Pharm to Table

How do you design a manufacturing process for a molecule as complex as MK-0616? In Part 1 of this Pharm to Table series, Dani and LC join Stephanie Galanie, Director in Biocatalysis, and Artis Klapars, Distinguished Scientist in Process Chemistry, to discuss the manufacturing route behind their Science paper on biocatalytic cascades for this macrocyclic peptide.

We start with a central question: why develop a new synthesis when an existing route already delivers hundreds of kilograms? Artis and Stephanie explain how the team worked backward from MK-0616’s complex structure to choose key disconnections, then developed three interconnected cascades to assemble it. Along the way, we unpack the tools behind those decisions, including directed evolution and enzymes that selectively form amide bonds without relying on protecting groups.

Part 2 takes us inside the cascades, from four enzymes working in one vessel to fragment ligation and macrocyclization, then tackles the final challenge: isolating MK-0616 in the right purity and salt form.

Read some of the papers we discussed today:

Biocatalytic cascades enable manufacture of the macrocyclic peptide MK-0616 - ⁠Science⁠

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Part 1 laid out the strategy. Now, it’s time to make the molecule. Four enzymes, one vessel, and plenty of competing amines. What could possibly go wrong? Dani and LC return with Stephanie Galanie, Director in Biocatalysis, and Artis Klapars, Distinguished Scientist in Process Chemistry, for a closer look at the chemistry behind MK-0616 manufacturing.

We start with the northern fragment, where making three bonds selectively means getting four engineered enzymes to play well together, ATP recycling included. Then we tackle fragment ligation with an evolved thioesterase and a hydrogen-borrowing cascade that closes a macrocycle. How do you drive an uphill reaction toward completion? And why would you start engineering an enzyme with the “wrong” substrate? Stephanie and Artis explain the solutions behind the synthesis.

Finally, traditional coupling chemistry gets its moment alongside enzymatic macrocyclization, and a “counterion dance” gets MK-0616 out of solution in the right purity and salt form. We wrap up with what it takes to turn ambitious chemistry into a manufacturing process, and why protecting-group-free fragment coupling, concentrated macrocyclizations, and crystallization could change how we make complex peptides.

Read some of the papers we discussed today:

Biocatalytic cascades enable manufacture of the macrocyclic peptide MK-0616 - ⁠⁠Science⁠⁠

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Last episode, we watched medicinal chemistry dream up enclitide (MK-0616) — this week we find out what happens when someone actually has to make it. Dani and LC are joined by David Thaisrivongs and Gao Shang to unpack their recent JACS paper on the total synthesis of enlicitide, a macrocyclic peptide complex enough to keep company with taxol, vancomycin, and eribulin. Along the way they get into the pivot from solid-phase to solution-phase peptide synthesis, the perpetual headache of sourcing non-canonical amino acids and how biocatalysis cracked it open, and the crystallization detective work that let the team ditch chromatography entirely. There's also a great discussion on why a late-stage macrolactamization became a late-stage RCM — the kind of route decision that looks obvious only in hindsight.

Fair warning: this one was among JACS's top-accessed papers of 2025, so you're in good company!

If you enjoyed this chapter of the enlicitide story, stay tuned—we've got plenty more peptide chemistry, process development adventures, and behind-the-scenes drug discovery stories coming your way this season.

Read some of the papers we discussed today:

Total Synthesis of Enlicitide Decanoate - ⁠⁠J. Am. Chem. Soc.⁠⁠

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What happens when the textbook SAR playbook stops working? On this episode of Pharm to Table, Rob Garbaccio joins Dani and LC to share the discovery story behind enlicitide (MK-0616), a journey filled with unusual SAR, creative problem-solving, and plenty of chemistry twists along the way. From issue-driven drug design to non-canonical amino acids and modular synthesis strategies, this conversation offers a behind-the-scenes look at how real medicines are discovered. If you're training as a chemist today, this is a story you won't want to miss.

If you enjoyed this chapter of the enlicitide story, stay tuned—we've got plenty more peptide chemistry, process development adventures, and behind-the-scenes drug discovery stories coming your way this season.

Read some of the papers we discussed today:

Discovery Process of Enlicitide, a Highly Engineered Macrocyclic Peptide Therapeutic, through Issue-Driven Fragment-Based Synthetic Assembly and SAR - ⁠J. Med. Chem.⁠

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To kick off Season 5, Dani and LC discuss a recent perspective published in the Journal of Organic Chemistry that highlights innovations in synthetic chemistry which trace their origins to the work of discovering, developing and commercializing novel therapeutics. This publication was the most accessed paper published in JOC in 2025!

