Highlights from the 54th EUCHEM Bürgenstock Conference on Stereochemistry, Brunnen, Switzerland, May 2019

During the last half century, each May the small town of Brunnen in the Swiss Canton of Schwyz has been transformed into a capital of European organic chemistry. Indeed, this picturesque village hosted, from the 5th to the 9th of May 2019, “the most secret and prestigious” conference in organic chemistry, the Bürgenstock conference. Although welcomed in the Swiss mountains by rain and snow, 120 participants discovered, when arriving on Sunday afternoon, with impatience and excitement, the top secret program of this mysterious conference and the list of participants.

The Bürgenstock conference is very different from any other meeting, and deeply steeped in tradition. The conference is limited to around 120 researchers and, most importantly, the speakers are not announced until the first day of the conference. This meeting which is held in the magnificent Seehotel Waldstätterhof, with a view of Lake Lucerne and the surrounding mountains, aims to bring together scientists from different fields of organic chemistry, from both academia and industry. The Bürgenstock conference is much more than sharing excellent science! It's also about encouraging and fostering the people-to-people contacts and discussions as all participants are hosted in the same hotel thus sharing several days together, from breakfast to a late evening glass of wine. All participants are also expected to attend for the duration of the entire conference. In contrast to rapid-fire short talks and multiple parallel sessions that are the favoured format of many meetings, the entire week comprised only thirteen carefully selected plenary lectures from researchers at the very peak of their careers. Of note is also that the regular participants of the Bürgenstock conference can rest assured that they will attend original lectures as even the most prominent researchers are invited only once in their career as speakers for this meeting. Each talk lasts for approximately sixty minutes and is supplemented by a thirty-minute discussion session during which a growing list is kept of participants who wish to ask questions. The nature of the questions varied greatly, from straightforward queries about approaches and methodology, through ideas for new applications and experiments, to conceptual questions that ask deep questions about where organic chemistry research will go in the future. A schedule that looked somewhat relaxed at the start of the week quickly revealed itself as an intense yet immensely satisfying programme of science.

The 54th edition of this famous conference was presided over by Professor Véronique Gouverneur FRS (University of Oxford), with Professor Janine Cossy (ESPCI-Paris) as Vice President, and was organised by a dedicated committee of leading scientists from Swiss academia and industry: Professor Christian Bochet, Dr Alain De Mesmaeker, Dr Fabrice Gallou, Professor Cristina Nevado, Professor Thomas Ward and Professor Jérôme Waser. As tradition dictates, fifteen young researchers had the privilege to attend this famous event as JSP Fellows, and we are very grateful to the organisers for generously awarding these fellowships.

The conference began with dinner and with a welcome address delivered by Professor Gouverneur from the balcony overlooking the ornate Fronaap-Saal, with high ceilings and large windows looking out across Lake Lucerne towards snow-topped mountains. Dr John Brown FRS, who was Véronique's mentor when she began her academic career, was introduced as the Guest of Honour. Véronique then continued to discuss the important heritage of the Bürgenstock meeting, highlighting the first ever meeting in 1965, which was presided over by Professor André S. Dreiding and featured many scientists who are now famous for their contributions to the areas of organic chemistry and biology; these include Vladimir Prelog ForMemRS (Nobel Prize in Chemistry, 1975), Jack Dunitz FRS, Stephen Mason FRS, Max Perutz FRS (Nobel Prize in Chemistry, 1962) and John Cornforth FRS (Nobel Prize in Chemistry, 1975). The opening session of the first meeting was moderated by Sir Derek Barton FRS (Nobel Prize in Chemistry, 1969).

