We kick off season 2 with a bang, talking about complex molecule synthesis with John McIntosh and Nastaran Salehi. Cyclic dinucleotides (CDNs) are a total synthesis fan's dream with 10 stereocenters (including 2 at phosphorus) arranged around a 13 membered macrocycle formed by 2 non-canonical nucleosides. These endogenous secondary messenger molecules have attracted attention because of their activation of the immune system via the STING pathway. We go into all aspects of the innovative biocatalytic cascade that the team designed for their synthesis, including: 1) How a bald eagle cyclic guanosine-adenosine synthase (cGAS) was engineered to form the macrocycle; 2) How cGAS was leveraged by medicinal chemists to greatly accelerate drug discovery; 3) How the team strung together and optimized a 4-enzyme cascade to deliver a CDN directly from nucleotide building blocks.

A kinase-cGAS cascade to synthesize a therapeutic STING activator - Nature

New Mechanism for Cinchona Alkaloid-Catalysis Allows for an Efficient Thiophosphorylation Reaction - J. Am. Chem. Soc.

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For our kickoff of Season 2, LC and Dani get together (in person!) to reflect on what’s changed since the Pharm to Table pod started in late 2020, answer a listener question (only 9 months late!) on whether a postdoc is needed for an industrial job, and give a sneak peak on what’s to come for Season 2. 

Whether you listen in the car or in the lab - buckle up and don that PPE - as Season 2 is destined to be full of energy, laughs and awesome #MerckChemistry.

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Cecilia Bottecchia is originally from Italy and Francois Levesque is native of Canada. Both have had very international pathways during their studies which have ultimately brought them to #MerckChemistry in the US. We asked them to tell us a little bit about this transition and have a little fun with a Canadian vs Italian food quiz!

For the 10th, and final course of season 1, Dani and LC jump in the hot tub flow time machine with Cecilia Bottecchia and Francois Levesque, co-recipient of the Peter Dunn Green Chemistry Award, and learn how to discover, develop and scale-up a photobromination in flow! But don't let this deceptively simple bromination fool you - this reaction turned out to be a full course meal of challenges! We go into all aspects of the reaction, including: 1) Why they decided to use light vs AIBN to facilitate this reaction; 2) How to design a photoreactor you can use on kilo scale; 3) How to design a robust reaction that can run on >50kg scale; 4) What does hot tub chemistry have to do with a radical bromination reaction. 

Read the paper we discussed today here:

A Continuous Flow Visible-Light-Induced Benzylic Bromination - Organic Process Research and Development

Elucidation of Reaction Mechanisms Using In Situ LED-NMR - Journal of Organic Chemistry

Design of a Kilogram Scale, Plug Flow Photoreactor Enabled by High Power LEDs - Organic Process Research and Development

Follow Cecilia Bottecchia - @cecibottecchia

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For the 9th course, Dani and LC do the robot dance with Melodie Christensen (@chemchristensen on Twitter) #MerckChemistry Enabling Technologies group. Melodie shares her unique career path with us, including her current PhD with @procastiprof - more >10 years after starting her career in pharma. Resident expert in reaction automation, robotics and self-optimizing reactions, Melodie shares her journey in high-throughput and data-rich experimentation. We discuss her award winning paper in JOC and how she was able to use some of the insights of this work to develop an autonomously optimized Suzuki reaction! Finally, Melodie schools us on her best smoothie recipes and three letter acronyms.

Read the paper we discussed today here:

Enantioselective Synthesis of α-Methyl-β-cyclopropyldihydrocinnamates - Journal of Organic Chemistry

Data-science driven autonomous process optimization - Communications Chemistry

The Evolution of High-Throughput Experimentation in Pharmaceutical Development and Perspectives on the Future - OPRD

Automation isn't automatic - Chemical Science

Follow Melodie Christensen - @chemchristensen

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ChemTwitter told us it takes 3 minutes to run a TLC plate, so today we‘re bringing you 3 good minutes with Sue Zultanski (Associate Principal Scientist, Discovery Process Chemistry). Sue first joined our #MerckChemistry Discovery group in 2006 before obtaining her PhD and then starting in Merck Process in 2016. Since joining, Sue has sought solutions across boundaries, weaving deep mechanistic understanding into developing robust manufacturing routes (OPRD) and also through an academic-industrial partnership Prof. Nilay Hazari (JACS).

In our last installment of the 'Spring ACS Sneak Peaks' -  we're flipping the tables and having Sue interview Dani on what motivated her to create a symposium on ‘Taming non-canonical amino acid synthesis’ – a symposium that they collaboratively organized for the upcoming Spring ACS in San Diego. We discuss what inspired Dani and Sue to take on this symposium together, highlight the speakers and share what they hope the audience walks away with.

