Organic Chemistry

570 CHIMIA 2012, 66, No. 7/8 Organic chemistry

doi:10.2533/chimia.2012.570 Chimia 66 (2012) 570–605 © Schweizerische Chemische Gesellschaft

OrganicChemistry Organic Chemistry Organic Chemistry,Talk 358 Organic Chemistry,Talk 359 Screening of Chiral Organocatalysts for the Aldol ReactionbyMass AConcise Organocatalytic Approachfor the Spectrometric Monitoring of the Retro Reaction Stereoselective FormalSynthesis of AnachelinH

Florian Bächle,Andreas Pfaltz* Suman De Sarkar andKarlGademann*

University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland DepartmentofChemistry, UniversityofBasel,St. Johanns-Ring 19, CH-4056 Basel, Switzerland Recently, our group developed anew high throughput screening method for

the determination of the intrinsic enantioselectivity of chiral catalysts for the 1 Pd-catalyzed allylic substitution based on electrospray mass spectrometry The iron chelator anachelin is an important secondary metabolite for cya- and mass-labeled quasi-enantiomeric substrates [1]. As well, this method nobacteria Anabaenacylindrica exhibiting dualrole of both self-growth ac- was successfully applied to organocatalyzed asymmetric Diels-Alder [2] and celerationand growth inhibition of competing green algae. Thus we decided Michael reactions [3]. Monitoring the back reaction, the ratio of the detected to investigate the specificbioactivityofdifferentfragments to getaclear intermediates reflects the enantioselectivity of the corresponding forward insight intothe dualmodeofactionofthe complex naturalproduct. Herein reaction. we presentaconcise route for the asymmetric synthesis of polyketidechain Herein, we present our results for the application of this method to organo- fragment. Starting from N-Boc-L-serine the synthesis comprises metalcata- catalyzed aldol reactions. In contrast to our previous studies in which the lyzedasymmetric allylation on GarneraldehydefollowedbyGrubbs me- iminium ion was the intermediate for ESI-MS analysis, the adol reactions tathesis.The crucial part of the synthesis is the one-pot organocatalytic proceed via enamines which are more challenging to visualize. epoxidation andafollow-upesterification by acarbene catalyzed internal redox process.2 Finallyamidation andremoval of protectinggroups complete the stereoselective formal synthesis of thismetabolite.

[1] For areview see: C. Müller, C. Markert, A. Teichert, A. Pfaltz, Chem. [1]K.Gademann, Y. Bethuel, Org. Lett. 2004, 6,4707; K. Gademann, Y. Commun. 2009,1607. Bethuel, Angew.Chem.Int. Ed. 2004, 43,3327. [2] A. Teichert, A. Pfaltz, Angew. Chem. Int. Ed. 2008, 47,3360. [2]H.Jiang, B. Gschwend, L. Albrecht, K. A. Jørgensen, Org. Lett. 2010, [3] I. Fleischer, A. Pfaltz, Chem. Eur. J. 2010, 16,95. 12,5052.

OrganicChemistry OrganicChemistry Organic Chemistry,Talk 360 Organic Chemistry,Talk 361 Mechanistic Insights into Electrophilic Trifluoromethylations with Hy- ChemicalProtein Synthesis using α-Ketoacid–Hydroxylamine (KAHA) pervalent Iodine Reagents Ligation with 5-Oxaproline

N. Santschi, N. Hauser, A. Togni* Vijaya R. Pattabiraman, Ayodele O. Ogunkoya, Jeffrey W. Bode*

Department of Chemistry and Applied Biosciences, Swiss Federal Institute Laboratorium für Organische Chemie, Wolfgang-Pauli-Strasse 10, of Technology, ETH Zürich, CH-8093 Zürich, Switzerland ETH Zürich, 8093 Switzerland

Chemoselective ligation reactions that can be performed in aqueous buffers with unprotected peptide/protein segments, ideally between any pair of amino acids, are valued reactions for chemical synthesis of proteins. The α- ketoacid–hydroxylamine (KAHA) ligation with 5-oxaproline is apromising method for the preparation of both natural and modified proteins. In this ligation, aC-terminal peptide α-ketoacidreacts chemoselectively with an N- Since the advent of reagent 1 and 2 aplethora of nucleophiles have been terminal 5-oxaproline peptide to give the target protein with an α- successfully targeted. Among the first functional groups to be trifluoro- homoserine at the ligation site. This ligation works well for the synthesis of methylated, thiols were the most promising ones due to short reaction times proteins in aqueous buffers with unprotected protein segments and produces and ahigh functional group tolerance.1 carbondioxide as the only by-product.

When comparing the reactivity of chalcogens towards the reagents very dif- R O O H O N ferent mechanistic behavior is observed. For example, hard oxygen nucleo- H3N Protein Segment 1 N OH N Protein Segment 2 H O O H OH philes such as hydrogen phosphates putatively form acomplex through co- α−Ketoacid 5-oxaproline ordination to the iodonium core followed by reductive elimination to furnish KAHA ligation 2 R the product. Thiols, on the other hand, display distinct characteristicsofa H O N O H3N Protein Segment 1 N N Protein Segment 2 radical mechanism where the S-Cbond formation event is proposed to occur H H through subsequent single electron transfers in aS 2type fashion. As afun- O OH N Synthetic OH Synthetic damental understanding of these mechanisms of action are important in or- cspA protein Synthetic proteins with α-homoserine (Hse, T §) Pup protein der to specifically design new nucleophiles and improve on the reactivity of The synthesis of Prokaryotic ubiquitin-like protein (Pup) and probable cold- 1 and 2,these differences will be discussed and experimental data corrobo- shock proteinA(cspA) using KAHA ligation with 5-oxaproline will be dis- rating either hypothesis presented. cussed along with the scope of the ligation reaction.

[1] Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, [1] J. W. Bode, R. M. Fox, K. D. Baucom. Angew. Chem. Int. Ed. 2006, 46,754. 45,1248. [2] Santschi, N.; Geissbühler, P.; Togni, A. J. Fluorine Chem. 2012, 135, [2] V. R. Pattabiraman, A. O. Ogunkoya, J. W. Bode. Angew. Chem. Int. 83. Ed. 2012,DOI: 10.1002/anie.201200907. Organic chemistry CHIMIA 2012, 66, No. 7/8 571

Organic Chemistry Organic Chemistry Organic Chemistry,Talk 362 Organic Chemistry,Talk 363 Synthesis andbiochemical characterization of triphosphates with side Pd-Catalyzed Oxy- andAmino-Alkynylation of Olefins chainscapable of organocatalysisand transitionmetal binding StefanoNicolai,Jérôme Waser Marcel Hollenstein1 LaboratoryofCatalysis andOrganic Synthesis, EPFL, 1 DepartmentofChemistry andBiochemistry, UniversityofBern, 1015 Lausanne,Switzerland Freiestrasse 3, CH-3012 Bern, Switzerland O- and N-containing heterocycles arecommon scaffolds in both natural Nucleoside triphosphates(dNTPs)haveadvanced as aversatile platformfor products andother bioactive compounds.Avaluable strategy for thesynthe- the generation of modifiednucleic acids andaviable alternativetothe tradi- sis of these compounds is basedonthe cyclizationofO-and N-nucleophiles tionalautomated solid-phase synthesis of oligonucleotides [1]. Various onto non-activated olefinscombinedwith afurther C-Cbond forming event. dNTPs embellished with side-chains capable of enamine-basedorganocatal- Despitethe enormous synthetic potential of acetylenes, no methods for the ysis (1-3), activationofLewis basic substratesthroughthe casting of ex- oxy- andaminoalkynylation of olefins hadbeen previouslydescribed. tendedhydrogenbond networks(4and 5), andbinding to transition metals We report herein twocomplementary approaches basedonPdcatalysis to via phosphane lignads(6)weresynthesized [2], [3]. achieve thiskind of transformation.The cyclizationof-alkenyl carboxylic acids1 and N-tosyl amides2 waseffectivelyaccomplishedthrougha Pd(II/IV)-catalyzed processusing the hypervalent iodine reagentTIPS- EBX. The -and -lactams accessed thisway could be then used for the two-step synthesis of pyrrolizidine andindolizidine heterocycles. By contrast, 2-propargyl tetrahydrofuransand pyrrolidinescould be obtainedin excellent yields anddiastereoselectivitybyPd(0/II)-catalyzed cyclizationof alkenyl alcohols andaminesusing TIPS-protected bromoacetylene.

The capacityofthese modifieddNTPs to act as substrates for DNApoly- merases in particular, andtheir compatibility withSELEX in general, was also assessed.

[1]Nicolai, S.;Erard, S.;Fernández-González,D;Waser,J.Org. Lett., [1]M.Hocek,M.Fojta, Org.Biomol. Chem. 2008, 6,2233. 2010, 12,384. [2]M.Hollenstein, Chimia, 2011, 65,770-775. [2]Nicolai, S.;Piemontesi, C.;Waser,J.Angew. Chem Int. Ed. 2011, 51, [3]M.Hollenstein, C. J. Leumann, Chem.Eur.J.2012,submitted. 4680. [3]Nicolai, S.;Waser,J.Org. Lett. 2011, 13,6324.

OrganicChemistry OrganicChemistry Organic Chemistry,Talk 364 Organic Chemistry,Talk 365 Enantioselective Allylic Amination, Etherification and Thioetherifica- In vitro Studies on the Phenol Coupling and Aromatic Chlorination tion with an uniquely reactive (P,alkene)-Ir Complex: Direct Substitu- Reactions in VancomycinBiosynthesis tion of racemicAllylic Alcohols Patrick C. Schmartz, K. Zerbe, E. Gad, K. Abou-Hadeed, J. A. Robinson* Markus Roggen, Erick M. Carreira University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland ETH Zürich, CH-8093 Zürich, Switzerland Glycopeptide antibiotics are promising candidates in the development of Chiral allylic amines, ethers and thioethers are valuable intermediates in or- novel antibacterial compounds that retain activity against Gram-positive ganic synthesis. bacteria. Striking features of this class of natural products are the extensive phenol coupling of alinear peptidic precursor catalyzed by dedicated P450 NH2 enzymes and the regiospecific aromatic chlorination catalyzed by asingle R flavin-dependent halogenase. We have shown in previous substrate specific- Stereospecific O ity studies with the vancomycin biosynthetic enzyme OxyB, which forms Cl O OH OR' the first cross-link between residues-4 and -6, that this phenol coupling reac- P N Enantioselective Ir N tion can occur on apeptide carrier protein (PCP)-linked model hexapeptide R R P O O including tyrosine in positions-2 and -6 [1]. The natural substrate of OxyB, Enantioconvergent however, should contain β-hydroxy groups in these residues. The exact tim- SR' ing of aromatic chlorination during non-ribosomal backbone assembly re- R mains unproven (before or after phenol coupling). Here, we present an efficient method to investigate the effect of β-hydroxy groups and chlorine sub- The reported iridium/phosphorous-olefin complex allows the direct conver- stituents in residues-2 and -6 on the OxyB catalyzed phenol coupling [2]. sion of branched allylic alcohols into various chiral products. Enantioselec- [1] [2] X X tive and enantiospecific allylic amination uses sulfamic acid as aconven- OH OH HO OH 1. OxyB, reduction O HO system, O ient ammoniasurrogate. Enantioselective allylic etherification was achieved X 2 R R 2. cleavage from R X R [3] O O O O O O through the identification of aBrønsted acid promoter. The catalyst toler- H H H H H PCP domain H H H H H Z 5 N 3 N 1 N Z N N N 6 N 4 N 2 N N N N ates thiols which enabled the development of an enantioselective allylic thi- H H H H H H O O O O O O oetherification, which was procedeeds via an unusual enantioconvergent O O NH H N [4] 2 2 mechanism, promoted by dibutyl phosphate. OH OH Z=H [1] C. Defieber, M. A. Ariger, P. Moriel, E. M. Carreira, Angew. Chem. Z=PCP 2NHN R=HorOH R=HorOH Int. Ed. 2007, 46,3139; b) M. Lafrance, M. Roggen, E. M. Carreira, X=HorCl X=HorCl Angew. Chem. Int. Ed. 2012, 51,3470 [1] K. Woithe et al., J. Am. Chem. Soc. 2007, 129,6887-6895. [2] M. Roggen, E. M. Carreira, J. Am. Chem. Soc. 2010, 132,11917. [3] M. Roggen, E. M. Carreira, Angew. Chem. Int. Ed. 2011, 50,5568. [2] P. C. Schmartz et al.,manuscript submitted, 2012. [4] M. Roggen, E. M. Carreira, 2012, submitted 572 CHIMIA 2012, 66, No. 7/8 Organic chemistry

OrganicChemistry Organic Chemistry Organic Chemistry,Talk 366 Organic Chemistry,Talk 367 Post CA-CRTransformations of PCBDs Synthesis of C(6’)-functionalized tricyclo-DNA forthe preparation of an oligonucleotideprodrug Adam Lacy1,FrançoisDiederich1,Jean-PaulGisselbrecht2,Corinne Bou- don2 Jory Liétard andChristian J. Leumann

1Laboratoriumfür Organische Chemie,ETH Hönggerberg, HCI, CH-8093, DepartmentofChemistryand Biochemistry, UniversityofBern, Zürich,Switzerland Freiestrasse 3, 3012 Bern,Switzerland 2Laboratoire d’Electrochemie et de Chimie Physique de CorpsSolide, Insti- tute de Chemie-LC3-UMR 7177, CNRS,Universitié LouisPasteur,4,rue Tricyclo-DNA (tc-DNA)isanoligonucleotide analog with therapeuticpo- de Blaise Pascal,F-67000 Strasbourg, France tential as antisense andsiRNA agent. Indeed,tc-DNAbinds to RNAwith increasedaffinity, is resistanttonucleasesand doesnot elicit RNaseH- Theclick-type cycloadditioncycloreversion(CA-CR) reactionbetween mediated cleavage.1 However,asmost of the otheroligonucleotide analogs, electron-rich alkynes, andpolycyanoethenes [1]has been employedexten- tc-DNAsuffers from poorcellular uptake. To addressthis issue, apromising sively forthe rapidformationofpoly-cyanobutadienes(PCBDs) bearing strategy consists in temporarilyintroducingfunctionalgroups with biolabile electrondonatingsubstituents[2]. moieties that areexpected to be cleavedbycytosolicenzymes oncethe oli- 2 CN gonucleotide is internalized (prodrugapproach). Therefore,inanattempt to R' CN NC CN R' R' prepareatc-DNAprodrug,wemodifiedthe tricyclic sugarstructure with a CN CN

R R biolabile ester function at position C(6’). We report on the synthesis of R R EDG EDG EDG R R C(6’)-functionalizedtc-DNAanalogs as well as their incorporation intooli-

EDG=Electron Donating Group gonucleotides. The biophysicalproperties of the modifiedoligonucleotides were investigated. Adecathymidylate containing five lipophilic ester side We reporthereinthatthe applicationofananilinefunctionality as theelec- chains (tchd-T)was showntoentercells without theuse of anytransfection tron donor in theCA-CR reactionfurnishes aflexibleplatformfor subse- agent. quent transformations of PCBDs. Hence, forthe firsttime,derivatives of this important classofcompounds lackinganelectrondonatingsubstituent have been prepared,and theirelectronreductionpotentials have been assessed experiementally. It hasalsobeen found that this novelclass of PCBDsare stable to awide range of reactionconditions,thus offering novelstrategiesfor theintroduc- tionofthisimportant motif into interestingscaffoldssuchasmacrocycles andfoldamers. [1]T.Michinobu,J.C.May,J.H.Lim, C. Boudon,J.-P. Gisselbrecht, P. [1] Leumann, C. J. Bioorg. Med.Chem. 2002, 10,841. Seiler, M. Gross, I. Biaggio, F. Diederich, Chem.Commun. 2005,737. [2] Tosquellas,G.; Alvarez, K.; Dell'Aquila,C.; Morvan, F.;Vasseur,J.- [2]M.Kivala, F. Diederich, Acc. Chem.Res. 2009, 42,235. J.;Imbach,J.-L.;Rayner, B. Nucleic Acids Res. 1998, 26,2069.

OrganicChemistry OrganicChemistry Organic Chemistry,Talk 368 Organic Chemistry,Talk 369 Towards the Synthesis of Substituted Cycloparaphenylenes Polar Effects in Hydrogen Atom Transfers from Catechols to Alkyl Radicals Anne-Florence Stoessel1,Elena Huxol1,Hermann A. Wegner1,* Guillaume Povie, Davide Pozzi, Giorgio Villa, Leigh Ford and 1University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland. Philippe Renaud

Universität Bern, Departement für Chemie und Biochemie, Freiestrasse 3, Strained aromatic macrocycles have attracted the attention of chemist for CH-3012 Bern, Switzerland over 80 years.[1] Recently the interest in cycloparaphenylene (CPP) in- creaseddramatically as they can be viewedasthe shortest fragment of an In combination with organoboranes, 4-tert-butylcatecholcan be used as an armchair carbon nanotube. The development of an efficient entry into these efficient hydrogen atom donor in radical chain reactions.[1] This surprising compounds might allow the controlled preparation of carbon nanotubes behavior of aclass of compounds generally seen as chain breaking anti- from a(CPP) precursor. In 2008, Bertozzi [2] presented the first synthesis of oxydants allowed the development of abroad scope method for the reduc- aCPP. Since then other groups contributed to this endeavor.[3] Amodified tion of organoboranes.[2] Extending this concept to the reduction of alkyl approach, allowing the introduction of substituents at alate stage of the syn- iodides, the hydrogen atom transfer step was found to be particularly sensi- thesis, was applied in this work. Differently substituted CPPs were successfully prepared. Such substituted CPPs will allow to further increase the un- tive to the polarity of the attacking radical. While alkyl substituted radicals derstanding of this interesting class of molecules as well as further chemis- are efficiently reduced, electron poor radicals slowly react with catechol de- try towards larger carbon nanotube fragments. rivatives giving them sufficient lifetime to undergo addition reactions.

4-tert-butylcatechol R' R' + CO2R CO2R Et3B R' R' I CO2R H 53% isolated 75 :25 R=neopentyl n-Bu SnH, AIBN R R 3 <1:99

R R This peculiar featurecould be used to trigger inter and intramolecular processes such as the contrathermodynamic 3-exo-trig cyclisation shown here. R, R' =Ph, Alk,CH2OH The Arrhenius parameters for the hydrogen atom transfer to different alkyl radicals could be determined using substituted 5-hexenyl radical clocks. The variations of the activation energies in function of the exothermicityofthe [1] Tahara,K.; Tobe, Y., Chem.Rev., 2006, 106,5274. reaction and of the polar effects affecting the transition state are discussed. [2] Jasti, R.; Bhattacharjee,J.; Neaton, J. B.; Bertozzi, C. R. J. Am. Chem. Soc. 2008, 130,17646. [1] G. Povie, G. Villa, L. Ford, D. Pozzi, C. H. Schiesser, P. Renaud, [3] For arecent review see: Sisto T. J.; Jasti, R.; Synlett. 2012, 23,483. Chem. Commun. 2010,803 –805. [2] G. Villa, G. Povie, P. Renaud, J. Am. Chem. Soc. 2011, 133,5913 – 5920. Organic chemistry CHIMIA 2012, 66, No. 7/8 573

Organic Chemistry Organic Chemistry Organic Chemistry,Talk 370 Organic Chemistry,Talk 371 N-Cylides:stability andreactivity Stereoselective synthesis of challengingly substituted lactones Tim den Hartog, Juan Manuel Sarria Toro, JoëlGubler, Viviana Valerio,NunoMaulide* ErikP.A.Couzijn and Peter Chen* Max-Planck-InstitutfürKohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Laboratorium fürOrganische Chemie, ETH Zürich, Mülheim an der Ruhr, Germany Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland We havediscoveredanunexpected, selectiveClaisen-like skeletal reorgani- Ever since the pioneering work of Nobellaureate GeorgeWittig in the 1960s, ylideshave becomeone of thecornerstonesoforganic synthesis.[1] sation of -alkoxyamides that likelyproceeds through the formation of However, in contrary to the widelyusedP-C ylides,N-C ylides are much keteniminiumintermediates andsuggestsanexceedingly conciseand pow- less frequently used. The lack of widespread application of N-C ylidesis erful access to challengingly substituted lactones [1] [2]. presumably duetothe generalconsensus that these reagents are much less stable than theirP-counterparts.[2,3] We are now able to preparearatherstable (up to 0 °C) N-C ylide in solution.Wehavestudies this N-C ylideextensively by NMR-studies. Further- more, with the help of both experimentaland computational studies we can pinpoint whythis N-C ylide is so stable. Finally, we will report on the reactivity of this ylide as alkylidene donor in organic synthesis.[4]

[1]G.Wittig, Science 1980, 210,600. [2] For common rearrangements of N-C ylides, see: a) T. S. Stevens, E. We also exploredthese reactionsbeyond the field of [3,3] sigmatropic rear- M. Creighton, A. B. Gordon, M. MacNicol, J. Chem. Soc. 1928,3193; rangement chemistry,designing unprecedented O–Cshifts [3]. b) M. Sommelet, C. R. Hebd. Sceances Acad. Sci. 1937, 205,56. [3] For theoretical discussion, see:a)J.A.Dobado, H. Martínez-García, J. M. MolinaMolina, M. R. Sundburg, J. Am. Chem. Soc. 2000, 122, 1144;b)I.A.Koppel, R. Schwesinger, T. Breuer, P. Burk,K. Herodes, I. Koppel,I.Leito,M.Mishima, J. Phys. Chem.A 2001, 105,9575;c)V.K.Aggarwal,J.N.Harvey, R. Robiette, Angew. Currentefforts are directed to thestudy of anovel methodfor the direct lac- Chem. Int. Ed. 2005, 44,5468; d) M. J. Calhorda,A.Krapp, G. Fren- tonisation of protected alcohols onto otherwiseinert, stable amides. king, J. Phys. Chem. A 2007, 111,2859; e) Y. Fu, H.-J. Wang, S.-S. Chong, Q.-X Guo, L. Liu, J. Org. Chem. 2009, 74,810. [1]C.Madelaine,V.Valerio,N.Maulide, Angew.Chem. Int. Ed. 2010, [4] T. den Hartog, J. M. Sarria Toro, P. Chen, EP12000223. 49,1583. [2]C.Madelaine, V. Valerio, N. Maulide, Chem.Asian J. 2011, 6,2224. [3]V.Valerio, C. Madelaine, N. Maulide, Chem. Eur. J. 2011, 17,4742.

OrganicChemistry Organic Chemistry Organic Chemistry,Talk 372 Organic Chemistry,Lecture 373

BF3OEt2-Promoted Ether-forming Cross-coupling Reactions of DiamideInsecticides:New Sulfonimidoyl andHeterocyclic Anthranilic Organotrifluoroborates and Acetals Derivatives

Cam-Van T. Vo, T. Andrew Mitchell, Jeffrey W. Bode* André Jeanguenat1,Christian Gnamm1, Andrew J. F. Edmunds1,Roger G. Hall1,Olivier Loiseleur1,MichelMühlebach1,AnthonyO’Sullivan1, Laboratorium für Organische Chemie Jagadish Pabba2,André Stoller1,StephanTrah1. Department of Chemistry and Applied Biosciences ETH–Zürich, Wolfgang Pauli Strasse 10, 8093 Zürich, Switzerland 1Syngenta Crop ProtectionMuenchwilen AG,Schaffhauserstrasse, CH-4332 Stein, Switzerland The ether linkage is fundamental in organic chemistry. Conventionally, it is 2 Syngenta Biosciences Pvt.Limited,, Santa MonicaWorks, Corlim,Ilhas prepared via Williamson reaction with abasic alkoxide and ahalide. Harsh Goa 403 110, India conditions, competitive elimination reactions, however, limit this method in preparing highly substituted ethers and modifying functionalized molecules. The anthranilic bisamidesconstitute anew class of crop protection agents, Recently, our group introduced an alternative strategy for the synthesis of activeagainst phytophagous insects1.Theyare activators of the ryanodine dialkyl ethers involving the combination of potassium organotrifluorobo- receptors (RyR)whichare ubiquitous Ca channels whichregulatethe Ca rates and O-methoxymethyl (O-MOM) acetals under mildly acidic condi- release from intracellular storeslocated in the sarcoplasmicreticulum. tions.[1] Alkynyl, aryl, vinyl trifluoroborates were suitable substrates;the The synthesis of derivatives with novelsulfonimidoyl functionalgroups2 chemistry could be extended to substituted acetals leading to secondary- andofheterocyclicanthranilic analogueswill be presented as well as struc- secondary ethers. However, as the substrates became more substituted, the ture/activitytrends. Anthranilamides such as 1 to 3 have in vitro activityin regiochemistry eroded. Besides, arelative large excess of organotrifluorobo- the nM rangeand showedabroadinsecticidal spectrum in vivo. rate and BF3OEt2 along with aprecomplexation step were required.

