UW-Madison School of Pharmacy

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Richard P Hsung, PhD

Laura and Edward Kremers Distinguished Chair





I. [4 + 3] Cycloaddition Chemistry of Allenamides We have been examining extensively the chemistry of allenamides in the last 15 years. We have developed a diverse array of major reactions associated with this new class of allenes and applied to a formal total synthesis of zincophorin. Most significantly, we achieved a tandem epoxidation and oxyallyl cation [4 + 3] cycloaddition using chiral allenamides. The epoxidation of allenamides proves to be an excellent source of chiral, nitrogen stabilized oxyallyl cations. We were able to develop highly regio- and stereoselective inter- and intramolecular oxyallyl cation [4 + 3] cycloadditions. Recently, not only were we able to achieve the first asymmetric [4 + 3] cycloaddition using copper-bisoxazoline systems, but more significantly, in collaboration with Professor Ken Houk at UCLA and Dr. Elizabeth Krenske at University of Melbourne, we are beginning to construct a theoretical model for understanding and predicting regioselectivities of this important cycloaddition.

II. Stereoselective Methods Using Chiral Ynamides In a related but different area, we have developed the chemistry of ynamides as stable equivalents of Ficini's ynamines, which has evolved into a burgeoning field with the followings of many research groups around the world. Our work has rekindled the interest of the synthetic community toward this very interesting class of functional group. 16 Years ago, we placed particular emphasis on developing a highly efficient synthesis of ynamides in order to provide the kind of accessibility that may allow the community to view ynamides as a user-friendly functional group in organic synthesis. Toward this goal, we developed a Cu(II)-catalyzed C-N bond formation involving sp-hybridized carbons. This catalytic amidation provides a direct entry to chiral ynamides via N-alkynylation of amides. Our work and those that followed have had a huge impact on the field, allowing many research groups to freely develop methods of their interest using ynamides as an organic functional group. Recently, we were able to finally succeed in developing an ynamide version of Ficini's thermal [2 + 2] cycloaddition with alpha,beta-unsaturated carbonyl systems.

III. Natural Product Total Syntheses We have developed a bio-inspired [3 + 3]-annulation reaction or formal cycloaddition of vinylogous amides or diketones with alpha,beta-unsaturated iminium salts that can be used to construct heterocycles. The transformation involves a tandem Knoevenagel-6pi-electron electrocyclic hetero ring-closure. This process has allowed us to achieve numerous total syntheses of complex natural products such as arisugacin A, simulenoline, huajiaosimuline, tangutorine, hongoquercin A, perhydrohistrionicotoxin, cylindricines, lepadiformine, the entire lepadin family, the aza-phenylene family, rhododaurichromanic acids, and most recently, phomactin A.

IV. Cyclic Acetal-Tethered Reactions and Natural Product Syntheses Cyclic acetal-tethered intramolecular reactions, specifically intramolecular Diels-Alder [IMDA] and RCM reactions, which are areas that have not been widely studied, are pursued in our lab, as well as approaches to fusidilactone C and spirastrellolide A, spiroketal-containing natural products that first provoked our interest in cyclic acetal-tethered strategies. These investigations are of significance because they can lead to conceptually and fundamentally different approaches to spiroketal-related complex natural products such as our recent success with a total synthesis of aigialospirol.

V. Cationic [2 + 2] Cycloadditions We have been developing thermally driven [2 + 2] cycloadditions for constructing cyclobutanes, which is an effort that will contribute significantly to an area of cycloaddition chemistry that is under-explored. A successful cationic version of [2 + 2] cycloaddition would also represent a bio-mimetic process to cyclobutanes. Specifically, we have succeeded in an intramolecular Gassman's cationic [2 + 2] cycloaddition and are currently exploring its application in natural product syntheses.

Richard P. Hsung went to Calvin College in Grand Rapids, MI, for his BS in Chemistry and Mathematics, and worked in Professors Ron Blankespoor and Ken Piers' laboratories. He attended The University of Chicago for his MS and PhD degrees in Organic Chemistry under supervisions of Professors Jeff Winkler and Bill Wulff, respectively. After pursuing post-doctoral research at Chicago with Professor Larry Sita, he completed his training as an NIH post-doctoral fellow with Professor Gilbert Stork at Columbia University. He began his independent career at University of Minnesota–Twin Cities and subsequently moved to University of Wisconsin–Madison. He was the recipient of an NSF Career Development Award and The Camille Dreyfus Teacher-Scholar Award, and served as the Chair of the 57th Gordon Research Conferences on Organic Reactions & Processes. He is currently the Laura and Edward Kremers Endowed Chair in Natural Products Chemistry.  He has co-authored over 250 publications, book chapters, and reviews, delivered over 200 invited lectures, and supervised over 160 students and post-doctoral fellows with research interests in developing cycloaddition and annulation approaches to natural product total syntheses and stereoselective methods using allenamides, ynamides, enamides, and cyclic acetals.

