively mild reaction conditions.

Literature:

[1] Verband der Chemischen Industrie e. V. (VCI), Gesellschaft für Chemische Technik und Biotechnologie e. V. (DECHEMA); Positonspapier: „Verwertung und Speicherung von CO2". [2] a) M. Peters, B. Köhler, W. Kuckshinrichs, W. Leitner, P. Markewitz, T. E. Müller, ChemSusChem 2011, 1216–1240; b) I. Omae, Coord. Chem. Rev. 2012, 256, 1384–1405. [3] a) O. Iwao, Catal. Today 2006, 115, 33–52; b) T. Sakakura, J.-C. Choi, H. Yasuda, Chem. Rev. 2007, 107, 2365–2387; c) M. North, R. Pasquale, C. Young, Green Chem. 2010, 1514–1539; d) M. R. Kember, A. Buchard, C. K. Williams, Chem. Commun. 2011, 47, 141–163; e) T. Werner, N. Tenhumberg, J. CO2 Util. 2014, http://dx.doi.org/10.1016/j.jcou.2014.04.002. [4] K. M. Doll, S. Z. Erhan, J. Agric. Food Chem. 2005, 53, 9608–9614. [5] J. Langanke, L. Greiner, W. Leitner, Green Chem. 2013, 15, 1173–1182. [6] Patent pending, publication in preparation. Studies Towards the Total Synthesis of Aetheramide A and B

L. Gerstmann, Hannover/D, C. Jahns, Hannover/D, M. Kalesse, Hannover/D

M. Sc. Lisa Gerstmann, Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1b, 30167 Hannover

Aetheramides A ( 1) and B ( 2) were isolated by the groups of Müller and Stadler in 2011 from the recently discovered myxobacterial genus “Aetherobacter ” (Strain SBSr003). The structures were elucidated by NMR analysis, chemical derivatizations and quantum mechanical calculations. Both depsipeptides contain a total of six stereocenters, four of which were determined, a unique polyketide moiety and two amino acid residues. In biological studies they showed cytostatic activity against human colon carcinoma (HCT-116) cells and potent inhibition of the HIV-1 infection. [1]

The retrosynthetic analysis of 1 and 2 leads to polyketide unit 3 and dipeptide 4. Depending on which hydroxy functionality reacts in the esterification either the precursor of aetheramide A or B can be obtained. We envisioned that in order for intramolecular macrolactamization to take place preferentially, trapping of a thermally formed acylketene, derived from the corresponding 1,3-dioxinone, would be required.[2] The key steps involved in the synthesis of northern fragment 3 would be a vinylogous Mukaiyama aldol reaction and a Horner-Wadsworth-Emmons olefination.

Literature:

[1] A. Plaza, R. Garcia, G. Bifulco, J. P. Martinez, S. Hüttel, F. Sasse, A. Meyerhans, M. Stadler, R. Müller, Org. Lett. 2012 , 14 , 2854–2857. [2] T. Yoshinari, K. Ohmori, M. G. Schrems, A. Pfaltz, K. Suzuki, Angew. Chem. Int. Ed. 2010 , 49 , 881-885.

Enantioselective, Multicatalytic Alcohol-Alcohol Cross-Coupling

C. Hofmann and Prof. Dr. P. R. Schreiner Institute of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 58, 35392 Giessen, Germany/DE

Recently, we designed and successfully developed a peptide catalyst for the kinetic resolution of (±)-trans-cycloalkane-1,2-diols. The catalyst is equipped with a nucleophilic N- π-methylhistidine moiety for enantioselective acyl transfer utilizing anhydrides as acyl source.[1] Starting from carbonic acids we realized the first enantioselective Steglich esterification.[2] Using aldehydes is advantageous because they are typically more soluble in organic solvents, easier to purify, and of higher reactivity. As such they are preferred intermediates in multistep syntheses.[3] Utilizing a multicatalyst[4,5] to initially oxidize aldehydes in Steglich-type esterifications we achieved good yields with high enantioselectivities both for the products and the recovered diols.[3] Alcohols would intrinsically even better acyl equivalents owing to their high stability and ubiquitous accessibility. Based on our multicatalyst concept we thus developed an enantioselective alcohol cross-coupling protocol of trans-cycloalkane-1,2-diols using an oligopeptide catalyst, mCPBA as oxidizer, and N,N′-diisopropylcarbodiimide as dehydrating agent achieving high selectivities and good yields for product and recovered diol.

Literature:

[1] C. E. Müller, L. Wanka, K. Jewell and P. R. Schreiner, Angew. Chem., Int. Ed., 2008, 47, 6180-6185. [2] R. Hrdina, C. E. Müller and P. R. Schreiner, Chem. Commun., 2010, 46, 2689-2690. [3] C. Hofmann, S. M. M. Schuler, R. C. Wende and P. R. Schreiner, Chem. Commun., 2014, 50, 1221-1223. [4] R. C. Wende and P. R. Schreiner, Green Chem., 2012, 14, 1821-1849. [5] C. E. Müller, R. Hrdina, R. C. Wende and P. R. Schreiner, Chem.-Eur. J., 2011, 17, 6309-6314.

A 1,5-Cyclooctadiene Approach to Polycyclic Polyprenylated Acylphloroglucinols (PPAPs) Feidt, E., Saarbrücken/D, Jauch, J., Saarbrücken/D Prof. Dr. Johann Jauch, Institut für Organische Chemie II, Universität des Saarlandes, Campus C4.2, 66123 Saarbrücken

Polycyclic polyprenylated acylphloroglucinols (PPAPs) such as hyperforin (1) [Figure 1] are a very interesting class of natural products whose antiseptic, antidepressant and antibiotic properties have been known for centuries. In recent years the interest in these biological active plant-ingredients has increased, because of their beneficial properties for medicinal technology and pharmaceutical applications. [1]

Figure 1: hyperforin

Here, we are reporting our first results towards the preparation of a model compound for PPAPs via a 1,5-cyclooctadiene strategy. Up to now different synthetic approaches for the synthesis of several PPAPs or precursors have been published. Each one starts with a 6-membered ring system and an adequate three-carbon-unit to build up the bicyclic system. [2] Completely different from the already published routes, we are using a substituted cyclooctene derivative as building block to synthesize the bicyclo[3.3.1]framework of PPAPs. The key step of our synthesis is the installation of the bridged carbonyl group via a transannular cyclization of a mixed anhydride (3) leading to the bicyclic core of PPAPs [Figure 2]. [3]

Figure 2: preparation of the substituted bicyclo[3.3.1]nonan-9-one structure

Literature: [1] a) J.-A. Richard, Eur. J. Org. Chem. 2014, 273-299. b) M. A. Medina et al., Life Sci. 2006, 79, 105-111. [2] a) J. T. Njardarson, Tetrahedron 2011, 67, 7631-7666. b) D. Y.-K. Chen et al., Angew. Chem. 2012, 124, 4612-4638; D. Y.-K. Chen et al., Angew. Chem. Int. Ed. 2012, 51, 4536-4561. [3] A. D. Gray, T. P. Smyth, J. Org. Chem.2001, 66, 7113-7117. Synthesis of 1,3-Dioxolan-2-ones

A. Pommeres, Rostock/DE, H. Büttner, Rostock/DE, T. Werner*, Rostock/DE

Dr. Thomas Werner, Leibniz-Institut für Katalyse e.V., Albert-Einstein-Str. 29a, 18059 Rostock

The utilization of CO2 as C1-building block in organic synthesis and industrial processes has recently been given great interest and has been studied widely in current research. [1] In this context the conversion of CO2 with epoxides to the corresponding cyclic carbonates is an attractive reaction. The obtained products can be used as synthetic building blocks or as green solvents, since carbonates, such as propylene carbonate or butylene carbonate, display some outstanding properties, including high boiling points, low toxicity and being odourless. [2] Several catalytic systems for the addition of CO2 to epoxides are known including organocatalysts. [3] However, often high reaction temperatures, high pressure and/or long reaction times are required. Herein we report the preparation of various bifunctional organocatalysts (BOC) and their application in the conversion of epoxides with CO2 to the corresponding cyclic carbonates. 15 bifunctional phosphonium salts were prepared and evaluated in a model reaction.