Initial work: R2 This work: BF •OEt H R2 3 2 2 4 BF3•OEt2 1 O R3 R R Me R2 R4 H (2.0-4.0 equiv) R (1.2-2.0 equiv) 3 H 3 H 1 + R BF K N Me + R BF K R O OMe 3 R1 O O 3 R1 O R3 Precomplexation MeO R3 No precomplexation 1 2 o O R ,R =H,alkyl 0!23 C, 60-120 min 0 oC, 5-60 min R1,R2,R4=H,alkyl Efficiency: R3=alkynyl>>alkenyl,aryl> halogenated aryl. Does not work with heteroaryl, alkyl Efficiency: R3=alkynyl>alkenyl, aryl, halogenated aryl,>heteroaryl

Herein, we report the improved ether-forming cross-coupling reactions of 123 new hydroxamic acid-derived acetalsand organotrifluoroborates, as well as the mechanistic studies.[2] [1]G.P.Lahmetal. in Modern Crop ProtectionCompounds,W.Krämer, U. Schirmer,P.Jeschke,M.WitschelEds, Vol. 3, ch.34.3,pp. 1409-1425, [1] Mitchell, T. A; Bode, J. W. J. Am. Chem. Soc . 2009, 131,18057. Wiley-VCH, Weinheim, 2012. [2] Vo, C.-V; Mitchell, T. A; Bode, J. W. J. Am. Chem. Soc . 2011, 133, [2]C.Gnamm,A.Jeanguenat,A.C.Dutton, C. Grimm, D. P. Kloer, A. J. 14082 Crossthwaite, Bioorg. Med. Chem.Lett. 2012, 22,3800. 574 CHIMIA 2012, 66, No. 7/8 Organic chemistry

Organic Chemistry Organic Chemistry Organic Chemistry,Talk 374 Organic Chemistry,Talk 375 Peptide Catalyzed 1,4-Addition Reactions of Aldehydes to Nitroolefins – ProteinContainers Evolvedfor Encapsulation of ChargedMolecules Challenging Nitroolefinsand Mechanistic Investigations Z.Pianowski,B.Wörsdörfer, D.Hilvert. Jörg Duschmalé, HelmaWennemers D-CHAB ETHZurich, Laboratorium fürOrganischeChemie, D-CHAB,ETH Zürich, Wolfgang-Pauli-Strasse 10,Zürich, Switzerland Wolfgang-Pauli-Strasse 10, 8093 Zürich,Switzerland Numerous proteins in nature form compartmentsthatservemanypurposes Conjugateaddition reactionsofaldehydes to nitroolefins areamong suchasstorage andtransportofminerals, protein folding, regulationofen- the most widely researchedorganocatalytic transformations.One of the zyme catalysis, or nucleic aciddelivery. Increasingnumbers of natural protein containers (mainlycapsid-formingviruses) or theirmodifiedversions most potent catalysts is thetripeptide H-D-Pro-Pro-Glu-NH2.[1] With its very high activity andselectivityatverylow catalystloadings (0.1mol%) are beingusedfor nanotechnology,with detailedapplications ranging from controlledsynthesis of novelmaterials, catalysisand bioimaging to drug H-D-Pro-Pro-Glu-NH2 underlines that short peptides of the type Pro-Pro- Xaa(Xaa=acidicamino acid) arepowerfulasymmetric catalysts.[1] deliveryand gene therapy. Research on basicmechanismsofencapsulation processesisalso important to understand compartmentalizationinside living organisms. In our lab, we have shown thepossibilityofengineering acapsid protein (Aquifexaeolicus lumazine synthase AaLS)toencapsulate charged guestmoleculesbyintroducingoppositely chargedresidueswhich drivese- lectiveelectrostaticbinding of theguestsinvivo. We also demonstrated that it is possible to optimize theloading of suchcapsids towardsadefined chargedguest.Atoxicenzyme(charged HIVprotease) wasproduced at The presentworkisaimed at the extension of the scope of such pep- high intracellularconcentrations, as its immediateencapsulation reduced the tidesascatalysts for the 1,4-addition of aldehydes to , -disubstituted ni- toxicity andallowedfor cellsurvival. Here,wereportselectiveloading of troolefins, amuch more challengingand scarcely examined substrate an engineered AaLS capsid in vitrowith largeamounts of desired cargore- class.[2] Two peptidesare presented that allowfor reactionofaldehydes sulting in astablecomplex,where formationisdrivenbysimple electrostat- with these less reactive nitroolefins. The resulting γ-nitroaldehydes bearing ic host-guestinteractions.Two typesofmodifiedAaLScapsids were pro- threeconsecutive stereogenic centerscan be further transformedtointerest- duced andusedfor encapsulation. One with anegativelycharged interior to ing productssuch as pyrrolidines or fullysubstituted -butyrolactams andγ- trap positivecargo,and theother with apositivelycharged internal surface aminoacids. Additionally, furtherinvestigations reveal mechanistic details to attract negativelycharged molecules. The former was used to capture po- that help to rationalize the successofsuch peptidesasorganocatalysts. sitively charged GFP; thelatterencapsulates negativelycharged GFPas [1]a)M.Wiesner, J. D. Revell,H.Wennemers, Angew. Chem.Int. Ed. well as oligonucleotides andgoldnanoparticles. 2008, 47,1871-1874.b)M.Wiesner, M. Neuburger, H. Wennemers, Chem. [1]B.Woersdoerfer, Z. Pianowski,D.Hilvert, J. Am. Chem.Soc. 2012, Eur. J. 2009, 15,10103–10109. c) M. Wiesner, G. Upert, G. Angelici,H. 134, 909. Wennemers, J. Am.Chem. Soc. 2010, 132,6-7. [2]B.Woersdoerfer, K.J.Woycechowsky, D.Hilvert, Science 2011,331, [2]J.Duschmalé,H.Wennemers, Chem.Eur. J. 2012, 18,1111–1120. 589.

OrganicChemistry Organic Chemistry Organic Chemistry,Talk 376 Organic Chemistry,Talk 377 MR-active LDL nanoparticles for in vivo imaging of atheroplaques Coppercatalyzedasymmetric conjugate addition of Yoko Yamakoshi1,Andrew N. Lowell2,Hui Quiao2,Takashi Ishikawa3, alkenylalanes to 2,3-dehydro-4-piperidones Rong Zhou2 Daniel Müller, AlexandreAlexakis*

1Laboratorium für Organische Chemie, ETH-Zürich, Wolfganf-Pauli-Strasse Department of OrganicChemistry, UniversityofGeneva, 10, CH8093, Zürich, Switzerland, 2Department of Radiology, University of Pennsylvania, 231 South 34th Street, Philadelphia PA19104-6323 USA, 30 Quai Ernest Ansermet,1211Geneve4,Switzerland 3Paul-Scherer Institute, CH5232, Villigen, Switserland Recently, we disclosedtwo methodologiesfor thecreationofquaternary Cardiovascular disease remains the leading cause of death in the western stereogeniccenters by additionofalkenyl alanes to β-substitutedcyclic world and early detection of vulnerable atheroplaque is highly demanded. enones.1 Next,wewereinterestedinother challengingsubstrates which In this study, we aim to detect atheroplaques using LDL as aselective deliv- might be more usefulfor synthetic applications. 2,3-dehydro-4-piperidones, ery vehicle. Anew DO3A-monoamide derivative with along alkenyl anchor potentialprecursorsfor piperidine alkoloids, appeared to be particularlyin- (A)was synthesized and used for the intercalation into the lipid monolayer teresting as no additionofalkenyl nucleophiles to this substrateclass is of LDL. Subsequentchelating reaction with Gd3+ citrate and removal of ex- known, andseveral research groups were not able to introducesuchgroups. cess Gd3+ by tropolone provided Gd3+-functionalizedLDL (Gd3+-LDL) with Therefore, we testedour methodologiesfor this classofsubstrates andwere ahigh payload (>200 Gd3+ per particle). The DLS and CryoTEM analyses pleased to seethatthe corresponding adducts were formed in high enantio- indicated that the Gd3+-LDL had similar particle size as LDL without aggre- selectivitiesand good yields.2 gation. In vivo tests using model mice (ApoE–/– and LDLr–/– fedwith high fat 3+ diet) showed that Gd was selectivelyaccumulated into the plaques of L* model mice as analyzed by ICP-MS of tissues from model mice and normal O O (S)N(S) wild type controls. In vivo MR imaging of ApoE–/– showed high enhance- L* (11mol%) R4 Cu(II)naphtenate(10 mol%) P ment in brachiocephalic artery (BA) and pulmonary trunk (PT). R3 N Me3Al (1.0 equiv) N O 1 1 2 HO R 2.0equiv. R4 R R O O O O O N HO N 1 R2Al 3 up to 83%yield O A R = t-Bu, Bn R N N H up to 97 %ee N N 2 H R OH PT 22 examples O O ApoB100 T [1]a)D.Müller, C. Hawner,M.Tissot, L. Palais, A. Alexakis,Synlett BA 2010,1694–1698. b) D. Müller, M. Tissot, A. Alexakis, Org. Lett. cholesterol 2011, 13,3040-3043.

DO3A derivative 48 hr-post Gd3+ 96 hr-post [2]D.Müller, A. Alexakis, Org. Lett. 2012, DOI: 10.1021/ol3004436. [1] Yamakoshi, Y. et al., Chem. Commun. 2011, 47,8835. Organic chemistry CHIMIA 2012, 66, No. 7/8 575

Organic Chemistry OrganicChemistry Organic Chemistry,Talk 378 Organic Chemistry,Talk 379 TotalSynthesis of theBacterial RNAPolymerase Inhibitor Ripostatin B Supramolecular Approaches to Intercalate Hydrogen-Bonded Surface Networks FlorianGlaus, Karl-HeinzAltmann Thomas R. Eaton,1 David Muñoz Torres,1 Baharan Karamzadeh,2 InstituteofPharmaceuticalSciences/ETH Zürich, Wolfgang-Pauli-Str. 10, Manfred Buck2 and Marcel Mayor1 CH-8093 Zürich 1University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland Due to the increasing number of bacterial pathogensresistant to antibiotic 2EaStCHEM School of Chemistry, University of St. Andrews,North Haugh, treatment, the search for newantibiotics with adifferentmode of action is St Andrews KY16 9ST, United Kingdom crucial. Ripostatin Bisa14-membered macrolide of myxobacterialorigin, first isolatedin1995.1 Thecompound shows anarrow spectrum of antibiotic Functionalised surfaces require precise control of substituent architecture activityand presumablyinhibitsbacterial RNApolymerasebyadifferent and surface morphology. Bottom-up approaches to achieve this surface mode of actionthan the well-established anti-tuberculosisdrugrifampicin. functionalisation have been achieved by intercalating amelamine based hy- In ordertoprovide abasis for SARstudies on ripostatin,wehavedeveloped drogen-bonded porous network from solution.[1]Expanding on this work an efficientmodular total synthesis of ripostatin B, basedonbuilding blocks we have used this porous network as atemplate to host single-molecule A, B,and C.2 The longest linear sequencecomprises 21 steps andfurnished rods. the targetmolecule in 3.6% overall yield. Keysteps arearingclosing olefin

H H OH NNN OH HO metathesis with ester D,anesterificationreaction(to produce D), aPaterson HNNH N N N OHHO O H O HNH O HH N N HN H aldol reaction(to setthe stereocenteratC13), andaTishchenko-Evans re- HO OH NN NN O O H H H H NNN NNN HHH HHH ONO ONO duction (to establish the stereocenter at C15);the latter transformations pro- HO OH HO

HO ceeded with exquisite stereoselectivity. OH ONO ONO HHH HHH NNN H H O NNN O HOH H HO OH NNH NN N NH Functionalisation HNH N O OHH O OH OH HHO HO OH of Au(111)surface N N N H H O NN H HO HO OH NNN OH OH H H

The synthesis of the stars was non-trivial and facilitated by extending an acetylene scaffold with amodular convergent approach.[2] Here we report the synthesis, crystal structure determination and STM investigations of a Thiscontributionwilldiscuss thedetails of the synthesesofbuilding blocks family of star shaped-molecular rods demonstrating single molecule organi- A, B,and C andtheirassemblyintoripostatin B. sation in an extended array. [1]Irschik, H.; Augustiniak, H.; Gerth, K.;Höfle, G.; Reichenbach,H.J. [1] R. Madueno, M. T. Räisänen, C. Silien, M. Buck, Nature 454,618. Antibiot. 1995, 48,787. [2] N. J. Jenny, M. Mayor, T. R. Eaton, Eur. J. Org. Chem. 2011,4965. [2]Glaus, F.;Altmann, K.-H.AngewChem. Int. Ed. 2012, 51,3405.

OrganicChemistry OrganicChemistry Organic Chemistry,Talk 380 Organic Chemistry,Talk 381 Towards Heterometallic Molecular Grids: Synthesis of Bipyridine and Anion-π Interactions andHalogen Bond in Action Terpyridine-Based PolytopicLigands AndreasVargas Jentzsch,DanielEmery,JiriMareda, Janis Veliks1,Karla Arias1,Jui-Chang Tseng2,Jay S. Siegel1 NaomiSakai,StefanMatile*

1Universität Zürich/Organisch-chemisches Institut, Winterthurerstr.190, Department of OrganicChemistry,UniversityofGeneva, 8057 Zürich, Switzerland Geneva,Switzerland 2Chaoyang University of Technology/ Department of Applied Chemistry, 168, Jifeng E. Rd., Wufeng District, Taichung, 41349 Taiwan, R.O.C. Thecreation of supramolecular functional systems is undoubly of para- mount importance. In this context, the available interactions should be wid- Tridentate 2,2!:6!,2!!-terpyridine and bidentate 2,2!-bipyridine have attracted ened as much as possible. Whereas anion-π interactions were only recently the attention of researchers because of their ability to form complexes of caught at work, here we extend this concept with insights on the processes different geometries with avariety of metals [1].Incorporation of these two underneath [1]. structural motifs into one ligand, as well as directing both terpyridine and F F F bypiridine units into alinear topology (Figure 1) open new perspectives in F F Cl- F F F I F the construction of heterometallic molecular grids [2]. F F F F I F I I F I I F F F 0.5 eq M12+ F Cl- F F F I F F F F F F 0.5 eq M2+ F F I N F F F R R O O O O F N N F F I O O N N F F F F F F F Tridentate F F F F F Bidentate F TMA+ F F F Figure 1. Mixed tridentate2,2!:6!,2!!-terpyridineand bidentate 2,2!-bipyridine based ligands. F In this report we mainly focus on halogen bonds, which are explored in a In our pursuit to construct heterometallic molecular grids, we have devel- systematic manner going from abig preorganized covalent systems [2] to oped arobust synthesis of 2,6-bis(2-substituted-furo[2,3-c]pyridine-5- the unexpected highlight of asingle carbon halogen-bond donor capable to yl)pyridine based ligands where the fused furan rings act as directing groups self-assemble in the lipid bilayer membrane and form asupramolecular an- placing substituents in an orthogonal topology. The synthesis of various ion transport system. metal complexes of these novel ligands reveals their feasibility as promising The power of supramolecular chemistry is underlined by this combination building blocks in supramolecular chemistry. of non-covalent self-assembly, intrinsic variations of the properties but, [1](a)Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100,3553- more importantly, function. 3590; (b)Loren, J. C.; Yoshizawa, M.; Haldimann, R. F.; Linden, A.; [1] Lin, N.-T.; Vargas Jentzsch, A.; Guénée, L.; Neudörfl, J.-M.; Aziz, S.; Siegel, J. S. Angew. Chem. Int. Ed. 2003, 42,5702-5705. Berkessel, A.; Orentas, E.; Sakai, N.; Matile, S. Chem. Sci. 2012, 3,1121. [2] (a) Petitjean, A.; Kyritsakas, N.; Lehn, J.-M. Chem. Commun. 2004, [2] Vargas Jentzsch, A.; Emery, D.; Mareda, J.; Metrangolo, P.; Resnati, 1168–1169. (b) Toyota, S.; Woods, C. R.; Benaglia, M.; Hardcastle, K.; G.; Matile, S. Angew. Chem. Int. Ed. 2011, 50,11675. Siegel, J. S. Angew. Chem. Int. Ed. 2001, 40,751-754. 576 CHIMIA 2012, 66, No. 7/8 Organic chemistry

OrganicChemistry Organic Chemistry Organic Chemistry,Talk 382 Organic Chemistry,Talk 383 Indoline Synthesisvia CatalyticAsymmetricCouplingofan Novel IntermolecularAzonia- andOxonia-Cope Rearrangements Unactivated Methylene Group A. Goeke,1 Y.Zou,2 L. Zhou,2 J. Ding,2 P. Kraft,1 F. Schoenebeck3 DmitryKatayev,MasafumiNakanishi,and E. Peter Kündig* 1GivaudanSchweiz AG, Őberlandstr.138, CH-8600Dübendorf, Department of OrganicChemistry,University of Geneva 2GivaudanFragrances (Shanghai) Ltd,298 Li ShiZhenRoad, Shanghai, 30 quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland 201203, P.R. China, Laboratoriumfür OrganischeChemie, 3ETH Zürich, Wolfgang-Pauli-Str.10, CH-8093 Zürich Herein we describe an extraordinarilyefficientpalladium-NHC catalyzed Aconceptually novelcross-dimerizationofβ,γ-unsaturated carbonyl com- synthesisofhighlyenantioenriched 2,3-trans-fused indolines viaasymmet- pounds[1] with anotheraldehydegives accesstohomoallylic esters andlac- 3 ricC(sp )-Hactivationofanunactivated methyleneunit. [1]Itisnotewor- tones. The transformation is Lewisacidcatalyzed andproceedsatom- thythatthisC-C coupling delivers theproductswithenantioselectivities of economically viadisproportionationofthe carbonylgroups throughorgan- up to 95%eedespite thehigh temperature(140 – 160 °C) required.Key in ized oxonia-Cope transition states. Astereoselective[n+4] ring enlargement leadingtoavarietyof9-16membered macrolides is described.[2,3] The ap- thisreactionwas theuse of newbulky chiral carbene ligandsand thehigh proach canbefurther extendedtoimines as reactionpartners,givingrise to thermalstabilityoftheir Pd-complexes. homoallylic amides andlactams. The scopeofthispreparativelyusefulreac- tionaswellasits stereochemical andmechanistic implications will be discussed.

Theinitial resultswereextendedtothe synthesisof2-substituted and2,3- disubstituted indolines.Racemic substrates reacted viahighlyasymmetric regiodivergent reactions.[2]

[1]Y.Zou, Q. Wang,A.Goeke, Chem.Eur. J. 2008, 14,5335-5345. [2]Y.Zou, C. Ding,L.Zhou,Z.Li, Q. Wang,F.Schoenebeck,A.Goeke, Angew.Chem. Int.Ed. 2012, 51,submitted. [1]M.Nakanishi,D.Katayev,C.Besnard,E.P.Kündig, Angew. Chem.Int. [3]Y.Zou, H. Mouhib, W. Stahl, A. Goeke, Q. Wang,P.Kraft, Chem. Ed. 2011, 50,7438. Eur.J.2012, 18,submitted. [2]D.Katayev, M. Nakanishi, T. Bürgi, E. P. Kündig, Chem.Sci. 2012, 3, 1422.

Organic Chemistry Organic Chemistry Organic Chemistry,Talk 384 Organic Chemistry,Talk 385 Etheno-adenine generation at specific sites Enol-Acetal Synthesis Via Carbenoid C-HInsertionsIntoTetrahydro- furans CatalyzedByCpRu Complexes David Egloff,Eva Freisinger* UniversityofZurich, Institute of Inorganic Chemistry, Winterthurerstr. 190, ThierryAchard, CeciliaTortoretoand Jérôme Lacour* 8057 Zürich,Switzerland Department of Organic Chemistry, UniversityofGeneva QuaiErnest Ansermet30, 1211 Geneva 4, Switzerland The so-calledetheno-bases (-bases)are known to be involvedincarcin- Email:[email protected],[email protected] ogenesis.Onthe one hand theyare found in genomes of organismsthat have been exposed to carcinogens such as vinyl chloride andonthe other hand theyare formedendogenouslyinvarious organisms, including humans CpRu complexes areknown to catalysetogetherthe decomposition of α- [1]. Another well-known featureespeciallyof-adenine (B)isits strong diazoderivatives[1].Recentlyour group hasshown that combinations of fluorescence that hasbeenexploited fordifferentapplications [2,3]. [CpRu(CH3CN)3][PF6]and diimine ligands leadtoO-H insertion andcon- densation reactions with nitriles, ketones andaldehydes[2].Inanewdevel- opment that use α-diazo-β-ketoesters andTHF moietiesassubstrates, we report the kineticallyfavoredformation of C-Oinstead of C-Cbond adducts [3]. The mild reactionconditions yieldnovelenol-acetal motifs throughun- precedented 1,3-C-H insertion reactions. ALewis acidcatalysed rearrangement to theclassicalC-C bound adducts is possible. The state of the arttoformshort oligodeoxynucleotides containing ε- adenine in specific positions is solidphase synthesis [4]. In thisstudy, however,wereport the successful developmentofanew methodstarting from an unmodified target sequence andthus allowing the facile site-specific generation of -adeninealso in longer strands.The site-specificconversion of adenine(A)toits corresponding -baseisinduced by aso-called reactive sequence carryingachemically reactivegroup which is guided to the modi- ficationsitebythe intrinsic base pairingproperties of nucleic acids. [1]A.Barbin, Mutat.Res. 2000, 462,55. [2]N.J.Leonard, Chemtracts Biochem. Mol. Biol. 1993,4,251. [3]T.Masuda,F.Ling, T. Shibata,T.Mikawa, FEBS J. 2010, 277,1440. [1]W.Baratta,A.Del Zotto, Chem.Commun. 1997,2163; W. A. [4]S.C.Srivastava,S.K.Raza, R. Misra, Nucleic Acids Res. 1994, 22, Herrmann, R. M. Kratzer, P. Rigo, Organometallics 2000,19, 3664. 1296. [2]M.Austeri, D. Rix, W. Zeghida, J. Lacour, Org. Lett. 2011,13, 1394- Financial support from the Swiss NationalScienceFoundation is gratefully 1397. acknowledged (SNSF-Professorship PP002-119106/1 to EF). [3]C.Tortoreto, T. Achard, W. Zeghida, M. Austeri, L. Guénée, J. Lacour, Angew. Chem.Int. Ed. 2012,DOI:10.1002/anie.201201541. Organic chemistry CHIMIA 2012, 66, No. 7/8 577

Organic Chemistry OrganicChemistry Organic Chemistry,Talk 386 Organic Chemistry,Talk 387 AConcise TotalSynthesis of (±)-TrigonoliimineB Chiral MonodentatePhosphinesand Carboxylic Acids:

Thomas Buyck, Qian Wang,Jieping Zhu* Cooperative EffectsinPalladium-Catalyzed EnantioselectiveC(sp3)-H Functionalization LaboratoryofSynthesis andNatural Products, EPFL-SB-ISIC-LSPN,CH-1015 Lausanne, Switzerland Tanguy Saget1,2,Nicolai Cramer1

Trigonoliimine B belongstothe familyofoxidativelyrearrangedbisindole 1LaboratoryofAsymmetric Catalysisand Synthesis, EPFLausanne. EPFL alkaloids. It wasisolated, along with trigonoliimines A and C,byHao and SB ISIC LCSA, CH-1015Lausanne, Switzerland coworkersin2010 fromthe leaves of Trigonostemon lii Y. T. Chang 2Laboratory of OrganicChmistry, ETH Zurich.Wolfang-Pauli-Strasse 10, collected in YunnanProvinceofChina.[1] Structurally,trigonoliimine A and CH-8093Zurich, Switzerland B containaquaternarycarbon whose four substituents are cross-linked to Theenantioselectivefunctionalization of C(sp3)Hbondsisachallenging form the5-, 6- and7-membered tricyclic core of thehexacyclic structure. task in asymmetric catalysis.Overthe lastdecade, elucidation of thecon- We presentour effortsthatculminated in totalsynthesis of trigonoliimine B certed metalation-deprotonation (CMD) mechanismfor thepalladium- 3 in 7steps fromcommerciallyavailablestartingmaterialswith an overall catalyzed C(sp )Hactivationhas largelycontributed to theprogressinthis yieldof12%.[2] The synthesisfeatures theuse of an α-isocyanoacetateasa area.[1]However,the harshreaction conditions required forsuchtransfor- glycinetemplatefor thepreparationofanα,α-disubstituted α-aminoester mationsand thelack of suitable ligands hampered thedevelopment of asymmetric versions.Herein,wereportthe enantioselective intramolecular thatisappropriately functionalized forthe constructionofC,DandErings. 3 Sulfolanewas found to be thesolvent of choice foranunprecedented arylationofunactivated methyl andmethyleneC(sp )Hbonds in excellent Bischler-Napieralski reactionimplemented forthe constructionofaseven- selectivities.[2]The keyofour strategyisbased on thedesignofnew elec- membered ring with concurrentformationofanexo-iminefunction. tron-rich monodentatephosphinesworking in cooperation with abulky car- boxylate whichacts as arelay of chiralityduringthe enantiodiscriminating CMDstep.

[1]C.-J. Tan, Y.-T. Di,Y.-H. Wang,Y.Zhang,Y.-K. Si,Q.Zhang,S. [1]S.Rousseaux, S. I. Gorelsky,B.K.W.Chung, J. Am.Chem. Soc. Gao, X.-J.Hu, X. Fang,S.-F. Li,X.-J. Hao, Org. Lett. 2010, 12,2370-2373. 2010, 132,10692. [2]T.Saget, S. J. Lemouzy, N. Cramer, Angew. Chem.Int.Ed. 2012, 51, [2]T.Buyck,Q.Wang, J. Zhu, Org.Lett. 2012, 14,1338-1341. 2238.

OrganicChemistry OrganicChemistry Organic Chemistry,Talk 388 Organic Chemistry 389 Asymmetric Imine Aziridination with Ru/PNNP: Ligand Tuning Redox-Switchable Resorcin[4]arene Cavitands

A. Schira,J.Egloff, A. Mezzetti* Igor Pochorovski1,Corinne Boudon2,Jean-Paul Gisselbrecht, Marc-Olivier Ebert1,W.Bernd Schweizer1,François Diederich1* ETH Zürich, D-CHAB, Wolfgang-Pauli-Str. 10, 8093 Zürich

1 1 We recently reported the use of [RuCl(OEt2)(1a)]PF6 (2aPF6)catalyzes the ETH Zürich, Wolfgang-Pauli-Strasse 10, asymmetric aziridination of imine 3 with ethyl diazoacetate 4 under astrict CH-8093 Zürich, Switzerland gradient temperature protocol. NMR spectroscopic studies showed that 4 coordinates to give the diazoester complex 5,which either transfers carbene 2Université de Strasbourg, rue Blaise Pascal, 67081 Strasbourg Cedex, to the imine to give aziridine 6 or decomposes to acarbene complex that is France responsible for the formation of diethyl maleate and, thus, for the low yield. Quinoxaline-bridged resorcin[4]arene cavitands have the ability to undergo + N - + COOEt Cl + Cl + atriggered conformational transition from acontracted, vase state, to an Cl N NN N N N N COOEt Ru 4 H Ru RuR open, kite state.[1] This precisely defined conformational change makes them 4 Et 2O P P P P P COOEt P C ideal for use as switches, receptors, or molecular grippers. However, to par- N H COOEt 2 N + lay the dynamic behavior of the cavitands into such advanced materials, it is - [2] Ar = important to create cavitands with more practical switching modes. H COOEt Cl + 5 Ph Ph 1a Ph N N N N Ru + N Ph N Ph P P P P 3 N EtOOC Ph Ar Ar 6 2 2 1b N Since bulky ligands are known to inhibit carbene formation from diazoester complexes,2 we prepared aseries of substituted PNNP ligands and used them in the catalytic aziridination of 3.With ligand 1b in particular,

[RuCl(OEt2)(1b)]BF4 (10 mol%)gave aziridine 6 in 25% yield and 93% ee Towards this goal, we developed quinone-based redox-switchable cavitands at 0°C. Using an excess of 4 (4 equiv) increased the yield of 6 to 39% with which can be applied in the area of nanorobotics, as molecular grippers. the same enantioselectivity, which is significantly improved with respect to 2aPF (26% yield, 84% ee). The use of BF – as counterion is pivotal, as PF – [1] V. A. Azov, A. Beeby, M. Cacciarini, A. G. Cheetham, F. Diederich, 6 4 6 M. Frei, J. K. Gimzewski, V. Gramlich, B. Hecht, B. Jaun, T. is hydrolyzed upon activation of [RuCl2(1b)] with (Et3O)PF6,and the resulting acid catalyzes anonenantioselective aza-Darzens background reaction Latychevskaia, A. Lieb, Y. Lill, F. Marotti, A. Schlegel, R. R. Schlittler, P. between 3 and 4.The results with other bulky ligands will be presented. J. Skinner, P. Seiler, Y. Yamakoshi, Adv. Funct. Mater. 2006, 16,147 – 156. [1] M. Ranocchiari, A. Mezzetti, Organometallics 2009, 28,3611. [2] I. Pochorovski, C. Boudon, J.-P. Gisselbrecht, M.-O. Ebert, W. B. [2] J. Zhang, M. Gandelman, L. J. W. Shimon, D. Milstein, Organome- Schweizer, F. Diederich, Angew. Chem. Int. Ed. 2012, 51,262-266. tallics 2008, 27,3526. 578 CHIMIA 2012, 66, No. 7/8 Organic chemistry

OrganicChemistry OrganicChemistry Organic Chemistry 390 Organic Chemistry 391 Substituent effectsonthe edge-to-face CH/π interaction Host–GuestComplexationwithResorcin[4]arene-Based Container Molecules HaraldurGardarsson1,W.Bernd Schweizer1,François Diederich1 D. Fankhauser1,J.Hornung1,L.D.Shirtcliff2,A.Praetorius1, 1 ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland W. B. Schweizer1,F.Diederich1

1ETH Zürich, Laboratoriumfür OrganischeChemie, Wolfgang-Pauli- O O Strasse 10, CH-8093 Zürich (Switzerland) O 2 O Oklahoma State University,Department of Chemistry, 107 Physical R H H Science, Stillwater,OK74074(USA) R N N R N R N

Folded Unfolded Parallel-displaced Edge-to-face Wilcox balance Noncovalentinteractions involving aromatic rings are pervasive throughout chemical and biological recognition.[1] Of the arene–arene interactions, two geometries are favoured, the parallel-displaced and the edge-to-face interactions. The quantification of the latter being the focus of this research. In particular the effect of substituents on the interaction will be investigated, as it is atopic under debate, both in theoretical and experimental studies.[2-5] To examine these interactions we have utilized the Wilcox balance.[5] This unimolecular torsion balance places two aromatic rings in the correct ge- ometry for an edge-to-face interaction. The thermodynamic equilibrium between the folded and unfolded atropisomers can be determined by 1HNMR Host–guestcomplexation studieswereperformed with aresorcin[4]arene- and utilized to calculate the foldingfree enthalpy. based container molecule as host and avariety of cycloalkanes and alicyclic heterocycles as guests. Association constantsweredetermined by 1HNMR [1] L. M. Salonen, M. Ellermann, F. Diederich, Ang. Chem. Int. Ed., and isothermal titrationcalorimetry (ITC). Thereversible conformational 2011, 50,4808. switching of the host(containing arigidifying bridge and two switchable [2] S. E. Wheeler, K. N. Houk, Mol. Phys., 2009, 107,749. flaps)was investigated by 1HNMR spectroscopy. Non-covalent interactions [3] C. A. Hunter, K. R. Lawson, J. Perkins, C. J. Urch, J. Chem. Soc. between hostand guestwerefurther studied using thermodynamic data from Perkin Trans., 2001, 5,651. ITC. [4] F. R. Fischer, W. B. Schweizer, F. Diederich, Chem. Comm., 2008, 4031. [1]J.Hornung, D. Fankhauser,L.D.Shirtcliff, A. Praetorius,W.B. [5] S. Paliwal, S. Geib, C. S. Wilcox, J. Am. Chem. Soc., 1994, 116,4497. Schweizer,F.Diederich, Chem.Eur.J.2011, 17,12362.