Dani and LC explore the motivations on writing it, its main thesis and lesson learned from reexamining nearly 75 years of chemistry innovations at Merck.

Be sure to listen through to the very end for a special Season 5 theme reveal!

Read and listen to some of the papers we discussed today:

From Cortisone to Enlicitide: A Journey of Synthetic Chemistry Innovations at Merck

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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 Intuition

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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.

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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 - Science

A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions - Chem Sci

LED-Illuminated NMR Spectroscopy: A Practical Tool forMechanistic Studies of Photochemical Reactions - ChemPhotoChem

From at-line to online NMR: coupling probe-based autosampler with benchtop NMR - Reaction Chemistry and Engineering

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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 - Science

Enabling Biocatalysis by High-Throughput Protein Engineering Using Droplet Microfluidics Coupled to Mass Spectrometry - ACS Omega

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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 CatalyzingInnovation

The medicinal chemist's toolbox for late stage functionalization of drug-like molecules

Highly Efficient Asymmetric Synthesis of Sitagliptin

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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 2024

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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 2024

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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

Join Dani and LC as they peel back the layers on podcasting in chemistry. This insightful episode dives into their recently published Organic Letters editorial "Should You Start a Chemistry Podcast?" with special contributor and corresponding author Matt Horwitz from Synthesis Workshop sharing his unique perspective.

But that's not all - get ready for an artistic twist as Brendan Burkett from Chemscrapes reveals how he transforms chemistry concepts into visually striking designs for the chemistry community (including CEN!).

Whether you're an aspiring podcaster, a chemistry communicator, or just someone fascinated by the interplay of science and art, this episode promises an engaging exploration. Tune in for a candid discussion blending personal experiences, creative insights, and a passion for making chemistry more accessible to all. Don't miss this multimedia showcase!"

Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠ Visit our website at ⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table Org. Lett. featured: https://pubs.acs.org/doi/full/10.1021/acs.orglett.3c04181

Time for the main course! Our #MerckChemistry hiring experts are dishing out more savory tips to help you get hired in pharma.

In this second part, they'll guide you through mastering the job talk, nailing those crucial on-site interviews, and evaluating offers strategically. Learn how to deliver an engaging presentation, handle tough questions, and leave a lasting impression. Get advice on navigating those 1:1 interviews with poise. Once you've aced the interviews, find out how to weigh compensation packages and negotiate the most appetizing offer for your career growth. Whether you're a fresh grad looking to land that first gig or a seasoned pro ready for the next opportunity, this episode is the secret sauce you need! Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠ Visit our website at ⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table

Looking to kickstart your career in the pharmaceutical industry? This episode is a must-listen! We have special guests Jamie McCabe Dunn, Val Shurtleff and our very own Dani Schultz - hiring managers in Discovery and Process Chemistry - to share insider tips. In part 1 we talk about building a rock-solid network, crafting a standout CV that gets noticed, and acing those crucial first interviews. We also answer listener questions submitted on LinkedIn. Whether you're a fresh grad or an experienced pro, our experts will give you the competitive edge to land your dream job in pharma!

Plus, stay tuned for Part 2 we tackle how to ace your job talk, prepare for interviews and steps to take after receiving an offer! Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠ Visit our website at ⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table

Alexandra Sun and Harrison Rose join the pod to share their work on a vision-guided automated liquid-liquid extraction (LLE) platform. That's right, before our robot overlords overtake us, they are going to help chemists and engineers with work-ups first! Even though it's often taken for granted, liquid-liquid extractions are part of virtually every chemical reaction for product isolation. Developing these unit operations is critical to chemists and engineers who design processes and Harrison and Alex's new tool can help expedite this. We also asked them for their secret to developing the best phase cuts! We learned a lot on this episode, and we hope you do too! Read the papers we discussed today: ⁠Vision-Guided Automation Platform for Liquid–Liquid Extraction and Workup Development - OPRD

General Principles and Strategies for Salting-Out Informed by the Hofmeister Series - OPRD Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod⁠⁠⁠⁠ Visit our website at ⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table

Patrick Fier and Suhon Kim join the pod to share their lates collaboration on a new C-N cross-coupling protocol which leverages a novel multifunctional template reagent. The work emerged from a side-project that started many years ago on the creation of the "Aminator" reagent which inspired the latest reaction. The couplings have very broad scope and Suhong and Patrick explain their motivation for pursuing the work and insights about the reaction enabled by this reagent. We learned a lot on this episode, and we hope you do too!

Read the papers we discussed today:
⁠Transition-Metal-Free C–N Cross-Coupling Enabled by a Multifunctional Reagent - JACS
A Multifunctional Reagent Designed for the Site-Selective Amination of Pyridines - JACS

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