O O 0.1–5 mol% BOC + CO2 O O = – ar – – R R' p(CO2) 1 40 b , 23 120°C, 1 5 h X R3Y OH R R' BOC 16 Examples up to 99% yield

The bifunctional organocatalysts show superior activity compared to their monofunctional counterparts. From the initial catalyst screening structure-activity relationships have been determined. A wide screening of parameters with the most active catalyst led to optimized reaction conditions. We were able to obtain the desired products in good to excellent yields up to 99% even at temperatures <100°C and reaction times of 3 h. Furthermore, we were able to recycle the catalyst at least 3 times with yields >94%. In addition the reaction was carried out in a 50 g scale and monitored by in situ pressure-FT-IR.

Literature:

[1] See, for example: a) M. Halmann, Chemical fixation of carbon dioxide: methods for recycling CO2 into useful products, CRC Press, Boca Raton, 1993. b) T. Sakura, J. Choi, H. Yasuda, Chem. Rev. 2007, 107, 2365‒2387. c) M. Aresta, Carbon Dioxide as Chemical Feedstock, Wiley-VCH, Weinheim, 2010. [2] a) B. Schäffner, J. Holz, S: P. Verevkin, A. Börner, ChemSusChem 2008, 1, 249‒253; b) B. Schäffner, J. Holz, S. P. Verevkin, S. Börner, Tetrahedron Lett. 2008, 49, 768‒771. [3] a) J.-W. Huang, M. Shi, J. Org. Chem. 2003, 68, 6705‒6709; b) J. J. Shim, D. Kim and C. S. Ra, Bull. Korean Chem. Soc. 2006, 27, 744‒746; c) T. Sakai, Y. Tsutsumi, T. Ema, Green Chem. 2008, 10, 337‒341; d) H. Zhou, W.-Z. Zhang, C.- H. Liu, J.-P. Qu, X.-B. Lu, J. Org. Chem. 2008, 73, 8039‒8044; e) Z. Yang, L. He, C. Miao, S. Chanfreau, Adv. Synth. Catal. 2010, 352, 2233‒2240; f) J. Sun, L. Han, W. Cheng, J. Wang, X. Zhang, S. Zhang, ChemSusChem 2011, 4, 502‒507.

A metathesis-acylation-approach to the bicyclic core of PPAPs S., Schmitt, Saarbrücken/D, J., Jauch, Saarbrücken/D Prof. Dr. Johann Jauch, Institut für Organische Chemie II, Universität des Saarlandes, Campus C4.2, 66123 Saarbrücken

Nemorosone (1) a member of the family of polycyclic polyprenylated acylphloroglucinols (PPAPs) is an interesting natural product which can be isolated from Clusia nemorosa.[1] Recently, we were able to synthesise a model compound 2 for PPAPs (Fig. 1).

1 2 Figure 1. Structure of nemorosone and the model compound

This straight forward synthetic route presents a completely new access to the bicyclic core of the PPAPs. We wish to report here our first results. The two key steps established in this synthesis are a ring closing metathesis (RCM)[2] and a transannular cyclisation.[3] This represents a completely different strategy in comparison to all the other syntheses of PPAPs which include a six-membered ring unit and a suitable three carbon unit for bridging the system.[4] By transformation of the carboxylic acid to a mixed anhydride it is possible to perform an instantaneous Friedel-Crafts-like cyclisation of the 8-membered ring to the bicyclic core of PPAPs. The formed ester can be easily hydrolysed to the corresponding alcohol and after a Dess-Martin oxidation we were able to get the model compound (Fig. 2).

3 4 5

7 6 Figure 2. Developed synthetic route to the bicyclic core of PPAPs

Literature: [1] R. Ciochina, R. Grossman, Chem. Rev. 2006, 106, 3963-3986. [2] D.Burgeois, A. Pancrazi, S. P. Nolan, J. Prunet, J.Organomet. Chem. 2002, 643-644. [3] (a) W. F: Erman, H. C. Kretschmar, J. Org. Chem. 1968, 33, 1545-1550. (b) A. Heumann, W. Kraus, Tetrahedron 1978, 34, 405- 411. [4] (a) J. T. Njardarson, Tetrahedron 2011, 67, 7631-7666. (b) D. Y.-K. Chen et al., Angew. Chem. 2012, 124, 4612-4638; D. Y.-K. Chen et al., Angew. Chem. Int. Ed. 2012, 51, 4536- 4561.

NHC-Catalysis: The Breslow Intermediate and Structurally Related Radicals

S. Ruser, Hamburg/DE, J. Rehbein, Hamburg/DE

Universität Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg

Classically, the NHC-catalyzed benzoin condensation is believed to progress via an ionic reaction path with 5, the Breslow-intermediate [1, 2], as the central intermediate (Figure 1).

Having the exceptional radical stabilizing ability of N-heterocyclic carbenes (NHCs) in mind [3], we envisioned radical intermediates (Figure 2) derived from either the Breslow intermediate 5 or its precursor 4 that might be formed during benzoin condensation processes. Based on computational predictions of bond dissociation and radical stabilization energies we were encouraged to conduct CW-EPR spectroscopy. Figure 1 Classical Breslow-mechanism. [1]

The obtained EPR-spectra recorded from typical reaction solutions of various NHC-catalyzed benzoin condensations (Figure 2) were analyzed in terms of radical structure and kinetics. These results in combination with mechanistic aspects derived of computational chemistry will be reported. Figure 2 Experimental and fitted EPR spectrum.

Literature: [1] Breslow R., J. Am. Chem. Soc. 1958, 80, 3719-3726. [2] Berkessel A.; Elfert, S.; Yatham, V. R.; Neudörfl, J.-M.; Schlörer, N. E.; Teles, J. H., Angew. Chem. 2012, 124, 12537-12541. [3] Walton, J.; Brahmi, M. M.; Fensterbank, L.; Lacote, E.; Malacria, M.; Chu, Q.; Ueng, S.-H.; Solovyev, A.; Curran, D. P., J. Am. Chem. Soc. 2010, 132, 2350-2358. Investigating the Role of Secondary Carbocations in Monoterpene Biosynthesis

B. R. Wulff, Hamburg/DE, J. Rehbein, Hamburg/DE

University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg

Carbocations play an important role as intermediates in a great variety of chemical reactions. For example in the biosyntheses of terpenes and terpenoids carbocations represent the key to the generation of an immense Fig. 1: experimental access to carbocationic structures within the bornyl pyrophosphate structural variety from a very reaction cascade limited amount of precursors. [1] In this context secondary carbocations are being assigned a special position among these intermediates as they are thought to be potential bifurcation points in the reaction cascade. [2, 3, 4] The understanding of how nature regulates product selectivity in chemical reactions is of great significance. Therefore it is important to clearly identify the role of secondary carbocations within this context and answer the question if nature uses reaction dynamics as a tool for the control of product selectivity. In order to investigate this, a synergetic approach of computational and experimental methods is used to examine the reactivity of certain carbocationic structures within the bornylpyrophosphate reaction cascade. The experimental goal is to find practical evidence for the results obtained by computational chemistry. The synthetic aim is mainly the design of suitable photolabile precursors that generate the carbocations of interest in situ by photolytic bond cleavage and thereby allow the observation of their inherent reactivity despite the short lifetime of the structures.

Literature: [1] Christianson, D. W.; Chem. Rev., 2006, 106, 3412-3442. [2] Weitman, M.; Major, D. T., J. Am. Chem. Soc., 2010, 132, 6349-6360. [3] Tantillo, D. J., Chem. Soc. Rev., 2010, 39, 2847-2854. [4] Pemberton, R. P.; Hong, Y. J.; Tantillo, D. J.; Pure Appl. Chem., 2013, 85, 10, 1949–1957. A short way to unsymmetrically substituted NHC-Pd-PEPPSI complexes

Anna Zeiler and A. Stephen K. Hashmi* *University of Heidelberg, Institute of Organic Chemistry, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany email: [email protected]

Recent publications described a series of air-stable, user-friendly NHC-Pd(II) precatalysts, the Pd-PEPPSI series (PEPPSI stands for Pyridine-Enhanced Precatalyst Preparation, Stabilization and Initiation).[1] The 3-chloropyridine ligand of the precatalysts functions as a `throw-away` ligand. Based on the applied synthetic strategy for the ligands, so far only symmetrically substituted Pd-PEPPSI complexes were accessible.