OrganicChemistry Organic Chemistry Organic Chemistry 392 Organic Chemistry 393 Synthesis andstructure determinationofbicyclicbridged peptides ACCESS Swiss Chemical Library: Design of aDiverse Screening Collection forChemical Biology using Molecular Shape Marco Bartoloni,Tamis Darbreand Jean-Louis Reymond* Ruud vanDeursen1,Gerardo Turcatti1 University of Bern,Departement of Chemistryand Biochemistry, Freiestrasse 3, 3012 Bern,Switzerland 1Biomolecular Screening Facility,NCCR Chemical Biology EPFL, CH-1015, Lausanne, Switzerland The useofbranching aminoacids in apeptidesequence, likediaminoacids (as usedinpeptidedendrimers[1])oraminodiacids,allows to design bicyclic homodetic peptides suchasthe “norbornapeptides” One of the important tasks within the NCCR Chemical Biology is the creation (bicyclo[2.2.1]heptapeptides),which were prepared using an orthogonal of the ACCESS high-throughput screening platform. Keyaspect during the protectionscheme. Thefirst cyclizationisperformed on resin afterselective creation is the purchase of achemically diverse collection of small molecules deprotectionofaglutamic acidresidue,whereas thesecond ring closureis that will be available to our research community during screening campaigns. achievedbyamidebond formationathighdilutions. Although the importance of shape during the drug discovery has been reported,[1] only asmall number of applications have been used to understand the importance of the shape diversity within ascreening collection in order to address a wide variety of biological targets seen in ascreening platform.[2,3] In particular for primary screening it is highly desirable that multiple distinct series of chemical compounds get identiﬁed to anticipate downstream issues that may arise for agiven chemical family.[2] Whereas these descriptors have been merely used for analytical purposes of existing screening collections, we herein present our approach for the creation of a50k large diverse screening collection, in which the use of descriptors of molecular shape has been privileged.

These peptides are structurally well-definedand coveranalmost pristine [1] Nicholls A et al., J. Med. Chem. 2010, 53,3862-86. [2] area of peptidetopological space. Their conformationalrigidity was [2] Sauer WHB, Schwarz MK, Chimia 2003, 57,276-83. investigated by meansof2D-NMRand X-ray crystallography andmay offer [3] Lovering F, Bikker J, Humblet C, J. Med. Chem. 2009, 52,6752-56. aplatformtodesigndrugs tacklingprotein-protein interactions.

[1]T.Darbre,J.-L. Reymond, Org. Biomol. Chem. 2012, 10,1483. [2]M.Bartoloni, R. U. Kadam, J. Schwartz,J.Furrer, T. Darbre, J.-L. Reymond, Chem.Commun. 2011, 47,12634. Organic chemistry CHIMIA 2012, 66, No. 7/8 579

Organic Chemistry OrganicChemistry Organic Chemistry 394 Organic Chemistry 395 Newdimers of benzenetriamidefor high organizationinliquidcrystal Formationofquaternarystereogeniccenters by NHC-Cu catalysed mesophases asymmetric conjugateaddition reactions with Grignard reagentson polyconjugated cyclic enones toward thetotal synthesisof Christian Invernizzi,Reinhard Neier* RiccardiphenolB.

Institute of Chemistry, UniversityofNeuchâtel, MatthieuTissot,ChristianBleschke,MarcMauduit*,AlexandreAlexakis* Av. De Bellevaux 51, casepostale158, 2009, Neuchâtel, Switzerland University of Geneva,30, quaiErnestAnsermet, 1211 Genève,Switzerland Discotic Liquid Crystals (DLc’s)are well knowninthe fieldoforganic materials[1],due to theirinterestingpropertieslike1Dchargetransport[2,3]. Reducingthe degree of freedombymakingdimers hasbeen showntoin- Thecoppercatalyzed conjugate additionofvarious Grignard reagents to creasethe conductivity[4].Our aimistouse an aromatic linkerasaprobeto polyconjugatedenones(dienonesand enynones derivatives)are reported. studythe intermolecularself-assembly. The synthesisofthe discogenic Thecatalystsystem, composed of coppertriflateand theNHC ligand L6, monomericprecursor 1 wascompleted,showingmesomorphic proprieties. ledtothe unsualselectiveformationofthe 1,4additionproducts.The reac- tionallows thecreationofall-carbon chiral quaternarycenters with enantiomeric excessupto99%.The remaininginsaturationonthe 1,4adducts gave an access to valuable synthetic transformations especially to thetotal synthesisofRiccardiphenol B. O O

O O Et

R MeO R R'MgBr (2 equiv) R' 6mol%Cu(OTf) 2, ee 86%-99% or 9mol% L6 OH Useful functions for furthertransformations O CH2Cl2,-10°C O

R' NN Riccardiphenol B O O Our attentionisnow focusedonthe design andscreeningofdifferenttypes R Cl R HO ee 77%-97% O of aromatic linkers,inorder to provide arationalunderstandingofthe self- L6 COOMe

assemblyinadiscotic liquidcrystal systems. COOMe [1]Henon, H.;Mauduit, M.;Alexakis, A. Angew. Chem., Int. Ed. 2008, 47, 9122. [1]Müllen. K., Science, 2001, 293,1119 [2]Tissot, M.;Pérez Hernandez, A.;Müller, D.;Mauduit, M.;Alexakis, A. [2]Destrade, C.;Mondom, M.C.; Malthete, J.;J. de Physique, 1979, C3 ;17 Org. Lett. 2011, 13,1524. [3]Laschat,S., et al., Angew. Chem.Int.Ed.2007, 46,4832 [3]Tissot, M.;Pogialli, D.;Müller, D.;Mauduit, M.;Alexakis, Chem.Eur. [4]Kumar, S., Liq. Cryst., 2005, 32,108 J. 2012 in press.

Organic Chemistry Organic Chemistry Organic Chemistry 396 Organic Chemistry 397 Asymmetricconjugateaddition to polyconjugated Michaelacceptors – Copperfree asymmetric allylicalkylation usingGrignardreagentson Applicationtowards thetotal synthesis of RiccardiphenolB bifunctional allylic bromides.

Christian Bleschke1,MatthieuTissot1,AlexandreAlexakis1 David Grassi,AlexandreAlexakis* 1Université de Genève,DepartementdeChimie Organique, Quai Ernest Ansermet 30, 1211 Genève,Schwitzerland 30 quaiErnestAnsermet,1211 UniversityofGeneva Asymmetric conjugateaddition(ACA) is apowerfultool to install quaternarystereogenic centers in five or sixmembered ringswith high Switzerland enantiomericexcess.[1] Alexakis andcoworkers recentlyachievedhigh1,4- [email protected] selectivityand excellent enantioselectivitieswith polyconjugatedsubstrates by using theprivilegedN-heterocyclic carbene 5 as ligand.[2] The remaining Aseries of substrates,containing avinylic bromide were employedincop- vinyloracetylenesubstituents constitute very versatile functionalgroups per-free methodology using bidendate NHC ligands.The desired com- which shall be demonstrated by thetotal synthesisofRiccardiphenol B. pounds are generallyobtainedwith good enantioselectivityand good re-

O Nu O 92 %ee gioselectivity. Importantly thecopper catalyzed system afforded loweren- antioselectivityvalue.The catalytic products could be transformedinto a NN MeO broadscope of new1,1-disubstitutedolefins in asingle steptransformation Cl 1 5 3 without erosion of the enantioselectivity. 9mol% HO OH O O Nu MeMgBr(2equiv), 2%L9 R2 R2 6mol %Cu(OTf)2 90 %ee 1,8equiv R2MgBr R1 Br R1 R1 100 %1,4-select. Et O, -15°C RiccardiphenolB Br 2 Br R3 24TIPS TIPS R1 =alkyl,aryl 17 examples R3 =ester,acid,aldehyde,silane, Sincethe conjugateadditionforms thecorresponding enolate,the reaction up to 93%ee aryl or heteroaryl. up to 100:0SN2'/SN2ratio 11 examples can also be usedtoselectivelyinstallthe adjacentsubstituentinthe up to 71%yield up to 87%yield α-Positionand representstherefore clearlythe keystepofthe envisaged totalsynthesis.[3] Ph Ph N+ N [1]T.Jerphagnon, M. G. Pizzuti, A. J. Minnaard,B.L.Feringa, Chem. Cl- Soc.Rev. 2009, 38,1039. Ph OH [2]H.Hénon, M. Mauduit,A.Alexakis, Angew. Chem.Int.Ed. 2008, 47,9122. L9 [3]T.L.May,J.A.Dabrowski,A.H.Hoveyda, J. Am.Chem. Soc. 2011, 133,736. [1]D.Grassi, A. Alexakis, Org.Lett. 2012,14,1568-1571. 580 CHIMIA 2012, 66, No. 7/8 Organic chemistry

OrganicChemistry Organic Chemistry Organic Chemistry 398 Organic Chemistry 399 Evaluation of theChiralDIANANE Backbone as Ligand forOrgano- Copper-Catalyzed AsymmetricAllylicAlkylation of lithiumReagents ExtendedMultiple BondSystems

Praz Jézabel 1,Laure Guénée1,Sarwar Aziz 2,AlbrechtBerkessel*2,and Alexandre Hailing Li1,Alexandre Alexakis1 Alexakis*1 1UniversityofGeneva, 30 QuaiErnest Ansermet, 1211 1 University of Geneva,30Quai Ernest-Ansermet, CH-1211 Geneva, Switzerland Geneva,Switzerland 2 UniversityofKöln, 4Greinstrasse, D-50939 Köln, Germany Copper-catalyzed asymmetric allylicalkylation (AAA)isone of the most useful andefficient carbon-carbon bond formation methods, leadingtoopti- [1] Chiral 1,2diaminesare compounds of greatinterest in organic synthesis, cally enriched molecules. Our group hasreportedhighlyregio-and particularly as chiral ligands for various asymmetric reactions. Previously in enantioselectivecopper-phosphoramiditecatalytic system for asymmetric our laboratory, we observed achirality transfer to the nitrogen atoms which allylicalkylation (AAA)onallylic chlorides employingorganomagnesium [2] become stereogenic upon chelation with ametal. reagents. Herein, aseriesofprochiral enynechlorideswas reportedassubstrate in the copper-catalyzed AAA, using Grignard reagents as nucleophile. Excellent 1,3-substitution regioselectivities andgood to excellent enantioselectivities were achieved.[3]

The accuracy of this concept was then illustrated in various reactions such as asymmetric bromine-lithium exchange, enantioselective additions of aryl and alkyllithium reagents to aromatic imines [1]. Toward this end, we de-

veloped anew type of C2-symmetric tertiary diamines derived from the DI- ANANEbackbone. These new chiral ligands owe arigid backbone and larger fixed distance between the two nitrogen atoms. They have been in- volved in diverse asymmetric synthesis using organolithium reagents and compared with the previous 1,2 chiral diamine ligands [2]. Substrate diversityisfurther extendedtodiene chlorides.

[1]For arecentreview, see:A.Alexakis, J. E. Bäckvall,N.Krause, O. Pamies,M.Dieguez, Chem.Rev. 2008, 108,2796. [2]K.Tissot-Croset, D. Polet, A. Alexakis, Angew. Chem.Int.Ed. 2004, [1] Q. Perron, A. Alexakis, Adv. Synth. Catal. 2010, 352,2611-2620 43,2426. [2] Praz Jezabel, Laure Guénée, Sarwar Aziz, Albrecht Berkessel and [3]H.Li, A. Alexakis, Angew. Chem.Int. Ed. 2012, 51,1055. Alexandre Alexakis , Adv. Synth. Catal. 2012, Accepted manuscipt.

Organic Chemistry OrganicChemistry Organic Chemistry 400 Organic Chemistry 401 Enantioselective Copper Catalyzed1,4-additiontochallenging1,2- Highly Enantioselective Direct Vinylogous MichaelAdditionof DicarbonyllikeMichael acceptors γ-Butenolide to Enals

SylvieGoncalves,Ludovic Gremaud, Alexandre Alexakis* Alice Lefranc,Adrien Quintard, Alexandre Alexakis*.

UniversityofGeneva, FacultyofSciences,QuaiErnest-Ansermet30 University of Geneva, Quai Ernest Ansermet 30, 1211 Geneva 4, Departmentoforganic chemistry, CH-1211 Geneva 4, Switzerland Switzerland. The copper-catalyzed asymmetric conjugate addition (ACA)oforganome- In recent years, aminocatalysis and particularly iminium catalysis has be- tallicreagents to Michael acceptors is amongthe most important methodol- come an essential activation mode for the asymmetric β-functionalization of ogies to formaC-Cbondinanenantioselectivemanner. In thisfield, avari- conjugated carbonyl compounds. Our group recently developed Aminal- etyof,-unsaturated compounds have been successfully used.1 However, PYrrolidine (APY) catalysts as powerful tools for aminocatalyzed reac- ,-unsaturated aldehydes aremorechallenging substrates because of their tions.[1] In this context, we disclosed the development of an unprecedented highreactivitytowardthe undesired1,2-addition andaldol by-products.2 and simple direct vinylogous addition of deconjugated butenolide to enals in More recently, ,-unsaturated 1,2-dicarbonyl compounds emergedtobea excellent stereoselectivities (>95% ee).[2] This methodology allows for the newclass of challengingMichael acceptors for thiskey transformation.3 efficient preparation of complex γ-butenolide from Angelica lactone deriva- Scope andlimitations of the ACA to such substrates will be presented as tives, directly obtained from readily available renewable resources. Fur- well as their potential synthetic applications. thermore, preliminary mechanistic investigations allowed for abetter under- previous work :Z=H this work :Z=EWG standing of the process. 2eq. R' Al R'MgBr or R'2Zn 3 H R' 5mol%CuTC Z 5mol%CuTC Z R' * 5.25 mol% chiral ligand 5mol%(R)-BINAP * O R O R O R Et2O/-78, -20or0°C THF/-78°C 1,4/1,2upto100/0 Z=H, EWG 1,4/1,2upto100/0 ee'supto92% ee'supto99% R' =alkyl,aryl R=alkyl,aryl R' =alkyl

[1](a) Alexakis, A.; Benhaim,C.Eur. J. Org. Chem. 2002,3221; (b) Alexakis, A.; Backväll,J.E.; Krause, N.;Pamies, O.; Dieguez,M. Chem.Rev. 2008, 108,2796; (c)Harutyunyan,S.R.; denHartog, T.; Geurts, K.; Minnaard, A. J.;Feringa, B. L. Chem.Rev. 2008, 108, 2824. [2]Palais, L.;Babel,L.; Quintard, A.; Belot,S.; Alexakis, A. Org. Lett. [1] a) A. Quintard, C. Bournaud, A. Alexakis, Chem. Eur. J., 2008, 14, 2010, 12,1988. 7504-7507 ;b)A.Quintard, S. Belot, E. Marchal A. Alexakis, Eur. J. [3]Gremaud, L.;Alexakis, A. Angew. Chem.Int. Ed. 2012, 51,794. Org. Chem., 2010,927-936. [2] A. Quintard, A. Lefranc, A. Alexakis, Org. Lett., 2011, 13,1540-1543. Organic chemistry CHIMIA 2012, 66, No. 7/8 581

Organic Chemistry Organic Chemistry Organic Chemistry 402 Organic Chemistry 403 Copper-Catalyzed AsymmetricConjugateAddition of Asymmetricbromine-lithium exchange:development of newchiral Organoaluminium Reagents to α,β-Unsaturated Lactams diamines andapplications in catalysis Julien Graff andAlexandre Alexakis1 Pierre Cottet,AlexandreAlexakis* 1Department of OrganicChemistry, UniversityofGeneva, UniversityofGeneva, Quai Ernest Ansermet, 30 30, Quai Ernest-Ansermet,CH-1211 Geneva,Switzerland CH-1211 Geneva,Switzerland Email: [email protected] Sincenitrogen heterocycles are ubiquitous in compounds of pharmaceutical interest, mucheffort hasbeen dedicated to thedevelopment of asymmetric Halogen-lithiumexchangeisapowerfultool in organicsynthesis. The methodologiestoaccesschiral nitrogen containing compounds. treatment of an aryl halide with an alkyllithiumreagent,like n-BuLi, pro- motesthe formationofthe correspondinglithiatedcompound. This Among themainreactions in organicsynthesis, theasymmetric conjugate aryllithiumspecies can be furtherfunctionalized to accesstomoleculesof addition(A.C.A.) is apowerfultool forenantioselectiveC-C bond for- higher complexity. mation. A.C.A.ofvariousalkyl andarylnucleophiles to α,β-unsaturated lactamshas been reported. However, theadditionofalkenyl substituents in Diamines,likeTMEDA, are known to be usefull acceleratorsofthisreac- β-positionremains challenging, andwould lead to interesting building tionbybreakingupthe correspondinglithium-aggregates.Therefore,we blocks. successfullyemployedchiral diamines forthe asymmetric bromine-lithium exchange of polybrominated aromatic prochiral compounds leadingtoaxial- We recentlyreportedthe copper-catalyzedasymmetricMichael additionof ly chiral moleculesingood yields (upto89%)and enantiomericexcesses alkenylalanestoN-substituted-2,3-dehydro-4-piperidones[1].The opti- (upto72%). Finally, it is important to mentionthatadouble bromine- mized conditions were then applied to six-membered α,β-unsaturated lac- lithiumchangehas to be performed to induceasymmetryinthe finalmole- tams, affording easilyfunctionalizable products. Moderatetogood yields cule. (upto82%)and high levels of enantioselectivity(up to 93%)were achieved, by using acombinationofcopper(II)-naphthenate andaphos- phinamineligand.

Fig. 1:Asymmetric bromine-lithiumexchangeon2,2’,6,6’- tetrabromobiphenyl 1. [1]D.Müller, A. Alexakis, Org. Lett. 2012, 14,1842. [1]PerronQ., Alexakis A., Adv. Synth. &Catal., 2010, 352,2611.

OrganicChemistry OrganicChemistry Organic Chemistry 404 Organic Chemistry 405 The Mechanism of the α-Ketoacid-Hydroxylamine (KAHA) Amide- One-Pot Synthesis of Peptide Libraries Forming Ligation Yi-Lin Huang, Jeffrey W. Bode* Ivano Pusterla, Jeffrey W. Bode ETH-Zürich,Wolfgang Pauli Strasse 10, 8093 Zürich, Switzerland ETH Zürich,Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland The interest in new therapeutic peptides has increased over the past decade. Methods that can quickly be used to generate alarge collection of various The α-ketoacid-hydroxylamine (KAHA) ligation reaction allows the compounds with minimum waste and easy purification are highly desirable. chemoselective formation of amide bonds under very mild conditions and We have developed anew methodology to synthesize unnatural peptide li- produces only water and carbon dioxide (type I)orbenzoic acid (type II)as braries in aone-pot fashion by applying chemoselecitve ketoacid- byproducts [1]. hydroxylamine (KAHA) ligation [1]. This methodology tolerates the pres-

DMF ence of various functional groups and produces only innocuous byproducts. O MeOH O As the reaction condition requires no coupling reagents, the resulting pep- or DMSO 2 OH HO R2 R (type I) R1 + N R1 N + CO2 + H2O tides can be subjected to bioassay directly without further purification. H 40 °C H O Strategies for peptide library synthesis, bioactive profiling, structure decon-

O aqueous O volution and lead optimization will be discussed. buffer 2 OH BzO R2 R (type II) R1 + N R1 N + CO2 + HOBz H 40 °C H O We have already demonstrated that the KAHA ligation is avery powerful M1 I Mn T tool for the synthesis of therapeutic peptides (30 residues) without interfer- ence from unprotected side chain functional groups.Inorder to explain the I M2 T I Mn Mn T discrepancies between type I and II ligation (different suitable solvents and M3 I reaction concentrations) and to identify appropriate ligation partners for the Mn Mn Mn T

synthesis of larger peptides we have elucidated the mechanism of the Initiator Monomers Terminator higher order peptides n=1 or 2or3 KAHA ligation. We found the type I ligation to proceed via an unexpected and remarkable pathway in which the oxygen atom of the hydroxylamine is incorporated into the amide product [2]. [1] J. W. Bode, R. M. Fox, K. D. Baucom, Angew. Chem. Int. Ed. 2006, 45,1248. [1] R. M. Fox, K. D. Baucom, J. W. Bode, Angew. Chem. 2006, 118, 1270–1274; Angew. Chem. Int. Ed. 2006, 45,1248–1252. [2] I. Pusterla, J. W. Bode, Angew. Chem. 2012, 124,528–531; Angew. Chem. Int. Ed. 2006, 51,513–516. 582 CHIMIA 2012, 66, No. 7/8 Organic chemistry

OrganicChemistry OrganicChemistry Organic Chemistry 406 Organic Chemistry 407 Friedel-Crafts Benzylation of Activated and Deactivated Arenes Expanded substrate scope and catalyst optimization for the catalytic kinetic resolution of cyclic secondary amines Gabriel Schäfer, Jeffrey W. Bode* Sheng-Ying Hsieh1 and Prof. Dr. Jeffrey W. Bode1 ETH Zürich, Laboratorium für OrganischeChemie, Wolfgang-Pauli-Strasse 10, 8093 Zürich 1 ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland

The Friedel-Crafts alkylation is aversatile method for C-Cbond formation Many pharmaceuticals and agricultural chemicals are enantiomerically pure from unactivated C-Hbonds [1]. Despite the power and historical im- amines. We have developed ageneral method for the catalytic kinetic reso- portance of Friedel-Crafts reactions, these processes often have major draw- lution of cyclic secondary amines;[1] however, there are afew limitations to backs such as their restriction to electron-rich arenes, harsh reaction condi- the substrates with special functional groups. New reaction conditions using

tions, low regioselectivity and the generation of large amounts of metal by- atuned hydroxamic acid co-catalyst with K2CO3 base in iPrOAc solvent products. Therefore there is an unmet synthetic need for refinements to the have been employed to give an expanded substrate scope and an improved Friedel-Crafts reaction to improve its substrate scope and sustainability, par- enantioselectivity. ticularly for substitutions of electron-deficient arenes [2].

CH 3 O BF •OEt HO H3C N 3 2 N R1 + O R1 R2 Br R2 25–85 °C O R O R 12–24 h O O R OH HN 5mol % HN N 1 2 50–99% yield R =H,CH3,Cl, CF3, R =H,CH3,Cl, CF3, Me Me 10 mol %RMesClO Mes 4 Mes CO2Me, etc CO2Me, CN, NO2 20 mol %K2CO3 racemic enantioenriched enantioenriched 3 iPrOAc, 23 °C We demonstrate that O-benzyl hydroxamic acids are activated by the inex- amine amine amide New substrates Improved substrate classes pensive, easily-handled Lewis acid BF •OEt to generatehighly reactive 3 2 O OR O R electrophiles for the Friedel-Crafts benzylation of both electron-rich and H N O N NH N electron-poor arenes [3]. The reactions proceed at mild temperatures, are HN R N R N R N R N R N operationally and environmentally friendly, and give the product diar- H H H H H R lymethanes in high yield. At slightly higher temperatures, electron-deficient S 21–23 S 9 S 17–30 S 20–29 S 46 S >100 arenes are cleanly alkylated with electron-deficent benzyl derivatives to give mono meta-substituted products. [1] C. Friedel, J. M. Crafts, Hebd. Seances Acad. Sci. 1877, 84,1450. [1] Binanzer, M.; Hsieh S.-Y.; Bode, J. W. “Catalytic Kinetic Resolution [2] D. J. C. Constable et. al. Green Chem. 2007, 9,411. of Cyclic Secondary Amines” J. Am. Chem. Soc. 2011, 133,19698–19701. [3] G. Schäfer, J. W. Bode, Angew. Chem. Int. Ed. 2011, 50,10917.