The welcoming dinner was followed by the first scientific session on Sunday evening, chaired by Vice-President Professor Janine Cossy. The opening lecture was from Professor Hagan Bayley FRS (University of Oxford), who showed us amazing applications of electrochemistry for biochemistry. He described the use of protein nanopores (<10 nm in diameter) as tools for single molecule chemistry, sensing and DNA sequencing. These pores, constructed from Staphylococcal α-hemolysin, can be studied using electrochemical techniques; tiny changes in current on the order of picoamps, generated by the passage of ca. 6 million ions per second through the pore, allow insight into the events occurring within the pore. Applications include the detection of As^III complexes and the sequencing of DNA. In addition, DNA chains featuring disulfide-functionalised groups at one end can be used to create switchable molecular ‘hoppers’ that can walk up and down the inside of the pore. This “directional movement” can be switched and controlled by adjusting the voltage.¹ In this way, a new level of control can be achieved over the behaviour of single molecules on the nanometre scale. As well as surveying the range of science that his group has achieved with protein nanopores, Hagan gave an honest appraisal of their capabilities and limitations.

Following this first talk, the Monday sessions continued our exploration of various aspects of chemical biology, and were chaired by Professor Jean-Louis Reymond. Professor Peng Chen (Peking University) presented research towards controlling chemical reactions that occur within living cells. This is achieved by conducting chemical reactions on and within proteins within the cell. For example, chemical reactions were used to enable the switching on of fluorescence by removing allyl or propargyl groups. Most excitingly, Peng showed a new approach to elucidate the active sites of enzymes. This unique strategy uses reversible incorporation of an amino acid to block the active site of an enzyme and the subsequent removal of such a blocking group revealing the active site.²

Professor Dario Neri (ETH Zurich) delivered a presentation on the use small organic molecules isolated from DNA-encoded chemical libraries for medicinal chemistry. In such systems the binding groups, i.e. ligands, are attached to coded DNA strands, with applications in various fields from imaging to the delivery of ‘armed’ antibodies and cytokines in vivo.³

After the first of many two course lunches, the afternoon session took place, chaired by Professor Francesca Paradisi (University of Bern). Professor Yasutero Urano (University of Tokyo) presented his work on the use of fluorogenic probes for the detection of analytes in living cells. These molecules, based on Rhodamine structures, can undergo spirocyclisation to quench fluorescence; this can be triggered in a variety of ways, including by demethylation, allowing for in vivo imaging. ‘Blinking’ fluorophores were developed that allow super-resolution imaging techniques to be applied.⁴

While these initial sessions were very much in the field of chemical biology, the work discussed therein relies very much upon the application of organic chemistry and spoke to the breadth of work that this valuable discipline enables.

The late afternoon was dedicated to the first of two poster sessions. First, five poster presenters were selected for short (8 minute) presentations as an ‘appetizer’ to the poster session itself: Dr Josep Cornella (MPI for Kohlenforschung), Professor Todd Hyster (Princeton University), Professor Jeremy Luterbacher (EPFL), Dr Elena Pazos (University of A Coruña) and Dr Joanna Wencel-Delord (Université de Strasbourg). Poster topics included the use of bismuth in catalysis, the development of radical reactions within enzyme active sites, the processing of lignin as a fine chemicals feedstock, peptides as tools for biomedicine and atroposelective C–H activation reactions. During the following poster session twenty-two posters were presented by both early career and established researchers resulting in stimulating discussions about many different fields of chemistry.

The evening session, chaired by Professor Edward Anderson (University of Oxford), marked a clear change of the topics and the following presentations were rather focused on organic synthetic chemistry. The presentation in this session was delivered by Professor Eric Jacobsen (Harvard) who spoke on the topic of enantioselective catalysis with a focus on understanding and developing ‘privileged chiral catalysts’ with widespread applications in organic synthesis.⁵ Eric shared a variety of work, developed over the last few years, concerning applications of hydrogen bonding interactions between an organocatalyst and the substrate to promote challenging transformations such as enantioselective nucleophilic substitution reactions and glycosylations. Elegant synthetic chemistry was complemented and rationalised by detailed and well thought-out mechanistic and kinetic studies. The examples discussed included one reaction where astute observations by a postdoctoral fellow led to the identification of far more effective reaction conditions, showing synergy between synthetic and physical organic chemistry. This intense scientific day finished with a glass of wine and more informal discussions.