In this contribution we report a short and efficient route to new unsymmetrically substituted NHC-Pd-PEPPSI complexes based on isonitrile precursors.[2] This methodology allowed us the preparation of a diverse set of different catalyst classes namely NHOCs, saturated, unsaturated and six-membered NHC complexes. Furthermore the catalytic activity of the obtained complexes was tested and compared in a number of cross-coupling reactions.

[1] C. J. O’Brien, E. A. B. Kantchev, C. Valente, N. Hadei, G. A. Chass, A. Lough, A. C. Hopkinson, M. G. Organ, Chem. Eur. J. 2006, 12, 4743 – 4748. [2] Anna Zeiler, Matthias Rudolph, Frank Rominger and A. Stephen K. Hashmi, submitted.

Supramolecular Affinity Materials for the Application on Quartz Crystal Microbalances based on (‒)-Isosteviol

Pyka I., Mainz/D, Ryvlin D., Mainz/D, Waldvogel S.R., Mainz/D Prof. Dr. S.R. Waldvogel, Johannes Gutenberg-Universität, Duesbergweg 10-14, 55128 Mainz, Germany

The naturally occurring diterpene (‒)-isosteviol 1 came into focus as building block for the construction of large and rigid molecular architectures. The unique properties can lead back to quite rare structural features[1] with the chemically inert hydrocarbon backbone and the concave array of the carboxylic acid and keto functions. The two functional groups can be easily transformed to afford a high variety of possible derivatives,[2] i.e. for the application in supramolecular systems.

(‒)-Isosteviol can be easily obtained by acidic treatment of stevioside. Stevioside is a commercially available natural sweetener which is isolated from stevia rebaudiana by alcoholic extraction. The rigid nature of architectures based on (‒)-isosteviol limits the degrees of freedom and guarantees a good preorganization. Because of their persistent cavities, these scaffolds are very potent supramolecular affinity materials for head space analysis by quartz crystal microbalances as could be shown before.[2,3] The scaffolds serve in particular as templates for tracing air borne arenes at low concentration. In addition to triphenylene ketal and triptycene-based structures,[3] we also tried to exhibit the geometrical requirements for the formation of new symmetric architectures with extended cavities based on tetraphenylmethane, 9,9'-spirobifluorene and hexaphenylbenzene. Therefore we generated a rigid geometry with a defined alignment of functional groups.

[1] a) E. Mosettig, U. Beglinger, P. Quitt, F. Dolder, H. Lichti, J. A. Waters, J. Am. Chem. Soc. 1963, 85, 2305–2309; b) F. Dolder, H. Lichti, E. Mosettig, P. Quitt, J. Am. Chem. Soc. 1960, 82, 246–247.

[2] C. Lohoelter, M. Weckbecker, S.R. Waldvogel, Eur. J. Org. Chem. 2013, 5539–5554.

[3] C. Lohoelter, M. Brutschy, D. Lubczyk, S.R. Waldvogel, Beilstein J. Org. Chem. 2013, 9, 2821–2833.

New Cross-linking Monomers for Dental Materials

J.Angermann, T.Bock, U.K.Fischer, N.Moszner

Ivoclar Vivadent AG, Schaan, Pricipality of Liechtenstein

Tooth-shaded dental restaurations are becoming more and more popular. For the restauration of anterior lesions, as well as for the supply of smaller and medium sized defects in the posterior region, direct filling materials are used. Currently used dental restorative materials are visible-light curing hybrid materials consisting of a resin matrix which is a mixture of various free radical cross-linking dimethacrylates, like Bis-GMA (2,2-bis[4-(2-hydroxy-3-methacryloyloxypropyl)phenyl]propane), and inorganic fillers, such as milled glasses or highly disperse silica.

Due to the structure of Bis-GMA, which is related to bisphenol A (2,2-bis(4-hydroxy- phenyl)propane), there is an endeavor for the substitution of Bis-GMA to improve the biocompatibility of dental materials. Bisphenol A is known for its estrogenic activity and it acts as an endocrine disruptor.[1]

O O

O O O O OH OH HO OH Bis-GMA Bisphenol A In this context, we synthesized a number of crosslinking monomers with other spacer groups. These monomers based on structures like TCD (tricyclo[5.2.1.02,6]decane), biphenyls and partially aromatic urethanes, respectively.

The synthesized monomers were tested in model composites to determine their influence on selected mechanical properties and polymerization behavior. Finally, the toxicological properties of the monomers were investigated.

[1] D.Miller, B.B.Wheals, N.Beresford, J.P.Sumpter, Environ. Health Perspect. 2001, 109, 133-138.

Characterisation of Potent Biocatalysts by in vitro Studies on the Biosynthesis of the Ambruticin Western Fragment – Enzyme Expression and Precursor Synthesis

Kandziora, N., Hannover/D, Hahn, F., Hannover/D

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

The ambruticins (1) are produced by myxobacterial strains of Sorangium cellulosum (Soce10).1,2 They are polyketide type I natural products that target the high-osmolarity glycerol (HOG) protein kinase signalling pathway, thereby exhibiting potent antifungal 3 activity. JULIEN et al. proposed a biosynthetic pathway basing on the results of a gene cluster analysis and characterisation of pathway intermediates that were isolated from gene knockout strains.4 It appeared that the ambruticin biosynthetic pathway harbours a plethora of enzyme-catalysed steps whose mechanisms are unprecedented and which lead to the formation of phamacophoric structural elements. The respective enzymes are thus excellent candidates for the development of biocatalytic tools that could find an application in chemoenzymatic ambruticin total synthesis.

This contribution will highlight our current progress in investigating the THP-ring formation in the western part of the molecule and its downstream modification. We conduct in vitro-studies with the purified post-PKS enzymes of the ambruticin biosynthesis that we previously cloned and expressed heterologously in E. coli. Furthermore, the synthesis of a biosynthetic precursor surrogate for the application in these enzyme assays will be presented. The key steps of this synthesis should be a Roush allylation and a Julia-Kocienski olefination.

References: [1] S. M. Ringel, R. C. Greenough, S. Roemer, D. Connor, A. L. Gutt, B. Blair, G. Kanter, M. von Strandtmann, J. Antibiot. 1977, 30, 371. 375; [2] G. Höfle, H. Steinmetz, K. Gerth, H. Reichenbach, Liebigs Ann. Chem. 1991, 91, 941-945; [3] L. Vechter, H. G. Menzella, T. Kudo, T. Motoyama, L. Katz, Anitmicrobial Agents & Chemotherapy 2007, 51, 3734-3736; [4] B. Julien, Z.-Q. Tian, R. Reid, C. D. Reeves, Chem. Biol. 2006, 13, 1277-1286.

In vitro reconstruction of the late-stage enzymology of jerangolid biosynthesis

Friedrich, S., Hannover/D, Hahn, F., Hannover/D Leibniz University Hannover, Schneiderberg 1B, 30167 Hannover/Germany.

Jerangolids 1 are heptaketide natural products with antifungal properties[1,2], first isolated from Sorangium cellulosum (So ce307).[3] Comparative gene cluster analysis revealed extensive tailoring enzymology responsible for the formation of jerangolid A (1a) from its ACP-bound precursor 2.[4] We believe that these tailoring enzymes have huge potential to be applied as biocatalysts for mild and regioselective transformations on complex structures in natural product chemistry. This includes C-H bond activation, which is still a challenging problem in organic synthesis.

Scheme 1: Structures of jerangolids 1a and 1b derived from the putative PKS product 2. Functional groups introduced by the post-PKS enzymes JerF,O,P,L and the thioesterase JerE7 TE are highlighted. ACP = acyl carrier protein.

By combining means of synthetic organic chemistry, enzymology and molecular biology we want to reconstitute the late stages of the jerangolid biosynthetic pathway[4] in vitro. We aim at the expression and biochemical characterisation of the single involved tailoring enzymes to elucidate their reactivity and substrate scope. The results will be harnessed for elegant chemoenzymatic total syntheses of jerangolids 1a and 1b as well as not yet accessible derivatives.

