Synthetic Chemistry Innovations

As Editor-in-Chief of Organic Process R&D I am excited to share a recent post from Qiang Yang and the scientists at Eli Lilly who scaled up a Negishi cross-coupling that enabled delivery of 36.6 kg of a key indole intermediate to support the synthesis of Orforglipron a novel non-peptide GLP-1 receptor agonist. To address scalability and efficiency, they developed an enantioselective Evans auxiliary-assisted 1,4-addition route was developed, eliminating the need for non-scalable chromatographic purification. This paper, part 1 of a 3-part series for this synthesis, not only established a robust foundation for large-scale manufacturing but also highlights the critical role of process innovation in accelerating clinical development. #ACS #OPRD #processchemistry Matt Saucier

Plants have been making fuel from sunlight for 500 million years. China just figured out how to copy them. A team at the Chinese Academy of Sciences built a system that takes CO₂ and water, hits it with sunlight, and produces the building blocks of synthetic gasoline. No oil wells. No drilling. No fossil carbon. Think about that. The secret was a "charge reservoir" — a material made from tungsten trioxide and tiny amounts of silver that traps solar energy like a battery and releases it precisely when needed. Previous systems failed because electrical charges disappeared instantly. This one stores them. The result: carbon monoxide — the industrial starting point for synthetic gasoline and jet fuel — at roughly 100 times the efficiency of previous catalysts. Water is the only ingredient consumed. Zero sacrificial chemicals. What stopped me: It works with existing engines. Existing pipelines. Existing infrastructure. No reinvention needed. The Multiplication Effect: 1 system proving the concept = validation that photosynthesis can be copied 10 systems producing fuel = regional energy without drilling 100 systems deployed = countries producing synthetic fuel from sunlight At scale = energy independence from fossil carbon For a century, we've drilled into the Earth for energy. This system pulls it directly from the sky. We've spent decades asking how to extract more efficiently. Maybe the better question was always: how do we copy what already works? ♻️ Follow me, Dr. Martha Boeckenfeld for innovations that reshape how we power the future. Share if you believe the next energy revolution will come from biology, not geology. 📚 Source: Chinese Academy of Sciences | Yu Huang et al. | Nature Communications, March 2026 | ECOticias — Adrian Villellas

Nature Chemical Biology paper (1 Jun 26) describes the first fully de novo discovery pipeline for membrane-permeable macrocyclic peptides targeting an intracellular protein-protein interaction (PPI), starting with zero prior structural knowledge. 🔅 The team chose Keap1-Nrf2 deliberately. Keap1 tags the transcription factor Nrf2 for proteasomal degradation; disrupting this interaction activates cytoprotective antioxidant gene expression, making it a target for oxidative stress, neurodegeneration, inflammation, and cancer. The interface spans ~650 Ų and relies on electrostatic contacts. Every known high-affinity inhibitor carries at least one negative charge, crippling membrane permeability and creating metabolic liabilities. A biologically validated, clinically relevant, and specifically resistant benchmark. 🔅 The team screened 15,360 fully random, uncharged cyclic peptides (600-800 Da) against the Keap1 Kelch domain by TR-FRET in 384-well plates, then ran three iterative design-build-test cycles to optimize both binding and permeability in parallel. The final lead, compound 30, achieved a Ki of 53 nM with only 2 hydrogen bond donors and a TPSA of 203 Ų, and showed dose-dependent activity in a Nrf2/ARE luciferase reporter assay. Crystal structure (PDB: 9QDU, 2.35 Å) confirmed compound 30 occupies the Nrf2-binding site on Keap1 but engages entirely through H-bond acceptors and hydrophobic contacts, with a backbone trajectory that has no spatial overlap with native Nrf2, confirming a truly de novo binding mode rather than a peptide mimic. The authors note that libraries of around 100K compounds will likely be needed to tackle more challenging targets with shallower or less well-defined binding pockets. 🔅 The paper also describes a covalent inhibitor branch. Exploiting Cys434 at approximately 8.8 Å from the peptide terminus, chloroacetamide compound 20-Cl achieved a kinact/Ki of 3,200 M-1 min-1, with intact MS confirming site-selective C434 modification on wild-type Keap1 but not the C434A mutant control. 🔅 The central remaining liability is active efflux. Compound 30 shows a Caco-2 apical-to-basal Papp below detection limit (less than 0.07 x 10-6 cm s-1), producing an approximately 1,000-fold in vitro-to-cell potency gap (53 nM Ki vs ~50 µM cellular IC50). Efflux pump susceptibility, not passive permeability, is the bottleneck for advancing this scaffold toward oral bioavailability. 🔅 Patent US20240279845A1 covers the core SPPS disulfide-cyclization and combinatorial diversification method used in this study. A patent directly tied to this paper has not yet surfaced. The group founded spin-off Orbis Medicines, which raised more than €90 million in Series A funding to advance oral macrocycle drugs (nCycles) against validated biologic pathways. 📑 Not Open Access: https://lnkd.in/g53Ufy5Y #MacrocyclicPeptides #DrugDiscovery

