Ryan Shenvi, PhD
Scripps Research Joint Appointments
Research Focus
Neuroscience: Your brain is chemical. Small molecules mediate its communication, maintenance, function and dysfunction. Our lab has published methods to synthesize important classes of CNS-active metabolites including potent nAChR inhibitors and Illicium terpenes, sometimes called ‘neurotrophic terpenes.’ We proposed that these latter metabolites enhance neurite outgrowth through binding to the CysLoop family of neurotransmitter-gated ion channels–probably GABAa receptors. Our chemistry allows us to match the combinatorial nature of these receptors with a combinatorial assembly of terpenes. More recently, we proposed a computational workflow called CANDOR (Computed Affinity / Dynamically Ordered Retrosynthesis) to rapidly synthesize a stabilized salvinorin A analog that potently and selectively agonizes the kappa opioid receptor (KOR), a target for next generation pain therapeutics. This synthesis is being used to generate important KOR tool compounds, but we anticipate the CANDOR workflow will accelerate the deployment of many other natural product scaffolds in medicinal chemistry campaigns.
Unusual pharmacophores. Chemical reactions underlie the biological mechanisms of many small molecules. Insight into chemical reactivity can therefore inform biology. Our laboratory has invented methods to easily access several classes of secondary metabolites that contain unique pharmacophores and whose covalent cellular reactivity is not understood. We are working to understand 1. the Nuphar dimers, which contain a covalently-reactive thiaspirane pharmacophore; 2. the asmarine alkaloids, whose N-hydroxydiazepine purine may react covalently or oxidatively; and 3. the isocyanoterpenes (ICTs), antimalarial marine metabolites whose isonitrile function may affect diverse bioinorganic processes. To study this latter class, we invented a general stereochemical inversion of tertiary alcohols.
Hydrogen Atom Transfer (HAT): Classical hydrofunctionalization of alkenes requires strong Bronsted acids to form fleeting, high-energy carbocations. In contrast, non-canonical reactions of metal hydrides can hydrofunctionalize alkenes through lower-energy carbon-centered radicals. We proposed that Co, Fe and Mn-catalyzed reactions pioneered by Drago and Mukaiyama proceed through Halpern’s HAT mechanistic paradigm. We have used our HAT hydrogenation and HAT isomerization to synthesize inaccessible secondary metabolites (drimane, epoxyhumulene-II, α-funebrene, 7,20-diisocyanoadociane). We were also the first to combine MH HAT catalysis with nickel-catalyzed cross coupling, which circumvents substrate prefunctionalization and expands the possibilities of each catalytic cycle. This work also represents a departure from prior nickel catalytic cycles in which atoms and bonds are lost to generate radicals, rather than gained.
Education
Ph.D. (Chemistry), Scripps Research, 2008B.S. (Chemistry), The Pennsylvania State University, 2003
Professional Experience
2010-2014 Assistant Professor, Chemistry, Scripps Research2008-2010 NIH Postdoctoral Fellow with Dr. E.J. Corey, Harvard University
Awards & Professional Activities
Tetrahedron Young Investigator Award (Organic Synthesis), 2019Society of Synthetic Organic Chemistry (Japan) Lectureship Award, 2017
NPR Emerging Investigator, 2016
Eli Lilly Grantee Award, 2015
Novartis Early Career Award, 2014-2016
Bristol-Myers-Squibb Grant in Synthetic Organic Chemistry, 2014-2016
Sloan Research Fellowship, 2014
NSF Career Award, 2014
Amgen Young Investigator Award, 2013
Baxter Young Investigator Award, 2013
Boehringer Ingelheim New Investigator Award, 2012
Eli Lilly New Faculty Award, 2011
Selected References
Green, S. A.; Vásquez-Céspedes, S.; Shenvi, R. A. Iron-Nickel Dual-Catalysis: A New Engine for Olefin Functionalization. J. Am. Chem. Soc. 2018, accepted.