OrganicChemistry OrganicChemistry Organic Chemistry 408 Organic Chemistry 409 α-Ketoacid–hydroxylamine (KAHA) ligation for the chemical synthesis Kinetic Resolution of Secondary Amines with aPolymer-Supported of modifier proteins Chiral Hydroxamic Acid

A. O. Ogunkoya, V. R. Pattabiraman, J. W. Bode* Imants Kreituss1,Yuta Murakami1,Michael Binanzer1 and Jeffrey W. Bode1

Laboratorium für Organische Chemie, Wolfgang Pauli Strasse 10, 1Lab. fur OrganischeChemie, Swiss Federal Institute of Technology (ETH) ETH Zurich, 8093 Zurich, Switzerland Zurich. Wolfgang-Pauli-Strasse 10, 8093 Zurich

Recently, we developed avariation of the α-ketoacid–hydroxylamine (KAHA)ligation1,between aC-terminal peptide α-ketoacid and aN- We have developed anew chiral polymer-supported hydroxamic acid for terminal 5-oxaproline.2 This ligation is useful for the synthesis of proteins kinetic resolution of secondary amines. Carboxylic acid 1 can be prepared from two unprotected protein segments. For the synthesis of larger proteins, on amultigram scale and immobilizedonthe polymer support. The enanti- asequential ligation strategy is necessary. oselective resolving agent can be regenerated by atreatment of the resin with an acyl chloride or anhydride O O OH OH H N Protein Segment 1 O Protein Segment 2 O Protein Segment 3 COOH 2 N N O O H PG O O Using this resin, various cyclic secondary amines have been resolved with good to excellent selectivities. Highly enantioenrichedunreacted amines can 1. KAHA ligation be recovered, and there is no erosion of reactivity or selectivity after multi- 2. PG Removal ple uses of the reagent. The development of this convienient process for KAHA ligation resolving racemic amines and further developments will be reported. OH OH

O O Protein Segment 1 Protein Segment 2 Protein Segment 3 COOH H2N N N H H O O O Our studies will show the synthesis of ubiquitin fold modier 1(UFM1, 83 HO O O O NH O N O N residues) through the development of asequential KAHA ligation strategy. 2 R HO N OH O H O [1] Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew. Chem. Int. Ed. both enantiomers 1 2006, 45,1248-1252 accessible [2] Pattabiraman V. R.; Ogunkoya A. O.; Bode J. W. Angew. Chem. Int. O O O O Ed. 14 Mar.2012, D.O.I. 10.1002/anie.201200907 R N N R H 1 N O N R N R H s=12-23 H 1 1 O R Organic chemistry CHIMIA 2012, 66, No. 7/8 583

OrganicChemistry OrganicChemistry Organic Chemistry 410 Organic Chemistry 411 α,β -Unsaturated Acyl Azoliums for Enantioselective Annulations NHC-Catalyzed Enantioselective Annulation of Sulfonyl Imines and α,β -Unsaturated Aldehydes Jessada Mahatthananchai1and Jeffrey W. Bode1 Alberto Kravina1,Jessada Mahatthananchai1 and Jeffrey W. Bode1 1Lab. für Organische Chemie,Swiss FederalInstitute of Technology (ETH) Zurich. Wolfgang Pauli Strasse 10, 8093 Zurich (Switzerland) 1Lab. für organische Chemie, Swiss Federal Institute of Technology (ETH) Zurich. Wolfgang Pauli Strasse 10, 8093 Zurich We have developed amethod for the generation of α,β-unsaturated acyl azoliums from enals or ynals and achiral N-heterocyclic carbene.These spe- We have developed anew enantioselective annulation of N-sulfonyl-imines cies serve as catalytically-generated activated carboxylates with aunique and α,β-unsaturated aldehydes catalyzed by achiral N-heterocyclic carbene property. They may be intercepted by enols or enamines to generate meta- (NHC). The catalytically-generated α,β-unsaturated acyl azolium (derived stable hemiacetals, which can undergo an enantioselective Claisen rear- from achiral NHC, enals, and an oxidant) undergo areaction with the rangement and cyclization to afford dihydropyranone or dihydropyridinone enamine tautomer of the imine via an aza-Claisen rearrangement as the key in excellent yield and enantioselectivity.[1] Both the development and the carbon-carbon bond forming step. High yields and enantioselectivities were [2] mechanistic aspects of these reactions will be discussed in detail. achieved using β-substituted, α,β-substituted and β,β-disubstituted unsatu- O OH rated aldehydes. This is the first example of ahighly enantioselective NHC- Me O O Cl– Me H R2 catatlyzed annulation to operate with α-substituted enals as substrates. N N O NH R1 R3 N O Me or or R1 R2 R1 R2 (10 mol %) R3 R3 Me NH2 Cl O Me O R2 high yield O N N O O O 1 high enantioselectivity O R H 3 S N S R O Me N H N R1 R1 via XH tBu tBu R2 O O 3 2 O O R3 R2 N 2 R R R 1 N R1 3 R R N R3 tBu tBu 50 -93% yield N X 75 -99% ee N N Mes X=NHorO Mes α,β-unsaturated NHC-catalyzed via O acyl azolium Claisenreactions O N O O O O R2 O O S 1 S S N N R NHC [1] (a) J. Kaeobamrung, J. Mahatthananchai, P. Zheng, J. W. Bode, J. Am. N NH Mes N Chem. Soc. 2010, 132,8810–8812. (b) B. Wanner, J. Mahatthanan- acyl azolium R1 chai, J. W. Bode, Org. Lett. 2011, 13,5378–5381. R3 R3 R3 R2 [2] (a) J. Mahatthananchai, P. Zheng, J. W. Bode, Angew.Chem., Int. Ed. aza-Claisenreaction 2011, 50,1673–1677. (b) J. Mahatthananchai, J. Kaeobamrung, J. W. Bode, ACS Catal. 2012, 2,494–503.

OrganicChemistry OrganicChemistry Organic Chemistry 412 Organic Chemistry 413 Graphical and Computational Insights into Interconversion of a Sensor Arrays based on Shapeshifting Organic Molecules Shapeshifting Molecule J.F. Teichert, K.K. Larson, M. He, A. Naganawa, J.W. Bode* Maggie He1,Jeffrey W. Bode1 Laboratorium für Organische Chemie, Department of Chemistry and Apl- 1Laboratorium für Organische Chemie, Department of Chemistry and Ap- lied Bioscience, ETH Zürich plied Biosciences, ETH Zürich, Wolfgang Pauli Strasse 10, 8093 Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich Switzerland

Substituted Bullvalene compounds (1)exist as amixture of rapidly equili- Bullvalene is acage-like molecule that undergoes the Cope rearrangement brating structural isomers that interconvert through spontaneousCope rear- spontaneously to give 1.2 million degenerate isomers [1]. Incorporation of rangements.1 By equipping the Bullvalene core with a 13Clabel as areport- different substituents onto the bullvalene core leads to a“shapeshifing” ing unit,2 and substituents allowing for the coordination of analytes (such as molecule by reorienting its substitutions as it undergoesrearrangements. A fullerenes or carbohydrates),2,3 all necessary components of asensor are giv- bullvalene with four different substitutionscan interconvert among up to en. The read-out of the 13CNMR spectrumdisplays the adjusted equilibrium 1680 structural isomers. We have synthesized tetrasubstituted bullvalenes population and distribution of the Bullvalene isomers and therefore serves and conclusively demonstrated that they are robust, dynamic organic mole- as apattern for analyte recognition.2 cules [2][3]. Due to the large number of isomers, the interconversionnet- work, which maps the rearrangements between all isomers, and the energy

landscape of tetrasubstituted bullvalenes are very complex. Insights into the analyte 13C 13 13C rearrangements of atetrasubstituted bullvalene based on NMR studies, net- C 13C 13C work analysis, and DFT calculations will be presented. substituted Bullvalene (1)

equilibrium adjusted equilibirum population 1680 constitutional population isomers

13CNMR 13CNMR

Tetrasubstituted bullvalene [1] A.R. Lippert, J. Kaeobamrung, J.W. Bode, J. Am. Chem. Soc. 2006, 128,14738–14739; A.R. Lippert, A.Naganawa, V.L. Keleshian, J.W. Bode, J. Am. Chem. Soc. 2010, 132,15790–15799. [1] W. v. E. Doering, W. R. Roth, Tetrahedron 1963, 19, 715-737. [2] K.K. Larson, M. He, J.F. Teichert, A. Naganawa, J.W. Bode, Chem. [2] A. R. Lippert, A. Naganawa, V. L. Keleshian, J. W. Bode, J. Am. Chem. Sci. 2012,Accepted Manuscript. (DOI: 10.1039/C2SC20238G) Soc. 2010, 132,15790-15799. [3] A.R. Lippert, V.L. Keleshian, J.W. Bode Org. Biomol. Chem. 2009, [3] M. He, J. W. Bode, Proc. Natl. Acad. Sci. U. S. A. 2011, 108,14752- 7,1529–1532. 14756. 584 CHIMIA 2012, 66, No. 7/8 Organic chemistry

OrganicChemistry Organic Chemistry Organic Chemistry 414 Organic Chemistry 415 Synthesis of Bifunctional Triazolium Salts for useasN-Heterocyclic Cinchona Alkaloid Catalyzed Mannich Reactions of Mono Thio- Carbenes malonates withImines forthe Synthesis of β-aminothioesters

Chenaimwoyo A. Gondo, Annette Bahlinger, Helma Wennemers, Jeffrey Annette Bahlinger1,2 andHelma Wennemers2 W. Bode 1DepartmentofChemistry,University of Basel, St.Johanns-Ring19, ETH Zurich, Wolfgang-Pauli-Str. 10, 8093 Zürich Switzerland CH-4056 Basel, Switzerland 2Laboratory of OrganicChemistry,ETH Zürich,Wolfgang-Pauli-Strasse10, CH-8093 Zürich,Switzerland Chiral, bicylic 1,2,4-triazolium salts, common precursors of N-heterocyclic carbenes (NHC’s), have emerged as the most general class of azolium salt Thestereoselectivesynthesisofβ-aminothioestersisofhighinterestsince precatalysts for NHC-catalyzed reactions [1]. There are few synthetic routes they arecommonchemicalbuildingblocks foravarietyofpharmaceutical for their preparation and modification [2]. Furthermore, the harsh conditions importantcompounds.[1] An attractive waytogeneratethioestersin required for the formation of the azole ring limit the choice of additional general, is theuse of thioesterenolates. Due to thelow acidityoftheir functionality. α-protons,thioester enolategenerationtypically requires harsh Ar conditions.[2] Recently ourgroup introduced mono thiomalonates(MTMs) N N+ as thioesterenolate-equivalents allowing formildorganocatalytic conditions in 1,4additionreactions with nitroolefins.[3] N X-

R We have successfully prepared libraries of bifunctional triazolium salts using precursors bearing suitable functional groups and solid phase peptide synthesis.Our current efforts involve screening these catalysts for new transformations, particularly those utilizing the additional functionality to Herein we show that also imines react readily with MTMs. Theaddition perform reactions not catalyzed by NHCs alone. products, β-aminothioesters,were obtained in excellent yields (upto99%) andstereoselectivities(up to 98% ee) usingonly 1mol%ofacinchona [1] D. Enders, O. Niemeier, A. Henseler Chem. Rev. 2007, 107,5606 alkaloid derivative. Furthermorewepresent β-aminothiostersaspre- [2] C. A. Gondo, J. W. Bode, Science of Synthesis, 2012, 13.33 activated β-amino acidsthatcan easily be used for β-peptide synthesis.

[1]T.Miyazaki, Y. Han-ja, H. Tokuyama, Synlett 2004,477. [2]F.G.Bordwell, Acc. Chem. Res., 1988, 21,456. [3]P.Clerici,H.Wennemers, Org. Biomol. Chem., 2012, 10,110.

Organic Chemistry Organic Chemistry Organic Chemistry 416 Organic Chemistry 417 Peptide-catalyzed Stereoselective Construction of -Nitroaldehydes Construction of AcyclicQuaternaryAll-CarbonStereogenicCenters BearingaQuaternary StereogenicCarbonCenter with -SubstitutedMonoThiomalonates

Robert Kastl,Helma Wennemers* Yukihiro Arakawa1 andHelma Wennemers1

Laboratorium fürOrganischeChemie, ETH Zürich 1ETH Zürich, Wolfgang-Pauli Strasse 10, CH-8093 Zürich,Switzerland Wolfgang Pauli-Strasse 10,8093 Zürich,Switzerland Quaternary stereogenic centers bearing fourdifferentcarbon substituents are The conjugate addition reactionofaldehydes to nitroolefins is an important present in many importantpharmaceuticals andnaturallyoccurring com- reactionthat provides syntheticallyuseful -nitroaldehydes.Our group suc- pounds. Catalytic asymmetric C-Cbond forming reactions that generate such cessfullyintroduced tripeptidesofthe type Pro-Pro-Xaa(Xaa=acidicami- all-carbon quaternary centersare thereforehighlyvaluableinorganic syn- no acid) as highlyefficientcatalysts for asymmetric conjugateaddition reac- thesis.[1]However,theirsuccessful developmenthas proven rather chal- tions of aldehydes to -mono-and ,-disubstituted nitroolefins [1][2]. lenging, especially in thecaseofacyclic stereocenters.[1] We report the Furthermore,webecameinterested in using ,-disubstituted nitroolefins as highly efficient andstereoselectivecatalytic generation of quaternary electrophiles since theywould afford the corresponding -nitroaldehydes all-carbon stereogenic centersinacyclic systembymeans of the novel with aquaternary stereogenic carbon center.Their constructionischalleng- prochiralnucleophile, mono thiomalonates(MTMs)[2] having acarbon ingas,-disubstituted nitroolefins aresignificantlyless reactivecompared substituent at the -position. to -monosubstituted nitroolefins due to their increased steric demand.

In the presenceofsmall amountsofbifunctionalcinchona alkaloidorgano- Here,weshow the peptide-catalyzedstereoselective conjugate addition re- catalysts (2-6 mol%), -substituted MTMs smoothlyreacted with actionofdifferentaldehydes to ,-disubstituted nitroolefins providing -nitroolefins to afford synthetically valuable -quaternary -nitrothioesters -nitroaldehydes bearingaquaternary stereogenic center in good yields and in excellent diastereoselectivities (≈ 10:1) andenantioselectivities (up to 99% stereoselectivities. ee). [1]a)M.Wiesner, J. D. Revell,H.Wennemers, Angew. Chem.Int. Ed. 2008, 47,1871-1874. b) M. Wiesner, G. Upert, G. Angelici,H.Wen- nemers, J. Am.Chem.Soc. 2010, 132,6-7.c)M.Wiesner, M. Neu- [1]For areview,see:J.P.Das,I.Marek, Chem.Commun., 2011, 47,4593. burger, H. Wennemers, Chem.Eur.J.2009, 15,10103-10109. [2]P.Clerici, H. Wennemers, Org. Biomol. Chem., 2012, 10,110. [2]J.Duschmalé,H.Wennemers, Chem.Eur.J.2012, 18,1111-1120. Organic chemistry CHIMIA 2012, 66, No. 7/8 585

Organic Chemistry Organic Chemistry Organic Chemistry 418 Organic Chemistry 419 Straightforward synthesis to Hyperforin analogues Asymmetricphotochemical synthesis by kinetic resolution usingchiral quenchers Isak Alimi, Michael Bersier,Christian. G. Bochet Lucile Bernet, MichaëlBersier, Christian G. Bochet* UniversityofFribourg,Ch. du musée9,CH-1700 Fribourg DepartmentofChemistryofFribourg, Due to itsstructuralcomplexityand biological activity, Hyperforin 1 has Chemin du Musée9,CH-1700 Fribourg, Switzerland emergedasachallengingtargetfor total synthesis. The first total synthesis of the ent-Hyperforin hasbeen reported onlyrecentlybyShibasaki et al [1]. There aretwo ways of promoting aphotochemicalreaction: the excitation by direct irradiation andthe indirect excitation by sensitization. In the direct excitation mode,asingletisthe first obtained, whichcan then evolve intoa triplet state,ifthe intersystem crossingisfasterthan the reaction. Forthe indirect excitation,the excitedstate is obtainedusing sensitizer.Ifachiral sensitizerisused,thereisapossibilityofobtaining the productofthe photochemical reactionwith acertain enantiomeric excess.1, 2 The principal problem for the modest resultspublished so farinthe literature is the weak interaction between the substrate andthe chiralsensitizerand the short lifetime of the excitedstate. The aimofour projectistouse aquencherinsteadasensitizer. In the presence of achiral triplet quencher,anenantiomeric excesscould be in princi- ple obtainedbykinetic resolution: thetriplet quencherdeactivates onlyone Scheme 1 :11steps sequence to hyperforin analogue 4 of the enantiomersofthe racemictriplet state.For an optimal interaction andselectivitybetween thesubstrate andthe chiral quencher, we useahost- Our effortstowards the total synthesis of Hyperforin 1 arefocused on the guestprinciple.Inthiswork, we will show our first resultsonthe intramo- formation of the bicyclo[3.3.1]nonane core 3. Thesynthesis of Hyperforin lecular photocycloaddition of racemicenones. analogue 4 wasachieved in 11 steps starting from cyclohexanone 2 [2].This [1]T.Bach,H.Bergmann, B. Grosch, K. Harms J. Am. Chem.Soc.2002, straightforwardroute shows also flexibility by thepossibilityofinstalling 124, 7982-7990. other functionalities on methylcyclohexenone 2, whichcould leadtothe [2]D.F.Cauble, V. Lynch, M. J. Krische J. Org. Chem.2003, 68, 15-21. synthesis of other PPAP’s naturalproducts like Clusianone or Nemorosone. [1] Shimizu, Y.; Shi, S.-L.; Usuda,H.; Kanai, M.; Shibasaki, M., Angew. Chem.Int. Ed. 2010, 49,1103-1106. [2]a)Ahmad, N. M.; Rodeschini,V.; Simpkins,N.S.; Ward, S. E.; Blake,A.J., J. Org. Chem. 2007, 72,4803-4815. b) Siegel,D.R.; Danishefsky, S. J., J. Am.Chem. Soc. 2005, 128,1048-1049.

Organic Chemistry Organic Chemistry Organic Chemistry 420 Organic Chemistry 421 Conditional Triggered Drug Release Synthetical approachestoinvestigateproteins-chemical warfareagents Elia Janett,Tatiana Cotting, Christian G. Bochet* adducts DepartmentofChemistry, UniversityofFribourg,Ch. du Musée9, Julien Ducry1,2,Christian Bochet1,Christophe Curty2 CH-1700 Fribourg, Switzerland 1UniversityofFribourg, Chemin du Musée9,CH-1700 Fribourg Nowadays, the need of internalfixationdevicesorjoint replacementisdra- 2Spiez Laboratory, CH-3700 Spiez maticallyincreasing, which means also increasingpercentagesofinfections. The solution to thisproblem wasuntilnow to coverthe implant with acoat- ing of antimicrobialagent. Unfortunately the constant presence of antibiot- Unequivocal methods to verifyexposure to chemical warfareagents ics leads oftentobacterialresistanceand the coatingsquick agingimplicate (CWAs) give credibility to the verification regime of the Convention on the areplacement. Prohibition of the Development, Production, Stockpiling andUse of Chemi- We propose encapsulated antimicrobialagent withatriggersystemtoopen cal Weapons andontheirDestruction.1 Because of theirstabilityand their thecapsules onlyinpresenceofbacteria as asolution to theactual situation. specificity, adductsformed between CWAs andproteins aregood candidates as biomarkers for theanalyticalinvestigation.2 Furthermore,these ad- We arecurrentlysynthesizing atrigger system composed of acyclohexane ducts cangive important indications about theCWAs’ actions in the body. ring kept in an unstable conformation with two almost complementary oligonucleotide strands. The mismatchpresent in thetwo DNAstrands should Our goal is to synthesizealibraryofpotential aminoacids-CWAsadducts 3, allowaconformationalchange in presence of fully complementary bacterial 4, 5 that could be then incorporated in SolidPhase PeptidesSynthesis afford- RNAstrand. With thisconformationalchange, two functionalgroups should ing referencestandards fortheir unambiguous identification. Their stability undergoachemical reaction andrelease aleavinggroup that is responsible in physiological medium will be testedtodetermine if thereisachance to for the openingofthe capsules liberating the antimicrobialagent. This post- recoverthem from contaminated biological samples,such as blood and er will focus on thesynthesis of the central coreand the side linkers. urine. Relevantbiomarkerswill be so identifiedfor the developmentofana- lytical methods. In thiscontribution, we will show the first resultsabout adducts’ synthesis,especially fororganophosphonatesCWAs. [1]http://www.opcw.org/chemical-weapons-convention/ [2]Black, R. M. J. Chromatogr. B, 2010, 878,1207-1215. [3]MacDonald, M.;Lanier, M.; Cashman, J. Synlett, 2010, 13,1951- 1954. [4]Noort, D.; Hulst, A. G.; Trap,H.C.; de Jong,L.P.A.;Benschop, H. P. Arch. Toxicol., 1997, 71,171-178. [5]KameswaraRao,M.; Sharma,M.; Raza,S.K.; Jaiswal, D. K. Phos- phorus, Sulfur Silicon Relat. Elem., 2003, 178:3,559-566. 586 CHIMIA 2012, 66, No. 7/8 Organic chemistry

Organic Chemistry Organic Chemistry Organic Chemistry 422 Organic Chemistry 423 ExploitingRh(I)-Rh(III) Cycles in Highly Substituted 1-Indenylamines Enantioselective Strain-promoted CCBondCleavages by Rhodium(I)-CatalyzedDirected C-HActivations

Laetitia Souillart,Nicolai Cramer* DucN.Tran,Nicolai Cramer

LaboratoryofAsymmetric Catalysis andSynthesis,EPFL SB ISIC LCSA LaboratoryofAsymmetric Catalysisand Synthesis, EPFL SB ISIC LCSA BCH4305, CH-1015 Lausanne,Switzerland BCH4305, CH-1015Lausanne, Switzerland Smallringsubstrates play an important role forC–C σ-bond activations as theirinherentringstrainfacilitatesmetal insertion.[1] Our group reported The activation of inert carbon-hydrogen bondsisapowerful, yet very chal- rhodium-catalyzed enantioselective β-carbon eliminations from tert- lenging tool to streamline synthesis. Usingthis approach, complexstruc- cyclobutanols giving rise to alkylrhodium intermediatesbearing an tures mightberapidly accessed from simple starting materials without the all-carbon quaternarystereogeniccenter. Thiskey intermediate enables requirements of prefunctionalization.[1]Our research focuses on thedevel- accesstoadiverserange of products viaanumberofdifferent downstream opmentofC-H activation processesusingsynthetically versatile directing reactionpathways.[2] So far, thesepathwaysdid not involve redox groups capableofparticipating in acascadereaction.[2] Such processes chemistryofrhodium as alltransformations proceed consistentlywith provide an additional handle to increase diversity and molecular complexity Rh(I)complexes.However, redox processescould greatlydiversifythe of the formed products. We report hereby our recent progress in using free accessible productrange.Towardsthisgoal, we envisionedthatalkyl ketimines as participativedirecting groupinrhodium(I)-catalyzedC-H func- rhodium intermediate 2 might undergoanoxidativeadditionwith an tionalization providing accesstoheavily substituted 1-indenylamines in a appendedarylhalidetoformarhodium(III)species 3.Wereport regio-,diastereo- and enantioselective manner. downstream pathways of 3 giving rise to newproductbranchesinhigh enantioselectivities.

[1]T.Seiser, T. Saget, D. N. Tran, N. Cramer Angew. Chem.Int.Ed. 2011, 50,7740. [2]for an overviewsee N. Cramer, T. Seiser, Synlett 2011,449-460; [1]Recentreviews: L. McMurry, F. O’Hara,M.J.Gaunt Chem. Soc. Rev. T. Seiser, N. Cramer, Chimia 2010,64, 153. 2011, 40,1885-1898. [2] a) D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2010, 49,8181. b) D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2011, 50,11098.

Organic Chemistry Organic Chemistry Organic Chemistry 424 Organic Chemistry 425 ARapid andModular Access to Arylsultams by ApplicationofchiralCp-ligands in asymmetric Rh(III)-catalyzed C-H Rh(III)-Catalyzed C-H Activation activations

Van-Manh Pham, Baihua Ye, Nicolai Cramer* Baihua Ye,Nicolai Cramer*

Laboratory of Asymmetric Catalysis and Synthesis, EPF Lausanne LaboratoryofAsymmetric Catalysis andSynthesis,EPF Lausanne EPFL SB ISIC LCSA, CH-1015 Lausanne, Switzerland EPFL SB ISIC LCSA,CH-1015 Lausanne, Switzerland The sulfonamide group is aclassical and important pharmacophore in me- Cyclopentadienyl(Cp)and pentamethylcyclopentadienyl(Cp*) ligands are dicinalchemistry. Arylsultamsrepresent as well an important motif due to of fundamental importanceinorganometallic chemistryand as well in cata- theirwide range of biological activities.[1] Several methods and strategies lysis. Althoughchiral analogsofCp-ligands areknown, thereare only to synthesize sultamshave been reported.However, all of them requiresev- scarceapplications in catalysis. [1]Despitetheir high potential, asymmetric eral steps from commercially availablematerials and/or functionalizedsub- reactions with late transition metalcomplexes,where thesolesource of chi- strates.[2] ralitystems frominthe Cp fragment,are completely elusive.Recently, a Directed C-Hbondactivations have recently attracted significant attention particular interestinCp*M(M=Rh,Ir, Co)complexes arose fromtheir because of theirefficiencyand atom economical alternativetoclassical syn- activityasC-H activationcatalysts. thesis.[3] In this respect, severalnew Rh(III)-catalyzedprocesses have emerged overthe past years.[4] We report our findings on applying Rh(III)- We have elaborated afacile andflexiblesynthesis of anew classofenantio- catalyzed C-Hactivationofarylsulfonamide derivatives and their subse- pure C2-symmetric Cp ligands. To showcasetheir utility, thecorresponding quent cyclisation with internalalkynes to provide an efficient and highly rhodium complexeswereapplied in thefirst asymmetric versionofisoqui- yielding routetoarylsultams. nolinone synthesis. [2]The chiral Cp-Rhcomplexes demonstratehighreac- tivity, delivering theproductswith excellent regio- andenantio-control.

[1] T. J. Carty, A. Marfat, P. F. Moore, F. C. Falkner, T. M. Twomey, Agents Actions 1993, 39,157. [2] a) I. R. Greig, M. J. Tozer,P.T.Wright, Org. Lett. 2001, 3,369; b) M. Jiménez-Hopkins, P. R. Hanson, Org. Lett. 2008, 10,2223. [3] D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110, [1]L.Halterman. Chem.Rev. 1992,92, 965. 624. [2]N.Guimond, C. Gouliaras, K. Fagnou. J. Am.Chem. Soc. 2010,132, [4] G. Song, F. Wang, X. Li, Chem. Soc. Rev. 2012, 41,3651. 6908 Organic chemistry CHIMIA 2012, 66, No. 7/8 587

Organic Chemistry OrganicChemistry Organic Chemistry 426 Organic Chemistry 427 Enantioselective HydrocarbamoylationApproachtowards Substituted RadicalCarboazidationReaction with Iodomethyl Sulfones -Lactams Nicolas Millius,Guillaume Lapointe, Philippe Renaud* PavelDonets,Nicolai Cramer* Universität Bern, Freiestrasse 3, CH-3012 Bern LaboratoryofAsymmetric Catalysis andSynthesis,EPF Lausanne EPFL SB ISIC LCSA,CH-1015 Lausanne, Switzerland Renaud et al. developed aradical carboazidation reaction [1] that formed a carbon-carbon bond and acarbon-nitrogen bond at once. This method was Nickel/phosphine/Lewis-acid(LA)catalyzed hydrocarbamoylationofun- performed with α-iodo esters and was applied to the total synthesis of natu- saturated bonds, formally constitutingasimultaneouscarbamoyland hydro- ral products as monomorine I[2] and lepadiformine [3]. The scope of the gentransfer of aformamidegroup, [1]providesadirect andanatom- carboazidation reaction was now extended to iodomethyl sulfones. efficientroute to arange of substitutedamides.The intramolecularreaction of readily accessible homoallylamineformamides 1 leadstochiral -lactams O O O O N3 2.However, despite the abundanceand wide useofchiral phosphines as S N I S N 3-PySO2N3 N ligands fortransitionmetal catalysis, no enantioselectiveexamplesofthis + N N N usefultransformationhavebeen describedsofar. N N Ph Ph We have developedanovelhighlyco-operativecatalytic systemcomprised Ph Ph by aphosphine andachiral secondaryphosphine oxide(SPO)incombina- 1 2 3 tionwith an activatingLA, which is considerably more efficient, than phosphine-onlysystems. The modularSPO-phosphine combinationaffordsvari- The introduced 1-phenyl-1H-tetrazole-5-yl group give the possibility for ous -lactams with high yields andgood enantioselection. performing aJulia-Koscienski olefination [4]. O O N3 N3 S N base benzaldehyde Ph N N Ph Ph N Ph

4 3 [1] P. Panchaud, L. Chabaud, Y. Landais, C. Ollivier, P. Renaud, S. Zig- mantas, Chem. Eur. J. 2004, 10,3606. [2] G. Lapointe, K. Schenk, P. Renaud, Chem. Eur. J. 2011,3207. [3] P. Schär, P. Renaud, Org. Lett. 2006, 8,1569. [4] P. R. Blakemore, W. J. Cole, P. J. Koscienski, A. Morley, Synlett, 1998, [1]Y.Nakao,H.Idei, K. S. Kanyiva, T. Hiyama J. Am. Chem.Soc. 2009, 26. 131,5070.