Tuesday morning brought some of the very best chemistry from the UK, with the scientific session chaired by Dr Joëlle Prunet (University of Glasgow). Professor Jonathan Clayden (University of Bristol), led us through a portfolio of work to understand and exploit long range chirality in a number of settings, targeting synthesis of molecular communication devices able to transfer information to a remote site, thus mimicking biological functions. Peptides comprised of primarily achiral amino acids, such as 2-aminoisobutyric acid, adopted conformations that were dictated by one chiral amino acid at the terminus. A variety of creative techniques, including ¹³C NMR spectroscopy of selectively-labelled peptides, were used to characterise these systems and quantify their degree of helicity. The structures of these peptides could be varied to introduce tendril perversions and thus control supramolecular architecture. These peptide systems were further developed to enable enantioselective chemistry at the non-chiral terminus,⁶ and to build systems that embed themselves in membranes. The incorporation of pyrene groups at the non-chiral terminus allowed binding events at the other terminus to trigger the switching on and switching off of fluorescence.⁷ In addition, Jonathan discussed recent work on enantioselective rearrangements that allow the synthesis of chiral aryl- and vinyl-substituted amino acids via intramolecular S_NAr reactions.

This was followed by a tour de force of synthetic organic chemistry from Professor Darren Dixon (University of Oxford), in which total synthesis endeavours inspired the development of new synthetic methods, which in turn allowed new targets to be completed successfully. Starting from his group's work on manzamine A, Darren talked us through the development of an iridium-catalysed reduction of amides to enamines, which was then exploited in various other transformations.^8,9 We also heard about the development of chiral hydrogen-bonding bifunctional iminophosphorane (“BIMP”) superbase organocatalysts for enantioselective nitro-Mannich reactions¹⁰ and their elegant application in the key Diels–Alder step of the total synthesis of (−)-himalensine A.¹¹

No scientific sessions were scheduled for Tuesday afternoon and delegates embarked on various activities. Bürgenstock tradition dictates that the Vice President of the conference is responsible for the weather; Professor Cossy did not disappoint us and we all enjoyed great sun and snow on the surrounding mountains! Several of us elected to take a boat to Trieb, ascend the mountain the funicular railway and walk down to Rütli, the birthplace of Switzerland.

In the evening, we were treated to a concert by a group of talented musicians playing the accordion, the seven-string guitar and percussion. Pierre Gillet, Benoît Minon, Thibault Dille and Marcos Della Rocha entertained us with a selection of numbers in the bossa nova musical style, which is a fusion of samba and jazz, before the conference retired to the bar.

The scientific sessions began again in earnest on Wednesday morning, chaired by Professor Christof Sparr (University of Basel), starting with Professor Tobias Ritter (Max-Planck Institute for Kohlenforschung). Tobias delivered an outstanding talk on the broad topic of ‘late stage functionalisation’, starting with his work to develop effective and rapid ¹⁸F labelling for PET imaging.¹² The presentation culminated in the discussion of a general method for site-selective C–H functionalisation that can then be used to achieve an impressive range of subsequent synthetic chemistry. Catalytic quantities of 2,3,7,8-tetrafluorothianthrene in acidic media, with stoichiometric 2,3,7,8-tetrafluorothianthrene-5-oxide enable exquisitely para-selective C–H functionalization reactions.¹² The resulting tetrafluorothianthrenium products can be diversified to produce an impressive variety of products.

Professor Paolo Melchiorre (ICIQ) covered a range of synthetic chemistry enabled by dual catalytic systems combining photocatalysis and organocatalysis. The intermediates in many of the organocatalytic reactions can form photosensitive electron donor–acceptor complexes; light irradiation then allows access to exciting new reaction pathways and mechanisms. Many of these reactions are true catalytic cycles, as established by quantum yield measurements (ϕ ≫ 1). Paolo shared a range of research from his group, including the design of new organocatalysts that enable reactions to be performed with high yields and excellent enantioselectivities. The reactions that were discussed included selective 1,4-additions to cyclic and acyclic α,β-unsaturated aldehydes and ketones¹³ and the addition of benzyl groups and boron-containing groups to alkenes.¹⁴