Witkin, J. M.; Shenvi, R. A.; Li, X.; Gleason, S. D.; Weiss, J.; Morrow, D.; Catow, J. T.; Wakulchik, M.; Ohtawa, M.; Lu, H.-H.; Martinez, M. D.; Schkeryantz, J. M.; Carpenter, T. S.; Lightstone, F. C.; Cerne, R. Pharmacological Characterization of the Neurotrophic Sesquiterpene Jiadifenolide Reveals a Non-Convulsant Signature and Potential for Progression in Neurodegenerative Disease Studies. Biochem. Pharmacol. 2018, 155, 61–70.
Lambrecht, M.; Kelly, J. W.; Shenvi, R. A. Mechanism of Action of the Cytotoxic Asmarine Alkaloids. ACS Chem. Bio. 2018, 13, 1299–1306.
Roach, J. R.; Shenvi, R. A. A Review of Salvinorin Analogs and their Kappa-Opioid Receptor Activity. Bioorg. Med. Chem. Lett. 2018, 28, 1436–1445.
Hirasawa, S.; Cho, M.; Brust ,T. F.; Roach, J. R.; Bohn, L. M.; Shenvi, R. A. O6C-20-nor-SalA is a stable and potent KOR agonist. Bioorg. Med. Chem. Lett. 2018, DOI: 10.1016/j.bmcl.2018.01.055.
Roach, J. J.; Sasano, Y.; Schmid, C. L.; Zaidi, S.; Katrich, V.; Stevens, R. C.; Bohn, L. M.; Shenvi, R. A. Dynamic Strategic Bond Analysis Yields a 10-step Synthesis of 20-nor-SalA, a Potent Κ-OR Agonist, ACS Central Science, 2017, 3, 1329–1336.
Ohtawa, M.; Krambis, M. J.; Cerne, R.; Schkeryantz, J.; Witkin, J. M.; Shenvi, R. A. Synthesis of (–)-11-O-Debenzoyltashironin: Neurotrophic Sesquiterpenes Cause Hyperexcitation, J. Am. Chem. Soc. 2017, 139, 9637–9644.
Reiher, C. A.; Shenvi, R. A. Stereocontrolled Synthesis of Kalihinol C, J. Am. Chem. Soc. 2017, 139, 3647–3650.
Green, S. A.; Matos, J. L. M.; Yagi, A.; Shenvi, R. A. Branch-Selective Hydroarylation: Iodoarene-Olefin Cross Coupling, J. Am. Chem. Soc. 2016, 138, 12779–12782.
Crossley, S. W. M.; Martinez, R. M.; Obradors, C.; Shenvi, R. A. Mn, Fe, and Co-Catalyzed Radical Hydrofunctionalizations of Olefins, Chem. Rev. 2016, 116, 8912–9000.
Tada, N.; Jansen, D. J.; Mower, M. P.; Blewett, M. M.; Umotoy, J. C.; Cravatt, B. F.; Wolan, D. W.; Shenvi, R. A. Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore, ACS Cent. Sci. 2016, 2, 401–408.
Lu, H.-H.; Pronin, S. V.; Antonova-Koch, Y.; Meister, S.; Winzeler, E. A.; Shenvi, R. A. Synthesis of (+)-7,20-Diisocyanoadociane and Liver Stage Antiplasmodial Activity of the ICT Class, J. Am. Chem. Soc. 2016, 138, 7268–7271.
Shenvi, R. A. Reinventing Radical Reactions, SynLett Cluster (Ed. T. Rovis and R. A. Shenvi), Thieme, 2016, 27, 678–679.
Martinez, R.; Crossley, S. W. M.; Zuluaga, S. G.; Shenvi R. A. Synthesis of the Privileged 8-Arylmenthol Class by Radical Arylation of Isopulegol, Org. Lett. 2016, 18, 2620–2623.