A labour of love 🧡 (and many hours in the labs, and many more writing up these results 😂), Marko Ivancevic’s first of a series of papers on the photophysics of organic molecules is out!👏🏻 https://lnkd.in/gMZQaRrx This paper details the discovery of a simple process to induce ultra-long (many seconds) phosphorescence 🌈 in a wide library of organic compounds at room temperature. Colloquially termed “afterglow”🌟 because the compounds continue to glow when the excitation light source🔦 is removed, this phenomenon – especially at room temperature – was thought to be exceedingly rare.😅 A handful of compounds were reported to exhibit afterglow when they are organized, and neatly and tightly packed in crystals.💎 Yet another handful were only reported to do so when they are isolated in an inactive, plastic matrix. How do we reconcile these observations?🤔 Is there a unifying framework that can help us understand and contextualise these observations?🤨 Enter Marko’s experiments.🧩 With more than 20 compounds, he showed that he can get them to exhibit afterglow when he disperses them in a non-interactive polymer matrix, and then heating them up to soften the polymer matrix.🌡️ This softening allows the compounds to diffuse and form small aggregates that activate afterglow. Why is this so cool?😎 Scientifically, quantifying this phenomenon has allowed Marko to develop a framework that bridges past observations with his findings.🌉 Turns out it’s all about creating structures that limit intramolecular motion and intermolecular exciton diffusion to minimise non-radiative recombination that give rise to afterglow.🪱 Technologically, this phenomenon can be leveraged for bioimaging.🩻 When phosphorescence extends beyond the initial excitation, it increases signal-to-noise, making detection much easier for physicians.🧑🏻⚕️ It can also be used for authentication and anticounterfeiting purposes as it adds a more sophisticated fingerprint.🐾 So stay tuned for the next few papers where Marko demonstrates he can 3D-print🖨️ structures in almost any form factor and create stable ink formations✒️ that glow for extended periods of time! Jesse Wisch, Quinn Burlingame, Barry Rand Princeton CBE, Princeton Engineering, Andlinger Center for Energy and the Environment, Wiley

🔬✨ A Historical Gap in Chemistry Finally Closed For over two centuries, calcium bicarbonate (Ca(HCO₃)₂) was a compound that existed only in theory. Despite its central role in the carbon cycle and its importance in biochemical processes, every attempt to isolate it as a pure crystalline material ended in failure. In a recent work published in the Journal of the American Chemical Society, researchers have now synthesised crystalline calcium bicarbonate for the very first time, filling what scientists call a “historical gap in textbooks.” This breakthrough not only resolves a long-standing structural mystery but also opens new avenues for studying carbon sequestration, biomineralisation, and environmental chemistry. 🌍 Why it matters: Carbon cycle clarity – Calcium bicarbonate is part of Earth’s largest carbon pool. Understanding its crystalline form could refine models of climate and geochemical processes. Materials science – Unlocking the structure of such elusive compounds may inspire new approaches in crystallography and mineral synthesis. Scientific perseverance – This achievement reminds us that even “simple” compounds can hold deep mysteries, waiting for the right tools and minds to solve them. 💡 Sometimes the most fundamental discoveries are the ones that reshape our understanding of the world. This is a reminder that science is as much about patience as it is about innovation. #chemistry #carboncycle #crystallography