Highlighted Publications:
  • "Cycloaddition Reactions of Novel Chiral 1,3,5-Dieneynes from 1,3-H-Shift of Allenamides." Ma, Z.-X.; Fang, L.-C.; Haugen, B. J.; Bruckbauer, D.; Feltenberger, J. B.; Hsung, R. P. Synlett 2017, 0000–0000. [Special Issue Dedicated to Professor Victor Snieckus on the Occasion of His 80th Birthday]
  • "Total Syntheses of (±)-Rhodonoids C, D, E, F, and G and Ranhuadujuanine B." Wu, H.; Hsung, R. P.; Tang, Y. Organic Lett. 2017, 19, 3505–3507.
  • "Cinchonine Induced Apoptosis in HeLa and A549 Cells Through Targeting TRAF6. "Qi, Y.; Pradipta, A. R.; Li, M.; Zhao, X.; Lu, L.; Fu, X.; Wei, J.; Hsung, R. P.; Tanaka, K.; Zhou, L. J. Exp. Clin. Canc. Res. (JECCR) 2017, 36, 1–15.
  • "Total Syntheses of (±)-Rhodonoids A and B and C12-Epi-Rhodonoid B."Wu, H.; Hsung, R. P.; Tang, Y. J. Org. Chem. 2017, 82, 1545–1551.
  • "Transition State Gauche Effects Control the Torquoselectivities of the Electrocyclizations of Chiral 1-Azatrienes." Patel, A.; Vella, J.; Ma, Z.-X.; Hsung, R. P.; Houk, K. N. J. Org. Chem. 2015, 80, 11888−11894. [A Special Issue Honoring The Woodward-Hoffmann Rules: "50 Years and Counting: The Woodward-Hoffmann Rules in the 21st Century"]
  • "A Computational View On the Significance of E-Ring in Binding of (+)-Arisugacin A to Acetylcholinesterase."  Al-Rashid, Z. F.; Hsung, R. P.  Bioorg. Med. Chem. Lett. 2015, 25, 4848–4853.  [A Special Symposium-in-Print: "Recent Advances in Medicinal Chemistry and Chemical Biology" Commemorating the 25th Anniversary Year for Bioorganic and Medicinal Chemistry Letters]
  • "AlCl3-Catalyzed Ring-Expansion Cascades of Bicyclic Cyclobutenamides Involving Highly Strained Cis,Trans-Cycloheptadienone Intermediates." Wang, X.-N.; Krenske, E. H.; Johnston, R. C.; Houk, K. N.; Hsung, R. P. J. Am. Chem. Soc. 2015, 137, 5596–5601.
  • "Highly Torquoselective Electrocyclizations and Competing 1,7-Hydrogen Shifts of 1-Azatrienes with Silyl-Substitution at the Allylic Carbon." Ma, Z.-X.; Patel, A.; Houk, K. N.; Hsung, R. P. Organic Lett. 2015, 17, 2138–2141.
  • "A Highly Regio- and Stereoselective Synthesis of α-Fluorinated-Imides via Fluorination of Chiral Enamides." Xu, Y.-S.; Tang, Y.; Feng, H.-J.; Liu, J.-T.; Hsung, R. P. Organic Lett. 2015, 17, 572–575.
  • "A Silver(I)-Catalyzed Intramolecular Ficini’s [2 + 2] Cycloaddition Employing Ynamides." Wang, X.-N.; Ma, Z.-X.; Deng, J.; Hsung, R. P. Tetrahedron Lett. 2015, 56, 3463–3467. [Dedicated to The Late Professor Harry H. Wasserman for His Life-Long Contributions to Tetrahedron Publications]
  • "Ynamides in Ring Forming Transformations." Wang, X.-N.; He, S.-Z.; Fang, L.; Yeom, H.-S.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560–578.
  • "An Approach toward Constructing The Trioxadispiroketal Core in DEF-Ring of (+)-Spirastrellolide A." Wu, Y.-B.; Tang, Y.; Luo, G.-Y.; Chen, Y.; Hsung, R. P. Organic Lett. 2014, 16, 4550–4553.
  • "Torquoselective Ring-Opening of Fused Cyclobutenamides. Evidence of A Cis,Trans-Cyclooctadienone Intermediate." Wang, X.-N.; Krenske, E. H.; Johnston, R. C.; Houk, K. N.; Hsung, R. P. J. Am. Chem. Soc. 2014, 136, 9802–9805.
  • "Novel Ynamide Structural Analogues and Their Synthetic Transformations." [An Invited Highlight] Lu, T.; Hsung, R. P. ARKIVOC: 2014, 127–141.
