Source: Interfolio F180
Ryan Shenvi
Research Focus
Chemical synthesis is the transformation of matter, converting one material with one set of properties into new materials with new properties. Fundamental advances in synthesis support material, agricultural and pharmaceutical sciences. Most syntheses, however, generate simple molecules with simple structures and low information density. Of all the varied, complex molecules that might exist—a theoretical set referred to as ‘chemical space’—few are easily accessible because current chemical tools are insufficient. Our group develops new tools to access ‘natural product space,’ compounds typified by cellular metabolites. These complex molecules contain unusually high information density, a measure of how molecular data is stored. These remote outposts of chemical space are challenging to access using traditional chemical synthesis and therefore require innovation. Our group connects different areas of chemistry in novel ways to uncover 1) ‘vehicles’, i.e. new chemical reactions to traverse chemical space, and 2) ‘locales,’ i.e. new molecules that might yield important discoveries for medicine, agriscience or materials. This model has moved our fundamental academic research into applications of interest to biotech companies and chemical vendors.
1. Our group proposed that a category of base metal (Fe, Mn, Co)-catalyzed chemical reactions observed in the 1980s proceeds through the elementary step of metal-hydride hydrogen atom transfer (MHAT). This elementary step would occur in an "outer-sphere" fashion - with no interaction between the metal atom and the reacting substrate, in contrast to prior work that suggested direct bond formation. We excluded the metal-insertion pathway based on our observation that an organometallic intermediate is parasitic and does not lie on the catalytic cycle. Since our publication of two JACS papers in 2014, our work in this area has been cited over 1400 times, our Mn-catalyzed hydrogenation is now widely used in academia and industry, our reagents (Shenvi hydrogenation catalyst, RubenSilane) have been commercialized by fine chemical vendors and the MHAT paradigm has driven basic research from our lab and many others. More recently, we pioneered MHAT dual catalysis in which a slow, canonical cross-coupling cycle “piggybacks” on the fast MHAT cycle. This catalytic relay causes bond formation at an internal position (Markovnikov selectivity) instead of terminal (anti-Markovnikov), effectively doubling the number of products available from feedstock hydrocarbons. Branched hydrocarbons are valuable as, for example, high-octane gasoline that reduces engine knocking. For our purposes, the branched products reflect metabolite space by increasing information density, i.e. packaging more information into a smaller volume than linear products.
2. Illicium plant metabolites have been reported to enhance neurite outgrowth, a phenotype associated with neuron repair. A mechanism had not been assigned, however, due to lack of material: these trace metabolites occur at low parts-per-million levels. Prior chemical syntheses—over 50—produced small quantities of material (10 mg, average) using lengthy sequences (22 steps, average). In contrast, our route to the most active member, jiadifenolide, stands as the shortest, highest-yielding and largest scale (8 steps, >1000 mg). We are the only group to study the ‘neurotrophic’ terpenes in vivo (with Eli Lilly) and have shown them to be: non-convulsive, anti-psychotic, hyperexcitatory, and mIPSC inhibitors in the low nanomolar range. Our chronic hyperexcitation/ calcium set point model remains the only unexcluded hypothesis to explain neurotrophic effects. Our chemical discoveries have been adapted to the shortest synthesis of the related non-convulsive GABAa receptor antagonist bilobalide, stabilization of the selective antagonist PXN, and to a general synthesis of rare attached-ring scaffolds. We discovered with Luke Lairson that this latter class includes potent and selective cGAS/STING pathway antagonists.
3. The recreational drug Salvia (Salvia divinorum) contains the potent hallucinogen salvinorin A (SalA). At the time of its discovery, it was the most potent naturally-occurring hallucinogen ever described. Unlike typical hallucinogens (LSD, mescaline), SalA lacks a nitrogen atom and does not target the 5-HT2A serotonin receptors, instead targeting the kappa-opioid receptor (KOR) with high selectivity. KOR has emerged as a potential target for next-generation, non-addictive analgesics, and SalA has co-emerged as an important lead compound. Over 500 papers describe its biology and three synthetic campaigns have been reported. Unfortunately, SalA contains several structural liabilities, including its tendency to epimerize and lose potency. We were the first group to describe why SalA epimerizes, the first to stabilize it by chemical synthesis and the first to describe a route amenable to scaffold optimization en route to therapeutic development. This work was highlighted by Faculty of 1000 and several news outlets. We are in talks with a private firm to advance this science.
