ACS Publications Symposium: Catalysis for Organic Synthesis will be two days of in-person innovative, scientific exchange where attendees will also have the chance to present their own research in poster sessions and Lightning Talks. Check out the full program below!
Prof. Scott Miller, The Journal of Organic Chemistry; Prof. Marisa Kozlowski, Organic Letters; Prof. Paul Chirik, Organometallics; Dr. Kai Rossen, Organic Process Research & Development; Prof. Erick Carreira, Journal of the American Chemical Society; Daniel Kaiser (Moderator)
14:15- 14:45 CEST
Lightning Talks Session 1
14:45- 15:25 CEST
Keynote | Prof. Phil Baran
Dr. Richard A. Lerner Endowed Chair
Professor, Department of Chemistry
Scripps Research, United States
Talk Title: Simplifying Synthesis with Electricity
A Cornucopia of Catalytic Commitments to Drive the MSD Portfolio
Dr. Rebecca Ruck; Associate Editor, ACS Catalysis
Associate Vice President, Process R&D; MSD
At MSD, we aspire to be the premier research-intensive biopharmaceutical company where we use the power of leading-edge science to save and improve lives around the world. One example of this is in our relentless pursuit of best chemistry, which means finding the optimal way to prepare our medicines and vaccines so they are easily accessible to patients. The development and application of new enabling technologies is critical to the ideal preparation of our Active Pharmaceutical Ingredients. Chemo- and Biocatalysis represent longstanding capabilities for achieving our goals. This talk will include how we think about these investments and examples of recent utilization toward the MSD portfolio.
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Searching for Selective Catalytic Reactions in Complex Molecular Environments
Prof. Scott Miller; Editor-in-Chief, Journal of Organic Chemistry
Irénée du Pont Professor of Chemistry, Yale University, United States
This lecture will describe recent developments resulting from our efforts to develop catalysts for asymmetric reactions, in particular for the preparation of densely functionalized, stereochemically complex structures. Over time, our foci have been on enantioselectivity, site-selectivity and chemoselectivity. In much of our current work, we are studying issues of enantioselectivity as a prelude to the extrapolation of catalysis concepts to more complex molecular settings where multiple issues are presented in a singular substrate. Complex natural products, for example, will be presented as quintessentially complex scaffolds for catalytic modification. Mechanistic paradigms, and their associated ambiguities – especially in light of catalyst or substrate conformational dynamics – will figure strongly in the lecture. Moreover, our focus on peptide-based catalysts has facilitated analogies to enzymes. Finally, several interesting collaborations – often unanticipated by us –will be discussed.
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New photochemical methods in halogen-atom transfer chemistry
Prof. Daniele Leonori
Chair of Organic Chemistry, URWTH Aachen University, Germany
The generation of carbon radicals by halogen-atom transfer (XAT) chemistry is one the most applied methods in synthetic radical chemistry.1 The broad availability of alkyl and aryl halides provides a large pool of commercial materials for divergent functionalizations.
These reactions have been generally approached using radicals able to form strong bonds with the halogen atom and of nucleophilic character to stabilize the transition state by charge-transfer. Tin and silicon species are the most used and versatile reagents to achieve this, despite their toxicity issues and often high cost.
In this presentation, I will discuss some recent work from my group aimed at developing novel photochemical approaches for carbon radical generation using XAT reactivity from highly nucleophilic carbon- and boron-based radicals.2
Catalysis with Earth Abundant Metals as an Enabling Tool for Chemical Synthesis
Prof. Paul Chirik; Editor in Chief, Organometallics
Edwards S Sanford Professor, Princeton University, United States
Transition metal catalysis has revolutionized chemical synthesis. Reactions such as metal-catalyzed cross coupling, asymmetric hydrogenation and C–H functionaliza-tion have changed the way chemists approach bond constructions and ultimately expand molecular space. Our group has been studying catalytic transformations with earth-abudnant, first row transition metals that exploit the unique electronic struc-tures available to these elements that provide new reactivity or selectivity. My lecture will focus on the ability of these catalysts to solve important challenges in organic chemistry, especially new reactions that find application in drug synthesis. Trans-formations of interest include site-selective C–H functionalization that is governed by the ability of the metal catalyst to engage in kinetically or thermodynamically con-trolled oxidative addition reactions. Other efforts are directed toward methods to increase three dimensionality in drug molecules. Transformations such as C(sp2)–C(sp3) Suzuki-Miyaura cross coupling and hetero(arene) hydrogenation are of particular interest. The role of electronic structure and the mechanisms of these transformations will be highlighted throughout.
