SE4:E8: From Discovery to Process, Part 2: Getting Ugi with it - scaling a 3CL protease inhibitor

In Part 2 of our Pharm to Table deep dive on MK‑7845, Dani and LC shift from invention to implementation, welcoming process chemists Nastaran Salehi Marzijarani and Ben Turnbull to the pod. We explore how the team re‑imagined the synthesis to enable robust, scalable supply—and why a classic multicomponent reaction you probably remember from school, the Joullié–Ugi reaction, ended up stealing the show. Along the way, we unpack route selection trade‑offs, lifecycle thinking in process chemistry, and what it really takes to bring an antiviral to life at scale. Read and listen to some of the papers we discussed today:Asymmetric Synthesis of MK-7845, an Investigational Treatment for COVID-19 - Org. Lett.Part 1 of MK-7845 series: SE4:E7: From Discovery to Process, Part 1: Building a 3CL Protease Inhibitor Through Smart Fluorine Placement and Design IntuitionFollow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠Visit our website at ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table⁠⁠⁠⁠⁠⁠

In this first installment of our two‑part Pharm to Table special on MK‑7845, Dani and LC sit down with medicinal chemist Valerie Shurtleff to unpack the discovery journey behind this 3CL protease inhibitor—from early structural insights to an unexpectedly effective difluorobutyl isostere. Val walks us through how the team balanced potency, VLE, metabolic challenges, and design intuition to land on a well‑rounded preclinical candidate - one of the most dynamic programs of her career. Along the way, she reminds us why asking good questions, collaborating relentlessly, and occasionally surviving a “Hot Ones” challenge are all essential scientific skills. It’s an episode packed with chemistry, creativity, and just enough fluorine to keep things spicy.Stay tuned for Part 2, where we shift from invention to implementation and explore how the process chemistry team brought MK‑7845 to life at scale.Read some of the papers we discussed today:Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic - J. Med. Chem.Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠Visit our website at ⁠⁠⁠⁠⁠⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table⁠⁠⁠⁠⁠

Join us for a conversation with Yining Ji Chen, recipient of the 2025 ACS Rising Star Award, on how mechanistic insight powers innovation in pharmaceutical process research. We dive into her career journey and standout projects—from Pd-catalyzed C–N coupling for HCV therapy to dynamic phosphorylation in nucleotide synthesis—plus her creation of LED‑NMR for real-time photochemical reaction monitoring. Hear how deep mechanistic understanding drives robustness and safety, why she moved to the Data‑Rich Measurements group, and which emerging analytical technologies excite her most. A celebration of scientific rigor shaping efficient, reliable pharma processes!Read some of the papers we discussed today:A multifunctional catalyst that stereoselectively assembles prodrugs - ScienceA rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions - Chem SciLED-Illuminated NMR Spectroscopy: A Practical Tool forMechanistic Studies of Photochemical Reactions - ChemPhotoChemFrom at-line to online NMR: coupling probe-based autosampler with benchtop NMR - Reaction Chemistry and EngineeringFollow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠Visit our website at ⁠⁠⁠⁠⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table⁠⁠⁠⁠

In this episode, Dani and LC welcome Jeff Moore, recipient of the 2025 ACS Affordable Green Chemistry Award, to discuss his pioneering work in biocatalysis at Merck. The conversation explores the evolution (pun intended) of biocatalytic processes in pharmaceutical manufacturing, highlighting key milestones such as the adoption of transaminases and imine reductases, and their impact on drug synthesis and sustainability. Jeff shares stories from his career, including how being 'lazy' when doing science can lead to major innovations and the practical benefits of enzyme-driven chemistry. He even leaves us with insights into the future frontiers of biocatalysis, from cascade reactions to microfluidics.Read some of the papers we discussed today:Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist - Organic Letters Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture - ScienceEnabling Biocatalysis by High-Throughput Protein Engineering Using Droplet Microfluidics Coupled to Mass Spectrometry - ACS OmegaFollow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠Visit our website at ⁠⁠⁠⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table⁠⁠⁠