Obradors, C. L.; Martinez, R.; Shenvi, R. A. Ph(i-PrO)SiH2: An Exceptional Reductant for Metal-Catalyzed Hydrogen Atom Transfers, J. Am. Chem. Soc. 2016, 138, 4962.
Shenvi, R. A. Neurite outgrowth enhancement by jiadifenolide: possible targets, Nat. Prod. Rep. 2016, 33, 535–539.
Wan, K. K.; Shenvi, R. A. Conjuring a Supernatural Product – Delmarine, SynLett (invited Accounts), 2016, 27, 1145–1164.
Lu, H.-H.; Martinez, M. D.; Shenvi, R. A. "An Eight-Step Gram-Scale Synthesis of (–)-Jiadifenolide" Nature Chem. 2015, 7, 604-607.
Tabor, M. G.; Shenvi, R. A. Synthesis of Lepadiformine Using a Hydroamination Transform, Org. Lett. 2015, 17, 5776.
Crossley, S. W. M.; Shenvi, R. A. "A Longitudinal Study of Alkaloid Synthesis Reveals Functional Group Interconversions (FGIs) as Bad Actors" Chem. Rev. 2015, 115, 9465–9531.
Roach, J. J.; Shenvi, R. A. "Supramolecular Catalysis: Terpenes in Tight Spaces" Nature Chem. (News and Views) 2015, 7, 187–189.
Wan, K. K.; Iwasaki, K.; Umotoy, J. C.; Wolan, D.; Shenvi, R. A. “Nitrosopurines en route to Potent Asmarine Cytotoxins” Angew. Chem. Int. Ed. 2015, 127, 2440–2445.
Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley, S. W. M.; Shenvi R. A. "Simple, Chemoselective Hydrogenation with Thermodynamic Stereocontrol" J. Am. Chem. Soc. 2014, 136, 1300–1303.
Crossley, S. W. M.; Barabé, F.; Shenvi, R. A. "Simple, Chemoselective, Catalytic Olefin Isomerization” J. Am. Chem. Soc. 2014, 136, 16788.
Jansen, D. J.; Shenvi, R. A. "Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery" Future Med. Chem. 2014, 6, 1127.
Shenvi, R. A.; Schnermann, M. J. "Syntheses and Biological Studies of Marine Terpenoids Derived from Inorganic Cyanide" Nat. Prod. Rep. 2015, 32, 543– 577.
Pronin, S. V.; Reiher, C. A.; Shenvi, R. A. "Stereoinversion of Tertiary Alcohols to Tertiary-Alkyl Isonitriles and Amines" Nature 2013, 501, 195–199.
Jansen, D. J.; Shenvi, R. A. "Synthesis of (–)-Neothiobinupharidine" J. Am. Chem. Soc. 2013, 135, 1209–1212.
Pronin, S. V.; Shenvi, R. A. “Synthesis of a Potent Antimalarial Amphilectene” J. Am. Chem. Soc. 2012, 134, 19604–19606.
Pronin, S. V.; Shenvi, R. A. “Synthesis of Highly Strained Terpenes by Nonstop Tail-to-Head Polycyclization” Nature Chem. 2012, 4, 915–920.
Pronin, S. V.; Tabor, M. G.; Jansen, D. J.; Shenvi, R. A. “A Stereoselective Hydroamination Transform to Access Polysubstituted Indolizidines” J. Am. Chem. Soc. 2012, 134, 2012–2015.
Shenvi, R. A.; Corey, E. J. "A Short and Efficient Synthesis of (–)-7-Methylomuralide, a Potent Proteasome Inhibitor" J. Am. Chem. Soc. 2009, 131, 5746–5747.
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. "Synthesis of (+)-Cortistatin A" J. Am. Chem. Soc. 2008, 130, 7241–7243.
Baran, P. S.; Shenvi, R. A. "Total Synthesis of (±)-Chartelline C" J. Am. Chem. Soc. 2006, 128, 14028–14029.