Columns CHIMIA 2017, 71, No. 6 387

doi:10.2533/chimia.2017.387 Chimia 71 (2017) 387–389 © Swiss Chemcial Society

Conference Report

The 52nd EUCHEMS Conference on Stereochemistry: Bürgenstock Conference 2017, Brunnen, April 30th–May 4th, 2017

Pablo Rivera-Fuentes*a and Matthias Weiss*b The Monday morning session, chaired by Anja Palmans (Eindhoven University of Technology), started off *Correspondence: Prof. P. Rivera-Fuentesa, Dr. M. Weissb, aLaboratorium für Orga- nische Chemie, ETH Zürich, HCI G329, Vladimir-Prelog-Weg 3, CH-8093 Zürich, with a presentation by Kay Severin E-mail: [email protected]; bSyngenta Crop Protection AG, (EPF Lausanne) on novel us- Schaffhauserstrasse 101, CH-4332 Stein, E-mail: [email protected] ing nitrous oxide as reagent in organic chemistry. He presented how this po- Keywords: Bürgenstock · EUCHEM · Stereochemistry tent greenhouse gas, which arises as a byproduct in nylon manufacturing, can Kai Severin serve as a mild oxidizing agent, enabling both the homo- and hetero-dimerization of Grignard reagents. Moreover, by sequestering it with N-heterocyclic carbenes it can serve as a source of nitrogen, which opens new avenues to azo- There is no conference like the Bürgenstock. What makes it imidazolium dyes. He then introduced the audience to the yet unique is not only history, prestige or traditions, it is that in every uncharted chemistry of alkenyl- and alkynyl-triazines, which are single one of its 52 editions, it has succeeded at bringing scien- readily obtained from nitrous oxide, lithium amides and Grignard tific excellence to an idyllic location, fostering a particularly col- reagents. The lecture concluded with an outlook on a number legial atmosphere in which scientific discussion flourishes. The of exciting transformations, which can be accessed from these significance of this conference can be summarized by paraphras- unusual intermediates. ing a lecturer of this year “If you are invited to the Bürgenstock and you had other plans, you change your plans”. The second talk was given by Joost The 52nd Bürgenstock conference started on April 30th and Reek (University of Amsterdam). By in- took place on the shores of Lake Lucerne (Vierwaldstättersee) troducing judicious supramolecular in- in Brunnen, Switzerland. The welcome dinner was the occasion teractions into his ligand designs, he has for an introductory speech by this year’s president of the confer- managed to orient substrates to control ence (Eindhoven University of Technology), who selectivity in transformations ranging presented the guest of honor François Diederich (ETH Zurich). from ruthenium-mediated hydrogenations The organizing committee of this year included Christian Bochet within self-assembled cages to hydrofor- (University of Fribourg), Alain de Mesmaeker (Syngenta), mylation reactions. A major theme of Joost Reek Guido Koch (Novartis), Jérôme Lacour (University of Geneva), the talk was the effect of confinement in Cristina Nevado (University of Zurich), and Helma Wennemers cages and effective concentration, in particular of metal ions. By (ETH Zurich). employing some of the Fujita cages, he showed that they could generate multinuclear complexes in which both the catalyst and After dinner, moderator Christina substrate are pre-organized in the nanosphere. He finished his talk Moberg (KTH Royal Institute of by introducing hydrogenase models in which the diiron active site Technology) introduced the first of the natural enzyme is embedded within Fujita cages to obtain speaker of the conference, Paul Chirik proton reduction at significantly decreased overpotentials. (Princeton University). In an authentic tour de force, he took us from the ba- The Monday afternoon session sic chemistry of (redox) non-innocent was chaired by Donald Hilvert (ETH ligands to how to pair them with iron, Zurich). The hunt for natural products Paul Chirik cobalt and nickel to create catalysts that in exotic places is a dangerous en- enable a variety of challenging trans- deavor, as demonstrated in an entertain- formations. Using small feedstock hydrocarbons and iron com- ing talk by David Craik (University of plexes, he demonstrated applications in [2+2] and [4+2] cyclo- Queensland). Ultra-stable, plant-derived addition reactions of unactivated alkenes and dienes, as well as cyclic peptides known as cyclotides hydrovinylations to produce structurally simple, yet otherwise were his hunting prey. These cyclotides David Craik difficult to synthesize skipped dienes. With cobalt-based cata- provided a versatile and stable scaffold lysts, he showed impressive borylation reactions, including rare for grafting biologically active peptide-epitopes. These con- 1,1-hydroborylations of alkynes, sequential and stereodefined structs are metabolically inert peptides that can be expressed in addition of electronically different borane substituents, and a genetically modified plant and hold great promise as potential synthesis of 1,1,1-triboryl alkanes. Many examples of C–H ac- drug candidates. In an extension of these findings, he also pre- tivation methods were presented, mostly utilizing cobalt pincer sented how the pharmaceutically interesting peptide Conotoxin complexes, which have reactivities that are orthogonal to iridium could be stabilized through cyclization and cysteine cross-linking complexes. He closed his talk with surprising discoveries in co- of the conserved epitope, resulting in IMB-007, a drug candidate balt-mediated hydrogenation reactions in methanol and the use to treat neuropathic pain. of zinc as an activating agent in the production of competent The first poster session took place on Monday afternoon, bimetallic species for catalysis. which started with five short presentations by junior faculty, in- 388 CHIMIA 2017, 71, No. 6 Columns