[1] P. J. Westfall, D. R. Ballon, J. Thorner, Science 2004, 306, 1511-1512. [2] K. Kojima, Y. Takano, A. Yoshimi, C. Tanaka, T. Kikuchi, T. Okuno, Mol. Microbiol. 2004, 53, 1785-1796. [3] S.Ringel, R. C. Greenough, S. Roemer, D. Connor, A. L. Gutt, B. Blair, G. Kanter, M. von Strandtmann, J. Antibiot. 1977, 30, 371-375. [4] B. Julien, Z.-Q. Tian, R. Reid, C. D. Reeves, Chem. Biol. 2006, 13, 1277-1286.

In vitro investigations on the pyran formation in the ambruticin biosynthesis G. Berkhan, F. Hahn, Leibniz University Hannover, Schneiderberg 1B, 30169 Hannover/Germany.

The ambruticins (1) are an unusual group of reduced polyketides that display potent antifungal activity.1,2 A characteristic feature of their biosynthesis is that all pharmacophoric structures are formed by discrete tailoring enzymes and non-standard PKS domains, mostly via ambiguous mechanisms. Our main focus is placed on the eastern part of the molecule harboring a dihydropyran ring, which is thought to be biosynthesised through a process involving dehydration followed by cyclisation, which may be carried out by a single dehydratase (DH). We aspire to elucidate the mechanism of the THP-ring formation by a multi-disciplinary approach that combines synthetic organic chemistry, molecular biology and protein biochemistry. Subsequent dehydration-cyclisation executed by a single DH domain of a polyketide synthase has not been studied on the enzymatic level until now. This enzyme could potentially be harnessed for application as late-stage biocatalyst in chemoenzymatic synthesis.

Scheme 1: Proposed dehydratase (DH) catalysed desaturation and THP-ring formation in the biosynthesis of the ambruticin eastern fragment. ACP = acyl carrier protein. We are currently investigating mechanistic details by in vitro reconstitution of the ambruticin eastern fragment biosynthesis. Progress in cloning and expression of the putatively responsible DH domain as well as assays involving synthetically derived intermediates will be presented.

1 S. M. Ringel, R. C. Greenough, S. Roemer, D. Connor, A. L. Gutt, B. Blair, G. Kanter, M. von Strandtmann, J. Antibiot. 1977, 30, 371-375. 2 G. Höfle, H. Steinmetz, K. Gerth, H. Reichenbach, Liebigs Ann. Chem. 1991, 91, 941-945.

Variants of the Prins cyclization for the synthesis of spiroethers and oxabicyclo[3.3.1]nonanes V. Weidmann, S. Kliewer, W. Maison*, Pharmaceutical and Medicinal Chemistry, University of Hamburg, Bundesstraße 45, 20146 Hamburg, Germany

The Prins reaction, the acid mediated addition of an alkene to an aldehyde, is a method of fundamental importance for the construction of C-C bonds.1,2 Various modifications are known and a number of different carbonyl derivatives such as ketones, imines, acetals, esters and orthoesters may be used as electrophiles instead of aldehydes. These cyclizations have been extensively used for the synthesis of pyran derivatives particularly in natural products.3-5 The TMSOTf-mediated ISMS is an attractive method for the assembly of substituted di- and tetrahydropyrans from various carbonyl compounds and a silylether.6 This Prins-type cyclization proceeds via a cationic intermediate, which may either eliminate a proton (or another nucleofuge) or may be trapped with a suitable nucleophile to give the final pyran derivatives. We have used a variant of the ISMS for the preparation of some spirocyclic ethers which are similar to norisoprenoid flavor compounds such as theaspirane and vitispirane. If ketones with aromatic side chains were used as starting materials, an alternative reaction pathway was observed and the intermediate cation was trapped by intramolecular Friedel-Crafts reaction. This rare example of an intramolecular tandem Prins-Friedel-Crafts cyclization gave oxabicyclononanes with good selectivity. The reaction proceeds under thermodynamic control at reflux in CH2Cl2 to give oxabicyclononanes in good yield. (1) Prins, H. J. Chem. Weekbl. 1919, 16, 1072. (2) Prins, H. J. Chem. Weekbl. 1919, 16, 1510. (3) Han, X.; Peh, G.; Floreancig, P. E. Eur. J. Org. Chem. 2013, 1193. (4) Hanschke, E. Chem. Ber. 1955, 88, 1053. (5) Olier, C.; Kaafarani, M.; Gastaldi, S.; Bertrand, M. P. Tetrahedron 2010, 66, 413. (6) Mekhalfia, A.; Marko, I. E. Tetrahedron Lett. 1991, 32, 4779.

Fluorescence labelling of arginine as amino-diaza-azulene

M. Derks, Düsseldorf/D, M. Braun, Düsseldorf/D

Prof. Dr. Manfred Braun, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf

In order to understand biochemical processes, structure, and interaction of proteins, efficient methods for labelling and localization are required. A valuable tool for this is the site-specific implementation of fluorescent dyes as chemical reporter in non-natural amino acids, which carry fluorophores. A particularly efficient way for that is the conversion of a functional group of a proteinogenic amino acid into a fluorescent marker, especially for peptide labelling. A wide range of non-natural fluorescent - amino acids have been disclosed; however, the specific conversion of a natural amino acid into a fluorophore is rare.[1] In the middle of the last century Nozoe et al.[2] already described the condensation of tropolone methyl ether 1 with guanidine hydrochloride to give a 2-amino-1,3-diaza- azulene. We have used this type of condensation to react tropolone ether 1 with N-BOC-protected arginine 2 to obtain compound 3 in a one-step procedure. Remarkably, we were able to elaborate reactions conditions that delivered the condensation product 3 in a completely regioselective manner.

A thorough characterization, in particular by absorption and emission spectroscopy, revealed an intensive fluorescence of the amino acid 3 with an emission at 420 nm in methanol. Furthermore, the introduction of the fluorescent amino-diaza-azulen unit into small peptides (like thymopentine (TP-5, RKDVY)) was studied. A selective labelling of arginine was observed; however, the presence of lysine led to an aminotropolone conjugate, which does not show any fluorescence. The presence of this chromophore and the fluorophore will be used for further spectroscopic studies of labelled peptides, e.g. by FRET experiments.

References: [1] A. Katritzky, T. Narindoshvili, Org. Biomol. Chem. 2009, 7, 627-643. [2] T. Nozoe, Proceedings of the Japan Academy 1953, 29, 452-456. ; T. Nozoe, T. Mukai, I. Murata, J. Am. Chem. Soc. 1954, 76, 3352-3353.

Investigations of the catalytic activity of [Mn,Fe,Co(bep)X2] complexes

Samuel Lorenz, Stuttgart/DE, Bernd Plietker*, Stuttgart/DE

Bernd Plietker, Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany

In the field of biomimetic catalysis mononuclear Fe-tetramine complexes are often used as model complexes for Rieske-Oxygenase. Compared to porphinoid ligands, the structure of the tetradentate ligand leads to a cis-orientation of the two other ligands, which causes different reactivities. Those ligands are not limited to oxidation reactions, as they were already employed in several transition-metal catalysed transformations e.g. allylic substitutions[1], nitro-aldol reactions[2] or cross-coupling reactions[3]. Our group developed such ligand motifs for Ru-based catalysts in the field of oxidations, reductions and transferhydrogenations.[4] This led to the idea to use the more abundant metals Mn, Fe and Co for further investigations (Scheme 1).

Scheme 1 Synthesis of [Met(bep)(X)2]

The shown complexes have been synthesised and used in several oxidation catalyses. Future work will concentrate on an extension into the application of these complexes in other transformations like aryl coupling reactions, reductions or cyclopropanations.