🌍 𝗖𝗢₂ 𝘁𝗼 𝗖𝗹𝗲𝗮𝗻 𝗘𝗻𝗲𝗿𝗴𝘆: 𝗔 𝗠𝗮𝗻𝗴𝗮𝗻𝗲𝘀𝗲 𝗖𝗮𝘁𝗮𝗹𝘆𝘀𝘁 𝗕𝗿𝗲𝗮𝗸𝘁𝗵𝗿𝗼𝘂𝗴𝗵! 🔋♻️ What if a greenhouse gas could become a safe, efficient energy carrier? Researchers at Yale University and the University of Missouri (Mizzou) have taken a major step in that direction by developing a low-cost, ultra-durable manganese-based catalyst that converts CO₂ into formate - a promising solution for hydrogen storage and clean energy systems. 🔬 𝗪𝗵𝘆 𝘁𝗵𝗶𝘀 𝗯𝗿𝗲𝗮𝗸𝘁𝗵𝗿𝗼𝘂𝗴𝗵 𝗺𝗮𝘁𝘁𝗲𝗿𝘀: ✅ 𝗟𝗼𝘄-𝗖𝗼𝘀𝘁 & 𝗦𝘂𝘀𝘁𝗮𝗶𝗻𝗮𝗯𝗹𝗲: The new catalyst replaces rare, expensive, and often toxic precious metals with abundant manganese, making large-scale deployment far more realistic and environmentally friendly. ✅ 𝗘𝘅𝗰𝗲𝗽𝘁𝗶𝗼𝗻𝗮𝗹 𝗗𝘂𝗿𝗮𝗯𝗶𝗹𝗶𝘁𝘆: Thanks to an innovative ligand design, the catalyst shows significantly higher stability than earlier versions—one of the biggest hurdles in CO₂ conversion technologies. ✅ 𝗦𝗮𝗳𝗲𝗿 𝗛𝘆𝗱𝗿𝗼𝗴𝗲𝗻 𝗦𝘁𝗼𝗿𝗮𝗴𝗲: Formate can store more hydrogen per liter than compressed hydrogen gas, without the risks associated with high-pressure tanks or explosion hazards 🛡️. This makes it a strong candidate for fuel cells and future hydrogen infrastructure. 🌱 𝗧𝗵𝗲 𝗯𝗶𝗴𝗴𝗲𝗿 𝗽𝗶𝗰𝘁𝘂𝗿𝗲: By transforming CO₂ into a stable liquid energy carrier, this research directly supports the vision of a circular carbon economy - where carbon emissions are not just captured, but reused to power the clean energy transition. 🚀 Innovations like this highlight how green chemistry and climate tech can converge to deliver scalable, real-world impact - bridging the gap between sustainability goals and industrial feasibility. The future of clean energy may well lie in turning today’s emissions into tomorrow’s power. 𝗗𝗲𝘁𝗮𝗶𝗹𝘀 𝗮𝘁: https://lnkd.in/grQk8aUy #GreenChemistry #CleanEnergy #Sustainability #CarbonCapture #HydrogenFuel #ClimateTech #Innovation #CircularEconomy #YaleResearch #Mizzou #EnergyTransition