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Simplifying Synthesis with Electricity
Prof. Phil Baran
Dr. Richard A. Lerner Endowed Chair
Professor, Department of Chemistry; Scripps Research
Organic synthesis is one of the great branches of Chemistry that has had a profound impact on the betterment and advancement of civilization. In its most modern manifestations, it renders the dream of alchemy (turning something worthless into something valuable) a reality. It places the practitioner into the role of artist, engineer, and astronaut. Thus, advances in this field are inherently of interest to a broad audience. Predicting the specific developments that will alter the course of this field is difficult. This talk will use case-studies from our lab to demonstrate how one of the oldest and least expensive reagents on Earth, electrons, can facilitate new retrosynthetic disconnections and aid in the pursuit of simple, ideal solutions to longstanding challenges.
References:
Gao, Y; Zhang, B; He, J; Baran, P. S. Ni-Electrocatalytic Enantioselective Doubly Decarboxylative C(sp3)–C(sp3) Cross Coupling. J. Am. Chem. Soc.2023, 145, 21, 11518-11523
Laudadio, G.; Palkowitz, M. D.; Ewing, T. E.-H.; Baran, P. S. Decarboxylative Cross-Coupling: A Radical Tool In Medicinal Chemistry. ACS Med. Chem. Lett.2022, 13, 9, 1413 – 1420
Hayashi, K.; Griffin, J.; Harper, K. C.; Kawamata, Y.; Baran, P. S. Chemoselective, Metal-free, (Hetero) Arene Electroreduction Enabled by Rapid Alternating Polarity. J. Am. Chem. Soc.2022, 144, 13, 5762 – 5768
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Unlocking The Photocatalytic Functionalities Of Polycyclic Heteroaromatics Through Oxidation Reactions
Prof. Davide Bonifazi, Chair Professor in Organic Chemistry
University of Vienna, Austria
Tailoring chromophores for catalytic applications represents a growing frontier in molecular engineering. Among the various contenders, polycyclic aromatic hydrocarbons, distinguished by their modifiable HOMO-LUMO gaps and excited state properties, emerge as exceptionally promising candidates. This is particularly evident in the realm of developing organic-based photocatalysts, with a special focus on applications in solar energy fuel production and organic transformations.
In the pursuit of heightened performance, a pivotal emphasis is placed on the controlled and meticulous substitution of carbon atoms with isostructural elements. This presentation will delve into how the distinctive electronic structures and adjustable π-conjugation of these chromophores can be effectively leveraged for example through chemical oxidations. The aim is to enhance their photoredox properties and broad their catalytic activity. Using concrete examples, we will explore the intriguing question of whether and how we can predictably tailor these properties. We will scrutinize the potential applications of these customized chromophores as versatile photocatalysts triggering new bonds formation for engineering selected functional chemical structures.
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New Strategies and Tactics in Natural Products Synthesis
Prof. Erick Carreira, Editor-in-Chief, Journal of American Chemical Society; Editorial Advisory Board, Journal of Organic Chemistry and Organic Letters
ETH Zurich, Switzerland
The presentation will include discussion and analysis of recent natural product targets that have been synthesized in the group. It will focus on target-oriented synthesis as an engine for the generation of novel methods and approaches to bioactive agents. The methods involve novel, unexpected reactivity and unusual building blocks that are fully integrated to lead to efficient routes. We will focus specifically two recently completed syntheses of (+)-Euphorikanin A and (+)-Pedrolide.