OrganicChemistry OrganicChemistry Organic Chemistry 428 Organic Chemistry 429 Toward theTotal Synthesis of Aignopsanoic Acid A Preparation of the Mitomycin Tricyclic Core via aDiastereoselective Radical Cascade C. Bürki,1 G. Villa,1 B. Bradshaw,2 J. Bonjoch2 and P. Renaud*1 François Brucelle and Philippe Renaud* 1Universität Bern, Freiestr. 3, CH-3012 Bern, Switzerland, Universität Bern, Departement für Chemie und Biochemie, Freiestrasse 3, 2University of Barcelona, Av. Joan XXIII sn, 08028 Barcelona, Spain CH-3012 Bern, Switzerland Aignopsanoic acid A, exhibiting amoderate activity against Trypanosoma Radical chemistry is apowerful tool to create carbon-heteroatom bonds and brucei,has been isolated in 2009 from Cacospongia mycofijiensis [1]. Two carbon-nitrogen bonds are readily formed when organic azides are used as features were identified as key steps in its synthesis:the all-cis configuration radical traps.[1] As part of our ongoing interest in the field of radical pro- of the methyl groups on the readily available Wieland-Miescher ketone [2] cesses involving azides and alkaloid synthesis, anovel mild approach to framework and the introduction of the missing carbonyl on the side chain. prepare indolines via atandem radical addition/cyclization onto ortho- azidoallylbenzenes will be described.

2 R R2 CO Et ICH2CO2Et 2 70-93%yield up to 97:3 dr Et B, air N Facing the failure of the metal catalysed hydrogenation of intermediate 1 to 1 N3 3 R rt R1 H afford the desired stereoisomer [3], we turned our attention to the hydroboration. We will present anew approach based on hydroborationand direct The mitomycins are an important class of bioactive naturalproducts exhibit- protonolysis [4] yielding selectively the all-cis stereoisomer. ing potent anticancer properties.[2] Our radical cascade allowed us to access their tricyclic core structure in ahighly diastereoselectivemanner.

OBn OAc OBn O OCONH OAc ICH2CO2Et 2 O Et3B, air O H H2N OMe toluene, rt, 4h N N then N NH We then focused on the second key step: the introduction of asingle carbon 3 CSA O O O atom on an unactivated double bond. Strategy featuring aformal radical reﬂux, 4h O one-pot Mitomycin C mediated Karash addition will be described. 80%, 97:3 dr [1] T. A. Johnson et al., Org. Lett., 2009,11, 1975-1978. [1] (a) Renaud, P. et al.Chem. Eur. J. 2004, 10,3606. (b) Minozzi, M.; [2] B. Bradshaw, J. Bonjoch, Synlett 2012,23, 337-356. Nanni, D.; Spagnolo, P. Chem. Eur. J. 2009, 15,7830. [3] Gorga Extebarria iJardi, 2010, PhD Thesis, University of Barcelona, [2] (a) Bradner, W. T. Cancer Treat. Rev. 2001, 27,35. (b) Andrez, J.-C. Beilstein J. Org. Chem. 2009, 5,33. [4] G. Villa, G. Povie, P. Renaud, J. Am. Chem. Soc., 2011,133, 5913-‐5920 588 CHIMIA 2012, 66, No. 7/8 Organic chemistry

OrganicChemistry Organic Chemistry Organic Chemistry 430 Organic Chemistry 431 Addition of Mono-organocopper Reagents to Thioiminium Ions α-Chloro B-alkylcatecholboranes as RadicalPrecursors

Pierre Mateo, Philippe Renaud* Gong Xu, PhilippeRenaud*

Universität Bern, Departement für Chemie und Biochemie,Freiestrasse 3, University of Bern, Department of Chemistryand Biochemistry, Freiestrasse CH-3012 Bern, Switzerland 3, CH-3012 Bern, Switzerland

In alkaloids synthesis, the creation of quaternary stereogenic centers by B-alkylcatecholboranes have been showntobeefficient alkyl radicalpre- gem-dialkylation of lactams is aattractive but still achallenging task. The cursors[1].Wehave developed aone-pot radicalprocedure involving methods developed to achieve this transformation involve, after an initial α-chloro B-alkylcatecholboranes which were generated from vinyl arenes via activation step, the successive addition of two nucleophiles.[1] However, the hydroboration with catecholborane followed by Matteson homologation[2] iminium intermediatewhich is formed upon addition of the first nucleophile [3]. The new α-chloro B-alkylcatecholboranescan be employed in awide is usually more reactive than the activated lactam and, in such conditions, range of reactions,such as allylation,reduction, chlorination, cyanation and the symmetrical gem-dialkylation side-product cannot be avoided.[2] conjugate addition to unsaturated ketones.

Nu1 Nu1 1) Activation Nu2 O Nu1 2 1 N 2) Nu1 N N Nu N Nu Bn Bn Bn Bn 1 We report here that with thioiminum ions, the use of mono-organocopper reagents as first nucleophiles offers anew approach, allowing the clean formation of non-symmetrical products. Our progresses towards more elaborated structures will also be disclosed.

R 1) "RCu" R=i-Bu, n-Bu, i-Pr, t-Bu, Ph N SMe N Nu2 2) Nu2 Nu2 =H,CN, Allyl Bn.I- Bn quant. from 1 up to 96% [1] K.-J. Xiao, J.-M. Luo, K.-Y. Ye, Y. Wang, P.-Q. Huang Angew. Chem. Int. Ed. 2010, 49,3037. This procedure also provides apotential approach to introduce –CClX groups [2] A. Agosti, S. Britto, P. Renaud Org. Lett. 2008, 10,1417. onto alkenes. [1] A.P.Schaffner, P. Renaud, Eur.J.Org. Chem. 2004,2291. [2] D.S. Matteson, D. Majumdar, Organometallics 1983, 2,1529. [3] D.S. Matteson, D. Majumdar, J. Am. Chem. Soc. 1980, 102,7588.

OrganicChemistry Organic Chemistry Organic Chemistry 432 Organic Chemistry 433 emlated elf�orting inelf�rganiing urface�Initiated Coaxial MultichromophoricPhotosystems Co�Polymeriation Giuseppe Sforazzini,Naomi Sakai, Stefan Matile* uyaDomoto, EdvinasOrentas, Adam Wilson, Naomi Saai,Stefan Matile* UniversityofGeneva, DepartmentofOrganic Chemistry, University of Geneva, DepartmentofOrganicChemistry,30uaiErnest 30 QuaiErnest Ansermet, 1211 Geneva 4, Switzerland Ansermet 1211 Geneva4,Switzerland Here we report preparationofmultichromophoric coaxial charge-transport Recently we have inventedself�organizing surface�initiated polymerization architectures consisting of phthalocyanine(Pc) andperylenediimide (PDI). SOSIPaspromising way to provide facileaccesstoorderedand oriented ArationallydesignedPccontainingstructurallysupporting peptide side- multicomponentarchitectures on surfaces [1]. hestacing of naphtha� chains, hydrazides, polymerizable disulfidesand diphosphonate anchoring lenediimidesNDIscores inSOSIP architectures offers electronhole groups wascovalentlybound onto the ITOsurface.Self-organizing surface- transporting channels, which can also be further developedtomultichannel initiated polymerization(SOSIP)was used to buildverticallyaligned Pc architectures withmulticomponentgradients [2,3].Ourcurrentstudies are assembly(p-typechannel)covalentlylinkedbydisulfide bonds. Hydrazone directed to precise control of self�sorting by templated�directed co�SOSIP. exchange of benzaldehydes with PDIaldehydes introduces an outer vertical opology and π�acidity of SOSIP initiatorspropagatorsdetermine sorting electron-transportingpathway(n-type channel).[1] The proposedbottom-up andtemplation efficiency.urthermore, tuning of side�chains isalso ex� approach affords formation of well-organized verticalcharge-transport pected to be an additional elementfor regulating thesurface�templation effect coaxial architectures which have largeinterestinthe optoelectronicsfield. andproperty of multicomponentphotosystems.

[1]N.Saaiet al., 2011, ,15224. [2]M.Lista et al., 2011, ,15228. [3]N.Saaiet al., 2011, ,18542. [1]Sakai,N.; Matile, S. J. Am.Chem.Soc. 2011, 133,18542-18545. Organic chemistry CHIMIA 2012, 66, No. 7/8 589

OrganicChemistry OrganicChemistry Organic Chemistry 434 Organic Chemistry 435 Cell-Penetrating Peptides(CPPs) with Disulfide Bonds Asymmetric Imine Aziridination with Ru/PNNP: Anion Tuning

Oleksandr Kucherak, Eun-Kyoung Bang, Stefan Matile* Joël Egloff,Amata Schira, Antonio Mezzetti*

University of Geneva,Geneva, Switzerland ETH Zürich, Wolfgang-Pauli-Str. 10, CH-8093 Zürich, Switzerland

1 Since the discovery in 1988, cell-penetrating peptides (CPPs) gained agreat Our group has reported that [RuCl2(PNNP)] (1), after activation with potential as delivery vectors for use in research and medicine. While design- (Et3O)PF6 (1 equiv), catalyzes the asymmetric aziridination of imine 2 with ing aCPP-molecule, the dynamiccovalent bonds can be used [1]. ethyl diazoacetate (3)with the intermediacy of the diazoester complex 4. The latter species either transfers carbene to the imine or decomposes to the Our research is focused on the development of CPPs containing the amino- carbene complex 5 that reacts with 3 to give diethyl maleate (6), hence low- acid molecules, functionalized with asparagusic acid moiety. The latter ering the yield of aziridine 7. includes adisulfide bond that plays the crucial role due to easiness of its formation and cleavage: desired peptide can be obtained by polymerization Cl Y Ph Cl Y N Y COOEt Ph Ph reaction, and after uptake it can be easily degraded inside acell. N N N N N N Cl N 2 Ru CHPh + Ru Ru 3 H 2 2 N Variation of CPPs’ composition by copolymerization opens aroad to the P P P P Et O library of potential synthetic delivery vectors. The exploration of uptake- 2 P N Ph COOEt N P activitiesofnewly synthesized peptides is done in lipid vesicles by fluores- 4 N 7 8 N cence assays [2,3] and the most active samples will be further used for H COOEt Y– EDA (equiv) yield (%) ee (%) – 17 80 experiments in live cells. PF6 1 BF – 1 25 78 –N2 4 Cl – The obtained results will extend current knowledge on the nature of CPP- N N BF4 4 43 78 – 4 45 70 uptake process and may result in an invention of the efficient delivery Ru Cl Y SbF6 P Cl P toolkit for wide applications both in science and medicine. Ph Ph N N COOEt 2 2 Ru 3 1 6 P P COOEt H COOEt 5

– – – We find now that, by changingthe anion from PF6 to BF4 or SbF6 ,the aziridine yield improves with little impact on the enantioselectivity in the – case of BF4 ,and reaches 45% with an excess of 3 (4 equiv). Interestingly, running the reaction in aclosed vessel, in which N2 pressurebuilds up, re- duces the yield of aziridine to 32% under the same conditions, in agreement [1] J. Montenegro, C. Gehin et al., Chimia 2011, 65,853. with the accumulation of the dinitrogen complex 8. [2] J. Montenegro, S. Matile, Chem. Asian J. 2011, 6,681. [1] M. Ranocchiari, A. Mezzetti, Organometallics, 2009, 28,3611. [3] J. Montenegro, A. Fin, S. Matile, Org. Biomol. Chem. 2011, 9,2641.

Organic Chemistry OrganicChemistry Organic Chemistry 436 Organic Chemistry 437 ForceFields forEnergetics and Dynamics of Organometallic Complexes AsymmetricHydrogenation of α,β�Unsaturated Esters using Chiral and Applications Iridium P,NCatalysts

Franziska Hofmann,Andreas Pfaltz and Markus Meuwly Marc�André Müller,AndreasPfaltz*

University of Basel, Department of Chemistry,Klingelbergstr.80, CH-4056 University of Basel,St. Johanns�Ring 19, CH�4056Basel,Switzerland

The development of transition metal catalysts requires an accurate waytopre- dict relative energies and activation barriers for multiple diastereomers. Afast Enantioselectiveconjugate reductions represent one of the most widely�used reaction types in metal catalyzed asymmetriccatalysis.[1] However there are approach is VA LBOND TRANS[1] (VBT) which is based on valence bond only few studies on thereduction of trisubstituted α,β�unsaturatedesters in theory and includes the trans influence of ligands on bond lengths and relative literature andespecially for α�substituted substrates high selectivities are energies. In the present contribution, the VBT force field is generalized for hard to be obtained.[2] In 2010 wereportedthefirst highly enantioselective model octahedral complexescontaining Ir,sothat DFT relative energies for reductions of α�substituted α,β�unsaturatedesters using chiral pyridyl different diastereomers can be reproduced. Forthis, the point charges and the phosphinites withlargearyl substituents as ligands.[3] Basedonthisresults vdW parameters[2] were fitted with INolls[3]. To examine the transferability wetestedseveral substitution patternstoget acloser insight intothesub� of the parameters, the homogeneous oxidation reaction of water[4] to dioxy- stratescope andabetter understanding intheapplicability andperformance gen wasinvestigated with VBT.Transition states were modeled with adiabatic of thesecatalysts. reactive MD[5] to qualitatively reproduce three different mechanisms, which were already suggested by DFT calculations[4].

Herein wedisclose expanded results inthehydrogenation of α,β�unsaturated esters andobservations with the usedcatalyst systems.

[1]W.S.Knowles,R.Noyori, 2007, ,1238. [1] Tubert-Brohman, I. et al, J. Chem. Theory.Comput. 2009, 5,530. [2]C.Hedberg,K.Kӓllström,P.Brandt,L.K.Hansen, P. G. Andersson, [2] Devereux, M. et al, J. Chem. Inf. Model. 2010, 50,349. 2006, ,2995. [3] Law, M. et al, J. Chem. Chem. 1997, 102,252. [3]D.H.Woodmansee, M.�A. Müller, M. Neuburger,A.Pfaltz, [4] Blakemore J. D. et al, J. Am. Chem. Soc. 2010, 132,16017. 2010, ,72. [5] Lutz S. et al, Chem. Phys. Chem. 2011, 13,305. 590 CHIMIA 2012, 66, No. 7/8 Organic chemistry

OrganicChemistry Organic Chemistry Organic Chemistry 438 Organic Chemistry 439 Synthesis and properties of linear and macrocyclic azocarbazoles LewisAcidCatalysedInverseElectron-DemandDiels-AlderReaction– ANew SyntheticEntry to Steroids Luca Schweighauser1,Raphael Reuter1,Daniel Häussinger1,Hermann A. Wegner1,* Miroslav Sisa1,HermannWegner1

1University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland 1Department of Chemistry, UniversityofBasel,St. Johanns-Ring19, CH- 4056 Basel, Switzerland

Azo compounds are well known for their application as dyes. In the last Ahighlyfunctionalized cyclopropanatednaphthalene is easilyaccessible in years, research has broadened their use for advanced materials [1]. The in- one step viaadomino inverseelectron-demand Diels-Alder(IEDDA)- corporation of azo units is acommon approach to realize switches on amo- cyclopropanationreactioncatalysed by abidentate Lewisacid[1].Thisin- lecular level [2]. In this work an azocarbazole macrocycle with π- termediate canbetransformed[2] to aprecursor ideally suitedfor ahomo- conjugation and four azo units was synthesized and its photochemical prop- Nazarovcyclization[3] yielding directly the6-6-6-5-tertacyclic steroid ring erties investigated. This molecule combines the properties of ashape- system. Thisstrategyprovidesastraightforward access to steroids, i.e. es- persistent macrocycle and the special electronic features of carabazole units trogens as potentialanticanceragents, which aredifficult to prepare by with the potential of amolecular switch. NMR measurements in the photo- standard steroid functionalizationprocedures. stationary state, UV-spectroscopy and x-ray crystallography were used for characterization of the complex properties. It was found that irradiation with visible light led to isomerization. Whereas, irradiation with UV-light in a chlorinated solvent led to the photo-formation of HCl and protonation of the azocarbazole. The wide range of qualities makes azocarbazoles suitable for the application as integrated molecular logic gates.

[1]S.N.Kessler, H. A. Wegner, in preparation. [1] B. Feringa, Molecular Switches;Wiley-VCH:Weinheim, 2001. [2]S.E.Denmark,R.Klix, Tetrahedron, 1988,4043. [2] R. Reuter, H. A. Wegner, Chem. Commun. 2011, 47,12267. [3]F.DeSimone,J.Andres,R.Torosantucci, J. Waser, Org. Lett., 2009, [3] L. Schweighauser, R. Reuter, D. Häussinger, H. A. Wegner, in prepa- 11,1023. ration.

Organic Chemistry Organic Chemistry Organic Chemistry 440 Organic Chemistry 441 Bidentate LewisAcidCatalysis: ANew Entry to HighlySubstituted Triangulene-derived Push-PullChromophores Naphthalenes Milan Kivala,* Bettina Gliemann,Natalie Gruner SimonN.Kessler,Hermann. A. Wegner Lehrstuhl fürOrganische Chemie I, UniversityofErlangen-Nürnberg, UniversityofBasel,St. Johanns-Ring19, CH-4056Basel,Switzerland Henkestraße42, D-91054Erlangen, Germany Multidentate interactions are thesecret to nature’scatalysis. Nonethelessthe applicationofthese principles remains an extremelychallengingendeavor. In organicsynthesis theLewis acid catalysis presents averyeffectivetool Push-pull chromophoresconsisting of strongdonor andacceptor moieties foravarietyofdifferenttransformations. Although effort hasbeen made connected through -conjugatinglinkers have attracted much attention due towards bidentateLewis acidcatalysts still they reactinamonodentate fa- to their stronglybathochromically shiftedUV/visabsorption bands as ab- shion.[1] Recently, we were able to show the catalysis of theinverseelec- sorbers in bulk heterojunction organic solar cells or as functional dyes for tron-demand Diels-Alder(IEDDA) reactionof1,2-diazines by abidentate nonlinear optics [1]. Lewisacidinabidentatefashion.[2] The general principleisbased on the Scheme 1:Synthesis of thetrian- following rational: The twofoldcoordinationofthe bidentateLewis acidto gulenepush-pullchromophores the1,2-diazinedecreases theenergylevel of theLUMOfacilitatingthe cyc- by Knoevenagel-type condensation of CH-acidicacceptors (A) loadditionstep. ConsecutiveeliminationofN2generates theproductand with thecorresponding carbonyl also liberates thecatalyst. precursors.

Bridgedtriphenylamine derivatives, so-calledtriangulenes,havebeen realized by Hellwinkel andco-workers about 40 yearsago [2]. However,the Thisnew conceptofcatalysis is furthermorecombinedwith anovelone-pot potential of these scaffoldsfor the constructionof-systems withinteresting synthesisof1,2-diazinoaromaticstoproducehighlysubstitutednaphtha- optoelectronic properties have by farnot been exhausted to date.Here, we lenesintwo steps fromaromatic aldehydes. presentthe synthesis andoptoelectronic propertiesofaseriesofnoveltrian- [1] K. Maruoka, Catal. Today 2001, 66,33. gulenechromophores featuring intramolecular charge-transferinteractions. [2] a) S. N. Kessler,H.A.Wegner, Org.Lett. 2010, 12,4062; b) S. N. Kessler,M.Neuburger,H.A.Wegner, Eur. J. Org.Chem. 2011,3238;c) [1]A.Mishra,P.Bäuerle, Angew. Chem.Int. Ed. 2012, 51,2020. H. A. Wegner,S.N.Kessler, Synlett 2011,699. [2]D.Hellwinkel, M. Melan, Chem.Ber. 1971, 104,1001. Organic chemistry CHIMIA 2012, 66, No. 7/8 591

Organic Chemistry Organic Chemistry Organic Chemistry 442 Organic Chemistry 443 Probing theMechanismofPost-lesion DNA Bypass Using 3’ Synthetic Nucleoside Probesfor Detecting O6-Alkyl-2’-deoxyguanosine in DNA Base Modified Primers HeidiA.Dahlmann, HaileyL.Gahlon, andShanaJ.Sturla1 Hailey L. Gahlon, ShanaJ.Sturla* 1ETHZürich,Institute of Food, Nutrition,and Health ETHZürich, Schmelzbergstrasse 9, CH-8092 Zürich, Switzerland

DNA mutations can arise from errorsduring polymerase-mediated DNA AlkylationofDNA to form nucleosideadducts is an important transfor- replication; for exampleduring translesionDNA synthesis (TLS).TLS in- mationleadingtomutagenesis andcarcinogenesis.Apossiblemeans for volvesspecialized polymerases (Y-familyDNA polymerases) that replicate detectingDNA adducts are hybridizationprobes, which are oligonucleotides past replication-blockingDNA lesions. Currently many studies investigate containingnucleosideanalogs designed to pair opposite specific adducts, themutagenic profileofnucleosidetriphosophate incorporation opposite such as O6-alkyl-2’-deoxyguanosine(O6-alkyl-dG).Alternatively,polymer- DNA lesions while less hasbeen studied regardingthe extensionimmedi- ase-mediated amplification of adducted DNA to facilitate detectionwould ately followinglesionbypass,i.e. post-lesionDNA synthesis (PLS).Inthis be desirable. We have evaluated aseries of nucleosideanalogs for utiliza- study themodelbulky DNA lesion O6-Benzylguanine (O6-BnG)and Dpo4, tioninbothhybridizationprobes andfor polymerase-mediated incorpora- aTLS polymerase,was used to investigate molecular leveldetails of PLS. tionopposite O6-alkyl-dGadducts. Results indicate that nucleosideanalog Structure activityrelationshipswere probed using aseries of 3’ modified size, shape, pi-stackingability, andhydrogen bonding capacity influence primers that pairedopposite O6-BnG to investigate theability of Dpo4- selectivity andeffectiveness in hybridizationand DNA synthesis. mediated primer extension. Data regardingsingle nucleotideincorporation, fulllengthprimerextension, steady-state kinetic incorporation efficiencies, andcomputationalmodelingofsynthetic base modified primers within the activesite of Dpo4will be presented.

OrganicChemistry OrganicChemistry Organic Chemistry 444 Organic Chemistry 445 Using Selenocysteine Substitutions to Steer Oxidative Protein Folding Directed Evolution of Escherichia coli K12 Transketolase Afor Im- proved Thiamin Pyrophosphate Analogs Binding Norman Metanis, Donald Hilvert Clément Dince, Donald Hilvert Laboratory of Organic Chemistry, ETH Zurich, Switzerland ETH Zürich, Wolfgang-Pauli-Str. 10, CH-8093 Zürich, Switzerland Bovine pancreatic trypsin inhibitor (BPTI) is asmall protein comprised of 58 amino acids and three disulfide bonds. Its folding mechanism has been Transketolase is akey thiamin-dependent enzyme in the pentose phosphate extensively studied.[1]Weanticipated that substituting cysteine residues in pathway for the synthesis of ribose. Its inhibition has been reported as a BPTI with selenocysteine might steer the oxidative folding of the protein, treatment for cancer [1] and adeficiency impairs the central nervous system since the greater stability of selenosulfide and diselenide bonds compared to [2]. The enzyme from E. coli is awell-studied and characterized protein disulfides can be exploited to populate specific intermediates. In addition, [3][4]. Mutations of specific residues of the active site were performed to given the ability of small molecule diselenides to catalyze oxidative protein investigate the binding of thiamin pyrophosphate analogs. We have used a folding, judiciously positioned Sec residues in BPTI could conceivably en- Benzyl thiazolium derivative and shown that it can be pyrophosphorylated hance folding efficiency.[2] To test these ideas, we chemicallysynthesized with Thiamin pyrophosphokinase. In this poster results will be presented several BPTI analogues containing Sec at key positions (5, 14, 30 and 38) showing the activity of this and other thiamin analogs with the modified using solid-phase peptide synthesis and native chemical ligation methods.[3] Transketolases.This work opens up possibilities for developing arange of These procedures were then applied to the preparation of the wildtype and novel, unnatural cofactor-dependent enzymes. selenium-containing BPTI variants. The effects of selenium incorporation on the folding of BPTI will be discussed.[4] [1] Thomas, A. A. et al., Bioorg Med Chem Lett 2008, 18 (6), 2206-2210. [2] Dreyfus, P. M.; Victor, M., Am JClin Nutr 1961, 9,414-25. [3] Turner, N. et al., Acta Crystallogr D 1995, 51,1074-1076. [1] a) T. E. Creighton, Prog. Biophys. Molec. Biol. 1978, 33,231-297; b) [4] Sprenger, G. A. et al., Eur JBiochem 1995, 230 (2), 525-532. T. E. Creighton, D. P. Goldenberg, J. Mol. Biol. 1984, 179,497-526; c) J. S. Weissman, P. S. Kim, Science 1991, 253,1386-1393. [2] a) J. Beld, K. J. Woycechowsky, D. Hilvert, J. Biotechnol. 2010, 150, 481-489; b) J. Beld, K. J. Woycechowsky, D. Hilvert, Biochemistry 2007, 46,5382-5390; c) J. Beld, K. J. Woycechowsky, D. Hilvert, Biochemistry 2008, 47,6985-6987; d) N. Metanis, C. Foletti, J. Beld, D. Hilvert, Isr. J. Chem. 2011, 51,953-959. [3] P. E. Dawson, T. W. Muir, I. Clark-Lewis, S. B. H. Kent, Science 1994, 266,776-779; b) D. Bang, S. B. H. Kent, Angew. Chem. Int. Ed. 2004, 43,2534-2538. [4] N. Metanis, D. Hilvert, Angew. Chem. Int. Ed. 2012, In press. 592 CHIMIA 2012, 66, No. 7/8 Organic chemistry

Organic Chemistry Organic Chemistry Organic Chemistry 446 Organic Chemistry 447 Exploration of Capsid Dynamics by PhotoisomerizableProtein Structure andFunctionofComputationally Derived Enzymes Modification Daniel M. Pinkas1,Rebecca Blomberg1,Hajo Kries1,PeerR.E.Mittl2, Eita Sasaki,Donald Hilvert Markus Grütter2,and Donald Hilvert1

LaboratoryofOrganic Chemistry,ETH Zürich, 8093 Zürich,Switzerland 1Laboratory of Organic Chemistry,ETH Zurich, Switzerland 2Department of Biochemistry,University of Zurich, Switzerland Lumazine synthase (LS) from the hyperthermophilic bacterium Aquifex ae- olicus is anonviralprotein that forms capsid-likestructuresconsisting of 60 or more subunits. EngineeredLSvariants have previously been shown to Understanding of enzymestructure and function has come to apoint where have greatpotential as protein containers for encapsulatingmacromole- simplecatalyticfunctions canberobustlydesigned into inert scaffolds on a cules.[1] Oneofthese variants (AaLS-13)was optimized by directed evolu- routinebasis [1]. Directed evolution can then be used to optimize theengi- tion to encapsulatepositivelycharged proteins.[2] It exhibits highloading neered activity to produce unnatural enzymeswith enhancedcharacteristics. capacity in vitro,but interestingly,unlike wild type LS,itdisplaystwo dis- However, theabilitytocreate increasingly efficientand sophisticated en- tinctive statescorresponding to the pentamerand capsid structures. Further zymesbycomputational design and directed evolution is limitedbycurrent analysis revealed that unusualstructuraldynamicsexist between these two understanding of engineeredenzymestructureand how it relates to designed states.[3] However, the mechanistic detailshaveremainedelusive.Toex- function. We areevolving acomputationally designed enzyme that catalyz- plore thisdynamical feature, we investigatedthe effectsofchemicalmodifi- es theKempelimination,asimplemodel reaction for proton abstraction cationonthe quaternary structure of the capsid using various thiol-reactive from carbon[2]. We have obtained high resolution X-ray crystal structures reagents. In addition,wedesignedtoincorporateaphosoisomerizable azo- of both the apoenzyme, and theenzymeincomplex with atransition state benzenemoietyintothe protein to alterorcontrol the structuraldynamics mimic. Thestructures haveprovided insightintothe evolved catalytic by light. The azobenezenemoietycan be either chemically introduced on mechanism, and havegiven feedback to focus further directed evolution and the mutated cysteine residue or geneticallyincorporated using an orthogonal redesign efforts. tRNAamino-acyl tRNA synthetase pair.[4] Successful photocontrol of the capsid dynamics is an attractivestrategy for encapsulation/release of cargo for various futureapplications. [1] Althoff EA,WangL,Jiang L, GigerL,Lassila JK,WangZ,Smith M, Hari S, Kast P, HershlagD,Hilvert D, BakerD,ProteinSci. 2012, 21,717- [1]Seebeck,F.P.; Woycechowsky, K. J.;Zhuang, W.;Rabe, J. P.; 26. Hilvert, D. J. Am.Chem. Soc., 2006, 128,45164517. [2]Privett HK,Kiss G, Lee TM,BlombergR,Chica RA,ThomasLM, [2]Wörsdörfer,B.; Woycechowsky, K. J.;Hilvert, D. Science, 2011, 331, Hilvert D, Houk KN,MayoSL, Proc. Natl. Acad. Sci. 2012, 109,3790-5. 5894517. [3]Wörsdörfer,B.; Pianowski, Z.;Hilvert, D. J. Am.Chem. Soc., 2012, 134,909911. [4]Bose, M.; Groff, D.;Xie,J.; Brustad, E.; Schultz, P. G. J. Am.Chem. Soc., 2006, 128,388389.