Complete speaker lineup for Taming the Unnatural - Innovative Noncanonical Amino Acid Synthesis for Drug Discovery and Beyond: H.C. Brown Award Symposium

Register for Spring 2022 ACS (in-person, hybrid, and virtual)

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ChemTwitter told us it takes 3 minutes to run a TLC plate, so today we‘re bringing you 3 good minutes with David Thaisrivongs (Director) and Jenny Obligacion (Associate Principal Scientist) from our Rahway, NJ Process Chemistry group. David and Jenny tell us about a symposia featuring Outstanding Chemists of Color, their motivation for creating this event and the broader implications highlighting Chemists of Color can have on the equity, diversity and inclusion in our field.

Complete speaker lineup for Outstanding Chemists of Color

Chemists of Color informational video on YouTube

Register for Spring 2022 ACS (in-person, hybrid, and virtual)

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Follow Jenny on Linkedin and on Twitter (@jobligac)

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ChemTwitter told us it takes 3 minutes to run a TLC plate, so today we‘re bringing you 3 good minutes with Marion Emmert (Principal Scientist, Catalysis and Enabling Technologies) and Colin Lam (Associate Principal Scientist, Computational and Structural Chemistry). Marion joined #MerckChemistry in 2018 (after a successful career in academia) and has brought her love for catalysis into drug discovery (Google Scholar). Colin joined #MerckChemistry in 2016 and has flexed his computational might on a myriad of projects spanning the portfolio (Google Scholar). Today, Marion and Colin stopped by to give a sneak peak on 'Theory to Therapy' - a symposium that they collaboratively organized for the upcoming Spring ACS in San Diego. We discuss what inspired Marion and Colin to take on this symposium together, highlight the speakers and share what they hope the audience walks away with.

Complete speaker lineup for From Theory to Therapy: New Developments in Quantum Mechanical Calculations for Driving Best Chemistry in Academia and Industry

Register for Spring 2022 ACS (in-person, hybrid, and virtual)

Follow Marion on Twitter - @emmertlab

Follow Colin on Twitter - @yhcolin

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ChemTwitter told us it takes 3 minutes to run a TLC plate, so today we‘re bringing you 3 good minutes with Xiaoshen Ma, Associate Principal Scientist in our Boston Discovery Chemistry group. Xiaoshen joined #MerckChemistry in 2018 and has been influential in advancing drug discovery through the exploration of bicyclo[1.1.1]pentanes (aka BCP's) as bioisosteres for arenes - the work of which is already making an impact (Google Scholar). Today, Xiaoshen stopped by to give a sneak peak on Synthetic Advances Toward Novel Bicyclo[1.1.1]pentanes - a symposium that he organized at the upcoming Spring ACS in San Diego. We discuss what inspired Xiaoshen to take on this symposium, highlight the speakers and share what he hopes the audience walks away with.  

Complete speaker lineup for Synthetic Advances Toward Novel Bicyclo[1.1.1]pentanes 

Register for Spring 2022 ACS (in-person, hybrid, and virtual)

Follow Xiaoshen on Twitter - @XMa75870843 

Follow the Pharm to Table podcast on Twitter - @PharmtoTablePod

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For the 8th course, Dani and LC ride the biocatalytic cascade with Ania Fryszkowska (@fryania on Twitter) and Greg Hughes (@greg_hughes on Twitter) from the #MerckChemistry Process Chemistry group. Greg, a process chemistry pro, kicks off this episode by giving a high-level overview of the drug development process and the differences in designing clinical supply route vs. a final commercial route. Ania, a biocatalysis superstar, then takes us on a retrosynthetic journey that ultimately led to a multi-enzyme biocatalytic cascade for the construction of non-canonical nucleosides - published in Science. Directed evolution was critical throughout this process, and Ania shares how #MerckChemistry internal capabilities allowed the discovery and optimization of each biocatalytic step (5 total!). We end with Greg and Ania sharing how far biocatalysis has come in commercial route development and the future that biocatalysis holds for sustainable pharmaceutical manufacturing.

Read the paper we discussed today here:

Design of an in vitro biocatalytic cascade for the manufacture of an antiviral (Science)

Biocatalysis in drug discovery and development

Follow Ania Fryszkowska - @fryania

Follow Greg Hughes - @greg_hughes

Follow the Pharm to Table podcast on Twitter - @PharmtoTablePod

Visit our website at https://anchor.fm/pharm-to-table