cluding Philipp Heretsch (Free University of Berlin), Rafal Klajn with great selectivity in glucagon or defensin peptides. These (Weizmann Institute of Science), Jirˇi Míšek (Charles University and other newly discovered enzymes from uncultured bacteria of Prague), Robert Phipps (University of Cambridge), and Pablo are opening new perspectives for post-translational modification Rivera-Fuentes (ETH Zurich). in protein engineering.

The evening session was chaired by A day with gorgeous weather and Patricia Dankers (Eindhoven University views of snowcapped mountains was of Technology) and featured a very dy- rounded off in the last session, chaired namic presentation by Tanja Weil (Max by Syuzanna Harutyunyan (University Planck Institute for Research). of ), with a presentation Using a peptide-decorated copolymer, by Timothy Jamison (Massachusetts she demonstrated the formation of fibril Institute of Technology) on the advan- aggregates that recruit viral particles to tages and pitfalls of doing chemistry in Tanja Weil its surface and facilitate their entry into continuous flow. A call was made to edu- Timothy Jamison hematopoietic stem cells, which are no- cate the next generation of chemists not toriously difficult to infect. Additionally, G2b, a small only in ‘batch-mode’-thinking, which deals with systems chang- globular dendrimer composed of multiple aromatic rings could ing over time but also in ‘flow-mode’-thinking where a system form a supramolecular complex with adenovirus 5 particles to fa- in steady-state changes over space. The impact of engineering cilitate their entry into cells independently from the typical CAR in this field was highlighted by several useful tools presented receptor-mediated mechanism. This strategy allows the infection like in-line separators for continuous phase separation, smaller of cells even in the presence of the coagulation factor X, which and more powerful pumps to allow for shrinking the required normally blocks entry of viruses into cells. Applications of this lab-space or continuous solvent evaporation, which allows for technology include induction of nerve growth and intracellular connecting more chemical steps in sequence. Providing exam- delivery of anticancer drugs. In the last part of her talk, she intro- ples of chemical transformations that benefit from large surface duced her recent work in the field of nanodiamonds doped with areas, exact temperature control, ‘extreme’ conditions, and ‘end- nitrogen-vacancy centers and presented some recent application to-end’ manufacturing of pharmaceutical ingredients in a single of these monodisperse, light emitting nanocrystals as sensors of machine, the evening lecture convinced the audience that chemi- magnetic fields. cal transformations in continuous flow will be an integral part of chemistry in the future Tuesday morning started with a ses- sion chaired by former president Paul The first session on Wednesday Knochel (LMU Munich). The first morning was chaired by Christian speaker was Thorsten Bach (Technical Hackenberger (Leibnitz Institute for University Munich), who delivered an Molecular Pharmacology) and started insightful talk on enantioselective syn- with a lecture by Jennifer Prescher using light. In a very