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Stereochemistry in All Its Shapes and Forms: The 56 th Bürgenstock Conference

2023; Wiley; Volume: 62; Issue: 39 Linguagem: Inglês

10.1002/anie.202309468

1521-3773

Adrián Gómez‐Suárez, Constanze N. Neumann,

Asymmetric Hydrogenation and Catalysis

Acknowledging the crucial role of stereochemistry in fields as diverse as total synthesis, synthetic methodology, spectroscopy, and the study of the origin of life, the 56th SCS Conference on Stereochemistry, better known as the Bürgenstock Conference, brought together a diverse range of chemistry expertise in Brunnen, Switzerland. The 56th Bürgenstock conference under the presidency of Alois Fürstner (Max-Planck-Institut für Kohlenforschung) brought together more than a hundred scientists from around the world at Brunnen, Switzerland, for five days of spirited scientific exchange. Not only the high caliber of all contributions, extensive discussion following each presentation, and thoughtful intermixing of junior and senior attendees from industry and academia, but also the splendid venue overlooking Lake Lucerne, gives the meeting its unique and memorable character. One of the many tasks of the president and the organizing committee members, Fabrice Gallou, Cristina Nevado, Francesca Paradisi, Maud Reiter, Thomas Ward, and Jérôme Waser, was to safeguard the numerous traditions of the conference. At the Bürgenstock each scientist may only speak once in their life,1 the list of speakers and participants is kept secret until the start of the conference, and all participants stay for the entire duration of the conference. One additional highlight was provided this year by Andreas Pfaltz (University of Basel), the guest of honor of the current president and a former Bürgenstock president himself, celebrating his birthday at the meeting. Following the welcome address by Alois Fürstner, the conference began with an evening lecture by Tanja Gaich (University of Konstanz). She discussed the total synthesis of cantaxpropellane, a natural product with a complex taxane core that includes three additional transannular C−C bonds (Figure 1).1 After a detailed explanation of the successful route her team had developed, she delved into key lessons they learned along the way, such as the notable influence of both the protecting group strategy and the configuration of different chiral centers on the conformation of the polycyclic synthetic intermediates. Throughout her talk, she stressed the importance of controlling the conformation to ensure the success and desired stereochemical outcome of transformations involving complex ring systems, as well as the necessity to draw the molecule of interest from different angles to identify new potential disconnections. Gaich also showed excerpts of her recent work on a deconvolution approach to total synthesis that furnishes rapid access to different taxane natural products via strategic fragmentations of transannular C−C bonds in a synthetic precursor to cantaxpropellane.1b, 2 Contributions relating to total synthesis.1a, 3b, 5 Another fascinating contribution on total synthesis was provided by Ryan Shenvi (The Scripps Research Institute). The talk detailed how subtle changes to the structure of Salvatorin A could yield compounds that retain high potency for κ-opioid receptor agonism, but are easier to assemble and more stable against epimerization than Salvatorin A itself (Figure 1).3 In a highly interactive lecture, Shenvi linked chess strategy to strategic approaches used in total synthesis. He questioned whether the chemistry community could better deliver on the promise of natural product total synthesis—as a means of accessing “properties” rather than “structures”—by viewing the target not as a single molecule but rather as a continuum, or an interesting area of chemical space.4 In this interpretation, the preparation of the natural product is not a necessary pre-condition to the synthesis of analogues, which may be more synthetically accessible, and thus permit a more rapid sampling of the chemical space of interest.3c, 6 Shenvi also discussed an extremely rapid entry into the chemical space of the Galbulimima alkaloids via the assembly of flat building blocks, followed by stereoselective reduction. Racemic syntheses of the alkaloids himgaline and GB22 could thus be achieved in 7–9 steps and 6–8 steps, respectively.7 Margaret Faul (Amgen Inc.) highlighted some of the changes experienced in process chemistry during the last couple of decades, such as the increase in the complexity of drug candidates (Figure 1), and the speed at which they need to be delivered to the clinic or the market. Time constraints were further exacerbated during the recent global pandemic. Quick development of new pharmaceuticals and their large-scale production for clinical trials and market distribution