References:
Classen, M. J.; Kicin, B.; Ruf, V. A. P.; Hamminger, A; Ribadeau-Dumas, L.; Amberg, W. M.; and Carreira, E. M. Total Synthesis of (+)-Euphorikanin A via an Atropospecific Cascade J. Am. Chem. Soc.2023doi: 10.1021/jacs.3c11000
Bulthaupt, H.; Glatz, F.; Papidocha, S. Wu, C.; Teh, S.; Wolfrum, S.; Balazova, L; Wolfrum, C; Carreira, E. M. Enantioselective Total Syntheses of Cassane Furanoditerpenoids and their Stimulation of Cellular Respiration in Brown Adipocytes" J. Am. Chem. Soc. 2023, doi: 10.1021/jacs.3c07597
Papidocha, S. M., Bulthaupt, H.; and Carreira, E. M. Synthesis of Neocaesalpin A, AA, and Nominal Neocaesalpin K; Angew. Chem. Int. Ed., 2023, e202310149.
Fadel, M., Carreira, E. M. Enantioselective Total Synthesis of (+)-Pedrolide; J. Am. Chem. Soc.2023, 145, 8332-8337; doi: 10.1021/jacs.3c02113.
Classen, M.; Boecker, M.; Roth, R.; Amberg, W. M.; Carreira, E. M., Enantioselective Total Synthesis of (+)-Euphorikanin A J. Am. Chem. Soc.2021, 143, 8261-8265.
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Catalysis via Gold(I) Carbenes
Prof. Antonio Echavarren
Institute of Chemical Research of Catalonia (ICIQ), Spain
Gold(I) complexes are the most efficient catalysts for the electrophilic activation of alkynes in unsaturated substrates,1 although relatively few broad scope intermolecular reactions between alkynes with alkenes have been developed. In this context, we have reported that acetylene gas reacts with some alkenes in the presence of gold(I) catalysts to form (Z,Z)-1,3-dienes or biscyclopropanes.2 This biscyclopropanation reaction was applied to the first total synthesis of the sesquiterpene waitziacuminone.
We have recently developed a gold(I)-catalyzed intermolecular reaction between acetylene gas and readily available o-allylphenols for the synthesis of 3-vinylchromanes,3 which is an intermolecular variant of the well-known alkoxycyclization of 1,n-enynes.1 In this aryloxyvinylation reaction, the initial acetylene gold(I) complex is the electrophile that reacts with the alkene to form cyclopropyl gold(I)-carbene, which reacts regio- and stereoselectively with the phenol at C-3 of the allyl chain to form a 6-membered ring. This new reaction combines the use of common feedstock reagents such as acetylene gas and phenols with gold(I) catalysis to obtain scaffolds that are widely abundant in natural products and pharmacologically active compounds. Further work along these lines will be presented.
References:
(a) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028–9072. (b) Echavarren, A. M.; Muratore, M. N.; López-Carrillo, V.; Escribano-Cuesta, A.; Huguet, A.; Obradors, C. Org. React.2017, 92, 1–288.
Scharnagel, D.; Escofet, I.; Armengol-Relats, H.; De Orbe, M. E.; Korber, J. N.; Echavarren, A. M. Angew. Chem. Int. Ed. 2020, 59, 4888–4891.
Medina, T.; Sadurní, A.; Hammarback, L. A.; Echavarren, A. M. ACS Catal. 2023, 13, 10751–10755.
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Catalysis to increase complexity: stereoselective synthesis of sp3-rich building blocks
Prof. Mariola Tortosa; Associate Editor, Organic Letters
Autonomous University of Madrid, Spain
Organic Chemistry Department, Universidad Autónoma de Madrid Campus de Cantoblanco, Madrid 28049, Spain
Catalysis is at the core of modern chemistry and has become increasingly important for the pharmaceutical industry. Catalytic synthetic methods have the potential to greatly enhance the sustainability of pharmaceutical products, leading to shorter and more efficient synthetic routes and more direct access to single stereoisomeric products. As the pharmaceutical industry is shifting from compounds with a strong sp2 character to libraries of compounds with enlarged three-dimensionality, the need to develop catalytic methods to provide compounds with an increased sp3 character becomes apparent. In our group, we have recently focused on the development of catalytic enantioselective and stereospecific transformations for the preparation of sp3-rich building blocks, providing tools for stereodefined carbon-boron bond formation and selective carbon-nitrogen bond cleavage. These methods have allowed us to prepare a broad variety of useful synthetic intermediates, with special emphasis on the synthesis of functionalized small rings.1 Some of these transformations will be presented in this talk.
References:
Selected references: a) Teresa, J.; Velado, M.; Fernández de la Pradilla, R.; Viso, A.; Lozano, B.; Tortosa, M. Chem. Sci. 2023,14, 1575. (b) Nóvoa, L.; Trulli, L.; Parra, A.; Tortosa, M. Org. Lett. 2021, 23, 7434. (c) Nóvoa, L.; Trulli, L.; Parra, A.; Tortosa, M. Angew. Chem. Int. Ed. 2021, 60, 11763. (d) Amenós, L; Novoa, L.; Trulli, L.; Arroyo-Bondía, A.; Parra, A.; Tortosa, M., ACS Catal. 2019, 9, 6583-6587. (d) Amenós, L.; Trulli, L.; Nóvoa, L.; Parra, A.; Tortosa, M. Angew. Chem. Int. Ed. 2019, 58, 3188. (e) Guisan-Ceinos, M.; Martin-Heras V.; Tortosa M. J. Am. Chem. Soc. 2017, 139, 8448-8451.
Figure 1: Novel sp3-rich building blocks
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Asymmetric Peptide Catalysis – From Simple to Complex Environments
Helma Wennemers; EAB, Journal of Organic Chemistry; ETH Zurich, Switzerland
In nature, proteins fulfill manifold different functions and are crucial as, for example, enzymes or templates for the controlled formation of structural components such as bones. The Wennemers group is intrigued by the question of whether also peptides with significantly lower molecular weights than proteins can fulfill functions for which nature evolved large macromolecules. Specifically, we ask whether peptides can serve as effective asymmetric catalysts, synthetic collagen-based materials, or imaging and targeting vectors.
The lecture will focus on stereoselective peptide catalysts of the general type H-Pro-Pro-Xaa. These peptides allow for catalysis via an enamine intermediate with loadings of as little as 0.05–1 mol% and provide synthetically versatile products from aldol and conjugate addition reactions with high stereoselectivities. The lecture will discuss the scope of the peptide-catalyzed reactions and insights into the mechanism. We will show which structural and functional features distinguish the peptides from other chiral amine catalysts and highlight how changes in the conformational properties enable tuning of the catalytic activity, stereoselectivity, and chemoselectivity. In addition, the lecture will present peptide catalysis in complex environments (e.g. cell lysates) and cascade reactions with enzymes.
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Accelerating Advances in Catalysis – Concepts, Insights, Strategies
Prof. Franziska Schoenebeck; Associate Editor, Journal of the American Chemical Society; Editorial Advisory Board, Journal of Organic Chemistry and ACS Catalysis; RWTH Aachen University, Germany
Modern catalytic strategies frequently rely on substantial optimization and high throughput screening for the identification of optimal conditions. To reach the next frontier in the construction of molecules via automation and programmable synthetic approaches, novel and fully orthogonal catalysis regimes are imperative to enable synthetic manipulations in an orthogonal manner to established bond forming approaches and associated catalysis regimes. This talk will give insights and developments towards this goal from our laboratory. The focus will be on multinuclear metal catalysis [1,2], the exploration of organogermanes[3] as coupling partner as well as strategies to accelerate the identification of new catalysts.[4]
Peptide and Protein Catalysts with Enzyme-like Properties
Prof. Morten Meldal
2022 Chemistry Nobel Laureate; University of Copenhagen
Enzymes, in addition to conformational changes in the active site to lower the TS-barrier, facilitate reaction by high affinity to their substrates and increased binding to the transition state. We have combined the structural diversity of peptides with synthetic building blocks that allow formation of peptide carbenes and peptide phosphines for metal coordination. The resulting catalysts were investigated in a range of organic reactions as well as in peptide bond cleavage. The catalysts are suited for combinatorial screening for catalyst activity. Further development to rigidify the catalyst structure involved the virtual design of L/D-micro-proteins. This was achieved by establishing a preferred fold of random L/D-peptides of up to 50-60 amino acids and then funneling into an energy minimum by interactive mutational molecular dynamics. Once a stable protein structure was obtained, an active site cleft on the surface of the L/D-micro-protein was identified and active site residues corresponding to the four natural classes of proteolytic enzymes were introduced in this site, and stabilized by introduction of CuAAC-click bridges. The micro-proteins could be synthesized in high purity by Fmoc-based SPPS on PEGA resin using a range of non-canonical amino acids in addition to the natural ones, and they were screened in OBOC hepta-peptide FRET substrate libraries. Active substrate beads were isolated and the substrate specificity determined by sequence analysis by MS. The most active micro-protein proteases showed activities approaching that of the very active protease Subtilisin BNP. The use of stable micro-protein structures thus seemed to have a marked influence on catalysis and we are currently attempting to transfer this approach to enzymes for organic reactions.