didactic (University of California, Irvine) on manner, Bach demonstrated how triplet new bioorthogonal reactions and biolu- Thorsten Bach induction using a chiral sensitizer is an minescent systems.After introducing the efficient way to impart enantioselectiv- state of the art in bioorthogonal chem- Jennifer Prescher ity in [2+2] cycloadditions. He also showed that using bathochro- istry to introduce ‘clickable’ functional mically shifted sensitizers increase the selectivity of the reactions groups, she presented their development of cyclopropene units by avoiding direct excitation of the substrate. Further extensions as strained alkenes for bioorthogonal reactions with tetrazines. of this concept include the use of chiral Lewis acids, which upon The advantages of cyclopropenes are multifold: they are meta- complexation with α,β-unsaturated ketones induce a red-shift bolically stable, sterically small and electronically tunable. In yet in absorbance and generation of thioketoxoniums intermediates another important contribution to bioorthogonal chemistry, she from dithianes, which also provide good spectral separation and introduced reactions between cyclopropenones and triaryl phos- improve catalytic performance. Interestingly, this strategy can phines. By appending a nucleophile close to the phosphine, they also be used to induce enantioselectivity in photochemical reac- were able to develop a new ligation reaction and demonstrated tions that occur primarily through the singlet manifold. this method in cell lysates. In the second part of her talk, she described the directed evolution of new luciferin/luciferase pairs The quest for new taxa of bacteria, for multi-signal imaging. These new luciferin/luciferase pairs which are talented producers of biologi- hold great potential for whole-animal imaging of cell mobility cally active natural products, and the and cell–cell contact visualization, and some proof-of-principle characterization of their biochemical applications have already been realized. machinery was at the center of the pre- sentation of Jörn Piel (ETH Zurich). Luc Brunsveld (Eindhoven Univer- He showed how the discovery of sity of Technology) presented how mul- Entotheonella symbionts and the com- tivalent interactions leading to the spa- Jörn Piel plex natural products produced by these tial organization of proteins in the form bacteria led to the identification of very of dimers or more complex aggregates unusual biosynthetic pathways and the underlying enzymatic can be manipulated by drug-like small modification machinery. He also demonstrated how the power molecules. Taking advantage of host– and promiscuity of these enzymes can be harnessed for protein guest chemistry involving phenylalanine engineering. Very unusual post-translational modifications were residues and the small-molecule recep- Luc Brunsveld described, including a rare peptide-splicing transformation. In tor cucurbit[8]uril, control over protein– another impressive example, an entotheonella-derived epimerase protein interactions was achieved. A proof-of-principle applica- was able to invert the stereochemistry of specific amino acids tion of this methodology was presented by demonstrating the as- Columns CHIMIA 2017, 71, No. 6 389

sociation of fluorescent proteins by resonance energy transfer as but also by the number of monomeric units and their conforma- well as by a split luciferase complementation assay. Additionally, tional flexibility, which has an effect on the efficiency of energy small-molecule regulation of caspase-9 activity via induced di- transfer. Stacks of merocyanine dyes were engineered through merization on the 14-3-3 protein scaffold was disclosed. backbone-supported self-assembly. The strong electrostatic forc- es in this class of dyes ensured H-stacking through very strong On Wednesday evening, the attendees of the Bürgenstock dipolar interactions. Using tailored backbones, multiple stacks were offered a musical treat. The Quadrivium ensemble of stu- and heterostacks were created and characterized by exciton cou- dents from Eindhoven University of Technology performed a pling theory. The goal of mimicking natural light harvesting sys- series of well-known classical and modern pieces, ranging from tems may still be far, but this work has certainly taken us closer. Mozart’s ‘Eine kleine Nachtmusik’ to Randy Newman’s ‘You’ve On Thursday afternoon, another five young present- got a friend in me’. After the concert, there was an opportunity ed eight-minute talks as appetizers for the second poster session. to meet the young artists, some of whom are scientists as well. Presenters were Pol Besenius (University of Mainz), Thomas Hermans (University of Strasbourg), Frank Kotch (Pfizer), On the final day of the Bürgenstock, Corinna Schindler (University of Michigan, Ann Arbor), and session chair and president elect Ilan Corey Stephenson (University of Michigan, Ann Arbor). Marek (Technion – Israel Institute of Technology) introduced Karl-Heinz The last presentation of the 52nd Altmann (ETH Zurich). Paying great at- Bürgenstock conference provided a tention to experimental details, Altmann dazzling outlook on the rapid progress described the synthesis and biological towards life-like systems based on ar- evaluation of mycolactones A and B, tificial cells. From biodegradable poly- Karl-Heinz Altmann which are macrocyclic, polyketide natu- mersome capsules to multicompart- ral products of bacterial origin. Using mentalized nanoreactors, a robust synthetic strategy, these products could be obtained in (Eindhoven University of Technology) sizable quantitites for downstream applications. For example, elegantly demonstrated how increasing Jan van Hest a biotinylated derivative was used to identify that these mole- levels of organizational and functional cules destabilize the mTORC1 complex, likely through FKBP12 complexity can be built into artificial polymer-based systems. signaling. In the second part of the talk (–)-zampanolide and Achieving control of polymersome surface topology to generate (+)-dactylolide were introduced. Both compounds stabilize tu- stomatosites not only allowed to load larger and more complex bulin but, curiously, their macrocyclic cores are assemblies of proteins into nanoreactors but also to generate enantiomeric. By developing a modular synthesis, structure–ac- oxygen-propelled molecular motors. Irrespective of how long it tivity relationships could be established and (–)-zampanolide was will still take to generate fully biomimetic, synthetic cells, this used to obtain the first X-ray diffraction structure of a polymer- final lecture highlighted again that there are few limits to where ization stabilizer bound to tubulin. the imagination of curious, scientifically minded spirits can lead.

Development of organic transfor- The 52nd Bürgenstock conference was a tremendous success mations that are compatible with condi- and the authors thank the organizing committee, president Bert tions found in living cells and their sub- Meijer, and the Junior Participation fellowship (P. R.-F.) sequent application in protein modifica- for the wonderful experience. We also want to express our grati- tion was the theme of a talk by Motomu tude to the two outgoing members of the organizing committee, Kanai (University of Tokyo). A nitrox- Jérôme Lacour and Helma Wennemers, for their passionate dedi- ide radical-based (ketoABNO) system cation to this conference over many years. We look forward to the allowed not only a serine site-selective next Bürgenstock, which, under the presidency of Ilan Marek will Motomu Kanai method for peptide cleavage but also certainly be another unforgettable meeting. opened up the possibility to exploit tryp- tophan residues as novel sites for bioconjugation with minimal Received: May 23, 2017 perturbation of protein structure. How surface patterns of large biopolymers like β-amyloid plaques can be used for achieving highly selective delivery of a therapeutic agent was beautifully demonstrated with a singlet oxygen generating catalyst, which is only active if bound to the target protein surface.

Rainer Haag (Free University of Berlin) moderated the final session of the conference. Dye development was an early driving force of synthetic chemistry in the 19th and 20th centuries, and Frank Würthner (University of Würzburg) guided us through the world of 21st century supramolecular dye chemistry. Frank Würthner Using perylenes as a platform, he has developed supramolecular assemblies in which stacking of the monomeric chromophores is controlled. In cyclophanes, the nature and orientation of the guest determine the photophysical properties of the assembly by HOMO-LUMO band gap tuning. Moreover, the properties of cyclic oligomers were shown to be modulated not only by the nature of the guest,