Today in Science Magazine, work from our IBM team, in collaboration with The University of Manchester, University of Oxford, ETH Zürich, EPFL and the University of Regensburg, shows the creation and simulation of a new molecule with an electronic structure that has never existed before — a half‑Möbius topology: https://lnkd.in/eFU5s9qR. The molecule was assembled using scanning probe microscopy at temperatures just above absolute zero — building it one atom at a time using STM, atom manipulation, and AFM. The electronic orbitals of this half‑Möbius molecule twist by 90 degrees with every loop around the ring, completing a full turn only after four revolutions. Why is this also important for quantum computing? This work demonstrates, for the first time, that quantum computing calculations can provide decisive scientific guidance and powerful characterization capabilities to support the discovery of new complex chemical molecules. In close collaboration with leading experimental laboratories, quantum simulations can now contribute directly to interpreting experimental observations and to guiding the design and understanding of novel molecular systems. The calculations performed in this project go well beyond the regime accessible to brute-force classical simulations, although we do not exclude the possibility that approximate classical methods could also provide valuable insights. Nevertheless, the discovery process itself benefited from quantum simulation, and we chose to employ quantum computing because it offers a natural and scalable framework for tackling problems of this kind. In particular, by comparing Dyson orbitals measured with scanning tunneling microscopy (STM) with images reconstructed from electronic structure calculations performed on a quantum computer using the SqDRIFT algorithm, we were able, for the first time, to contribute directly to the discovery and characterization of a new molecule exhibiting entirely novel electronic structure properties. paper: https://lnkd.in/esg9sHqV

🧬 Life Science Spotlight 💊 𝗔 𝗿𝗮𝗱𝗶𝗰𝗮𝗹 𝗳𝗹𝗶𝗽𝘀 𝗶𝘁𝘀 𝗰𝗼𝗻𝗳𝗶𝗴𝘂𝗿𝗮𝘁𝗶𝗼𝗻 𝗶𝗻 𝗽𝗶𝗰𝗼𝘀𝗲𝗰𝗼𝗻𝗱𝘀. 𝗖𝗮𝗻 𝘄𝗲 𝗰𝗮𝘁𝗰𝗵 𝗶𝘁 𝗳𝗮𝘀𝘁𝗲𝗿? Some problems in chemistry are so old that we stopped challenging them and accepted them as facts of life. A good example is the epimerization of a chiral centre upon formation of a radical. Take a single enantiomer, make a radical at the chiral centre (often a carbon atom), and within picoseconds the optical purity is gone, generating a 50:50 mixture of stereoisomers because the radical centre inverts almost freely. Till now, synthetic chemists built an arsenal of methods to work around it, quietly accepting the limitation. A new paper in Science from Phil Baran's group at Scripps Research, led by Yu Wang, Jiawei Sun and co-workers (with a contribution from Pfizer), set out to challenge it. 𝗪𝗵𝗮𝘁 𝗶𝘀 𝗻𝗲𝘄 They report a scalable, stereoretentive radical-radical cross-coupling of two distinct, transient alkyl radicals, one derived from an enantioenriched sulfonylhydrazide and the second from achiral primary and secondary alkyl halides, achieved without chiral ligands, directing groups, or exogenous redox agents. 𝗖𝗼𝗿𝗲 𝗶𝗱𝗲𝗮 🔸 Chirality is encoded in one precursor, an enantioenriched sulfonylhydrazide, not in a chiral catalyst 🔸 The radical is formed inside a solvent cage right next to nickel, which grabs it back before it can flip its configuration 🔸 This Ni(II) intermediate then undergoes cross-coupling 𝗛𝗶𝗴𝗵𝗹𝗶𝗴𝗵𝘁𝘀 ✅ Yields around 40 to 90%, enantiospecificity 80 to 96% ✅ Broad substrate scope, tolerates ethers, acetals, heterocycles, CF3, terminal olefins, free amines, coumarins, phthalimides ✅ Optically pure precursors cost around a dollar per gram 𝗠𝘆 𝗰𝗼𝗺𝗺𝗲𝗻𝘁𝘀 One point worth mentioning is that the method is stereoretentive, not enantioselective. It transfers chirality from an enantiopure precursor instead of creating it, so you still need that building block in hand. The chiral pool of amines and alcohols is, however, vast, so in most instances it shouldn't be an obstacle. Of note, this is not the first work to exploit the solvent cage effect. Another great study recently used the same phenomenon to control asymmetric geminate recasting, and you can read more about it in my older LinkedIn post. In summary, this research article presents a bona fide scientific story. And as it is coming from Baran's lab, I expect it to reproduce pretty well. Full blog article with the original paper linked, on my blog Life Science Spotlight, where I cover advances in drug discovery, chemical biology and synthetic chemistry: https://lnkd.in/gJ49V__3 🤔 𝗦𝗵𝗮𝗿𝗲 𝘆𝗼𝘂𝗿 𝘁𝗵𝗼𝘂𝗴𝗵𝘁𝘀 Would you reach for this in a medchem campaign, or would the need for an enantiopure hydrazide discourage you? And which sp3-rich targets would you redesign around it?