4. A foundational rule of organic chemistry is that tertiary alcohols do not undergo inversion of stereochemistry. Instead, ionization and planarization lead to indiscriminate addition of nucleophiles to either face: inversion and retention in equal measure. Our group demonstrated that water- stable Lewis acid catalysts could effect a stereochemical inversion of tertiary alcohol esters to their corresponding amines (C–OH?C–NH2), through the intermediacy of isonitriles (C–N=C). Combined with new dendralene reagents from our lab, this overall process mimicked a putative biosynthetic step of the isocyanoterpenes, sponge metabolites that selectively kill Plasmodia, parasites that cause malaria. Prior reports proposed anti-malarial activity via inhibition of heme detoxification. However, we showed with Elizabeth Winzeler that these isocyanoterpenes also kill liver-stage parasites, where heme detoxification is absent. Ongoing work with the Parker lab has indeed identified an alternative target.
5. Bacterial, fungal and plant metabolites teach chemists how evolution imparts biological function at the molecular level. We reported the first syntheses of the Nuphar dimers and a new method to form their reactive pharmacophore, the structure required for biological activity. This unusual motif, an iminium tetrahydrothiophane, had been posited to react as a carbon electrophile. In contrast, we showed it could react as a sulfur electrophile and release a molecular warhead to adduct proteins. In a related project, we annotated the function of the asmarine alkaloids, scarce sponge metabolites that exhibit potent cytotoxicity. Through a combination of cellular assays, flow cytometry and protein function, we identified these metabolites as potent binders of the labile iron pool. This knowledge allowed us to simplify the asmarines’ structures to purine analogs available in only two steps, enabling their widespread study.
Education
Ph.D. (Chemistry), The Scripps Research Institute, 2008B.S. (Chemistry), The Pennsylvania State University, 2003
Awards & Professional Activities
2021 E.J. Corey Award, ACS2020 Blavatnik Award Chemistry Finalist, Blavatnik Family Foundation
2019 Tetrahedron Young Investigator Award, Elsevier
2018 SSOC Lectureship Award, Society of Synthetic Organic Chemistry of Japan Lectureship Award
2016 NPR Emerging Investigator, Royal Society of Chemistry
2015 Eli Lilly Grantee Award
2014 Novartis Early Career Award
2014 Bristol-Myers-Squibb Grant in Synthetic Organic Chemistry
2014 Sloan Research Fellowship, Sloan Foundation
2014 NSF Career Award, National Science Foundation
2013 Baxter Young Investigator Award, Baxter Family Foundation
2013 Amgen Young Investigator Award, Amgen Inc.
2013 Thieme Chemistry Journal Award, Thieme Medical Publishers
2013 Boehringer-Ingelheim Young Investigator Award
2011 Eli Lilly New Faculty Award
2007 Roche Symposium: Excellence in Chemistry Award
2007 Poster Session Winner, TSRI Scientific Retreat, Scripps Research
2007 Lesly Starr Shelton Award for Excellence in Chemistry Graduate Studies, Scripps Research
2005 NDSEG Predoctoral Fellowship, Department of Defense
2003 Penn State University Sponsors Poster Session
2002 Pfizer Summer Undergraduate Research Fellowship
2001 John and Elizabeth Holmes Teas Scholarship, Penn State
2000 William G. and Elizabeth K. Leitzell Scholarship, Penn State
1999 National Merit Corporate Scholarship
Selected Publications
Gan, X. C.; Kotesova, S.; Castanedo, A.; Green, S. A.; Møller, S.; Shenvi, R. A. Iron-Catalyzed Hydrobenzylation: Stereoselective Synthesis of (-)-Eugenial C. 2023, 145, 15714-15720.
Shenvi, R. A. Hidden Lives. Early Childhood Care as an Academic: The Slow Burn. 2023, 62, e202301979.
Hill, S. J.; Dao, N.; Dang, V. Q.; Stahl, E. L.; Bohn, L. M.; Shenvi, R. A. A Route to Potent, Selective, and Biased Salvinorin Chemical Space. 2023, 9, 1567-1574.
Shevick, S. L.; Freeman, S. M.; Tong, G.; Russo, R. J.; Bohn, L. M.; Shenvi, R. A. Asymmetric Syntheses of (+)- and (-)-Collybolide Enable Reevaluation of -Opioid Receptor Agonism. 2022, 8, 948-954.
Woo, S.; Shenvi, R. A. Synthesis and target annotation of the alkaloid GB18. 2022, 606, 917-921.
Landwehr, E. M.; Baker, M. A.; Oguma, T.; Burdge, H. E.; Kawajiri, T.; Shenvi, R. A. Concise syntheses of GB22, GB13, and himgaline by cross-coupling and complete reduction. 2022, 375, 1270-1274.