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Metal- or metal-free? Complementarity towards the sustainable synthesis of complex molecules via C-H functionalization.
Prof. Joanna Wencel-Delord
Editorial Advisory Board, Organic Letters
University of Würzburg, Germany
Sustainable, rapid, and efficient synthesis of complex organic molecules is one of the key challenges of modern synthetic chemistry. Aiming for this goal, the design of original transformations converting simple substrates into the desired, more complex products via C-H bond functionalization has been attracting expanding attention of the scientific community.[1] Accordingly, a diversity of transformations, requiring either metal-based catalysts or alternative activation modes have been proposed. Herein, we would like to discuss our contribution to this field. We have developed various asymmetric C-H activation reactions to access rapidly atropisomeric molecules in high yields, using 3d metal-catalyzed enantioselective protocols.[2] Remarkably, 3d-metal catalyzed C-H activation established itself as a privileged approach to build up complex chiral molecules containing multiple chiral elements. In parallel, we have also discovered that rare, hypervalent bromine and chlorine reagents provide an alternative, metal-free solution to expand the molecular complexity via direct functionalization of a C-H bond.[3]
References:
T. Rogge, N. Kaplaneris, N. Chatani, J. Kim, S. Chang, B. Punji, L. L. Schafer, D. G. Musaev, J. Wencel-Delord, C. A. Roberts, R. Sarpong, Z. E. Wilson, M. A. Brimble, M. J. Johansson, L. Ackermann, Nat Rev Methods Primers 2021, 1, 43.
a) N. Jacob, Y. Zaid, J. C. A. Oliveira, L. Ackermann, J. Wencel-Delord, J. Am. Chem. Soc. 2022, 144, 798–806. b) A. Luc, J. C. A. Oliveira, P. Boos, N. Jacob, L. Ackermann, J. Wencel-Delord, Chem Catalysis 2023, 3, 100765.
a) M. Lanzi, Q. Dherbassy, J. Wencel‐Delord, Angew. Chem. Int. Ed. 2021, 60, 14852–14857. b) M. Lanzi, T. Rogge, T. S. Truong, K. N. Houk, J. Wencel-Delord, J. Am. Chem. Soc. 2023, 145, 345–358. c) M. De Abreu, T. Rogge, M. Lanzi, T. Saiegh, K. N. Houk, J. Wencel-Delord, Angew. Chem. Int. Ed. 2024, doi: 10.1002/anie.202319960
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Catalytic regulation of chemical reaction networks
Prof. Syuzanna Harutyunyan
Stratingh Institute for Chemistry, University of Groningen, Netherlands
The catalytic activity in living cells is often governed by a varying, non-linear and out-of-equilibrium environment. Metabolic pathways rely heavily on enzymes that catalyze individual reaction steps, commonly occurring in parallel, within complex, multicomponent chemical reaction networks. To ensure that the various transformations in cells proceed without unwanted interference from other reaction pathways, enzyme activity is spatially and temporally modulated through feedback loops and trigger-induced effects. In contrast, modern synthetic chemistry has insufficient spatiotemporal regulatory tools, primarily because for most of it’s history, chemistry has focused on the synthesis of thermodynamically stable systems and on man-made catalysts designed to work under stable conditions and concentrations. An autonomous mechanism that promotes different reactions at different points in time through temporal regulation of component concentrations and activities, will allow for construction of complex biomimetic chemical systems. In this talk I will present our recent results in feedback regulated (oscillating) catalysis aimed at developing autonomous time-controlled complex systems.