  • "A Formal [3 + 3] Cycloaddition Approach to Natural Product Synthesis." [An Invited Book Chapter] Deng, J.; Wang, X.-N.; Hsung, R. P. In Methods and Applications of Cycloaddition Reactions in Organic Syntheses.  Nishiwaki, N., Ed.  Wiley-VCH: 2014, Chapter 12.
  • "Practical Synthesis of Novel Chiral Allenamides. (R)-4-Phenyl-3-(1,2-Propadienyl)oxazolidin-2-one[2-Oxazolidinone, 4-Phenyl-3-(1,2-Propadienyl)-, (4R)-]." [An Invited Discussion Addendum] Teo, Y. C.; Hsung, R. P. Organic Synth. 2014, 91, 12–26.
  • "An Approach to Cyclohepta[b]indoles Through an Allenamide (4 + 3) Cycloaddition–Grignard Cyclization–Chugaev Elimination Sequence." He, S.; Hsung, R. P.; Presser, W. R.; Ma, Z.-X.; Haugen, B. J. Organic Lett. 2014, 16, 2180–2183.
  • "A Stereoselective Synthesis of Isoquinuclidines Through an Aza-[4 + 2] Cycloaddition of Chiral Cyclic 2- Amidodienes." Fang, L.-C.; Hsung, R. P. Organic Lett. 2014, 16, 1826–1829.
  • "Synthesis of de novo Chiral gamma-Amino-Ynamides Using Lithiated Ynamides. Observation of a Unique 5-Endo-Dig Cyclization with an Inversion of S-Center." Wang, X.-N.; Hsung, R. P.; Rui, Q.; Fox, S. K.; Lv, M.-C. Heterocycles 2014, 89, 1233–1254. [Special Issue Dedicated to Professor Victor Snieckus on the Occasion of His 77th Birthday]
  • "A Highly Stereoselective Diels-Alder Cycloaddition of Chiral Cyclic 2-Amidodienes Derived from Allenamides." Fang, L.-C.; Hsung, R. P.; Ma, Z.-X.; Presser, W. R. Organic Lett. 2013, 15, 4842–4845.
  • "Total Syntheses of Cannabicyclol, Clusiacyclol A and B, Iso-Eriobrucinol A and B, and Eriobrucinol." Yeom, H.-S.; Li, H.; Tang, Y.; Hsung, R. P. Organic Lett. 2013, 15, 3130–3133.
  • "Allenamides: A Versatile Synthetic Building Block in Organic Synthesis." Lu, T.; Lu, Z.; Ma, Z.-X.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2013, 130, 4862–4904.
  • "Intramolecular Oxyallyl–Carbonyl (3+2) Cycloadditions." Krenske, E. H.; He, S.-Z.; Huang, J.; Du, Y.; Houk, K. N.; Hsung, R. P. J. Am. Chem. Soc. 2013, 135, 5242–5245.
  • "Total Synthesis of Phomactin A." Tang, Y.; Cole, K. P.; Hsung, R. P. In Total Synthesis of Natural Products: At the Frontiers of Organic Chemistry. Li, J. J., Corey, E. J., Eds. Springer: Heidelberg, Germany, 2013.
  • "Control of Regioselectivity and Stereoselectivity in (4+3) Cycloadditions of Chiral Oxyallyls with Unsymmetrically Disubstituted Furans." Du, Y.-F.; Krenske, E. H.; Antoline, J. E.; Lohse, A. G.; Houk, K. N.; Hsung, R. P. J. Org. Chem. 2013, 78, 1752–1759. [Special Issue Honoring Professor Howard Zimmerman]
  • "Total Syntheses of Putative (±)-Trichodermatide B and C." Li, Q.; Xu, Y.-S.; Ellis, G. A.; Bugni, T. S.; Tang, Y.; Hsung, R. P. Tetrahedron Lett. 2013, 54, 5567–5572.
  • "A Convenient Synthesis of γ−Amido-Ynamides via Additions of Lithiated Ynamides to Aryl Imines. Observation of An Aza-Meyer-Schuster Rearrangement." Rui, Q.; Wang, X.-N.; DeKorver, K. A.; Tang, Y.; Wang, C.-C.; Li, Q.; Li, H.; Lv, M.-C.; Yu, Q.; Hsung, R. P. Synthesis 2013, 45, 1749–1758. [Special Issue Dedicated to Professor Scott E. Denmark on the Occasion of His 60th Birthday]
  • "Catalytic Asymmetric (4 + 3) Cycloadditions Using Allenamides." Du, