Highlights from the 51st EUCHEM conference on stereochemistry, Bürgenstock, Switzerland, May 2016

On Sunday 1st May 2016, 104 chemists made their way to the picturesque town of Brunnen, located on the banks of the Vierwalstättersee (Lake Lucerne) to participate in the 51st EUCHEM conference on stereochemistry. This conference, commonly known as ‘Bürgenstock’, is internationally recognised as one of the most preeminent meetings in the scientific calendar. A select number of junior and senior scientists from both academic and industrial backgrounds congregate for intense scientific discussion while enjoying each others’ company through various recreational activities in the surrounding Swiss Alps.

The conference is steeped in tradition, with the guidelines essentially unchanged for the last 50 years since its inception in 1965. Of the conference rules, arguably the most important is that the names of the fourteen plenary speakers are kept strictly secret prior to the opening of the meeting. Naturally, this leads to a bustling sense of excitement upon arrival, with the question on everybody's lips being ‘do you know who is talking this year?’ It is this tradition of mystery, coupled with the mountainous surroundings of Brunnen (Fig. 1), that provides a very special ambiance to this meeting.

Fig. 1 Lake Lucerne from the banks of Brunnen.

The President of this year's conference, Prof. Paul Knochel (Ludwigs-Maximilians-Universität), and the organising committee: Prof. Christian Bochet (University of Fribourg), Dr Alain De Mesmaeker (Syngenta Crop Protection Research), Dr Guido Koch (Novartis), Prof. Jérôme Lacour (University of Geneva) and Prof. Helma Wennemers (ETH Zürich) assembled a fantastic interdisciplinary line up consisting of world renowned scientists with expertise across many facets of chemistry.

With registration complete, the conference programme commenced with dinner and President Paul Knochel welcoming the Guest of Honour, Prof. Dieter Seebach (ETH Zürich), with great fondness. Prof. Seebach had himself been President of the Bürgenstock meeting in 1987 and in fact, this was the third time that Prof. Seebach had been the Guest of Honour at this prestigious conference, and highlights not only the respect that he commands from his peers, but also the impact he has had on the chemical sciences during his incredible career. Following this, the President introduced Prof. E. W. (Bert) Meijer (Technische Universiteit Eindhoven), who assumed the post of Vice President (President Elect 2017). In accordance with the responsibilities of this role, Prof. Meijer was immediately tasked with ensuring good weather in Brunnen for the duration of the conference. This initially appeared difficult given that it was raining upon arrival, but Prof. Meijer's abilities clearly extend beyond chemistry and into weather modification as we were gifted with beautiful sunshine for the latter part of the week!

The first scientific lecture of the conference was provided by Prof. Oliver Trapp (Ruprecht-Karls-Universität Heidelberg), with Prof. Ilan Marek (Technion-Israel Institute of Technology) chairing the session. The lecture opened with the topic of molecular recognition and catalysis where Prof. Trapp introduced the concept of self-amplification of chirality and showcased the use of stereodynamic catalysts. Interestingly, ligands such as 5,5′-disubstituted tropos 2,2′-bis(diphenylphosphino)biphenyl (BIPHEP) were shown to be easily deracemised and applied to asymmetric catalysis, enabling chirally switchable catalytic systems.^1a The second part of the talk focused on chirotropic methods, with emphasis on the application of foil-induced Coulomb Explosion Imaging to overcome the formidable challenge of determining the absolute configuration of small, gas phase molecules. This method was used to unambiguously establish the absolute configuration of cryptochiral (R,R)-2,3-dideuterooxirane.^1b The synthesis of (R,R)-2,3-dideuterooxirane also presented the opportunity to determine the absolute stereochemistry of (+)-glyceraldehyde, which historically was arbitrarily assigned as being D-configured by Emil Fischer. A key intermediate of the synthesis was chemically manipulated and directly correlated with (+)-glyceraldehyde, thereby unambiguously confirming the correct D-configuration.^1c Following the lecture there was a welcome drinks reception allowing the conference delegates to interact and informally discuss the finer aspects of the opening lecture. Thought-provoking discussions continued well into the night.

Monday morning started with the theme of C–H activation, and was chaired by Prof. Shu Kobayashi (The University of Tokyo). The first lecture of the day was provided by Prof. Olivier Baudoin (University of Basel) who discussed the design and application of intramolecular C–H activation processes for the construction of numerous ring systems. Prof. Baudoin began with describing the synthesis of cyclobutarenes^2a and progressed to asymmetric C(sp³)–H arylation reactions.^2b Further topics presented included the formation of hexa- and octahydroindoles using C(sp³)–H activation methodology and its application to the synthesis of several marine natural products (e.g., aeruginosin 298A^2c,d). Prof. Baudoin's lecture thoroughly demonstrated the power of C–H activation and highlighted the excellent chemo-, regio-, and stereoselectivity that can be achieved using careful design and application.

Following the coffee break, Prof. Kobayashi introduced Prof. Lutz Ackermann (Georg-August-Universität Göttingen) whose talk was entitled ‘Ruthenium(II)-catalysed C–H activation and beyond’. Prof. Ackermann began by detailing the use of ruthenium catalysis in order to carry out C–H bond activation of several arenes,^3a but quickly progressed to study further metals with which this, and related chemistry, could be achieved. An impressive array of examples using iron,^3b cobalt,^3c and nickel^3d (as well as other metals) catalysis were then discussed. The scope and efficiency of the C–H activation chemistry presented further underlined the considerable progress being made in this field, thereby expanding the set of tools available to synthetic chemists. The morning session was followed by a group photo consisting of all the conference delegates and the organising committee.

After lunch, the focus of the meeting switched topic to proteins, beginning with an afternoon lecture from Prof. Itaru Hamachi (Kyoto University), with Prof. E. W. (Bert) Meijer acting as the moderator. Prof. Hamachi firstly detailed aspects of his research involving protein labelling using ligand directed chemistry.^4a Selective chemical modification of the protein using a small label that doesn't interfere with the function of the protein in its native environment represents a significant challenge. This is an area that his group have been pioneering for a number of years, with several techniques having been developed.^4b The second part of the talk progressed to a discussion of protein imaging by application of ligand conjugated supramolecular assemblies.^4c

Monday afternoon continued with the first of two poster sessions, and provided an excellent opportunity for further discussions between the junior and senior academic/industrial participants. Of the nineteen scientists who presented posters in this two-hour slot, the organising committee selected five speakers to deliver eight minute ‘appetiser’ talks prior to the session. The short lectures were provided by Jovica Badjic (Ohio State), Christopher Cordier (Imperial College London), Ali Coskun (Korea Advanced Institute of Science and Technology (KAIST)), Bill Morandi (Max-Planck-Institut für Kohlenforschung) and Yu Zhao (National University of Singapore).

The evening lecture was once again chaired by Prof. Meijer, who introduced Prof. Stephen Kent (University of Chicago). Prof. Kent gave an entertaining lecture concerning the total synthesis of non-natural ‘mirror image protein molecules’ (i.e., D-proteins).^5a He presented his laboratory's efforts concerning the exploration of interactions between D-proteins with L-targets, and outlined the concept of generating unique therapeutic candidates using this method. Further applications whereby these D-proteins were screened against existing chiral molecule libraries were also discussed. The talk finished with the topic of ‘racemic protein crystallography’.^5b This fascinating technique involves the co-crystallisation of a D-protein with the naturally occurring L-protein to enable X-ray structural determination of proteins that have been previously difficult to crystallise.^5c

The Tuesday morning slot was chaired by Prof. Peter Chen (ETH Zürich), with the first lecture provided by Prof. Giuseppe Resnati (Politecnico di Milano). During his talk, Prof. Resnati shared his research on halogen bonding,^6a firstly providing a basic overview of the details surrounding this non-covalent interaction, and then moving on to its application in controlling self-assembly.^6b Prof. Resnati showcased an impressive array of 1D and 2D networks that could be designed and built by exploiting halogen bonding, and then progressed to discuss the tuning of the incredibly diverse properties of these systems.^6c One remarkable example indicated that the hydrophobic nature, strength, and directionality of halogen bonds could be used to transport anions across lipid bilayers.^6d

The second lecture of the morning was delivered by Prof. Valery V. Fokin (University of Southern California), who gave an outstanding session focusing on the mechanistic intricacies of complex catalytic systems. In his lecture entitled ‘Interrogating nature with her own tools’, Prof. Fokin described how a thorough mechanistic understanding can allow modification of the observed kinetics to ultimately accelerate a reaction. Prof. Fokin demonstrated the application of this concept with two examples including within small molecule chemistry in the Cu-catalysed azide–alkyne cycloaddition (CuAAC or ‘click’ reaction)^7a–d as well as in polymerisation processes to gain access to useful materials with high levels of control over polydispersity.

After lunch, the theme of the conference shifted towards organic synthesis, with chair Prof. Tanja Gaich (Universität Konstanz) introducing speaker Prof. Janine Cossy (ESPCI). The chair fondly recounted memories of when she first met Prof. Cossy and how supportive and influential she had been in the early stages of her own career. Highlights of the session included the synthesis of C-aryl and C-vinyl glycosides from 1-bromo glycosides using cobalt catalysis^8a and the demonstration of the utility of cyclopropenes in synthesis.^8b The latter were shown to undergo electrophilic ring opening to provide metal carbenoid species and provide small to medium-sized rings by C–H insertion. The final part of the lecture introduced the synthesis of new [n]paracyclophanes from readily available building blocks. Indeed, [9]-, [10]-, and [16]paracyclophanes could be straightforwardly accessed using this methodology, which relied on a thermal electrocyclisation reaction followed by sequential cycloaddition and cycloreversion.^8c

Following the lecture, a second set of poster appetiser talks were delivered, this time by Suzanne Blum (University of California, Irvine), Ivana Fleischer (University of Regensburg), Michal Juríček (University of Basel), Kathrin Lang (Technische Universität München) and Uday Maitra (Indian Institute of Science). These speakers, in addition to a further thirteen researchers, then presented their posters to the conference delegates.

After dinner, the evening lecture was provided by Prof. Jonas Peters (California Institute of Technology) with last year's President Antonio Togni (ETH Zürich) chairing the session. Prof. Peters delivered a wonderful talk detailing the catalytic conversion of N₂ to NH₃ using a strategically designed tris(phosphine) triarylborane-supported iron complex.^9a The session began by introducing the traditional Bosch–Haber industrial process before moving onto how iron-rich cofactors of nitrogenase enzymes enable this transformation in naturally occurring systems. It was the active sites of these enzymes that inspired the development of Peters’ single site nitrogenase catalysts. The design plan and mechanistic operation of the iron complexes were discussed, as were the many spectroscopic techniques used to tease out the intricacies of the complex reaction mechanism (Scheme 1),^9b leading to a system with high TONs for this very challenging process – up to 64 NH₃ per Fe.^9c

Scheme 1 Diagrammatic representation of the catalytic operation of Peters’ single site nitrogenase catalyst. Specific details have been omitted – see ref. 9c for full details.

The next morning Prof. Helma Wennemers (ETH Zürich) introduced Prof. Annette Beck-Sickinger (Leipzig University), who spoke about the ‘Ligand binding and trafficking of G protein coupled receptors (GPCRs)’. Her lecture outlined how important it is to understand how GPCRs recognise larger peptide ligands and, in the case of the peptide hormone neuropeptide Y, modelled the binding to its G-protein-coupled Y₂ receptor using a combination of NMR, molecular modelling, and double-cyclic mutagenesis studies.^10a The chemical modification of peptides, their subsequent mode of action and potential use as new therapeutics was also discussed.^10b The final part of the lecture concerned the use of peptide drug shuttles.^10c

The second speaker of the morning was Prof. Judith Klinman (University of California, Berkeley) with the session once again moderated by Prof. Helma Wennemers. Prof. Klinman delivered a fascinating talk combining physics, biology, and enzyme catalysis with the theme of cracking the code of enzyme catalysis. The mechanism of proton-coupled electron transfer C–H breaking enzymes was interrogated using a variety of tools revealing extremely large kinetic isotope effects (KIE).^11a,b This was the result of tunnelling based on very close proximity between the iron hydroxo unit and the C–H of the substrate. Prof. Klinman also described how the overall structure of the enzyme can influence the distance between the reacting sites and thereby increase or decrease the rate of reaction, as well as how energy (heat) is transferred from the solvent to the active site.^11c The results presented generated a very lively discussion session.