became crucial to reduce the pandemic's impact and save countless lives. Faul stressed how the increased complexity of drug candidates has compelled process chemists to design new and more efficient routes to access key intermediates. She also highlighted that this can lead to the development of more robust, scalable, sustainable, and faster synthetic routes for the preparation of drug substances.5 Providing a wealth of historical context,8 Ryan Gilmour (University of Münster) illustrated how both Switzerland and stereochemistry, traditionally the central topic of the Bürgenstock conference, have shaped his current research program on contra-thermodynamic alkene isomerization. Whereas approaches to selectively obtain the E- or Z-isomer of an alkene are highly dependent on the transformation used to forge the C=C bond, his team has demonstrated that E to Z isomerization can be generalized over a range of olefins carrying different substitution patterns using cheap photosensitizers and operationally simple procedures.9 Suitable substrates carry substituents that extend the π-system more effectively for the E than the Z isomer. As a result, a deconjugation-induced change in photophysical signatures serves as basis for directionality in the isomerization.10 Notably, Gilmour and co-workers achieved the contra-thermodynamic isomerization of β-boryl acrylates and fluoro-acrylates without aryl substituents.11 In this case, nO to pB donation in the product leads to chromophore bifurcation and enables B-based stereoelectronic gating (Figure 2). The ability to readily invert the geometry of double bonds increasingly enables preparation of the thermodynamic isomers of alkenes followed by late-stage isomerization to serve as a general strategy for the stereodivergent preparation of multiple isomers of a target molecule from the same building blocks.12 Contributions relating to novel synthetic methods.11a, 16, 17b, 19, 24b Tim Donohoe (University of Oxford) highlighted how the C6Me5 (Ph*) auxiliary, popularized by his research group, can bring order to crossed aldol reactions (Figure 2).13 In an effort to extend the scope of hydrogen-borrowing α-alkylation of aromatic ketones,14 Donohoe and co-workers realized that Ph*CO enables the use of secondary alcohol coupling partners.15 Additionally, Ph*CO protects the carbonyl substituent from undesired reduction or nucleophilic attack,16 resulting in crystalline reaction products, which facilitates enantio-differentiating recrystallization,17 and grants access to various carbonyl derivatives via retro-Friedel–Crafts acylation.18 Furthermore, Donohoe discussed how the Ph* auxiliary enables an uncommon [5+1] disconnection of cyclohexanes,19 which can be assembled from Ph*COMe and a 1,5-diol via iridium-catalyzed hydrogen borrowing catalysis. A related transformation of diols and primary amines yields piperidines.20 Determining where on the cyclohexane ring stereochemical information could be retained or introduced (Figure 2) permitted the development of a catalytic asymmetric variant where a chiral diphosphine ligand controls the facial selectivity of enone reduction by Ir−H.17b, 19, 21 Donohoe emphasized that stress-testing their synthetic methodology in target-oriented synthesis endeavors is the modus operandi in his group,22 as shown by the use of hydrogen borrowing alkylation in the total synthesis of (−)-γ-lycorane.23 Contrary to a standard dictum in organic chemistry that NaH functions as a base rather than as a nucleophile, Shunsuke Chiba (Nanyang Technological University) presented several transformations that his team had developed in which NaH serves as a hydride nucleophile in the reduction of polar π electrophiles.24 Through simple solvothermal treatment of NaH with LiI or NaI in THF, NaH becomes capable of acting as a hydride donor towards nitriles, amides, and imines (Figure 2).24b While hydride reduction of amides furnishes aldehydes or α-branched amines, nitriles yield alkanes through decyanation, which is proposed to proceed via hydride attack on the nitrile (ΔGǂcalc=13.3 kcal/mol for a single molecule of NaH), followed by concerted C−C bond cleavage and H-atom transfer with elimination of NaCN (ΔGǂcalc=4.6 kcal/mol, Figure 2).24b, 25 In addition to the work on NaH, Chiba also provided an overview of his group's use of potassium, magnesium, and zinc hydride species as both basic and nucleophilic reagents.26 Particularly striking is the conversion of 1-naphthylmetylamine into the 1,4-dihydronapthalene-1-carbonitrile, where KH facilitates the oxidation of a primary amine to a nitrile. Repeated β-hydride elimination from the potassium salt of the amide/imininyl anion was invoked to account for the formation of nitriles.27 Sukbok Chang (Korea Advanced Institute of Science and Technology & Institute for Basic Science) provided an overview of his group's nearly decade long exploration of the use of dioxazolones as amidating reagents in transition-metal-mediated C−N bond-forming reactions.28 Through a series of fundamental mechanistic studies, his group demonstrated that these nitrenoid precursors can react with transition metals either via inner- or outer-sphere pathways. They leveraged this finding to develop unique reactivity patterns (Figure 2). For example, the use of inner-sphere pathways led to the development of general and mild C−H amidation reactions, circumventing the use of hazardous acyl azide reagents,28 while the use of outer-sphere pathways enabled, for example, the synthesis of γ- or β-lactams.29 Didier Bourissou (University of Toulouse & CNRS) showcased how rational ligand design can promote challenging redox processes, such as the oxidative addition of AuI species into C(sp2)-halogen bonds. He explained how initial stoichiometric studies led to the discovery that AuI complexes bearing chelating phosphine ligands undergo oxidative addition with aryl iodides and bromides (Figure 2).30 Further studies on the influence of the ligand architectures on gold redox cycles enabled his team to develop a suite of AuI/AuIII catalytic reactions involving aryl halides.31 Some of the key advantages of these AuI/AuIII redox cycles are their mild reaction conditions and broad functional group tolerance. In addition, Bourissou also highlighted the potential applications of gold catalysis in the chemical industry. While the high price of gold is often viewed as a handicap for industrial applications, he pointed out that gold can be selectively recycled in high yields from complex transition-metal-containing mixtures, thus providing a good platform for the development of more sustainable chemical processes. Since time immemorial, humans have been fascinated by the question of how life started on Earth. Joseph Moran (Laboratory of Chemical Catalysis at ISIS, University of Strasbourg & CNRS) is trying to uncover the answer by unlocking the chemistry behind the prebiotic origin of life. His main hypothesis is that metabolic life originated from a self-organizing reaction network, driven into existence by a far-from-equilibrium environment, and catalyzed by naturally occurring minerals and metal ions. To support the “metabolism-first” hypothesis, his team focuses on identifying key far-from-equilibrium conditions and catalysts that could enable ancient, core metabolic processes to take place.32 At the Bürgenstock conference he presented some of his latest results in this area, such as the reductive amination of α-keto acids to form α-amino acids,33 and how hydrogen can drive parts of the reverse Krebs cycle under metal catalysis.34 One of the highlights of the latter project was the demonstration that the reaction can be catalyzed using powdered meteorites, thus closely resembling the catalysts available on a prebiotic Earth (Figure 3). Contributions pertaining to living organisms and their origin (portions of the Figure have been reproduced from Schwille et al.).34, 36, 38 Elucidating how fundamental biological processes operate can be incredibly difficult due to the intrinsic complexity of living organisms. Petra Schwille's (Max-Planck-Institut of Biochemistry) strategy to tackle this great challenge is to use a reductionist approach, reducing this complex system to its minimum (functional) expression to be able to study what is going on.35 Her team aims to build a minimal living organism, a synthetic cell, from scratch through this bottom-up approach. During her talk, she highlighted some of her group's latest results, including their studies on reproducing the underlying mechanism of cell division (Figure 3).36 Starting from the observation that every cell division begins with an increase in curvature, her team developed ways of positioning filaments (structural proteins) around spherical vesicles and induce vesicle indentation through filament contraction. Emily Balskus (Harvard University) introduced the audience to the vast and fascinating world of the human gut microbiome. Her unique research, at the interface of chemistry and microbiology, focuses on developing tools to better understand gut microbes and leveraging this knowledge to develop novel enzymatic reactions, manipulate microbial activity, or design new small-molecule inhibitors. In her talk, she highlighted her research on colibactin, a genotoxic metabolite believed to cause mutations that lead to colorectal cancer. Some notable examples were the discovery of an unusual amidase, which helped her team explain colibactin's DNA cross-linking activity,37 and the development of a series of boronic acid mimics of the biosynthetic precursor precolibactin (Figure 3). These mimics can prevent colibactin biosynthesis by potently inhibiting the colibactin-activating peptidase ClbP.38 Serena DeBeer (Max-Planck-Institute for Chemical