References [1] B. M. Trost, I. Hachiya, J. Am. Chem. Soc. 1998, 120, 1104-1105. [2] C. J. Cooper, M. D. Jones, S. K. Brayshaw, B. Sonnex, M. L. Russell, M. F. Mahon, D. R. Allan, Dalton Trans. 2011, 40, 3677-3682. [3] P. Srinivas, P. R. Likhar, H. Maheswaran, B. Sridhar, K. Ravikumar, M. L. Kantam, Chem. Eur. J. 2009, 15, 1578-1581; J. H. Lee, H. J. Kim, Y. W. Choi, Y. M. Lee, B. K. Park, C. Kim, S.-J. Kim, Y. Kim, Polyhedron 2007, 26, 1388-1396. [4] D. Weickmann, W. Frey, B. Plietker, Chem. Eur. J. 2013, 19, 2741-2748.

Modular Strategy Towards Resveratrol-Based Natural Products

F. Klotter, Münster/DE-NW

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

Controlled access to resveratrol-dimers is offered by a novel, modular concept.[1] 1-Benzyl-1H-indene-1-carboxylic acid readily available on a large scale (43% over 8 steps) serves as the starting material for the introduction of structurally important aryl groups by a Pd-catalyzed decarboxylative arylation followed by an oxidative Heck- reaction. After deprotection of all phenol ethers natural products quadrangularin A and ampelopsin D are obtained. Pallidol is accessible through a two-step sequence using hydroboration and Friedel-Crafts alkylation followed by demethylation of all phenol ethers. This novel and highly modular concept delivers higher overall yields compared to previous total synthesis (13% versus 7% and 5%). The route benefited particularly from the development of the new decarboxylative aryl coupling reaction and shows the flexibility needed for the preparation of these derivatives.

Figure 1: Modular Approach Towards Ampelopsin D, Quadrangularin A and Pallidol.

Literature:

[1] F. Klotter, A. Studer; Angew. Chem. 2014, 126, 2505-2509; Angew. Chem. Int. Ed. 2014, 53, 2473-2476.

Functionalization of Alkyl-Allenoates Using Guanidine Organocatalysis: An Efficient Entry to Highly Substituted Heterocycles

Selig, P., Aachen/DE, Turočkin, A., Aachen/DE

Dr. Philipp Selig, RWTH Aachen University, Landoltweg 1, 52074 Aachen

The nucleophilic activation of allenoates by conjugate addition of Lewis basic catalysts (e.g. tertiary phosphines and amines) has recently emerged as a versatile method for the construction of heterocycles. Unfortunately however, this powerful methodology has been largely limited to - and -unsubstituted substrates, as alkyl-bearing allenoates are both too unreactive for nitrogen nucleophiles, and highly prone to ylide formation with phosphorus nucleophiles.

We recently introduced the cheap, commercially available bicyclic guanidine bases TBD (1) and MTBD as novel multifunctional Lewis- and Brønsted-base catalysts for the activation of alkyl-allenoates.[1] The catalytic activity of these guanidines is exception- ally high, reaction conditions are very simple and convenient, and a wide variety of hitherto unobtainable – and often very densely substituted – products were readily accessible from simple starting materials in high yields. The reactions are very robust, reproducible and scalable.

We here present the syntheses of 1,3-dioxines 2, oxetanes 3, dihydropyranes 4 and quinolines 5 by simple one-pot reactions,[2,3] as well as the formation of pyrones 6 and dihydrofuranes 7 by 2-step sequences.[4] Furthermore, reaction intermediates such as Rauhut-Currier products 8 and Morita-Baylis-Hillman products 9 were also isolable in high yields and can serve as valuable, highly functionalized building blocks.

Literature:

[1] P. Selig, Synthesis 2013, 45, 703; [2] P. Selig, A. Turočkin, W. Raven, Adv. Synth. Catal. 2013, 355, 297; [3] P. Selig, A. Turočkin, W. Raven, Chem. Commun. 2013, 49, 2930; [4] P. Selig, A. Turočkin, W. Raven, Synlett 2013, 2535-2539.

Exploring the Potential of Bifunctional Silica-Nanoparticles – A Combinational Aproach to Cooperative Metal Catalysts

S. Surmiak, Münster/DE-NW, C. Doerenkamp, Münster/DE-NW

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

The application of mesoporous silica-materials in acid-base- as well as in metal- catalyzed processes has become a well-established method in organic synthesis.[1-4] Our investigations are focused on, but not restricted to, the synthesis and catalytic application of bifunctional palladium catalysts.[5,6] This approach features a “click to ligand” strategy applying an orthogonal synthesis. The bifunctional precursor system was achieved by co-condensation of functionalized organosilanes, e.g. azides or alkoxyamines and TEOS. These functionalities could be addressed in subsequent modification reaction steps via ‘click’-chemistry, Staudinger-reaction and nitroxide exchange.

Currently sulfoxide ligand functionalized palladium catalysts that feature basic as well as acidic additives on the silica surface are tested in hydrogenation reactions of alkynes. In addition to this, phosphonate-borane-functionalized nanoparticels were prepared using the Staudinger-reaction in order to investigate the functional group distance. Therefore solid state NMR-measurements (REDOR-experiments)[7] were conducted in collaboration with Carsten Doerenkamp, member of Eckert-group from the Physical Chemistry Department.

Literature:

[1] D. Y. Zhao, Q. Huo, J. Feng, B. Chmelka, N. Melosh, G. Fredrickson and G. Stucky, Science, 1998, 279, 548; [2] a) L. Henry, Compt. Rend. Hebd. Séances Acad. Sci. 1895, 120, 1265; b) M. L. Kantam, P. Sreekanth, Catal. Lett. 1999, 57, 227; [3] J. M. Notestein, A. Katz, Chem. Eur. J. 2006, 12, 3954; [4] S. Huh, H. T. Chen, J. W. Wiench, M. Pruski and V. Lin, Angew. Chem. Int. Ed. 2005, 44, 1826; [5] A. T. Dickschat, F. Behrends, S. Surmiak, M. Weiß, H. Eckert, A. Studer, Chem. Commun. 2013, 49, 2195; [6] A. T. Dickschat, S. Surmiak, A. Studer, Synlett 2013, 24, 1523; [7] S. Elbers, W. Strojek, L. Koudelka, H. Eckert, Solid State Nucl. Magn. Reson. 2005, 27, 65.

How specific is bacterial adhesion? Analysis of carbohydrate inhibitors in fimbriae-mediated bacterial adhesion

C. Fessele, Kiel/D, Th. K Lindhorst*, Kiel/D

Christiana Albertina University of Kiel, Otto Diels Institute of Organic Chemistry, Otto-Hahn-Platz 4, 24098 Kiel, Germany

Adhesion of bacteria to the glycosylated surface of their target cells is typically mediated by fimbrial lectins, exposed on the bacterial surface. Among the best-investigated and most important fimbriae are type 1 fimbriae and P fimbriae. Whereas type 1 fimbriae are αMan specific, P fimbriae are specific for the disaccharide Gal(α1,4)Gal. This carbohydrate specificity is mediated by the fimbrial lectins FimH and PapG, respectively.[1] We have reported in the past about carbohydrate specificity of lectin- mediated bacterial adhesion and influence of the aglycone moiety,[2,3] and we have extended our work on testing of P fimbriae-mediated bacterial adhesion. In parallel with the synthesis of suitable carbohydrate derivatives, it has been our goal to increase the sensitivity of the available assay systems. In this account we will report on the various approaches we took in this interdisciplinary project (cf. Figure 1).

Man, Glc, Gal

UPEC

Inhibitors Mannan

Inhibition Adhesion

Surfaces Figure 1. Illustration of testing systems for inhibition of fimbriae-mediated bacterial adhesion.

[1] P. Klemm, M.A. Schembri, Int. J. Med. Microbiol. 2000, 290, 27–35. [2] M. Hartmann, Th. K. Lindhorst, Eur. J. Org. Chem. 2011, 3583-3609. [3] C. Fessele, Th.K Lindhorst, Biology, 2013, 2, 1135-1149.

