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 described 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 analgesics and psychotropic therapeutics. This synthesis is being used to generate important KOR agonists, but we anticipate the CANDOR workflow will accelerate the deployment of many other natural product scaffolds in medicinal chemistry campaigns. For example, we recently showed that dynamic retrosynthetic methylation stabilizes the GABAaR antagonist picrotoxinin and increases its structural complexity, but also opens a dramatically shortened, eight-step route.
80. Dao, N.; Gan, X.-c.; Shenvi, R. A. “Metal-Hydride C–C Cross-Coupling of Alkenes Through a Double Outer-Sphere Mechanism” [invited] J. Org. Chem. 2024, 89, 16106–16113.
78. Tong, G.; Griffin, S.; Sader, A.; Crowell, A. B.; Beavers, K.; Watson, J.; Buchan, Z.; Chen, S.; Shenvi, R. A. C5 Methylation Confers Accessibility, Stability and Selectivity to Picrotoxinin Nature Commun. 2023, 14, 8308.
ChemRxiv DOI: 10.26434/chemrxiv-2022-0l4nt
65. Huffman, B. J.; Chu, T.; Hanaki, Y.; Wong, J. J.; Chen, S.; Houk, K. N.; Shenvi, R. A. Stereodivergent attached ring synthesis via non-covalent interactions: a short formal synthesis of merrilactone A Angew. Chem. Int. Ed. 2022, 61, e202114514.
64. Tong, G.; Shenvi, R. A. Revision of the unstable picrotoxinin hydrolysis product Angew. Chem. Int. Ed. 2021, 60, 19113.
62. Woo, S.; Shenvi, R. A. Natural Product Synthesis through the Lens of Informatics Acc. Chem. Res. 2021, 54, 1157–1167.
61. Tong, G.; Baker, M. A.; Shenvi, R. A. Change the channel: CysLoop receptor antagonists from Nature. Pest Manag. Sci. 2020, 77, 3650–3662. [Special Issue honoring Tom Sparks for the Kenneth Spencer Award]
59. Demoret, R. M.; Baker, M. A.; Ohtawa, M.; Chen, S.; Lam, C.-C.; Khom, S.; Roberto, M.; Forli, S.; Houk, K.; Shenvi, R. A. Synthetic, Mechanistic and Biological Interrogation of Ginkgo biloba Chemical Space en route to (–)-Bilobalide. J. Am. Chem. Soc. 2020, 142, 18599–18618.ChemRxiv DOI: 10.26434/ chemrxiv.12132939.v2
57. Crossley, S. W. M.; Tong, G.; Lambrecht, M. J.; Burdge, H. E.; Shenvi, R. A. Total Synthesis of (–)-Picrotoxinin J. Am. Chem. Soc. 2020, 142, 11376–11381.
ChemRxiv DOI: 10.26434/chemrxiv.8263415.v1
54. Huffman, B. J.; Chen, S.; Schwarz, J. L; Plata, R. E.; Chin, E.; Houk, K. N.; Lairson, L. L.; Shenvi, R. A. Electronic Complementarity Permits Hindered Butenolide Heterodimerization and Discovery of Novel cGAS/STING Pathway Antagonists, Nature Chem. 2020, 12, 310–317.
51. Baker, M.; Demoret, R.; Ohtawa, M.; Shenvi, R. A. Concise Asymmetric Synthesis of (–)-Bilobalide Nature 2019, 575, 643–646. DOI: 10.1038/s41586-019-1690-5. ChemRxiv DOI: 10.26434/chemrxiv.8202053.v1 Featured in Org. Chem. Highlights
42. Jeffrey M. Witkin, Ryan A. Shenvi, Xia Li, Scott D. Gleason, Julie Weiss, Denise Morrow, John T. Catow, Mark Wakulchik, Masaki Ohtawa, Hai-Hua Lu, Michael D. Martinez, Jeffrey M. Schkeryantz, Timothy S. Carpenter, Felice C. Lightstone, Rok Cerne Pharmacological characterization of the neurotrophic sesquiterpene jiadifenolide reveals a non-convulsant signature and potential for progression in neurodegenerative disease studies. Biochem. Pharm. 2018, 155, 61–70.
DOI: 10.1016/j.bcp.2018.06.022
37. 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.
Featured in Org. Chem. Highlights
28. Shenvi, R. A. Neurite Outgrowth Enhancement by Jiadifenolide: Possible Targets. Nat. Prod. Rep. 2016, 33, 535-539.
24. Lu, H.-H.; Martinez, M. D.; Shenvi, R. A. Eight-Step, Gram-Scale Synthesis of (–)-Jiadifenolide. Nature Chem. 2015, 7, 604-607.
13. 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.
- In top ten most accessed articles of J. Am. Chem. Soc. for January 2012.
- Highlighted in Nature Chemistry, May 2012.