After lunch, Professor Abigail Doyle (Princeton University) shared some of her work in nickel catalysis during a session chaired by Edward Anderson. The presentation covered two pieces of work around ligand design for nickel catalysis, focussing on the development of bespoke new ligands rather than relying upon ligands that are most commonly used in palladium catalysis. Alkenes functionalised with sulfonamide groups (such as the so-called Fro-DO ligand) are extremely effective for activating N-tosylaziridines towards cross-coupling (i.e. breaking rings…).¹⁵ A detailed and systematic mechanistic study using experimental and computational techniques showed that the efficacy of this ligand was due not only to d → π*_CC back bonding, but also relied upon energetically favourable interactions between the nickel centre and the sulfonamide group. The second topic was new phosphine ligands for aryl halide cross-coupling reactions. Two new ligands – named TriceraPhos and TyrannoPhos by Abby's son – were shown to be excellent for these cross-coupling reactions. Again, detailed analyses were used to understand the properties of these ligands and why they are most effective.

The second of the poster sessions, dedicated to twenty-one posters, took place on the Wednesday afternoon. A series of ‘appetizers’ were delivered by Professor Edward Anderson (University of Oxford), Professor Yimon Aye (EPFL), Professor Rene Koenigs (RWTH Aachen University), Professor Francesca Paradisi (University of Nottingham) and Professor Simon Duttwyler (Zhejiang University).

The final scientific session of the day was held after dinner and chaired by Professor Francesca Paradisi. Professor Marc Fontecave (College de France) presented his work on transforming CO₂ into valuable feedstocks such as ethene and ethanol.¹⁶ This exciting work culminated in a system that can achieve 2.3% efficiency in the light-driven conversion of CO₂ to ethanol.¹⁷

The final morning of the conference brought the last scientific session, chaired by Past President Professor Ilan Marek (Technion, Haifa). Professor Miguel Costas (IQCC Girona) discussed a wide range of iron- and manganese-catalysed oxidation reactions, beginning from early inspiration from biological systems and working towards synthetic reactions using highly active and carefully designed systems. Reactions included epoxidation, hydroxylation and dihydroxylation. The use of metal complexes that had ligands functionalised with crown ether groups allowed for the position-selective, distal oxidation of alkylammonium species as a result of cation binding to these groups.¹⁸ The synthetic applications of the work were complemented by detailed spectroscopic and mechanistic studies to identify and characterise the active catalysts.

Finally, Professor Shannon Stahl (University of Utah) shared his work on oxidation reactions using molecular oxygen, from reactions for synthetic organic chemistry to larger scale oxygen reduction reactions that could one day play a role in fuel cells that are driven by hydrogen.¹⁹ Shannon commented that he rarely travels to Europe, but that he could not turn down the opportunity to contribute to the Bürgenstock conference! Shannon discussed reactions including the oxidation of alcohols catalysed by palladium and copper, with a detailed focus on the underlying reaction mechanisms. Many of these reactions are very straightforward to execute²⁰ and several modifications to the reaction conditions were discussed that render this chemistry suitable for industrial applications, taking into account the safety hazards that oxygen presents.²¹

The conference was brought to a close as the hard work of the President, organising committee and assistants was acknowledged and the entire conference expressed their gratitude. It was announced that the next President will, of course, be Professor Janine Cossy and that the 2021 President (and 2020 Vice President) will be Professor Alois Fürstner (Max Planck Institute for Kohlenforschung).

The conference was excellent from start to finish. We are very grateful to the speakers for sharing their scientific results and insights during the week and to all of the participants for contributing questions and comments that further enriched the scientific discussion. Special thanks must also be addressed to the President of this meeting and the whole organisation committee; thanks to their remarkable work and organisation this conference will certainly remain an unforgettable memory for all participants. The Bürgenstock conference is certainly a unique occasion to meet the most prominent researchers and to discuss science, not only during the presentation sessions, but also in less formal settings.

DJN and JWD thank the organising committee for JSP Fellowships to attend this prestigious event and hope to return to this famous conference on the banks of Lake Lucerne in the future.

References

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