[7] and [8] Cycloparaphenylenes – A Divergent and Selective Synthesis

F. Sibbel, Münster/DE-NW, K. Matsui, Nagoya/JP, Y. Segawa, Nagoya/JP

Prof. Dr. Kenichiro Itami, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602

The synthesis and characterization of hoop-shaped conjugated systems, as well as their unique properties and their potential applications captivated the interest of scientists for decades. [1] Cycloparaphenylenes (CPPs) form a remarkable class of these macrocycles. Due to their simple structure and the representation of the shortest sidewall segment of armchair carbon nanotubes (CNT) CPPs gained significant attention. [2] Up to date, different synthetic routes from Itami, Yamago and Jasti have been published and [n]CPPs (n = 5,6,9-16) have been synthesized. [3] Herein, we present a size selective synthesis of [7]- and [8]CPP using a divergent approach and present the first X-ray crystal structure of [7]CPP. [4]

Figure 1: Divergent synthesis of [7] and [8] Cycloparaphenylenes.

Literature:

[1] T. Kawase and C. Kurata, Chem. Rev., 2006, 106, 5250. [2] H. Omachi, T. Nakayama, E. Takahashi, Y. Segawa and K. Itami, Nat. Chem., 2013, 5, 572. [3] Selected publications: a) H. Takaba, H. Omachi, Y. Yamamoto, J. Bouffard and K. Itami, Angew. Chem. Int. Ed., 2009, 48, 6112; b) S. Yamago, Y. Watanabe and T. Iwamoto, Angew. Chem. Int. Ed., 2010, 49, 757; c) J. Xia and R. Jasti, Angew. Chem. Int. Ed., 2012, 51, 2474. [4] F. Sibbel, K. Matsui, Y. Segawa, A. Studer and K. Itami, Chem. Commun. 2014, 50, 954.

“Click”-mediated labeling of the cell wall of Mycobacterium tuberculosis with azido-modified sugars

K. Kolbe 1,2 , Kiel/D, Borstel/D, L. Möckl, Munich/D, C. Bräuchle, Munich/D, N. Reiling 2* , Borstel/D, Th. K. Lindhorst 1* , Kiel/D

1Bioorganic Chemistry, Otto Diels Institute of Organic Chemistry, Christiana Albertina University of Kiel, D-24098 Kiel, Germany, [email protected] 2Microbial Interface Biology, Research Center Borstel, Leibniz Center for Medicine and Biosciences, D-23845 Borstel, Germany

About 130 years after the discovery of Mycobacterium tuberculosis by Robert Koch, tuberculosis still kills an estimated 1.5 million people each year and is according to the WHO one of the most dangerous infectious diseases world-wide. Pathogenicity of M. tuberculosis is based on the structure of the carbohydrate-rich mycobacterial cell wall. Only recently, trehalose-derivatives have been shown to be taken up and metabolized by mycobacteria. These structures were subsequently introduced into the cell wall, without being modified by the microorganism. [1] Integrated azido- functions were addressed by bioorthogonal “click”-reactions. [2] In our current project we have searched for further azido-functionalized carbohydrates, which can be used for this labeling strategy of Mycobacterium tuberculosis, possibly leading to signals with even higher intensity. It is our aim to employ metabolic labeling of mycobacteria to improve insight into the uptake and metabolism of carbohydrates and to provide the opportunity for global modification of the bacterial surface.

[1] K. M. Backhus et al., Nat Chem Biol. 2011 , 7, 228-235. [2] B.M. Swarts et al., J. Am. Chem. Soc . 2012 , 134 , 16123-16126.

Oxidative Ring Rearrangements based on Oxygen-activating Enzymes

J. Deska, Köln/D, Daniel Thiel, Köln/D, Diana Doknić, Köln/D

Dr. Jan Deska, Department Chemie, Universität zu Köln, DE-50939 Cologne, Germany

In 1971, Achmatowicz reported on an oxidative transformation of α-heterosubstituted furans to yield functionalized pyran derivatives via ring expansion upon treatment with bromine in methanol and subsequent acidic hydrolysis.[1] In the sequel, the Achmatowicz rearrangement evolved into an elegant tool for the preparation of six- membered O- and N-heterocyclic building blocks and found application in the total synthesis of complex natural products.[2] However, the true synthetic capability of this reaction seems not yet been reached. In the course of the ubiquitously discussed medium to long-term reorganization of our value chains towards sustainable raw materials as sources for bulk and fine chemicals, the efficient and resource-sparing use of biogenic furans, accessible from second generation biorefinery, is attracting more and more attention,[3] both regarding the development of novel applications as well as the improvement of existing synthetic strategies. A truely biocatalytic, artificial Achmatowicz monooxygenase-like process was successfully designed based on the combination of oxidases as oxygen-activating catalyst and hydrogen peroxide-dependent oxygen transfer systems.[4] In concert with enzymatic transformations for the enantioselective synthesis of optically active furylcarbinols, purely biocatalytic reaction cascades for the stereocontrolled construction of highly functionalized pyranones are obtained. Substrate scope and limitations, mechanistical details and the expansion towards redox-neutral Achmatowicz rearrangements will be presented.

O OH

HO O

[1] O. Achmatowicz, P. Bukowski, B. Szechner, Z. Zwierzchowska, A. Zamojski, Tetrahedron 1971, 27, 1973-1996. [2] (a) M. A. Ciufolini, C. Y. W. Hermann, Q. Dong, T. Shimizu, S. Swaminathan, N. Xi, Synlett 1998, 105-114; (b) M. C. Cassidy, A. Padwa, Org. Lett. 2004, 6, 4029-4031. [3] J. P. Lange, E. van der Heide, J. van Buijtenen, R. Price, ChemSusChem 2012, 5, 150-166. [4] D. Thiel, D. Doknić, J. Deska, 2014, manuscript submitted.

Migratory Dynamic Kinetic Resolution of Carbocyclic Allylic Alcohols

J. Deska, Köln/D, C. Manzuna Sapu, Köln/D

Dr. Jan Deska, Department Chemie, Universität zu Köln, DE-50939 Cologne, Germany

Enzyme catalyzed kinetic resolution processes enjoy great popularity when it comes to the preparation of enantiopure chiral building blocks. In cases where both enantiomers are required, acylative resolutions represent a valuable tool providing scalable and reliable access to the desired compounds. From a synthetic perspective, however, the limitation to a maximum yield of 50% needs to be regarded a major drawback. Over the years, various ways to selectively racemize enzyme substrates have been developed allowing for the in situ interconversion from one stereoisomer to the other giving rise to dynamic kinetic resolutions with theoretical yields of 100% of one enantiomer.[1] While most systems focus on the implementation of transition metal complexes or additional biocatalysts to achieve racemization, in certain cases simple acid or base promoters qualify as cheap and practicable alternative.[2] Herein, we present an easy-to-use teabag setup in a metal-free one-pot approach for the coupled isomerization/dynamic kinetic resolution employing resin-bound catalysts (lipase & Brønsted acid). Tertiary allylic carbinols, readily obtained through addition of organolithium or organomagnesium reagents to enones,[3] rapidly rearrange to form racemic secondary alcohols triggered by a polymer-supported sulfonic acid. Concurrently, the same acid catalyst acts as racemization promotor while lipases selectively consume the (R)-configured alcohols. That way, carbocyclic allylic esters are obtained in high yields and enantiopurities greater 98% ee.

[1] (a) N. J. Turner, Curr. Opin. Chem. Biol. 2004, 8, 114-119; (b) O. Pàmies, J.-E. Bäckvall, Chem. Rev. 2003, 103, 3247-3261. [2] (a) O. May, S. Verseck, A, Bommarius, K. Drauz, Org. Proc. Res. Dev. 2002, 6, 452-457; (b) S. Wuyts, K. De Temmerman, D. E. De Vos, P A. Jacobs, Chem. Eur. J. 2005, 11, 386-397. [3] J. Ramharter, J. Mulzer, Org. Lett. 2011, 13, 5310-5313.

Investigations on synthesis and structure activity of dihydropyridines as NOTCH signaling inhibitors

R. Nohl, Jena/D, P. Rohland, Jena/D, A. Krämer, Jena/D, M. Wesolowski, Jena/D, C. Käther, Jena/D and H.-D. Arndt, Jena/D

Prof. Dr. Hans-Dieter Arndt, Friedrich-Schiller-Universität Jena, Humboldtstr. 10, 07743 Jena/D

Inhibiting the secretion at the rough ER side dihydropyridine 1 was found to disrupt the NOTCH signaling in a new and unique fashion.[1]

An optimized one-pot synthesis[2] of asymmetric dihydropyridines opens up an area of synthetic structure variation.