The Wednesday afternoon was left free for the attendees to enjoy some social activities. As promised, Prof. Meijer had delivered excellent weather by this point, with clear blue skies and sunshine as far as the eye could see! As such, many of the conference delegates chose to make the most of the fantastic weather and explore the surrounding area of Brunnen by hiking or taking a cruise along Lake Lucerne. Upon return and following dinner, the attendees were treated to a delightful piano concert delivered by the extremely talented Tatjana Živanović-Wegel.

Thursday was the final day of the conference and began with a lecture from Prof. Hiroyuki Isobe (Tohoku University), with Prof. Suzanne Blum chairing the session. Prof. Isobe gave an excellent talk concerning the synthesis, structure, and dynamics of carbonaceous supramolecular systems. The highlight of the talk detailed the synthesis of so-called ‘pea-pod’ bearings, which consist of a finite single-wall carbon nanotube with a fullerene molecule held within the bearing by van der Waals interactions.^12a Various spectroscopic and computational techniques were then used to probe the dynamics of the guest fullerene molecule within the host.^12b,c

The second of the morning's lectures was provided by Prof. Michinori Suginome (Kyoto University), who delved into the area of synthetic helical polymers and their application to enantioselective synthesis.^13a Prof. Suginome presented multiple examples (both published and unpublished) of how either manipulation of the backbone of poly(quinoxaline-2,3-diyl)s or the reaction media can result in pure left- or right-handed polymer-based helices that can be used as ligands for asymmetric synthesis.^13b,c It was remarkable that the chirality of the helices (and hence the products) could be switched by the effects of heating, solvent, or pressure.^13d The asymmetric induction bestowed by these polymers could also be amplified by the majority rule effect delivering some incredibly effective catalysts for a number of synthetic applications.

Since the beautiful weather had continued to Thursday, mid-morning coffee and lunch were moved outside to the shoreline of Lake Lucerne. The break also allowed the attendees one final afternoon of exploration of the surrounding areas by either hiking or boat trips on the lake.

After dinner, the final lecture of the conference was delivered by Prof. Stuart Schreiber (Broad Institute/Harvard University), with Prof. Dirk Trauner (Ludwigs-Maximilians-Universität) acting as the moderator. Prof. Schreiber discussed how organic chemistry could be leveraged to allow the rapid production of structurally diverse compound libraries for medicinal chemistry.^14a,b Prof. Schreiber demonstrated how diversity-oriented synthesis strategies based on novel chemistries enable access to novel pharmacophoric space and that this could lead to the identification of new mechanisms of action against challenging biological targets with a discussion of case studies of this approach in the context of microbial and cancer drug research.^14c,d

The conference was brought to a close on the Thursday evening, with final remarks from Prof. Jérôme Lacour and Prof. Helma Wennemers of the organising committee. Gifts were presented to President Paul Knochel (Kirsch and wine), followed by a short speech from President Elect Prof. E. W. (Bert) Meijer. At this point the honour of being the 2017 Conference Vice President (President Elect 2018) was passed to Prof. Ilan Marek, whilst Prof. Cristina Nevado (University of Zürich) was introduced as a member of the 2017 organising committee. These last words were followed by a final social mixer where now new friends and colleagues were able to enjoy a final evening together before departing on the Friday morning.

A. J. B. W and J. R. F. would like to thank the organising committee for Junior Scientist Programme (JSP) Fellowships.

Notes and references

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11. (a) M. P. Meyer and J. P. Klinman, J. Am. Chem. Soc., 2011, 133, 430; (b) L. M. Mirica, K. P. McCusker, J. W. Munos, H. W. Liu and J. P. Klinman, J. Am. Chem. Soc., 2008, 130, 8122; (c) J. P. Klinman and A. Kohen, Annu. Rev. Biochem., 2013, 82, 471.
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