In this episode, Dani and LC interview Dr. Shane Krska, recipient of the ACS Arthur C. Cope Award, and Dr. Petr Vachal, recipient of the ACS Earle B. Barnes Award for Leadership in Chemical Research Management. Shane shares his pioneering work in catalytic methods and high-throughput experimentation (HTE) for drug discovery, while Petr discusses his leadership role driving innovation at Merck. They reflect on their career journeys from graduate school to industry, emphasizing personal growth and the importance on taking on diverse roles. We wrap it up by asking Shane and Petr what has made them the most proud over their 20+ year careers - which spans from innovations in direct-to-biology for accelerating design-make-test to advancing peptides as a modality of the future!Read the papers we discussed today:The Catalysis Laboratory at Merck: 20 Years of CatalyzingInnovationThe medicinal chemist's toolbox for late stage functionalization of drug-like moleculesHighly Efficient Asymmetric Synthesis of SitagliptinFollow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠Visit our website at ⁠⁠⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table⁠⁠

This month we sit down with Damien Valette, Olivia Boyd and David Petrone to chat about their latest paper in Organic Letters on the desymmetrization of prochiral dienones to control all-carbon quaternary centers. This reaction leverages biocatalysis, specifically an ene-reductase [ERED] enzymes (which are making their second appearance on the pod - see S1:E5).David, Damien and Olivia walk us through the discovery of the reaction and why it's uniquely suited to set these challenging stereocenters. This work was done in the context of work at the med-chem/process interface which we explore as well.Damien and Olivia hail from our London UK MSD site and give us details on the progress of our company's build in the region as well as chat with us about how to be successful when collaborating with scientists on another continent (David).Read the papers we discussed today:HTE-Enabled Development of an Ene-Reductase-Catalyzed Desymmetrization: Remote Control of All-Carbon Quaternary γ-Centers ⁠- Org Lett 2024Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠Visit our website at ⁠⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table⁠

Join us on the Pharm to Table podcast for a delightful chat with Ethan Wappes from our South San Francisco site, as we dive into the exciting world of thiophene synthesis! Ethan is a member of our Discovery Process Chemistry group and worked alongside medicinal chemists to devise a better synthetic route towards substituted thiophenes. Ethan shares insights from his recent Org. Lett. on a novel Rh-catalyzed [3+2] method that opens the door to highly substituted dihydrothiophenes, enhancing our medicinal chemistry toolkit. We explore how this strategy not only simplifies complex thiophene syntheses but also paves the way for new drug development possibilities!Read the papers we discussed today:Fully Substituted Thiophene Synthesis via (3 + 2) with Thiadiazoles - Org Lett 2024Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠Visit our website at ⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table

We're kicking off Season 4 (holy cow!) by having a lively discussion answering listener questions on everything from our favorite Boc deprotection methods to the role of AI in the world of chemistry. We also share how flow chemistry is being used in discovery and process chemistry and conclude with what we feel would be disruptive chemistry innovations that could shape 2025. Plus, find out how you can influence the conversation by sharing what you want to hear more of in 2025!

Antibody drug conjugates, or ADCs, are all the rage in the industry right now and chemists play an important role in their development. This month we sat down with Serge Ruccolo and Marion Emmert to talk about their papers in this area. Their work addresses two main challenges of ADC development: 1) potent handling of cytotoxic payloads and 2) selective unmasking of cysteine residues to enable conjugation to the antibody. Tune in to hear how one develops these chemistries; How electrochemistry and microfluidics can be useful tools for the chemistry of these important molecules. You'll learn a ton, we did! Read the papers we discussed today: “Build Your Own” ADC Mimics: Identification of Nontoxic Linker/Payload Mimics for HIC-Based DAR Determination, High-Throughput Optimization, and Continuous Flow Conjugation - OPRD Electrocatalytic Reduction of Disulfide Bonds across Chemical Modalities - Org Lett Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠ Visit our website at ⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table

Ready to go with the flow? Then this episode is for you! In this episode, we dive into the exciting world of Continuous-Flow Solid-Phase Peptide Synthesis (CF-SPPS) with special guests Kyle Ruhl and Mike DiMaso. We kick off the episode with a brief overview on various techniques used to synthesize peptides and how each method fits within the drug discovery/development timeline. From there, we serve up their recent paper on leveraging flow to synthesize peptides - exploring the challenges they faced, such as accommodating resin swelling and optimizing synthesis times. We do our best to shield you from any discussions about math when they dive into linear velocity which helped drive peptide synthesis optimization. Discover how CF-SPPS is unleashing rapid, multigram peptide deliveries, culminating in a remarkable 20-gram yield of a 10-mer peptide in just 4 hours! Read the paper we discussed today: Continuous-Flow Solid-Phase Peptide Synthesis to Enable Rapid, Multigram Deliveries of Peptides Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠ Visit our website at ⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table