By stepwise structure diversification of the lead compound 1, we prepared a focused compound collection to explore structure activity relationships by SAR analysis. These data might be especially useful in the light of recently discovered bioactivities of the dihydropyridine scaffold.[3],[4]

Literature:

[1] A. Krämer, T. Mentrup, B. Kleizen, E. Rivera-Milla, D. Reichenbach, C. Enzensperger, R. Nohl, E. Täuscher, H. Görls, A. Ploubidou, C. Englert, O. Werz, H.-D. Arndt & C. Kaether, Nat. Chem. Biol., 2013, 9, 731-738. [2] C. G. Evans and J. E. Gestwicki, Organic Letters, 2009, 11, 2957-2959. [3] L. Bärfacker, A. Kuhl, A. Hillisch, R. Grosser, S. Figueroa-Pérez, et al., Chem. Med. Chem., 2012, 7, 1385-1403. [4] E. Willems, J. Cabral-Teixeira, D. Schade, W. Cai, P. Reeves, P. J. Bushway, et al., Cell Stem Cell, 2012, 11, 242-252.

Synthesis of tripodal oligosaccharide mimics and evaluation of binding properties by STD-NMR and lectin arrays

Carsten Fleck,[a] Elisabeth Memmel,[b] Moritz Fölsing,[c] Thomas Hackl,[c] Jürgen Seibel*[b] and Wolfgang Maison*[a],

[a] Pharmaceutical and Medicinal Chemistry, University of Hamburg, Bundesstraße 45, 20146 Hamburg, [b] Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, [c] Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg

Carbohydrates are a common structural element on cell surfaces. They play a crucial role in various biological recognition phenomena responsible for cell adhesion and motility, antigen/antibody interactions, cancer metastasis and viral or bacterial infections. Most of these interactions are

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

mediated by sugar residues which interact O

with specific biological receptors.(1,2) In O

O H O biological systems, sugar residues are H generally arranged in geometrically well defined multivalent clusters on the surface of cells to improve the affinity between carbohydrates and their receptor by a multivalency effect.(3) Multivalent carbohydrate conjugates have been used frequently to study and manipulate these interactions.(4,5) Herein we present the synthesis of trimeric glucose and mannose conjugates, assembled with an adamantanescaffold.(6) Evaluation of the binding properties of the resulting neoglycoconjugates was performed in solution by STD-NMR and and lectin arrays.

Literature:

(1) Dwek, R. A. Chem. Rev. 1996, 96, 683. (2) Pieters, R. J. Org. Biomol. Chem. 2009, 7, 2013. (3) Kiessling, L. L.; Gestwicki, J. E.; Strong, L. E. Angew. Chem., Int. Ed. 2006, 45, 2348. (4) Reina, J. J.; Bernardi, A. Mini-Rev. Med. Chem. 2012, 12, 1434. (5) Wehner, J. W.; Hartmann, M.; Lindhorst, T. K. Carbohydr. Res. 2013, 371, 22. (6) Fleck, C.; Franzmann, E.; Claes, D.; Rickert, A.; Maison, W. Synthesis 2013, 45, 1452.

Toward a Total Synthesis of Urukthapelstatin A

S. Schwenk, Jena/D, C. Ronco, Jena/D, M. Brensing, Jena/D, H.-D. Arndt, Jena/D

Prof. Dr. H.-D. Arndt, Friedrich Schiller University Jena, Institut of Organic and Macromolecular Chemistry, Humboldtstr. 10, 07743 Jena

Urukthapelstatin A (1) is a peptide derived natural product isolated from

Mechercharimyces asporophorigenenes YM11-542 and shows a promising GI50 of 15 nM on cancer cell panels.[1] The related compound telomestatin is an inhibitor of telomerase.[2]

An approach for the total synthesis of Urukthapelstatin A (1) could be the selective and high yielding azoline synthesis via aza-Wittig[3] and a one pot thioester formation-aza- Wittig reaction. The thiazole and oxazole containing natural product could arise from the reduced form 2. Applying macrothiolactonization and aza-Wittig-reactions, the macrocylic structure could be simplified to a linear depsipeptide. The linear chain precursor of 2 could be assembled from commercially available amino acids. Progress along these research directions will be presented.

Literature:

[1] Y. Matsuo, K. Kanoh, T. Yamori, H. Kasai, A. Katsuta, K. Adachi, K. Shin-ya, Y. Shizuri, J. Antibiot. 2007, 4, 251-255. [2] A. De Clan, G. Cristofari, P. Reichenbach, E. De Lemos, D. Monchaud, M.-P. Teulade-Fichou, K. Shin-ya, L. Lacroix, J. Lingner, J. L. Mergny, Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 17347-17352. [3] P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt, Eur. J. Org. Chem. 2013, 16, 3290-3315.

Recent Total Syntheses of Biscarbazole Alkaloids

S. K. Kutz, Dresden/D; C. Börger, Dresden/D

Prof. Dr. H.-J. Knölker, TU Dresden, Bergstraße 66, 01069 Dresden

A wide range of tri- and tetracyclic carbazole alkaloids has been isolated, synthesised and investigated towards their biological activity over the past decades. [1] However, only a few synthetic approaches to biscarbazole alkaloids, like oxydimurrayafoline (1), murrastifoline-A (2), bismurrayafoline-A (3), or murrafoline-D (3), have been developed so far. [2–5]

We would like to present selective syntheses of biscarbazole alkaloids. Different techniques for the connection of the monomeric carbazole units have been applied, like nucleophilic substitution, Ullmann coupling, Goldberg-Ullmann coupling, or a Sonogashira coupling followed by Claisen rearrangement and electrocyclisation.

Literature:

[1] A. W. Schmidt, K. R. Reddy, H.-J. Knölker, Chem. Rev. 2012, 112, 3193. [2] C. Börger, M. P. Krahl, M. Gruner, O. Kataeva, H.-J. Knölker, Org. Biomol. Chem. 2012, 10, 5189. [3] C. Börger, O. Kataeva, H.-J. Knölker, Org. Biomol. Chem. 2012, 10, 7269. [4] V. P. Kumar, K. K. Gruner, O. Kataeva, H.-J. Knölker, Angew. Chem. 2013, 52, 11073. [5] C. Börger, A. W. Schmidt, H.-J. Knölker, Org. Biomol. Chem. 2014, DOI: 10.1039/c4ob00609g.

Design of Fluorescent, Cation-Sensitive Pyranoindoles

Tobias Glißmann, Thomas J. J. Müller Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf/D

In 2010 we found an access to the class of 2,4-diarylpyrano[2,3-b]indoles, which were unknown in literature and which exhibit an interesting luminescence generation in the presence of Brønsted or Lewis acids[1].

The use of a donor-functionalized alkyne in the synthesis of the 2,4-diarylpyrano[2,3-b]indoles leads to a donor-π-acceptor chromophore with the indole moiety furnishing as an acceptor. The electronic environment of the nitrogen atom can be strongly influenced upon addition of Brønsted acids or metal salts resulting in a redshift of the absorptions and an induction of fluorescence detectable on eyesight. This behavior makes the pyranoindoles interesting sensors for acids or metal cations, and even for bases, in case where the donor is an OH-group. The current work’s main goal is to introduce water solubility for this class of compounds. This can be realized by the formal implementation of a sulfonic acid group in the molecule.

[1] J. Schönhaber, W. Frank, T. J. J. Müller, Org. Lett. 2010, 12, 4122-4125.

Synthesis of a rotaxane with an unsymmetrical axis

M. Berg, Bonn/DE

Prof. Dr. A. Lützen, Rheinische Friedrich-Wilhelms-University of Bonn, Gerhard- Domagk-Str.1, 53121 Bonn .

The design of artificial transmembrane channels has been widely investigated in organic chemistry.[1] In order to make these channels usable for sensors or molecular machines, they have to be able to undergo a directional motion. Rotaxanes, in which a wheel is threaded onto an axis with blocking groups on the ends, are very promising for this purpose because the ability of the wheel to slide along the axle can be influenced by an external stimulus.[2] Therefore, we designed an acid-base switchable rotaxane that consists of a non- symmetrical axis with a cholesterol blocking group and a bisparaphenylene-34-crown- 10 wheel. The synthesis of this rotaxane will be presented.

