My research interests are in the broad field of organic synthesis. Projects in my group range from developing new synthetic methods and asymmetric reactions to the total synthesis of natural products possessing interesting structural features and biological properties. Our work often involves epoxide opening reactions and requires detailed analysis of NMR spectra to characterize synthetic intermediates.
Total Synthesis of Guaipyridine Alkaloid Natural Products
The guaipyridines are a small family of alkaloids isolated from various Asian plants. Cananodine is isolated from the fruit of Cananga odorata (ylang-ylang), a tree whose bark, leaves, and oil have been used in the folk medicine of SE Asia. Cananodine exhibits encouraging activity against two types of hepatollular carcinoma. Cananodine was also detected recently as a minor component of cypriol oil. The rupestines are isolated from the dried flowers of Artemesia rupestris (rock wormwood), a plant native to SW China. This plant has also been used in traditional Chinese medicine for a variety of maladies, including to protect the liver. To date, very little work has been done on the synthesis of guaipyridine alkaloids. Our synthetic strategy for approaching the guaipyridine skeleton involves alkylation at the picolyl position and Pd-catalyzed coupling to the pyridine ring to form the seven-membered carbocycle.
table of molecule diagrams
Hsieh, T.-J.; Chang, F.-R.; Chia, Y.-C.; Chen, C.-Y.; Chiu, H.-F.; Wu, Y.-C. Cytotoxic Constituents of the Fruits of Cananga odorata. J. Nat. Prod. 2001, 64, 616-9.
Su, A.; Wu, H.-K.; He, H.; Slukhan, U.; Aisa, H. A. New Guaipyridine Sesquiterpene Alkaloids from Artemesia rupestris L. Helv. Chim. Acta 2010, 93, 33 – 38.
He, F.; Nugroho, A. E.; Wong, C. P.; Hirasawa, Y.; Shirota, O.; Morita, H.; Aisa, H. A. Rupestines F-M, New Guaipyridine Sesquiterpene Alkaloids from Artemesia rupestris. Chem. Pharm Bull. 2012, 60, 213-218.
Craig, D.; Henry, G. D.; Total Synthesis of Cytotoxic Guaipyridine Sesquiterpene Alkaloid (+)-Cananodine. Eur. J. Org. Chem. 2006, 3558-3561.
Shelton, P.; Ligon, T. J.; Dell, J. M.; Yarbrough, L.; Vyvyan, J. R. Synthesis of cananodine by intramolecular epoxide opening. Tetrahedron Lett. 2017, 58, 3478-3481. DOI: 10.1016/j.tetlet.2017.07.080.
Starchman, E. S.; Marshall, M. S.; Vyvyan, J. R. Synthesis of (±)-rupestines B and C by intramolecular Mizoroki-Heck reaction. Tetrahedron Lett. 2020, 61, 151837. https://doi.org/10.1016/j.tetlet.2020.151837
Shelton, P. M. M.; Grosslight, S. M.; Mulligan, B. J.; Spargo, H. V.; Saad, S. S.; Vyvyan, J. R. Synthesis of guaipyridine alkaloids (±)-cananodine and (±)-rupestines D and G using an intramolecular Mizoroki-Heck reaction. Tetrahedron 2020, 76, in press. https://doi.org/10.1016/j.tet.2020.131500.
New Gold-Catalyzed Reactions
We have found that gold(I) complexes catalyze the conversion of allyl aryl ethers to provide both branched [formal [3,3] (Claisen)] and linear (formal [1,3]) rearranged products. The ratio of branched to linear products depends in part on the steric bulk of the remote allyl substituent (R'). We are currently investigating the mechanism as well as the scope and limitations of this transformation.
Vyvyan, J. R.; Dimmitt, H. E.; Griffith, J. K.; Steffens, L. D.; Swanson, R. A.; Gold-catalyzed rearrangement of substituted allyl aryl ethers Tetrahedron Lett. 2010, 51, 6666-6669.
We have also studied the Au-catalyzed of aryl allyl ethers to from cis-1,2-disubstituted tetrahydropyrans leading to a short synthesis of centrolobine.
Au-catalyzed of aryl allyl ethers to from cis-1,2-disubstituted tetrahydropyrans leading to a short synthesis of centrolobine.
Vyvyan, J. R.; Longworth (née Dimmitt), H. E.; Nguyen, S. Synthesis of (±)-centrolobine using a gold-catalyzed cycloetherification Synlett, 2016, 2221-2224. Featured in Organic Chemistry Highlights edited by Douglass F. Taber, January 8, 2018: http://www.organic-chemistry.org/Highlights/2018/08January.shtm
Current investigations include rearrangements of aryl propargyl ethers and sulfides to make aromatic heterocycles.