Glutarimide-based CRBN ligands are key building blocks for PROTACs, molecular glues, and CELMoDs. However, their synthesis is often slow and complex, limiting rapid optimization. Here, the authors from AstraZeneca describe a simple and modular organocatalytic platform that enables the rapid preparation of diverse glutarimides from readily available starting materials. The procedure is metal-free, selective, and easy to run, and it is suitable for both small- and large-scale synthesis. This procedure is suitable for the rapid generation of CRBN binder libraries, the preparation of control compounds, and late-stage modification of bioactive molecules. Overall, it simplifies access to important CRBN ligands and helps overcome long-standing synthetic challenges. https://lnkd.in/ecDH8ptv #CRBN #compoundlibraries #E3-ligase #organocatalysis #molecularglues #PROTAC #HTE #medchemistry

I’m thrilled to share our latest publication in Nature Machine Intelligence: “Advancing molecular machine learning representations with stereoelectronics-infused molecular graphs” (link to paper in the comments) Led by Ph.D. student Daniil Boiko, our work introduces stereoelectronics-infused molecular graphs (SIMGs), a novel molecular representation that explicitly incorporates stereoelectronic effects: stabilizing electronic interactions maximized by specific geometric arrangements through favorable orbital overlap. Traditional molecular representations (e.g., molecular graphs, fingerprints, SMILES strings) often overlook critical quantum-chemical details. SIMGs explicitly address this limitation by embedding orbital interactions, significantly enhancing molecular property predictions. For example, using SIMGs improved the prediction of HOMO-LUMO gaps substantially compared to traditional methods. Models trained on small molecules can accurately predict orbital interactions in much larger systems like proteins, achieving orders of magnitude speed improvement over traditional DFT+NBO calculations. Recognizing that directly computing these orbital interactions is computationally intensive, we developed SIMG*, a machine-learned approximation enabling rapid predictions. This methodology enables stereoelectronically enhanced analysis of macromolecular systems where traditional quantum-chemical calculations are computationally prohibitive, facilitating systematic investigation of stereoelectronic interactions governing protein stability and reactivity. To facilitate broader access, we’ve launched an interactive web application where researchers can easily explore stereoelectronic information in their molecules: https://simg.cheme.cmu.edu. This work exemplifies our group’s mission to revolutionize chemical discovery by integrating quantum chemistry, machine learning, and automation. At the Gomes group, we’re committed to developing intelligent systems that transform how we design molecules, materials, and reactions: from foundational representations like SIMGs to autonomous agents capable of planning and executing experiments. Our goal is to accelerate innovation across domains, from (bio-, organo-)catalysis to materials science. Great work by my trainees Daniil Boiko and Thiago Reschützegger, along with our collaborators + great friends, Benjamin Sanchez-Lengeling (University of Toronto, Google DeepMind) and co-corresponding author Samuel Blau (Lawrence Berkeley National Laboratory). #MachineLearning #QuantumChemistry #MolecularModeling #StereoelectronicEffects