Figure 1 . Structure of the [2]rotaxane with a permanent (red) and a pH dependent (green) binding site.

[1] a) I. Tabushi, Y. Kuroda, K. Yokota, Tetrahedron Lett. 1982 , 23 , 4601-4604. b) L. Jullien, J.-M. Lehn, Tetrahedron Lett. 1988 , 29 , 3803-3806. c) G.W. Gokel, O. Murillo, Acc. Chem. Res. 1996 , 29 , 425-432. d) N. Yoshino, A. Satake, Y. Kobuke, Angew. Chem. 2001 , 113 , 471-473 [2] a) J. D. Badjic, V. Balzani, A. Credi, S. Silvi, J. F. Stoddart, Science 2004 , 303 , 1845-1849. b) J. Berna, D. A. Leigh, M. Lubomska, S. M. Mendoza, E. M. Perez, P. Rudolf, G. Teobaldi F. Zerbetto, Nature 2005 , 4, 704-710. V. Blanco, A. Carlone, K. D. Hänni, D. A. Leigh, B. Lewandowski, Angew. Chem. 2012 , 124 , 1- 5.

Self-Sorting Processes of Dinuclear Hetero – and Homochiral Rhombs and their Deposition on HOPG

Christina Tenten, Bonn/DE, Caroline Stobe, Bonn/DE, Gregor Schnakenburg, Bonn/DE, Filip Topić, Jyväskylä,FI, Kari Rissanen, Jyväskylä/FI, Stefan Jester, Bonn/DE, Arne Lützen, Bonn/DE

Prof. Dr. Arne Lützen, Rheinische-Friedrich-University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn

One major issue of our group’s research program is the investigation of diastereoselective self-assembly processes of metallosupramolecular complexes. The comparison of racemic and enantiomerically pure dissymmetrical ligands based on, e.g., the Tröger’s base, the BINOL, or the 9,9’-Spirobifluorene scaffold, reveals interesting self-sorting processes of the racemic compounds.[1] An example of such dinuclear metallosupramolecular rhombs is shown in Figure 1.

Figure 1. Structure of the heterochiral (left) and homochiral complexes (right) obtained from bis(pyridine) ligands with a Tröger’s base scaffold as determined by X-ray diffraction.

Having learnt much about the self-assembly process we are now working on the decoration of solid surfaces like HOPG with these diastereomerically pure metallosupramolecular aggregates in order to achieve highly ordered surface patterns. Therefore, we have to modify the ligands backbone with long alkyl chains to optimize the interaction between the complexes and surface.

Literature:

[1] a) U. Kiehne, T. Bruhn, G. Schnakenburg, R. Fröhlich, G. Bringmann, A. Lützen, Chem. Eur. J. 2008, 14, 4246. b) T. Weilandt, U. Kiehne, J. Bunzen, G. Schnakenburg, A. Lützen, Chem. Eur. J. 2010, 16, 2418. c) C. Gütz, R. Hovorka, C. Stobe, N. Struch, F. Topić, G. Schnakenburg, K. Rissanen, A. Lützen, Eur. J. Org. Chem. 2014, 206. d) R. Hovorka, S. Hytteballe, T. Piehler, G. Meyer-Eppler, F. Topić, K. Rissanen, M. Engeser, A. Lützen, Beilstein J. Org. Chem. 2014, 10, 432

One-pot synthesis of heterocyclic compounds via butadiynes followed by superbase-mediated cyclization F. Klukas, Düsseldorf/D, T. J. J. Müller, Düsseldorf/D Prof. Dr. T. J. J. Müller, Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf

Multicomponent Reactions (MCRs) [1] are diversity-oriented syntheses (DOS) [2] and have been developed to powerful tools for exploring broad ranges of structural and functional characteristics. Besides lead identification in pharmaceutical and medicinal chemistry MCRs have also been recognized as a DOS tool for approaching functional π-systems such as luminescent chromophores. usymmetrically substituted conjugated thiophenes 16 examples (23 - 84 %) (hetero)aryl (hetero)aryl SH S (hetero)aryl

Sonogashira-Glaser sequence DMSO, KOH, MW (hetero)aryl

(hetero)aryl (hetero)aryl iodine (hetero)aryl

H O 2 (hetero)aryl O (hetero)aryl DMSO, KOH, MW

intensively fluorescent furans 15 examples (19 - 65 %) Scheme 1: One-pot pseudo-five-component syntheses of functionalized thiophenes and furans. Recently, we became particularly interested in sequentially Pd-catalyzed processes starting from (hetero)aryl iodides. Based upon the Sonogashira-Glaser sequence [3] we developed straightforward one-pot syntheses to 2,5-di(hetero)arylfurans with remarkably high quantum yields [4] and unsymmetrically substituted conjugated 2,3,5- tri(hetero)arylthiophenes [5].

Literature: [1] T. J. J. Müller in “Multicomponent Reactions 1”, Müller, T. J. J. et al. Thieme, 2013 . [2] M. D. Burke, S. L. Schreiber Angew. Chem. Int. Ed. 2004 , 43 , 46-58. [3] E. Merkul, D. Urselmann, Müller, T. J. J. Eur. J. Org. Chem. 2011 , 238–242. [4] F. Klukas, A. Grunwald, F. Menschel, T. J. J. Müller Beilstein J. Org. Chem. 2014 , 10 , 672–679. [5] F. Klukas, J. Perkampus, D. Urselmann, T. J. J. Müller, manuscript in preperation.

Carbohydrate Ligands in the Enantioselective Cyclopropanation of Indoles

T. Schubach, Hannover/D, G. Özüduru, Hannover/D, M. M. K. Boysen, Hannover/D

Jun.-Prof. Dr. Mike M. K. Boysen, Leibniz University of Hannover, Schneiderberg 1B, 30167 Hannover, Germany

Bis(oxazoline) (Box) ligands are important chiral inductors for metal-catalysed asymmetric reactions. [1] Our group develops new carbohydrate-based ligands for asymmetric catalysis, [2] and we have introduced the glucoBox ligand series based on glucosamine, [3] giving high asymmetric induction in Cu(I)-catalysed cyclopropanation even for challenging aliphatic olefins. [3b] When using carbohydrates for ligand design, obtaining both enantiomers of a ligand can be difficult, as L-sugars are often prohibitively expensive. This issue can be circumvented by using pseudo-enantiomeric ligands prepared from suitable D-carbohydrates. Currently we are working towards the design of pseudo-enantiomers for glucoBox ligands containing D-altrose and D-idose scaffolds.

Our glucoBox ligands proved highly useful in the asymmetric cyclopropanation of indoles, for which only racemic [4] and diastereoselective [5] examples are known. 3- Methyl-N-Boc indole yielded a cyclopropane with a new quaternary stereocentre in excellent ee. [6] This product is a valuable intermediate for the synthesis of indole alkaloids, as we demonstrated in the synthesis of (-)-desoxyeseroline. [6] We are currently working towards the enlargement of the reaction scope to indoles carrying functionalised 3-substituents.

Literature: [1] H. A. McManus, P. J. Guiry, Chem. Rev. 2004, 104, 4151. [2] a) M.M.K. Boysen (Ed.), Carbohydrates – Tools for Stereoselective Synthesis, Wiley-VCH, Weinheim, Germany, 2013; b) S. Woodward, M. Diégeuz, O. Pàmies, Coord. Chem. Rev. 2010, 254, 2007. [3] a) T. Minuth, M. Irmak, A. Groschner, T. Lehnert, M. M. K. Boysen, Eur. J. Org. Chem. 2009, 7, 997; b)T. Minuth, M. M. K. Boysen, Synthesis, 2010, 2799. [4] E. Wenkert, M. E. Alonso, H. E. Gottlieb, E. L. Sanchez, J. Org. Chem. 1977, 42, 3945. [5] H. Song, J. Yang, W. Chen, Y. Qin, Org. Lett. 2006, 8, 6011. [6] G. Özüduru, T. Schubach, M. M. K. Boysen, Org. Lett. 2012, 14, 4990.