OrganicChemistry Organic Chemistry Organic Chemistry 448 Organic Chemistry 449 IncorporationofO-Propargyl-tyrosine into Diketopiperazinesbyan AsymmetricMichael ReactionsCatalyzed by an Artificial Retro- Engineered Non-RibosomalPeptide Synthetase Aldolase Enzyme

Hajo Kries1,Rudolf Wachtel2,AnjaPabst3,BenediktWanner1,Donald Xavier Garrabou,Reinhard Zschoche, Donald Hilvert* Hilvert1 LaboratoryofOrganic Chemistry, ETH Zurich, 8093 Zurich,Switzerland 1ETH Zürich,CH-8093 Zürich, 2TU München, D-85747 Garching, 3 UniversitätZürich,CH-8057 Zürich Innovativeapproaches to the computational de novo designofproteins are affordingartificial enzymes with unprecedented activities. Recently, our In acontinuousstrugglewithpathogens andcompetitors,many group participatedinthe creation of protein scaffolds with incipient retro- microorganisms have developedanarsenal of secondarymetabolites for aldolaseactivity[1],which were substantially improvedbydirected evolu- defense, amongthemnonribosomalpeptideslikepenicillin. Sincemanyof tion [2]. thesesecondarymetabolites canbesuccessfully repurposedasdrugs, reliablemethods fortheir combinatorialdiversification andoptimizationfor medicalapplications aredesirable.Biological approaches to tailor the properties of nonribosomal peptides benefitfromthe modulararchitecture of thenonribosomalpeptide synthetases(NRPSs)responsible fortheir biosynthesis. We setout to explorethe substratescope of NRPS modulesby introducingsinglemutations at thesubstrate recognition site of an adenylationdomain(PheA)governing substrateselectivityinthe first module of thegramicidin Ssynthetase.PheAwas mutatedand then screened forpromiscuousactivitiesinaplate-basedenzymatic assay. A We areexploring the catalytic promiscuityofRA95.5-8, an outstandingly tryptophan to serine mutation switched thesubstrate selectivityfrom activeretro-aldolase, towards alternative amine-mediated reactions. phenylalaninetotyrosine. Furthercharacterizationrevealedanevenhigher RA95.5-8catalyzes theasymmetricMichael reaction of 2 andactivated es- selectivityfor O-propargyl-tyrosineand otherphenylalaninederivatives ters(3)with comparable kinetics to the retro-aldol cleavage of 1,which with largesubstituentsatthe para-positionofthe phenyl ring.Reintroduced guided the designand evolution of the enzyme.The reaction mechanism, into atwo module domain excisedfromtyrocidinesynthetase,thissingle stereochemical outcome,and substrate scope of these enzymatic conjugate mutation enabledenzymatic synthesisofacyclic dipeptide additions arecurrentlyunderstudyinour lab. (diketopiperazine) from O-propargyl-tyrosineand prolineeveninthe presence of competingphenylalanine. Diketopiperazinesoften show [1]L.Jiang,E.A.Althoff,F.R.Clemente, L. Doyle, D. Rothlisberger, A. biologicalactivitiesthemselves. More importantly,the same type of Zanghellini,J.L.Gallaher, J. L. Betker, F. Tanaka,C.F.BarbasIII,D. phenylalanineactivatingmoduleinvestigated here is foundinabroadrange Hilvert, K. N. Houk, B. L. Stoddard, D. Baker, Science 2008, 319, of NRPSs.Consequently,our approach forsubstituting phenylalaninewith 1387. O-propargyl-tyrosineshouldbegenerally applicable to theproduction of [2]L.Wang, E. A. Althoff,J.Bolduc, L. Jiang,J.Moody, J. K. Lassila, L. nonribosomal peptides that can be easily modified by clickchemistry. Giger,D.Hilvert, B. Stoddard, D. Baker, J. Mol. Biol. 2012, 415,615. Organic chemistry CHIMIA 2012, 66, No. 7/8 593

OrganicChemistry OrganicChemistry Organic Chemistry 450 Organic Chemistry 451

NIR Imaging Probe for Atherosclerosiswith MMP2-Specific 1,3-dipolar cycloaddition to C60 and TNT-EMF Ligand Site Safwan Aroua, Yoko Yamakoshi*

Sean Oriana, Yoko Yamakoshi* Laboratorium für Organische Chemie, ETH-Zürich, Wolfgang-Pauli- Strasse 10, CH-8093, Zürich, Switzerland ETH-Zürich, Wolfgang-Pauli-Strasse 10, CH-8093, Zürich, Switzerland The discovery of Trimetallic Nitride Template Endohedral MetalloFuller- enes (TNT-EMF) by Dorn and co-workers [1] provided anew class of To date, atherosclerosis remains one of the most elusive symptoms to be metallofullerenes with awide range of applications such as solar cells and accurately detected and non-invasively diagnosed. Several probes for in vivo MRI contrast agent [2]. Derivatization and functionalization of TNT-EMF detection of matrix metalloproteinase (MMP) family have been previously attract ahigh interest [3]. reported[1][2]. However, none of them allows quantification of atheroscle- In this study we investigated 1,3-dipolar cycloaddition reaction to C60 and rosis progression. To overcome this limitation, we focus on the development M N@C (M =Sc, Lu, Y, Gd)tocompare their reactivity and regioselec- of NIR-imaging agents targeting MMP2, which is overexpressed in athero- 3 80 tivity. While only [6,6]-adduct was obtained in the reaction of C60,both sclerosis using ligands with high binding and selectivity for MMP2. [5,6]- and [6,6]-adducts were provided in M3N@C80 with reactivity of Gd > Y > Lu > Sc (from higher to lower).

MMP-2 specific ligand peptide acceptor water soluble moiety "LIGHT" donor [5,6] junction MMP-2

donor "LIGHT" + [6,6] junction [6,6] junction

Polymer backbone FRET No LIGHT C M N@C Shown above is the outline of the molecular design of aNIR imaging probe 60 3 80 for atherosclerosis detection with MMP2-specific peptide ligands. Based on Our present effort is to develop ametallofullerene material with awater soluble anchors forMRI-applications. the current literature [3], we have chosen apeptide sequence to serve as our prototype sequence of our first generation NIR imaging agent due to its high selectivity and binding potency at MMP2 compared to MMP9 and other [1] H. C. Dorn and co-workers, Nature 1999,401, 55-57. MMPs. [2] H. C. Dorn and co-workers, Bioconjugate Chem. 2010,21, 610-615. [1] Weisleder, R., Tung, C. H., Mahmood, U., Bogdanov, A. Jr., Nat. Bio- [3] L. Echegoyen and co-workers, J. Am. Chem. Soc. 2005,127, technol. 1999, 17,375-378. 10448-10453. [2] Zhang, Y., So, M. K., Rao, J. Nano Lett. 2006,6,1988-1992. [3] Chen, E.I., Kridel, S. J., Howard, E. W., Li, W., Smith, J. W., J. Biol. Chem. 2002,277, 4485-4491

OrganicChemistry Organic Chemistry Organic Chemistry 452 Organic Chemistry 453 Tröger’s base analogues: Methodology and Catalysis AbietaneDiterpenoidsfrom Salvia sahendica -Antiprotozoal Activity andDetermination of TheirAbsolute Configurations Raul Pereira, Ján Cvengroš* Samad N. Ebrahimi1,2,Stefanie Zimmermann1,3,Janine Zaugg1,Martin 4 3 1 Department of Chemistry and Applied Biosciences, ETH Zurich, Smiesko ,Reto Brun ,Matthias Hamburger Wolfgang-Pauli-Str. 10, 8093 Zurich, Switzerland 1 Division of PharmaceuticalBiology,UniversityofBasel 4056 Basel 2 Medicinal Plants andDrugs Research Institute, Shahid Beheshti Universi- Tröger’s base1 and its analogues are usually viewed as chiral molecules pos- ty,G.C., Tehran,Iran sessing stable stereogenic nitrogen atoms. Reports pertaining to their use in 3DepartmentofMedicalParasitologyand InfectionBiology, Swiss Tropi- 2 cal and Public Health Instituteand UniversityofBasel,4003 Basel catalysis are limited. We explore the Tröger’s base scaffold as apotential 4 motif for bulky tertiary phosphines. Here we report the synthesis, character- Division of Molecular Modeling,UniversityofBasel,4056 Basel ization and catalytic potential (Suzuki coupling) of novel P,N-ligands based on Tröger’s base. In ascreeningofIranian plants for antiprotozoalactivity, an-hexaneextract of roots of Salvia sahendica potentlyinhibited the growth of Plasmodium falciparum K1 strain.Subsequent HPLC-based activityprofiling led to iden- tificationofseven known andone newabietane-typediterpenoids.Structure elucidation wasachievedbyanalysis of spectroscopic data including 1D and 2D NMR. The absolute configurationofsahendoland sahandonewereas- signedbycomparison of experimental CD spectra with calculated ECD data,using time dependencedensityfunction theory (TDDFT)and methanol as solvent (B3LYP-SCRF /6-31G**). In vitro biologicalactivityagainst Plasmodium falciparum and Trypano- soma bruceirhodesiense STIB 900 strain,and cytotoxicityinrat myoblast (L6) cells were determined. The IC50 values of the compounds ranged from 0.85 µMtoover8.79 µMagainst P. falciparum, andfrom1.79 µMtoover 32.3 µMagainst T. brucei rhodesiense.Selectivityindices were from 0.1 to 18.2. These first generation phosphines with their modest catalytic activity motivated us to carry out further research. Our current efforts are concentrated on permutation of the position of the phosphine on the Tröger’s base scaffold. [1] J. Tröger, J. Prakt. Chem. 1887, 36,225-245. [2] S. Sergeyev, Helv. Chim. Acta 2009, 92,415-444. 594 CHIMIA 2012, 66, No. 7/8 Organic chemistry

Organic Chemistry OrganicChemistry Organic Chemistry 454 Organic Chemistry 455 Flow Chemistry as aUsefulTool forthe Modern SyntheticChemist Towards the Total Synthesis of JBIR-02 and RelatedPiericidins

Christoph Kuratli, Rainer E. Martin,FalkMorawitz,MarioLenz Johannes Hoecker,Gregor Meier and Karl Gademann* F. Hoffmann-La RocheAG, pRED,PharmaResearch &Early Develop- ment,Small Molecule Research,Medicinal Chemistry, Grenzacherstrasse University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland. 124, Basel, Switzerland Piericidins –structural homologs to ubiquinones (coenzyme Q) –are known for their very potent inhibition of Complex I(NADH:ubiquinone Flow chemistryhas attractedconsiderable attentionoverrecentyears as an oxidoreductase) of the mitochondrialelectron transport chain (Ki =0.6 – enablingand innovativetechnologythatsignificantly enhances theclassical 1.0 nM). In our program of modifying natural scaffolds to obtain biological processwindow typically accessible with standard batchlaboratoryequip- tools to understand their mode of action and use this knowledge to enhance ment.Unconventionaland harshreactionconditions suchasgreatly elevated their therapeutic potential,[1] the pyridone JBIR-02[2],which showed promis- temperatures andpressures can be generated easilyallowing thesuperheat- ing anticancer properties was chosen as astarting point. ingoforganic solvents far beyond theirboilingpoint in acontrolled and safe manner. Furthermore, reactions which were formerly avoideddue to O serious safetyconcernscan now be conductedconvenientlyinflowasonly smallquantitiesofreactivematerialsorhazardousintermediatesare within OH thereactor at agiven time.Flowchemistrythus offers an idealopportunity MeO N H to revisit challenging, difficult to operate or dangerous reactions that have [1] been underutilized in thepast. In addition, flow chemistryalso allows for JBIR-02 automationofoperations thus speedingupthe chemical synthesisprocess. We will show someselectedsynthetic examples that illustratethe usefulness In this context, we report our versatile synthetic strategy in the total synthe- of flow chemistryfor thepreparationofpharmaceutically relevant struc- sis of this target and related natural piericidins. tures. [1] S. Bonazzi, O. Eidam, S. Güttinger, J.-Y. Wach, I. Zemp, U. Kutay, K. Gademann, J. Am. Chem. Soc. 2010, 132,1432-442; J.-Y. Wach, S. Güttinger, U. Kutay, K. Gademann, Bioorg. Med. Chem. Lett. 2010, 20, 2843-2846; J.-Y. Wach, K. Gademann, Synlett 2012, 23,163-170. [2] J. Ueda, T. Togashi, S. Matukura, A. Nagai, T. Nakashima, H. Komaki, K. Anzai, S. Harayama, T. Doi, T. Takahashi, T. Natsume, Y. Kisu, N. Goshima, N. Nomura, M. Takagi, K. Shin-ya, J. Antibiot. 2007, 60, [1]R.E.Martin,F.Morawitz,C.Kuratli, A. M. Alker, A. I. Alanine, Eur. 459-462. J. Org. Chem. 2012, 54,47-52.

OrganicChemistry OrganicChemistry Organic Chemistry 456 Organic Chemistry 457 AUnified Approach Towardsthe TotalSynthesis of Majucin-Type Towards the Synthesis of Ophiodilactones Aand B seco-Prezizaanes José Gomes,Elias Kaufmann, ChristopheDaeppen, and Karl Gademann* Samuel Bader,Jean-Yves Wach, Michael Lüscher, Karl Gademann* University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland University of Basel, Department of Chemistry, St. Johanns-Ring 19, CH-4056 Basel, Switzerland

The progression of Alzheimer’s, Parkinson’s, and Huntington’sdisease Recently, Matsunaga et al. isolated the tetrameric phenylpropanoids ophio- have been linked to decreased neurotrophic support. Therefore, neurotro- dilactones A(1)and B(2)from the starfish Ophiocoma scolopendrina.Both phins have been selected as candidates for asuccessful therapeutic strategy compounds showed moderate cytotoxic activity against P388 murine leu- [1] aimed at controlling these medicinal challenges. An attractive approach is kemia cell lines [1]. The γ,δ-dilactonic core structure is uncommen in nature based on the search for orally bioavailable small organic molecules that and synthetic examples are rare in literature [2][3]. The intriguing architec- could mimic or enhance neurotrophin (e.g. nerve growth factor)action. ture combined with the biological activity of ophiodilactone Aand B O aroused our interest and let us start aprogram directed towards their total 3steps O synthesis. O CO Me O 2 7steps O O OH O OH HO O O O CO2Me O O D-pulegone 2steps O O O O HO HO O O H

O O O O O HO OH HO O O O O O

OH O OH O OH O OH OH O O HO HO O O O HO HO HO O O O O O 12 majucin jiadifenolide neomajucin jiadifenoxolaneA jiadifenoxolane B Key challenges of the synthesisare the four contiguous stereogenic centers, In search for such compounds, some majucin-type seco-prezizaanes, found the dilactone moiety, and the unusual α-arylated lactone in compound 2.We in the pericarps of Illicium majus,have shown to exhibit neurotrophic activ- will present our achievements towards the total synthesisofthe ophiodilac- [2] ity at very low concentrations. We will present our results towards the to- tones Aand B. tal synthesis of majucin-type seco-prezizaanes. [1] J. Corcoran, M. Maden, Nat. Neurosci. 1999, 2,307. [1] R. Ueoka, T. Fujita, S. Matsunaga, J. Org. Chem. 2009, 74,4396. [2] Y. Fukuyama, J.-M. Huang,Studies in Natural Products Chemistry, [2] W. Borsche, Chem. Ber. 1916, 49/II,2538. Elsevier 2005 Vol. 32. [3] T. Kapferer, R. Brückner, Eur. J. Org. Chem. 2006, 9,2119. Organic chemistry CHIMIA 2012, 66, No. 7/8 595

OrganicChemistry OrganicChemistry Organic Chemistry 458 Organic Chemistry 459 Neuritogenic Pyridone Alkaloids: an SARStudy Total Synthesis of Gelsemiol and Studies Towards Glycosylated Natural Congeners Fabian Schmid1,Henning J. Jessen2,Patrick Burch1,Karl Gademann1 PatrickBurch,Manuel Scherer, Massimo Binaghi, Karl Gademann 1 University of Basel, Department of Chemistry, St. Johanns-Ring 19, 4056 Basel, Switzerland University of Basel, Department of Chemistry, St. Johanns-Ring 19 2 University of Zürich, Institute of Organic Chemistry, Winterthurerstrasse CH-4056 Basel, Switzerland 190, 8057 Zürich, Switzerland

Increasing life expectancy in industrialized regions is accompanied by a In an aging society, certain neurodegenerativediseases such as Alzheimer’s higher incidence of neurodegenerativediseases such as Alzheimer’s or or Parkinson’s become more and more accentuated. Today’s treatments are Parkinson’s disease. The treatment of such diseases, as well as the recon- mainly symptomatic and do not address the regeneration of damaged neu- struction of damaged nervous tissue in general (e.g. after spinal cord inju- ronal networks.Therefore, our research is focused on the stimulation of neu- ries) is either cumbersome or not possible today. Small organic molecules [1] rite outgrowth applying natural products and their derivatives, capable of might provide avaluable approach towards this task. mimicking neurotrophic factors.1

HO HO Gelsemiol is known to induce neutrite outgrowth in the PC-12 cell OH O H3CO O line.2 The enantioselective total synthesis of gelsemiol (1)ispresented in H3CO OEt nine steps with an overall yield of 14%.Chemical studies towards its con- N O N O geners 2, 33 and biological evaluation in multiple cell models will be dis- H H cussed. Natural producthit structure Optimised synthetic lead compound Glesemiol(1): As apart of our total synthesis program on neuritogenic pyridone alka- R =H,R' =H O OR loids,[2] we were intrigued to further investigate the relationship between O Gelsemiol3-O-β-D-Glucoside(2): their molecular structure and biological activity. Here, we present the results R' =H,R= OH H H of an SAR study wherein we were able to encircle the neuritogenic core HO OH O OH structure, reduce molecular complexity and increase biological activity in a Verbanabraside A(3): O reductionist approach. OR' R =H,R' = OH HO O O [1] For reviews see: a) D. M. Skovronsky, V. M.-Y. Lee, J. Q. Troja- OH nowski, Annu. Rev. Pathol. Mech. Dis., 2006, 1,151; b) D. Dawbarn, OH S. J. Allen, Neuropath. App. Neuro. 2003, 29,211; c) R. M. Wilson, S. J. OH Danishefsky, Acc. Chem. Res, 2006,39,539. [1] DeKosky, S. T.; Scheff, S. W. Ann. Neurol. 1990, 27,457. [2] H. J. Jessen, A. Schumacher, T. Shaw, A. Pfaltz, K. Gademann, [2] Jensen, S. R.; Krik, O.; Norrestam, R.; Phytochem. 1987, 26,2735. Angew. Chem. Int. Ed. 2011, 50,4222; H. J. Jessen, A. Schumacher, [3] Ono, M.; Oishi, K.; Abe, H.; Nohora, T.; Chem. Pharm. Bull. 2006, F. Schmid, A. Pfaltz, K. Gademann, Org. Lett. 2011, 13,4368. 54, 1421.

OrganicChemistry Organic Chemistry Organic Chemistry 460 Organic Chemistry 461 Total Synthesis of Taiwaniaquinone FBased on aBiogenetic Hypothesis Auto-Tandem Catalysis with Ruthenium: Remote Hydroesterification of Olefins ChristopheThommen, Chandan Kumar Jana and Karl Gademann Nicolas Armanino1,Erick M. Carreira*1 Universität Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland 1 Laboratorium fürOrganische Chemie, ETH Zürich, CH-8093 Zürich, Taiwaniaquinoids are natural rearranged diterpenoids that were first isolated Switzerland. from Taiwania cryptomerioides.[1] Taiwaniaquinones Fand Hpossess interesting biological activitiessuch as potent cytotoxicity against epidermoid One-pot processes that involve cascading reactions provideattractive tools carcinoma.[2] The uncommon 6-5-6 tricylic structure of these rearranged for organic synthesis by simplifying operationsand reducing the numberof diterpenes led us to formulate ahypothesis concerning their biogenesis requiredintermediate isolations. Of particularinterestare reactionsthat use based on a benzilic acid type rearrangement for the key ring contraction.[3] asinglecatalytic entity capable of promoting multiple distinctstepswithout the need foroperator intervention. In the course of our investigations,we O O have developedanauto-tandem catalyticsystemfor the isomerization- hydroesterification sequence of internal olefins.

O H CHO taiwaniaquinone F Herein, we provide further experimental support for this hypothesis by

demonstrating that also C20 taiwanaiquinoidssuch as the title compound can be accessed. Synthetic taiwaniaquinone Fwas obtained by aconcise, protecting group free approach. Consequences for the biogenesis of related Thesystem is based on low-valent ruthenium carbonyl clusters, enabling the congeners will be discussed. incorporation of aC1-unit by C-C bond formation onto abroad scope of allylic aminesand alcohols. The process is characterized by operational sim- [1] (a) Lin, W. H.; Fang, J. M.; Cheng, Y. S. Phytochemistry 1995, 40, plicity, results in thefunctionalizationofaremoteposition of thesubstrate 871–873; (b) Lin, W. H.; Fang, J. M.; Cheng, Y. S. Phytochemistry 1996, andpermits easy accesstochiral lactone and lactam building blocks. Our 42,1657–1663. mechanistic working model suggeststhat the keytosuccessinthis cascade [2] Chang, C. I.; Chang, J. Y.; Kuo, C. C.; Pan, W. Y.; Kuo, Y. H. Planta is the formation of an active ruthenium cluster hydride by metal protonation, Med. 2005, 71,72–76. capable of promoting fast olefin isomerization that prevailsover undesired [3] (a) Jana, C. K.; Scopelliti, R.; Gademann, K. Synthesis 2010, 13, decarbonylation pathways. 2223–2232; (b) Jana, C. K.; Scopelliti, R.; Gademann, K. Chem. Eur. J. 2010, 16,7692–7695. 596 CHIMIA 2012, 66, No. 7/8 Organic chemistry

Organic Chemistry Organic Chemistry Organic Chemistry 462 Organic Chemistry 463 TotalSynthesis and Stereochemical SyntheticStudies To ACollection of Isoprostanes Associated With In- Reassignment of (±)-Indoxamycin B fectiousAnd Inflammatory Disease

Oliver F. Jeker, Erick M. Carreira* Julian Egger,Erick M. Carreira*

Laboratorium fürOrganische Chemie, ETH Zürich, ETH Zurich,LaboratoryofOrganic Chemistry, Wolfgang-Pauli-Str. 10, Wolfgang-Pauli-Strasse10, CH-8093 Zürich, Switzerland 8093 Zurich,Switzerland

The indoxamycins are anovel classofsix antitumorantibiotics thatwere isolated in 2009 form saline cultures of marine-derived actinomycetes [1]. Thoughitiswellestablishedthatprostaglandins andstructuralrelated iso- Theirhighlycongested carbon skeleton,inconjunction with thebiological prostanesfeatureavarietyofbiological activities, by farnot allaspectsof activity,renders theseunusual polyketides notable as targetsfor synthetic theirphysiological effectsand molecularmechanisms are known[1].Recent studies. results showthatour target molecules 1-3,seemtoplayapivotal role in in- flammationprocessesassociatedwith diseases like atherosclerosisorrheu- Me Me matoid arthritis [2]. Me stereochemical Me Me Me H reassignment Me Me H 2 2 O CO2H CO2H C H O 1'' Me 1'' 5 11 O O Me OH OH OH 1

Me Me O C15H31 O C15H31 indoxamycinB indoxamycinB O O O [originally assigned structure] [revised structure] O O O O O O O O O O O O P NMe3 O P NMe 3 O The first total synthesis of (±)-indoxamycinBculminates in the stereo- O H C H C5 11 chemical reassignment of the natural product[2]. The synthetic route relies 5 11 HO on an efficient carboannulation sequence to rapidly accessakey dihydro- 2 3 indenone intermediate. Moreover, aseries of modern metal-catalyzed transformations allowsfor theconstructionofthe tricyclic core framework. We have implemented noveltacticsincluding some highly selectivetrans- [1] a) S. Sato, F. Iwata, T. Mukai, S. Yamada,J.Takeo, A. Abe, H. formations into innovative synthetic routes to accessthese synthetically Kawehara, J. Org. Chem. 2009, 74,5502–5509; b) S. Sato, F. Iwata, challengingmolecules 1-3 in an efficient mannerand therebyprovide pure T. Mukai, S. Yamada, J. Takeo, A. Abe, H. Kawahara, (Nippon synthetic material that will allowfurther biological studies. Suisan Kaisha, Ltd.), WO 113725, 2010. [2] O. F. Jeker, E. M. Carreira, Angew. Chem. Int. Ed. 2012, 51,3474– [1]J.U.Scher, M. H. Pillinger, ClinicalImmunology 2005, 114,100. 3477. [2]U.Jahn, J.-M.Gallano, T. Durand, Angew. Chem.Int.Ed. 2008, 47, 5894.