Energy Conversion) detailed how her team used Fe Kβ X-ray emission (XES) spectroscopy to determine that the central atom in the nitrogenase enzyme active site, FeMoCo, is a fully deprotonated carbon atom (Figure 4).39a, 40 During the XES experiment, electrons are removed from the Fe 1s orbital, and the photons emitted when electrons from higher lying orbitals on Fe or its surrounding ligands (valence to core or VtC-XES) repopulate the Fe 1s orbital are observed.41 Based on their prior work on VtC-XES spectra of mono- and multi-nuclear iron complexes,42 DeBeer and co-workers could hone in on emission lines that are most sensitive to the identity of the ligands directly coordinated to iron,43 not only in FeMoco, but also in FeFeco and FeVco.44 They found that all nitrogenases, as well as the biosynthetic precursor to FeMoco, the Fe8S9 L-cluster,45 contain a μ6-carbide. She speculated that the presence of the μ6-carbide may imbue the nitrogenase cofactors with enhanced stability and enable the large changes in total oxidation state required for N2 reduction. Further illustrating the insight provided by modern spectroscopic techniques into (biological) catalysts,41 DeBeer detailed her team's use of phosphorus Kβ XES at the PINK tender X-ray beamline at BESSY II to detect structural changes in phosphate-containing biomolecules in aqueous solution (Figure 4).39b Contributions relating to spectroscopy and theoretical chemistry (portions of the Figure have been adapted from DeBeer et al. and Neese et al.).39 Frank Neese (Max-Planck-Institut für Kohlenforschung) delivered a thought-provoking discourse on the role of theory in general, and that of ORCA in particular, in chemical catalysis research.46 Developed and continuously improved by Neese and co-workers over the last three decades, ORCA is the second most used quantum chemistry package.47 It provides users access to multiple ab initio, DFT, and semi-empirical methods, including a natural orbital-based local coupled cluster method DLPNO-CCSD(T) developed by Neese and his team. The computational cost of DLPNO-CCSD(T) scales almost linearly with N, the number of atoms in a system, while it retains over 99.9 % of the accuracy of CCSD, for which computational cost scales with N7.48 Unlike DFT methods, correlated wavefunction-based methods are able to accurately treat extremely complex bonding situations. One such example is the triplet ground state of a bismutinidene recently reported by Cornella and Neese, for which a record zero-field splitting of 4500 cm−1 was determined that renders the molecule diamagnetic despite its triplet nature (Figure 4).39c Neese emphasized how the notion of “proving” a reaction mechanism using theory directly contravenes the approach to scientific research outlined by Sir Karl Popper. Instead, theory can serve to establish hypotheses for which falsification should be repeatedly attempted via experiments.46b, 49 In addition to 13 excellent talks from the plenary speakers, the conference also featured 10 short presentations from academic and industrial researchers. This year's selected speakers were: Rebecca Buller (Zurich University of Applied Sciences), Aurélien De la Torre (Institut de Chimie Moléculaire et des Matériaux d'Orsay CNRS & Paris-Saclay University), Jovana Milić (University of Fribourg), Ben Schumann (Francis Crick Institute, Imperial College London), Nicole Goodwin (GSK plc.), Alicia Casitas (University of Marburg), Laurence Grimaud (École normale supérieure—PSL), Loïc Roch (Atinary Technologies Inc.), Mario Waser (Johannes Kepler University Linz), and Zachary Wickens (University of Wisconsin-Madison). The final highlight of the conference was the concert organized by the president. The duo Nebiolo-Marenco delivered an energizing and passionate performance entitled “non solo tango”, captivating the audience with their program dedicated to the music of the great Tango composer Astor Piazzola. Just as the 56th Bürgenstock conference provided enlightening and enlivening content, forged and renewed connections between many (Figure 5), and ensured a fantastic forum for scientific discussions, the 57th Bürgenstock conference under the presidency of Erick Carreira (ETH Zürich) promises to be another highlight in the scientific calendar. President Alois Füstner with the Junior Scientists Participation (JSP) Fellows of the 56th Bürgenstock conference (photo copyright by Jeannette Meier-Kamer, Meier & Kamer GmbH). The authors are grateful to the President of the 56th Bürgenstock conference, Prof. Alois Fürstner, the organizing committee (Dr. Fabrice Gallou, Prof. Cristina Nevado, Prof. Francesca Paradisi, Dr. Maud Reiter, Prof. Thomas Ward, Prof. Jérôme Waser), and the sponsors of the Junior Scientists Participation (JSP) fellowships. Open Access funding enabled and organized by Projekt DEAL. The authors declare no conflict of interest.