Organic Chemistry OrganicChemistry Organic Chemistry 464 Organic Chemistry 465 Redoxactive Push-Pull ChromophoresBased on Dialkynylazulene Construction of All Carbon Quaternary Centre: An Efficient Trichlo- roacetonitrile-assisted Nucleophilic Substitution on Michael Koch,Olivier Blacque and KoushikVenkatesan 3-Hydroxyindolin-2-one

University of Zurich/ InstituteofInorganic Chemistry, Winterthurerstrasse Cyril Piemontesi1,Qian Wang1,Jieping Zhu1 190, CH-8057 Zurich, Switzerland 1Ecole PolytechniqueFédérale de Lausanne, SB-ISIC-LSPN CH-1015 Lausanne, Switzerland During recent years push-pull chromophores have been extensively studied owing to their promising optoelectronic properties,1 especially second- and The construction of all-carbon quaternary center remains achallenging third-order optical nonlinearities (NLO).2 Atypical organic push-pull problem in organic chemistry, especially at the 3-position of oxindoles.1 Re- chromophore consists of an electron acceptor and adonor bridged by a - cently, our group reported anew methodology to access 3-hydroxyindolin- conjugated spacer. This arrangement facilitates efficient intramolecular 2-ones and their transformation into spirooxindoles in asingle step.2 The charge-transferand enables further tuning of the polarisability of the present work reports the access to 3,3-disubstituted oxindoles directly from chromophore. Additionally, aplanar structure ensures to retaining the - 3-hydroxyindolin-2-one in aone-pot stepwise sequence by using first acata- conjugation over the entire donor-spacer-acceptor system.4 Azulene possess lytic amount of DBU and trichloroacetonitrile followed by acatalytic areversible redoxbehaviour and is as well achromophore due to the inher- amount of diphenylphosphoric acid and various nucleophiles. In this meth- ent donor-acceptor property. Asmall donor-acceptor molecule with asmall odology, different nucleophiles were tested, providing 3,3-disubstituted ox- HOMO-LUMO gaplikeazulene is expected to haveatremendous advan- indoles in good to excellent yields via the formation of C-C, C-OorC-N tage as acore structure for optoelectronic materials andcould function as an bonds. valuable alternative to other organic structures and could aid in the devel- One pot, mild conditions, catalytic, high yields opment of new metal-free conducting materials. An in deptstudy of the az- HN ulene system with different disubstitution patterns regarding fluorescence as HO Nu R DBU 0.1eq CCl Nu 1.5eq R well as conductingproperties has not been done until now. Since theelec- 1 O 3 1 Cl3CCN 1.3eq R (PhO)2PO2H0.2eq O 1 O tron distribution is very different at different positions of the azulene moiety N DCM, RT,M.S. 4A O DCM, RT,M.S. 4A N N the compounds show distinct properties.Based on theirfacile synthesisand R2 R :Me, Ph R2 R 1 their interesting emission properties, azulenesare interesting candidates for 2 R2:Me, Bn, MOM 6 organic optoelectronicmaterials. Thefact that azulene is aredoxactive Nucleophiles

chromophore also makesitapromising candidate as core structure for H O OH NH2 O N SnBu3 photoswitching conducting systems. CH3OH N N H H [1] Ito, S.;Morita, N. Eur. J. Org. Chem. 2009,4567. 95% 92% 98% 86% 82% 87% 90% 83% R1=Me R1=Me R1=Ph R1=Ph R1=Me R1=Ph R1=Me R1=Ph [2] Pasini, D.; Righetti,P.P.; Rossi, V. Org. Lett. 2002, 4,23. R2=Me R2=Me R2=Me R2=Me R2=Bn R2=Me R2=Bn R2=Me [3] Kival, M.; Diederich, F. Acc.Chem. Res. 2009, 42,235. [4]Yu, Y.-Y.; Fu,Y.; Lei, L.; Guo, Q.-X. Chin.J.Chem., 2007, 25,1041. [1] Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352,1381-1407. [5] Koch, M.; Blacque, O.;Venkatesan, K. Org.Lett., 2012, 14,1580. [2] Gorokhovik, I.; Neuville, L.; Zhu, J. Org. Lett. 2011, 13,5536-5539. Organic chemistry CHIMIA 2012, 66, No. 7/8 597

Organic Chemistry Organic Chemistry Organic Chemistry 466 Organic Chemistry 467 An Atom-Economicaland Stereoselective Domino Synthesis of Catalytic Asymmetric Diastereodivergent Deracemization

Functionalised Dienes MariaTeresaOliveira,NunoMaulide* Caroline Souris,Davide Audisio and Nuno Maulide* Max-Planck-InstitutfürKohlenforschung,Kaiser-Wilhelm-Platz 1, 45470 Max-Planck-Institut fürKohlenforschung,Kaiser-Wilhelm-Platz 1, 45470 Mülheimander Ruhr, Germany Mülheim (Germany) The electrocyclic ring-opening of cyclobutenesisapowerful, yet underutil- Deracemization is an important strategy through which aracemate can be ised tool for the synthesis of diene building blocks [1].Wehavedeveloped an converted into a100% theoretical yield of asingle enantiopure product. [1] atom-economical synthesis of functionalised,stereodefined dienes that Our grouphas developed apalladium-catalysed highly diastereoselective hinges on anovel domino allylic alkylation/electrocyclic ring-opening[2] se- synthesis of functionalized cis-cyclobutenes starting from lactone 1.The quence and allows direct access to doubly vinylogousesters and azido- intermediacy of asymmetric intermediate raised the exciting prospect of dienoicacidsbearing challenging substitution patterns (Scheme 1). deracemization of 1.[2] We report herein an unusual ligand-controlledDiastereodivergent Derace- mization.Thus, either cis-ortrans-disubstituted cyclobutenes canbeob- tained at willingood yields and excellent selectivites, starting from racemic 1.[3]

Scheme 1. Domino allylic alkylation/4 electrocyclic ringopening usingO-and N-nucloephilesand its applications

In this communication, adetailed overview of the scope and limitations of this transformation, as well as applications of the products obtained to target-oriented synthesis and chemical biology will be presented (Scheme1). [1] a) R. B. Woodward, R. Hoffmann, Angew. Chem. Int. Ed. 1969, 8,781.; b) T. Durst, L. Breau, Comprehensive Organic Synthesis,Trost B. M., FlemmingI., Paquette L. A., Eds Pergamon Press: Oxford 1991; Vol 5, [1] J. Steinreiber, K. Faber, H. Griengl, Chem.Eur.J.2008, 14,8060. chapter6.1 pp 665-697 [2] F. Frébault,M.Luparia, M. T. Oliveira, R. Goddard,N.Maulide, [2] C. Souris,M.Luparia, F. Frébault, D. Audisio,C.Farès, N. Maulide, Angew. Chem.Int. Ed. 2010, 49,5672. Submitted. [3] M. Luparia,M.T.Oliveira, D. Audisio, F. Frébault, R. Goddard, N. Maulide, Angew. Chem. Int. Ed. 2011,12631.

Organic Chemistry OrganicChemistry Organic Chemistry 468 Organic Chemistry 469 Workflowdriven cheminformatics: easy ways to help you choose your Tandem Pd(II) Catalyzed Oxycyclization and Trifluoromethylation Us- next synthesis strategy ing aHypervalent Iodine Reagent Julie Charpentier, Antonio Togni* David Evans1,Juergen Swienty-Busch2,PiederCaduff1

1Reed ElsevierProperties SA,Espace de l’Europe 3, 2000,Neuchâtel, Swit- Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zürich, CH-8093 Zürich, Switzerland zerland 2ElsevierInformation System GmbH, Theodor-Heuss-Allee 108, 60486 Trifluoromethylated building-blocks are widely recognized as being very FrankfurtamMain, Germany valuable in medicinal chemistry and drug-discovery. Synthetic methodolo- gies include nucleophilic, radical and electrophilictrifluoromethylations. Accesstoaccurate, timelyand completeinformation is crucial to the plan- We have contributed to the latter approach with the development of hyper- ning andexecution of anyexperiment. Reaxys® provide synthesis and valent iodine (III) compounds, such as 1,allowing the transfer of aformal “CF +”group to various nucleophiles.[1] propertyinformation from journals andpatents to support organic, inorganic 3 3 andorganometallicchemists.This presentation will describe howReaxys Our current research includes the formation of C(sp )-CF3 bonds to access supportschemists’everydayactivities by providing information for the lactones via atandem palladium-catalyzed intramolecular addition of car- planning andoptimizing synthetic routes, including commercial availability boxylic acids to olefins and electrophilic trifluoromethylation. of starting materials,integrationwith inventorysystems andavarietyof electronic lab notebooks.Inaddition we’ll showhow the latest analysis

toolsenable chemiststoquicklyand effectivelydrill down throughlarge F3C I O resultssetsinorder to identify the most appropriate information for their O synthetic route. O O O PdII OH 1 R R O R O

[Pd] CF3 23

[1] a) Eisenberger, P.; Gischig, S.; Togni, A. Chem. Eur. J. 2006, 12, 2579. b) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, 46,754. c) Koller, R.; Stanek, K.; Stolz, D.;Aardom, R.; Niedermann, K.;Togni, A. Angew. Chem. Int. Ed. 2009, 48,4332. d) Niedermann, K.; Früh, N.; Vinogradova,E.; Wiehn, M.S.; Moreno, A.; Togni, A. Angew. Chem. Int. Ed. 2011, 50,1059. 598 CHIMIA 2012, 66, No. 7/8 Organic chemistry

OrganicChemistry Organic Chemistry Organic Chemistry 470 Organic Chemistry 471 Access to Quaternary α-Trifluoromethylated Lactones Direct Electrophilic N-Trifluoromethylation of Azoles

Václav Matoušek, Julie Charpentier, Raffael Koller and Antonio Togni Remo Senn,Katrin Niedermann,Nataljy Früh, Barbara Czarniecki, René Verel, Antonio Togni Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zurich, CH-8093 Zürich, Switzerland DepartmentofChemistryand Applied Biosciences ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich

OTMS O Due to itsunique physiologicalproperties,1 thetrifluoromethyl group has 1mol %TMSNTf2 R become overthe last decade aprivilegedstructural motive in drug develop- R 2 O 2 DCM, -78 °C O ment. CF ()n ()n 3 F C I O We recentlyreportedthe direct electrophilic N-trifluoromethylaton of ava- R 3 R 1 n=1or2 1 n=1or2 riety of nitrogencontaining heterocycles,such as tetrazoles, triazoles, inda- zoles andpyrazoles2 using the hypervalent iodine reagent 1,originallyde- up to 96% isol. yield 3 1 veloped in our group. After in situ trimethylsilylation, the heterocyclicsubstrates were converted underacidicconditions to the N-trifluoromethylated species in good to ex- Arange of five- and six-membered lactones were transformed into their cor- cellent yields. responding trimethylsilyl ketene acetals which could be efficiently α-

trifluoromethylated using hypervalent CF3-iodine reagent 1 in the presence

of catalytic amounts of TMSNTf2 -aLewis acid of remarkable oxophilicity. The presented mild transformation opens access to quaternary α- trifluoromethylated carbonyl compounds which are otherwise difficult to synthetize.

Based on our experimental observations,weassume that trifluromethylation of trimethylsilyl keteneacetals proceeds through the intermediacy of acti- [1]K.Müller,C.Faeh, F. Diederich, Science 2007, 317,1881-1886. vated O-silylated hypervalent iodine reagent 1 with amore pronounced io- [2]K.Niedermann,N.Früh, R. Senn, B. Czarniecki, R. Verel, A. Togni, donium character. Angew. Chem.Int. Ed. 2012,inpress (DOI:10.1002/anie.201201572). The scope of these transformations and aplausible reaction mechanism will [3]P.Eisenberger,S.Gischig, A. Togni, Chem.Eur. J. 2006, 12,2579- be discussed. 2586.

Organic Chemistry Organic Chemistry Organic Chemistry 472 Organic Chemistry 473 Reductive Eliminations from λ3-Iodanes: Understanding Selectivity and CatalyticFormal[3+2] Annulations of Aminocyclopropanes forthe En- the Crucial Role of the Hypervalent Bond antiospecificSynthesis of Five-MemberedRings.

Halua Pinto de Magalhaes˜ ,Hans Peter Luthi,¨ Antonio Togni de Nanteuil Florian, Benfatti Fides, WaserJérôme*

ETH Zurich,¨ Wolfgang-Pauli-Strasse 10, CH-8093 Zurich,¨ Switzerland EcolePolytechnique FédéraledeLausanne, Lausanne,Switzerland Donor-Acceptor cyclopropanes1 are powerfuland versatile building blocks λ3-iodanes were shown to be powerful agents for the selective functionaliza- fororganic synthesis as they leadstoareactiveformal1,3 dipoleintermedi- tion of arenes[1]. The present computational study is focused on the investiga- ates. tion of the properties which govern the selectivity of the reductive elimination When considering theimportanceofnitrogen-containingfunctionalgroups of arene groups in iodanes. It wasshown that diaryliodoniums are the pre- in drugsand naturalproducts, it is surprisingthatdonor-acceptoraminocy- cursor compounds, which form areactive λ3-iodane with anucleophile estab- clopropanes2 were neverusedinformalcycloadditionreactions. This is lishing a3-center-4-electron bond. The result is an intermediate equilibrium probablydue to theformidable challengeassociatedwith thesynthesis and between twoiodane isomers. From each of the twoisomers areductive elim- catalytic activationofthese compounds, which have been usedonlyas ination is possible, leading to twodifferent products. The twoisomers are in structural elements so far. Through Lewis-Acidactivation, we reportherein rapid equilibrium (Curtin-Hammett) such that each reductive elimination step thefirst catalytic formal [3+2]annulations of aminocyclopropane with silyl is rate-determining. Furthermore, the selectivity of the reductive elimination enol ethers3,aldehydes4 andketones5. correlates with the polarity of the hypervalent bond.

Complete control overthe diastereoselectivityofthe reactionwas achieved. The obtained aminocyclopentanes or aminotetrahydrofuransare useful building blocks andfurther functionalizationgives easyaccesstoscaffolds found in various bioactivecompounds. [1] B. Wang, J. W. Graskemper,L.Qin, S. G. Di-Magno, Angew. Chem. Int. [1]Reissig,H-U.;Zimmer, R. Chem.Rev.2003, 103, 1151-1196. Ed. 2010, 49,4079. [2]Reisser, O. Chem.Rev.2003, 103, 1603-1624. [3]deNanteuil, F.;Waser J. Angew.Chem. Int. Ed.2011, 50, 12075. [4]Benfatti F.;deNanteuil, F.;Waser J. Org.Lett. 2012, 14, 386. [5]Benfatti F.;deNanteuil, F.;Waser J. Chem.Eur.J., 2012, Earlyviews Organic chemistry CHIMIA 2012, 66, No. 7/8 599

OrganicChemistry OrganicChemistry Organic Chemistry 474 Organic Chemistry 475 The formal homo-Nazarov cyclization -apowerful tool for the synthesis Pd-Catalyzed C-HAlkynylationofHeterocycles of alkaloidnatural products GergelyLaszloTolnai,Stephanie Ganss, Jonathan P. Brand, Jerome Waser1 Reto Frei, Filippo De Simone and Jérôme Waser* 1 * Laboratory of Catalysisand OrganicSynthesis, EPFL,1015 Lausanne, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Switzerland Heterocyclic scaffolds occupy aprivileged position among natural and synthetic drugs. Consequently, the discovery and implementation of cyclization Heterocycles areomnipresent in organicand medicinalchemistry.Inthe reactions to efficiently access such cyclic structures are highly sought after contextofsustainable chemistry, it is essentialtodevelop direct C-Hfunc- in organic chemistry. In this context, our laboratory developed the first cata- tionalizationmethods to generate newheterocyclicstructures.[1] Whereas lytic formal homo-Nazarov cyclization of vinyligous cyclopropyl ketones arylationand vinylation methodsare alreadywelldeveloped,alkynylation for the synthesis of polycyclic hetero and non-hetero cyclohexenone deriva- hasbeen much less investigated,despite thefactthatacetylenesare oneof tives.[1] Herein we report application of the developed mild and highly regi- themostusefulbuildingblocksinorganic chemistry. oselective reaction for the cyclization of acyl indole substituted aminocy- In ourlaboratory, we have introduced ethynyl benziodoxolone (EBX)rea- clopropanes. The effectiveness of the methodology is demonstrated by the gentsaselectrophilic alkynylation reagents andusedtheminthe gold- efficient formal total synthesis of aspidospermidine and the total synthesis catalyzed functionalizationofbiologically importantindoleand pyrrole of goniomitine.[1b] The generalizability of the method is further showcased heterocycles.[2] In particular,the useofTIPS-EBX(1)gaveexcellent selec- by the first synthesis of the highly electron-rich, apidosperma type alkaloid tivity forthe 3-alkynylation of indoles.. jerantinine E. In this work,wereportthe useofPdcatalysis foranunprecedentedC2- CO2Me H selectivealkynylation, aprocessthathas been realized only for3-substituted N [3] Et indolesinthe past. In addition,the synthesisofnew hypervalentiodine Cbz MeO H reagents andtheir useinthe alkynylation reactionwillalsobepresented. O N HN N Et cat. Cu(I) cat. TsOH H HO N TIPS Jerantinine E MeCN HN CH2Cl2 Et R Au cat. H H R (previous work) N TIPS I O R Et R Goniomitine R OH O Pd cat. N H N N (This work) H R Aspidospermidine TIPS-EBX (1) N H [1] a) F. De Simone, J. Andres, R. Torosantucci, J. Waser, Org. Lett. TIPS 2009, 11,1023-1026; b) F. De Simone, J. Gertsch, J. Waser, Angew. Chem. Int. Ed. 2010, 49,5767-5770; c) F. De Simone, T. Saget, F. [1]Godula, K.;Sames,D.Science 2006, 312,67. Benfatti, S. Almeida, J. Waser, Chem. Eur. J. 2011, 17,14527-14538. [2]Brand,J.P.; CharpentierJ.; Waser, J. Angew. Chem., Int. Ed. 2009, 48,9346. [3]Yang, L.;Zhao, L. A.;Li, C. J. Chem.Commun. 2010, 46,4184.

OrganicChemistry OrganicChemistry Organic Chemistry 476 Organic Chemistry 477 Green synthesisoftrisubstitutedimidazolesindeep eutectic solvent Ultrasound mediated synthesisof1,3-oxathiolane-2-thionesinwater

Najmaddin Azizi, AminRahimzadeh Oskooee AminRahimzadeh oskooee

Chemistryand Chemical EngineeringResearch Center of Iran. P.O.Box: Chemistryand Chemical EngineeringResearch Center of Iran,P.O.Box 14335-186, e-mail:[email protected] 14335-186, Tehran,Iran.Email:[email protected]

Great effortshavebeenfocused on synthesizing librariesofsmall Organicdithiocarbamatesare valuable syntheticintermediates whichare heterocyclic moleculesbecause of theirhighdegreeofstructuraldiversity ubiquitouslyfoundinthe varietyofbiologically activecompounds.Func- andextensive utility as therapeuticagents. Also,multi-component reactions tionalizationofthe carbamate moiety offers an attractive method forthe areconvergentreactions in whichthree or more starting materialsreact to generation of derivatives, which mayconstituteinteresting medicinaland form aproduct, wherebasically allormostofthe atomscontributetothe biologicalproperties. Forthese reasons, thesynthesis of dithiocarbamate newlyformedmolecule [1]. Undoutedlt,naturally occurringsubstituted derivativeswithdifferent substitution patterns at thethiolschain hasbe- imidazoles, as well as syntheticderivatives thereof, play an important role in come afield of increasing interestsinsyntheticorganic chemistryduringthe chemical andbiologicalsystems [2]. Therefore, thedevelopmentofanew past fewyears[1,2]. catalytic system to overcome theseshortcomings andfulfill thecriteriaofa Therefore, thesynthesesofbiologicallyimportant 1,3-oxathiolane-2-thiones mild,efficient andenvironmentallybenignprotocolfor thesynthesisof have received considerable attention, andthere aresomereports forthe syn- highly substitutedimidazolesisanimportant task fororganic chemists. thesis of dithiocarbamatederivatives in theliterature. However, thereare In this studythe possibilityofperformingthese organictransformations by variouslimitations such as long reactiontimes, useoforganic solvents,high usingwater as green solventorunder solvent-free conditions evaluated. temperatures,moderateyieldsand limitedsubstrate.Giventhe widespread Herein,wereport, asimple andpractical synthesisoftrisubstitutedimidaz- availabilityofcarbondisulfide andepoxides, thereissubstantial interest in oles promoted by deep eutectic solventunder mild reactionconditions. developing efficientreactionfromthese simple starting materials. Herein, we report theextension of this methodology to theultrasoundpromoted H Ph O Ph green synthesisof1,3-oxathiolane-2-thiones in pure waterwithaview to ChCl/ZnCl2 N + RCHO + NH OAc R explorethe yields andrateofreaction. 4 100 oC, 4h Ph O Ph N S CS water, 5min [1]Dömling, A. Chem.Rev. 2006, 106,17. (b)Tour, B. B.;Hall, D. G. O 2, O S Chem.Rev. 2009, 109,4439-4486. (c)Trost,B.M.Science 1991, 254, R )))) 1471. (d)Trost,B.M.Angew.Chem. 1995, 107,285. ) R [2](a) Lambardino,J.G.; Wiseman, E. H. J. Med. Chem. 1974, 17,1182- [1].Azizi.N, SaidiMR,OrgLett.2005,87,3649. 1188.;(b) Sundberg,R.; Martin,R.B.Chem.Rev. 1974, 74,471-517 (c)M. [2].Azizi.N,Aryanasab.F,Saidi.MR,Org,Biomol Chem.2006,4,4275. R. Katritzky, A. R.;Rees,C.; ScrivenE.F.V.InComprehensive Heterocy- cleChemistry II; Eds.;PergamonPress:Elmsford,NY, 1996; Vol. 3, pp 77- 220. 600 CHIMIA 2012, 66, No. 7/8 Organic chemistry

OrganicChemistry Organic Chemistry Organic Chemistry 478 Organic Chemistry 479 Halogenated ligands for the structure determination of proteins One-StepSynthesis of Functionalized PolyetherMacrocycles

Tobias Beck1,Tim Grüne2,George M. Sheldrick2 Mahesh Vishe1,Radim Hrdina1,Daniele Poggiali1,Céline Besnard2, LaureGuénée2, Jérôme Lacour1* 1ETH Zürich, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland 1DepartmentofOrganic Chemistryand 2LaboratoryofCrystallography, 2Georg-August-Universität Göttingen, Tammannstr. 4, 37077 Göttingen, UniversityofGeneva, Quai Ernest Ansermet30, CH-1211 Geneva Germany

Obtaining phase information for the solution of macromolecular structures Macrocycles aregenerally synthesized from linear molecules using [1] is still one of the major challenges in X-ray crystallography. Anew class of intramolecular reactions. Recentlyour group hasdeveloped severalone- [2] halogenated ligands has been established for heavy-atom derivatization of step synthesesofmediumsized rings andpolyether macrocycles by multi- biological macromolecules. I3C and B3C contain an easily recognizable ar- condensation reactions of simple (naked) ether anddiazoreactants under [3] rangement of three anomalous scatterers (iodine or bromine, respectively) highconcentration andnon-templatedconditions. and three functional groups for hydrogen bonding to proteins. Here in an extension of thisresearch we presentaseriesofRh(II)- catalyzed[4] reactions of diazocarbonylsand substituted tetrahydrofuranes andtetrahydropyranes that afford 16-to18-membered macrocycles in asin- glestep andyields up to 84 %. Arather high functionalgroup tolerance is exhibited. Mechanistic rationals for these macrocyclisationreactions will also be presented.

It was demonstrated that I3C is suitable for structure solution using single- wavelength anomalous dispersion [1,2]. The brominederivative B3C, suitable for multi-wavelength anomalous dispersion experiments, was employed for experimental phase determination using synchrotrondata [3]. Recently, I4C and B4C, each containing four halogen atoms, have been utilized for structure determination of several proteins. These compounds provide greater anomalous signal per molecule and possess different binding properties. [1]H.An, J. S. Bradshaw,R.M.Izatt, Chem.Rev. 1992, 92,543. [1] T. Beck, A. Krasauskas, T. Gruene, G. M. Sheldrick. Acta Crystal- [2]R.Ballesteros-Garrido, D. Rix, C. Besnard, J. Lacour, Chem.Eur. J. logr. Section D 2008, 64,1179. 2012,inpress [2] K. H. Sippel, A. H. Robbins, R. Reutzel, J. Domsic, S. K. Boehlein, L. [3]W.Zeghida, C. Besnard, J. Lacour, Angew. Chem.Int. Ed. 2010, 49, Govindasamy, M. Agbandje-Mckenna, C. J. Rosser, R. McKenna, Ac- 7253.; D. Rix, R. Ballesteros Garrido, W. Zeghida, C. Besnard, J. Lacour, ta Crystallogr. Section D 2008, 64,1172. Angew. Chem.Int. Ed. 2011 ,50, 7308. [3] T. Beck, T. Gruene, G. M. Sheldrick, Acta Crystallogr. Section D 2010, 66,374.

OrganicChemistry OrganicChemistry Organic Chemistry 480 Organic Chemistry 481 On the Mechanism of One-Step Multi-Component Macrocyclization Modular Synthesis, OrthogonalFunctionalization and Properties of Reactions Novel Cationic [6]Helicenes Daniele Poggiali, Diane Rix, Rafael Ballesteros-Garrido, Walid Zeghida, Johann Bosson,Franck Torricelli, Jérôme Lacour Jérôme Lacour 1 University of Geneva, Department of Organic Chemistry 1 Department of Organic Chemistry, University of Geneva, Quai Ernest An- 30 quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland sermet 30, CH-1211 Geneva. [email protected] ;[email protected] Recently it has been shown that functionalized polyether macrocycles can be obtained in asingle step by the condensation of 4components, and this Helicenes are omnipresent in chemistry, biochemistry and physics as are- under high concentration and no-template effect.[1, 2, 3] sult of their many different properties and applications [1]. These can be modulated by selectively introducing substituents to the periphery of the Herein we present amechanistic study of such aRh(II)-catalyzed reaction of helical cores or by changing the nature of the atoms within. However, such diazodicarbonyls and 1,4-dioxane that affords 18-membered macrocycles. modifications are not always trivial to perform. To overcome this limitation, Kinetic information was gathered trough NMR and FT-IR monitoring. Fur- we developed anew class of cationic diaza, azaoxo and dioxo [6]helicenes. ther information was obtained via trapping reactions of intermediates.

O O O O O O O O Rh (L) ++ ++Rh (L) N 2 4 O ? O 2 4 2 O O O N2 O O 0.01 1.0 6.0

30 °C,5h,0.6 M, CHCl3

[1] W. Zeghida, C. Besnard, J. Lacour, Angew. Chem. Int. Ed. 2010, 49, 7253. These derivatives were prepared in one step from acommon advanced in- [2] D. Rix, R. Ballesteros Garrido, W. Zeghida, C. Besnard, J. Lacour, termediate.Straightforward and orthogonal functionalizations afforded a Angew. Chem. Int. Ed. 2011 , 50,7308. series of polysubstituted [6]helicenes. The importance of these transforma- [3] R. Ballesteros Garrido, D. Rix, C. Besnard, J. Lacour, Chem. Eur. J. tions was further evidenced in the strong modulation of the visible absorp- 2012,DOI :10.1002/chem.201103870. tion properties of those cationic dyes.

[1] Y. Shen, C.-F. Chen,Chem. Rev. 2012, 112,1463. Organic chemistry CHIMIA 2012, 66, No. 7/8 601

OrganicChemistry Organic Chemistry Organic Chemistry 482 Organic Chemistry 483 Carbenoid C-HInsertionsintoTetrahydrofuransCatalyzed by CpRu Modular synthesis of pH-sensitive helical dyes Complexes Antoine Wallabregue, Petr Sherin, JoyramGuin, Jérôme Lacour * Cecilia Tortoreto, ThierryAchardand Jérôme Lacour* 1 UniversityofGeneva, QuaiErnest Ansermet30, CH-1211 Geneva. Department of OrganicChemistry, University of Geneva Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland Helicenes are ortho-condensed polyaromaticcompounds which arechiral Email: [email protected], [email protected] due to the helical conformation of their backbone.1 Whereashundreds of neutralhelicenes can be found in the literature,onlyfew cationic derivatives 2 CpRu complexesare interestingalternativestocopperand dirhodium spe- have been reported. Previously,wehaveshownthat cationic dia- cies forthe catalyzed decompositionofdiazo compounds[1].Recently, our za[4]helicenes of type 1 can be readilypreparedand resolved;these moieties displayinghighbarriersofracemization(∆G‡172.8 kJmol-1 at grouphas shownthatcombinationsof[CpRu(CH3CN)3][PF6]and diimine 3,4 ligandslead to O-H insertionand condensation reactions with nitriles, ke- 200°C). tonesand aldehydes[2].Herein, in anew development, using -diazo-- ketoesters andTHF moieties as substrates,wereportthe formationofnovel enol-acetal motifs through unprecedented1,3-C-Hinsertion reactions[3]. Interestingly, usingmalonates -ketoester diazocompounds,the same conditions providethe formationofthe C-Cbound adducts only. Mechanisticinformationsonthisinteresting dichotomy will be provided.

Herein, we report the chemical (pH-sensitive, pKa 8.95) andphysical properties of novelquinacridine-based [4]helicenes 2.Wealso report the extension of thischemistrytoneutraldioxa-aza, diaza-oxa andtriazatriangulenes.3 Applications of such derivativesinsynthetic chemistrywill also be presented. [1]Shen, Y.; Chen,C.Chem.Rev. 2012,112, 1463and references therein. [2]Yamagishi,T., et al.J.Chem. Soc., Perkin Trans I, 1998, 9,1561. Laali, K., et al.J.Org. Chem. 2007, 72,8383. Teply, F. Chem.Eur.J. 2009, 15, [1]C.M.Che,J.S.Huang, Coord. Chem.Rev. 2002, 231,151; G. Maas, 1072. Chem.Soc.Rev. 2004, 33,183. [3]Laursen,B.W.; Krebs, F. C. Angew. Chem.Int.Ed. 2000, 39,3432. [2]M.Austeri,D.Rix,W.Zeghida,J.Lacour, Org. Lett. 2011, 13,1394- [4]Lacour, J., et al.Angew.Chem. Int. Ed. Engl. 2005, 44,1879. Lacour, 1397. J., et al. J. Am. Chem.Soc. 2008,130, 6507. Magnussen,O.; Herges,R.,et [3]C.Tortoreto, T. Achard,W.Zeghida,M.Austeri,L.Guénée, J. Lacour, al. J. Am. Chem.Soc. 2009,131, 442. Lacour, J.; et al.Chem. Sci., 2011, 2, Angew. Chem.Int. Ed. 2012,DOI:10.1002/anie.201201541. 425.

OrganicChemistry Organic Chemistry Organic Chemistry 484 Organic Chemistry 485 Design, synthesis and application of apolymyxin Bderivative suitable Stereoselective Synthesis of aBicyclic THP for photoaffinity labelling Peloruside AAnalog andits BiologicalEvaluation

Benjamin van der Meijden, L. Alexander, J. A. Robinson* ChristophWullschleger,Jürg Gertsch, Karl-HeinzAltmann

University of Zurich, Winterthurerstr.190, CH-8057 Zurich, Switzerland Institute of Pharmaceutical Sciences/ETH Zürich, Wolfgang-Pauli-Str. 10, CH-8093 Zürich, Switzerland Polymyxin Bisanantibiotic of last resort. It is active against gram-negative Peloruside A(1)isamarine natural product which was isolated in 2000 [1]. bacteria and displays ahigh binding affinity for lipid A, which is part of the It was shown to exhibit potent taxol-like microtubule-stabilizing activity and bacterial lipopolysaccharide (LPS) and amajor endotoxin. Unfortunately, to inhibitthe growth of humancancer cell lines at nM concentrations[2]. The stereoselectivesynthesis of the two simplified monocyclic peloruside A polymyxin Bhas severe side effects, such as neurotoxicity and acute renal analogs 2 and 3 have only recently been accomplished in our group [3]. In tubular necrosis. Therefore, understandingits mode of action is crucial to order to provide information on the importance of the substituents on the pyranose ringinnatural peloruside A(1), the bicyclic THP analog 4,which improve antibacterial activity. Membrane disruption,channel formation or lacks the anomeric OH group at C9 as well as both oxygen substituents on mediation of contact between outer and inner membrane have been pro- C7 andC8, wastargetedfor synthesis.

posed as the major antibacterialeffect. However, another mode of action has O OMe O OMe O OMe HO HO HO O O O been proposed due to the following observations: pore formation effects OH OH OH HO O HO HO O OH 7 7 have been reported at higher concentration than the minimal inhibitory con- 9 MeO 9 MeO 8 OMe MeO OH OH centration, and polymyxin Bbinds to the N-terminal domain of the prokary- PelorusideA(1) 2:7S-Monocyclic Analog BicyclicTHP Analog 4 3:7R-Monocyclic Analog otic Hsp90 to inhibit its chaperone activity. We report the efficient synthesis In this contribution we will present the stereoselectivesynthesis of bicyclic of polymyxin B3 and aderivative suitable for photoaffinity labelling using THPanalog 4 together with data on its effects on the tubulin/microtubule an orthogonal protecting group strategy on asolid support. The polymyxin system and its in vitro antiproliferative activity,incomparison with monocylic analogs 2 and 3.Our synthesisof4is based on ahighyielding B3 photoprobe contains aphotoleucine and an alkyne-tag for detection us- Prins cyclizationfollowed by macrolactonizationofthe corresponding seco- ing click chemistry. Preliminary photoaffinity labelling experiments will be acid precursor.

presented. [1] L. M. West et al., J. Org. Chem. 2000, 65,445. [2] K. A. Hood et al., Cancer Res. 2002, 62,3356. [3]C.W.Wullschleger et al., Org. Lett. 2010, 12,1120. 602 CHIMIA 2012, 66, No. 7/8 Organic chemistry

Organic Chemistry Organic Chemistry Organic Chemistry 486 Organic Chemistry 487 Amodular system forthe post-synthetic point-specificlabeling of TheStandard ElectrodePotential of 3-Nitrotyrosine naturalnucleic acids LeilaMahmoudi,Reinhard Kissner and Willem H. Koppenol Igor A. Oleinich,Eva Freisinger ETH Zürich, Wolfgang-Pauli-Str.10, 8093 Zürich, Switzerland UniversityofZurich, Institute of Inorganic Chemistry, Winterthurerstr. 190, 8057 Zurich,Switzerland Tyrosine andthe associatedtyrosyl radical are important one-electron trans- Non-natural modifications of oligonucleotides have unusualpropertiesand fer reactants in biology [1], and the according electrode potential at pH=7 can be usedfor arange of therapeuticand analytical purposes, including the has been determined by different methods [2]. 3-nitrotyrosine cametothe regulation of gene expression, DNA-peptide interaction,aswellasinvesti- attentionofbiologistsand biochemists when its formation in vivo was de- gation of DNAand RNAtertiarystructures[1].Restriction of thelengths of tected [3]. The standard electrode potential of 3-nitrotyrosyl/3-nitrotyrosine suchmodifiedoligonucleotides accessible by automated phosphoramidite- has not been determined yet. basedsynthesis promptedustoapplyanalternative approach. We used cyclic voltammetry to study the electrode reactions of N- acetyl-3-nitrotyrosine ethyl ester. Voltammogramsatscan rates up to 250 V/s at acarbon microelectrode were recorded for pH valuesof0.8,3.8 and 7.4. All traces obtained show only anodic waves, the radicals produced by the oxidation disappear too fast to be detected in the cathodic scan. The peakpotentialsofthe anodiccurrentsdonot depend on the scan rate, therefore the reaction must be reversible, and the equilibrium potential canbe The basic principles of thisapproach rely on the annealingofthe donor estimated from these waves alone. We applied the samemethod to tyrosine molecule bearingareactive group with the target oligonucleotide andon to obtain areference value. Anodic peak potentials were independent of the localizing the reactive group close in space to the targetnucleotide [2]. The scan rate, as before. Theelectrode potentials of both couplesobey normal reactivegroup wasdesigned in suchawaythat it can selectively modify a pH dependence with aslope of -59 mV per unit at room temperature. This specific nucleotide (cytosine, guanine, or thymine) in the presence of the corresponds to four others. The newlyintroduced group wasefficientlyusedfor labeling with afluorophore, andhence the generation of anew bioorthogonalgroup YHe YH wasshown. E°' at pH=7.4 for tyrosine was 0.95 V, for 3-nitrotyrosineitwas 1.10 V, vs. NHE. Financial support by theSwiss NationalScience Foundation (SNSF- Professorship PP002-119106/1 to EF)isgratefullyacknowledged. [1]J.J. Warren, J.R. Winkler, H.B. Gray, FEBS Letters, 2012, 586,596- [1]TaylorM.J., DervanP.B. BioconjugateChem. 1997, 8,354-364. 602. [2]Kellner S., Seidu-Larry S.,BurhenneJ., Motorin Y.,HelmM.Nucleic [2] M.R. DeFelippis,C.P. Murphy,F.Broitman, D. Weinraub, M. Farag- Acids Res. 2011, 39,7348-7360. gi, M.H.Klapper, J. Phys.Chem., 1991, 95,3416-3419. [3] I.Y. Haddad, G. Pataki, P. Hu, C. Galliani J.S. Beckman, S. Matalon, J. Clin. Invest., 1994, 94,2407-2413.

OrganicChemistry OrganicChemistry Organic Chemistry 488 Organic Chemistry 489 Newextendedpolycondensed aromatichydrocarbon of theC60 class Excess Electron Transfer in DNA Containing Multiple Phenanthrenes

SofiaMartin Caba1,Titus A. Jenny* Pascal Röthlisberger, Filip Wojciechowski and Christian J. Leumann

Université de Fribourg, Chemin du Musée9,1700 Fribourg, Switzerland University of Bern, Departement of Chemistry and Biochemistry, Freiestrasse 3, CH-3012 Bern, Switzerland

Aclassical Scholloxidation of precursor AunderKowacic conditions In order to investigate excess electron transfer (EET) within aDNA duplex PTZ Br (FeCl3/CH3NO2 in CH2Cl2)yields predominantlyand selectively the we synthesized oligonucleotides containing dU, PTZ, dU and dPhen. dimeric structure Cinsteadofthe expectedtribenzopentaphene B, opening The hybridization properties of these duplexes were determined by UV mel- therebyaroutetothisstrongly fluorescingC60 core structure,which dis- ting curve analysis. The thermal melting temperatures revealed that PTZ, playsapronounced tendencyfor extended п-п stacking. being anon-hydrogen bonding/intercalating base surrogate, is accommo- dated within the DNA duplex when paired against an abasic site. Selective photoexcitation of duplexes containing PTZ or PTZdU initiated EET, which was quantified by polyacrylamide gel electrophoresis (PAGE). Preliminary results indicate that electron transfer through aDNA duplex containing three dPhen residuesindeed occurs, suggesting interstrand stacking of the dPhen residues.

N O N O S Br HN S NH DNA DNA DNA DNA O N N O O O O O O O O O

O O O O DNA DNA DNA DNA

PTZdU PTZ BrdU dPhen

[1] N.A. Grigorenko, C.J. Leumann, Chem. Eur. J. 2009, 15,639. [2] N.A. Grigorenko, C.J. Leumann, Chem. Commun. 2008, 14,5417.

[1] Alameddine,B.; Martin Caba,S.; Schindler, M.;Jenny,T.A.; Synthe- sis 2012, imprint. . Organic chemistry CHIMIA 2012, 66, No. 7/8 603

Organic Chemistry Organic Chemistry Organic Chemistry 490 Organic Chemistry 491 Homo-DNAasaReporting Unit forthe Detection of Single Nucleotide Synthesis andIncorporation of Diazirine-Modified Uridine Polymorphism Phosphoramidite

CamilleDésiron1,Matthias Stoop1 andChristian J. Leumann1 Christine CSmith1,Christian JLeumann1

1UniversitätBern/Departement fürChemieund Biochemie, Freiestrasse 3, 1DepartmentofChemistry andBiochemistry, UniversityofBern, 3012 Bern Freiestrasse 3, 3012 Bern Switzerland

Althoughhomo-DNA is composed of asix-memberedring sugarmoietyit Adiazirine-modifieduracil analogue wassynthesised andincorporated into can formduplexes in an anti-parallelfashion with itself but not with natural threeRNA 21-mersfor useindetecting RNA –RNAbinding protein (RBP) nucleic acids.[1] Forsingle nucleotide polymorphism (SNP) detection, both interactions. the sensing of the mismatchand the generation of asignalare necessary.In ordertoenhancesensitivity,templatedchemistrycan be employed.We showedpreviously that homo-DNA canbeusedasatemplate for the bioorthogonalStaudingerreduction of rhodamine azide by triphenyl- phosphine (TPP). [2]Hereweshow that chimeric oligonucleotides composed of an orthogonal homo-DNA andDNA domain, can successfullybe applied for selectivenucleic acidsensing, via homo-DNA templatedfluo- rescence dequenching.

Target

Figure 1.Synthesis of phosphoramidite X. a) DMTCl, DMAP, pyridine; DNA/RNA Rhodamine Rhodamineazide DNA b) TBSCl,DMF,62% over2steps; c) 4-pentyn-1-ol, CuI, Pd(PPh3)2Cl2, TPPoxide 1 TPP Homo-DNA Et3N, DMF, 71%; d) 3-(α-iodo-p-tolyl)-3-(trifluoromethyl)-3H-diazirine , NaH, THF, 51%; e) TBAF,THF,73%; f) TBSCl,AgNO3,pyridine,THF, [1]Hunziker,J., Roth, H. J.,Bohringer, M., Giger, A., Diederichsen,U. 72%; g) CEPCl, DIPEA, THF,75%. Gobel, M. Krishnan, R.,Jaun, B. Leumann, C.,Eschenmoser,A.Helv. Chim.Acta., 1993, 76,259-352. Their crosslinking potential to single stranded binding proteins hasbeen evaluated [2]Stoop, M.,Leumann, C. J. Chem.Commun., 2011, 47,7494-7496. [1]Shih, L. B.;Bayley, H. Analytical Biochemistry 1985, 144,132-141.

OrganicChemistry Organic Chemistry Organic Chemistry 492 Organic Chemistry 493 Synthesis of iso-bicyclo DNA Palladium-CatalyzedAsymmetric α-Arylation of Aldehydes Anna-BarbaraGerber,Christian Leumann Pradeep Nareddy,LucaMantilli, Clément Mazet* DepartmentofChemistryand Biochemistry,University of Bern, DepartmentofOrganic Chemistry,UniversityofGeneva Freiestrasse 3, 3012 Bern,Switzerland 30 QuaiErnest Ansermet, 1211 Geneva,Switzerland In thelasttwo decades,avarietyofmodified nucleosides havebeen E-mail:[email protected] developed to improve antisenseorsiRNA oligonucleotideproperties suchas targetaffinity,nuclease resistance, and pharmacokinetics1.Itiswell Our group hasaninterestindeveloping catalytic methods to accesschiral established that conformational restriction leads to an enhancement in aldehydes in view of further use in synthesis. In thiscontext,wehavere- binding affinity andbiostability due to an entropic advantage. In thecontext centlydeveloped an asymmetric isomerizationofprimary allylicalcohols of conformationalrestrictionour laboratorysynthesized andcharacterized [1]and an asymmetrichydroboration of terminalalkenes[2].Although, theanaloguebicyclo-DNA 12.Incontinuation of this work we now highlevelsofenantioinduction were obtainedfor both reactions, none of envisaged thesynthesis of 6’-hydroxybicyclo nucleosides to investigate its thesemethods provides -chiralaldehydes with aquaternary stereocenter. structure-affinity relationshipincomplementary binding to DNA and RNA. The underdeveloped Pd-catalyzed α-arylation of aldehydes pioneered by Miura[3] is an attractive strategy to accesssuch motifs [4]. We present thesynthesisofthe buildingblocksA,C,Gand T(2a), the incorporationintoDNA and their pairing as well as their biological properties. DNA We will presentthe synthesis of an original classofchiral (P,N) ligands O H H which, in combination with the properpalladium source, display unprece- O O dented selectivitylevelsfor the intra-moleculararylation of -substituted Base RO Base aldehydes [5]. [1]a)L.Mantilli,D.Gérard, S. Torche, C. Besnard, C. Mazet, Angew. O OR Chem.Int. Ed. 2009, 48,5143; b) L. Mantilli,D.Gérard, S. Torche, C. DNA Besnard, C. Mazet, Chem.Eur.J.2010, 16,12736. 2a R=H [2]C.Mazet,D.Gérard, Chem.Commun. 2011, 47,298. 1 2b R=DNA [3]Y.Terao,Y.Fukuoka,T.Satoh, M. Miura, M. Nomura, Tetrahedron [1]J.Kurreck., Angew. Chem.Ed. 2009, 48,1378-1398. Lett. 2002, 43,101. [4]J.García-Fortanet, S. L. Buchwald, Angew. Chem.Int. Ed. 2008, 47, [2]M.Bolli, H. U. Trafelet,C.Leumann, Nucl. AcidsRes. 1996, 24, 8108. 4660-4667. [5]P.Nareddy,L.Mantilli, L. Guénée, C. Mazet. Angew. Chem.Int. Ed 2012 (in press). 604 CHIMIA 2012, 66, No. 7/8 Organic chemistry

OrganicChemistry Organic Chemistry Organic Chemistry 494 Organic Chemistry 495 Chiral N-HeterocyclicCarbenesinAsymmetricGoldCatalysis andin Synthesis of Oxindoles andAza-oxindoles theSynthesis of NHC-boranecomplexes ChandanDey,Yi-Xia Jia, andE.Peter Kündig* DipshikhaBanerjee,AndreaK.Buzas andE.Peter Kündig DepartmentofOrganic Chemistry, UniversityofGeneva Department of OrganicChemistry, University of Geneva 30 quaiErnest Ansermet, CH-1211 Geneva 4, Switzerland 30 quaiErnestAnsermet, CH-1211 Geneva 4, Switzerland Oxindoles andaza-oxindoles arecommon andimportant substructuresin We have reported anew family of chiral NHCs utilizingthe conceptofmin- naturalproductsand biologicallyactivemolecules. We here showthat a imizationofallylic strain to setthe stereocontrolelementsofthe catalyst[1], robust, cheap andefficientcoppermediated Csp2-H,Csp3-H coupling proto- which have been very successfully appliedinthe intramoleculararylation of colgives accesstooxindoles andaza-oxindoles in good to excellent yields amides to give 3,3-disubstitutedchiraloxindoles[1] andinthe firsthighly [1,2].The keystepofthistransformation is an intramolecular radical addi- asymmetric Pd-catalyzed C‒H couplinginvolving an unactivated methylene tion reaction(Scheme 1). groups yielding highly enantioenrichedfused indolines.[2] In this contribution we report: Initialresults of chiral NHC-gold catalyzed 1,6-enyne methoxycyclization reactions usingthe same ligands.

Scheme 1

In the course of thesestudies we have discoveredanewroute to accessaza- oxindoles as shown below (Scheme2). Optimization andmechanistic studies of thisinteresting rearrangement/cyclization protocol will be presented in this communication. Chiral NHC-borane complexeswithafocusonsynthesisand struc- turalfeatures.[3]

[1]Jia,Y.X.; Katayev, D.;Bernardinelli,G.; Seidel, T. M.;Kündig,E.P. Chem.Eur.J.2010, 16,6300. [2]a)Nakanishi,M.; Katayev, D.;Besnard,C.; Kündig,E.P.Angew. Chem. Int. Ed. 2011, 50,7438. b) Katayev, D.;Nakanishi,M.; Bürgi, T.; Scheme 2 Kündig,E.P.Chem.Sci. 2012, 3,1422. [3]Banerjee, D.;Besnard,C.; Kündig,E.P.Organometallics, 2012, 31, [1]C.Dey,E.P.Kündig, Chem.Commun. 2012, 48,3064-3066. 709. [2]Y.X.Jia,E.P.Kündig, Angew. Chem. Int. Ed. 2009, 48,1636-1639.

OrganicChemistry OrganicChemistry Organic Chemistry 496 Organic Chemistry 497 Getting control over Macrocyclization using Conformation Directing Amphiphilic oligopyrenes as units forsupramolecular Groups polymerization Christof Storz, Andreas F. M. Kilbinger* M. Vybornyi,V.L.Malinovskii, R. Häner University of Fribourg,Chemistry Departement, Chemin du Musée 9, CH- 1700 Fribourg, Switzerland Department of Chemistryand Biochemistry, University of Bern Freiestrasse 3, CH-3012 Bern Shape persistent macrocycles are of special interest due to their rigid backbone, which results in many applications such as self-aggregation into co- Oligoalkynylpyrenes (Sn)inaqueous medium form well definedsupramolecular assemblies lumnar stacks for transport processes and separation, or usage as rigid scaf- underthermodynamicconditions.Temperature-and concentration-dependent UV/visand fluorescence measurements canbeusedtoprobe thetransitionfromthe dissolved to the folds with well-defined cavities for catalytic or biomimetic applications, aggregated state. The obtaineddatasuggest that polymerizationoccurs through acoopera- [1] etc. Since they occurred, their preparation represents amajor challenge tivemechanismvia nucleationstep. The stability of aggregates is highlysensitivetovari- and has been intensively studied. Yet, most of the one-step cyclizations de- ablessuchastemperature,concentration, ionicstrengthand presence of co-solvents. Mor- scribed so far leads to low yields and need many purification steps. phologyofthese materialswill be discussed.[1],[2],[3].

R O N R 0 N O 30 C R 900C O N O 0.4

R N O O O or R=? P N R N O R

O N A R 0.2 O O N O n R N S O R

Here, we present the controlled one-step formation of tri- and hexa-oligo(p- 0.0 250300 350400 benzamide) macrocyclesfrom N-alkylated phenyl p-aminobenzoates. These wavelength,nm monomeric building blocks contain conformation directing groups, whose -6 nature determines whether they form cyclic trimers or hexamers in excep- Fig.1. TemperaturedependenceofUV/visfor 10 MS3in aqueousmedium (pH=7.05 10mMNaCl) tionally high yields. The cyclization is presumably induced by the curved [1] Pascal Jonkheijm, Paul vander Schoot,AlbertusP.H.J.Schenning,E.W.Meijer structure of the linear oligomer intermediatebecause of the favored cis con- Science313, 80 (2006) formation of the N-alkylated aromatic amide bond.[2] [2] Nussbaumer, A. L.,Studer, D., Malinovskii, V. L. andHäner,R.(2011), Angew.Chem. Int.Ed., 50, 5490–5494. [1] (a) Grave, C.; Schlüter, A. D. Eur. J. Org. Chem. 2002,3075. (b) [3] Malinovskii, V. L.,Nussbaumer, A. L. andHäner,R.(2012), Angew.Chem. Int. Ed.. Höger, S. Chem. Eur. J. 2004, 10,1320. (c) Zhang, W.; Moore, J. S. doi:10.1002/anie.201201352 Angew. Chem., Int. Ed. 2006, 45,4416. [2] Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.; Shudo, K. Tetrahedron Lett. 1989, 30,6177. Organic chemistry CHIMIA 2012, 66, No. 7/8 605

Organic Chemistry OrganicChemistry Organic Chemistry 498 Organic Chemistry 499 The DNAthree-wayjunction as amould fortripartitechromophore Bilaterally symmetric corannule derivatives assembly. Amit Kumar Dutta, Jay S. Siegel* Institute of Organic Chemistry, University of Zurich, Winterthurstrasse 190, CH- 8057, Zurich, Switzerland Markus Probst,Daniel Wenger, SarahM.Biner andRobert Häner Corannulene is abowl shaped molecule, with alarge π-conjugated surface area and therefore great potential to form ordered materials.1 Bilaterally DepartmentofChemistryand Biochemistry, UniversityofBern symmetric diester diethynyl corannulene can function as asynthetically Freiestrasse 3, CH-3012 Bern important intermediate2 to achieve different classes of compounds with diverse scientific application. Acorannulene-hemi- coronene hybrid from TheDNA three-wayjunction(3WJ) is formed by threemodified strandsthatare partially this intermediateisexpected to be abent-flat system. Photophysical and complementaryinapairwise fashion. TheDNA 3WJservesasascaffold forthe molecular organizationofnon-nucleosidicpyreneand perylene buildingblocks, located at thebranch redox behavior of such asystem should help better understand the π- pointofthishigherorder DNAstructure.Depending on thecomposition of thetripartite conjugation behavior of afullerene-graphene system. Appropriately tuned assembly, theconstructs possess distinct spectroscopicproperties,ranging from pyrene substituents in acorannulene-hemi-coronene architecture could be monomerorexcimer fluorescence to completelyquenchedtripartite aggregates. Thespec- instrumental in the formation of supramolecular aggregates with material troscopicproperties of these aggregates arelargely controlled by thenatureofthe interstrand stacking interactions of thechromophores. [1] [2] [3] applications. Herein, we report asynthesis of acorannulene-hemi-coronene compound (2), starting from dichloroacenaphthene. The diester-bis(phenylethynyl)- corannulene (1)isacrucial intermediate in this synthesis.Photophysical, redox and stacking behavior of this class of compounds as well as other possibilities from diester diethynyl corannulene strategic intermediates will be presented.

O O O O O O O O

4- steps X Pd-PEPPSI-IPent, CsF + mol.sieve 4 oA,1,4- dioxane Microwave, 1h 20% overall 70% Sn

Cl Cl F F

C12H25 C12H25 [1]M.Probst, D. Wenger,S.M.Biner andR.Häner, Org.Biomol. Chem. 2012, 10,755- 1 2 759. [1] Wu, Y. T.; Bandera, D.; Maag, R.; Linden, A.; Baldridge, K. K.; Siegel, [2] H. Bittermann,D.Siegemund, V.L. Malinovskii, R. Häner, J. Am.Chem. Soc. 2008, 130,15285-15287. J. S. J. Am. Chem. Soc. 2008, 130,10729. [2] Wu, Y. T.; Hayama, T.; Lin- [3]N.Bouquin,V.L.Malinovskii,R.Häner, Chem. Commun. 2008,1974-1976. den, A.; Baldrige, K. K.; Siegel, J. S. J. Am. Chem. Soc. 2006, 128,6870

Organic Chemistry Organic Chemistry 500 ManganeseOxide Hybrid Nanocomposites Used as Mild Oxidantand Recyclable Catalyst ChristelleJablonski1,ChristianSiebenhaar1,MarcusWaser1,Michael Lie- betanz2,Stefan Graber2,Edwin Constable2,Uwe Pieles1,Gerhard Grundler1,MurrayHeight3

1 School of Life Sciences FHNW,Chemistryand Bioanalytics

2 UniversityofBasel, 3 HeiQ MaterialsAG

Manganeseoxide andsilicamanganese oxide nanoparticleswereproduced by flamespray pyrolysis andoxidizedwith sulphuricacidtogenerateparti- cles which demonstratedenhanced oxidantpropertieswhenusedunder microwave irradiation(T=100-150°C,300W,P=10-11barfor 1h).Avarietyof functionalized benzylic andallylic alcohols were transformedtothe corresponding aldehydesingood yields within ashorttime andinhighpurity. Results were compared to theyieldsand puritiesofcompounds obtained using commercially availablemanganese oxide (Sigma-Aldrich): undermi- crowave conditions considerable loss of products were observed in most of thecases with thecommercial reagent,comparableyieldsand qualityof products were obtained at room temperatureafter 1-2days. Theactivityof MnO2 nanoparticles(pure andsilicasupported)was proventobestableafter half ayearand more than one year.The newoxidant offeredthe advantage of afacile separationafter reactioninadditiontothe shorterreactiontime.

The FSPprocess wasextendedtothe preparationofMnO2/Pd/ silica nanoparticlesanewclass of multifunctionalcatalytic composite materials. Several Sonogashirareactions, Suzuki couplingswith bromo- andiodo aromatic derivatives demonstrated acomparable reactivityofthe newcatalyst to standard palladium catalysts. Hybrid nanocompositescouldbeusedupto three timesinaspecificcaseofSuzuki reactionwith phenylboronic acid without loss of activity. Tandem reactions involving firstaC-Ccoupling followedbyacontrolledoxidationofalcohol to aldehyde areundercurrent investigationaswellasfurther characterizationofthe hybrid material.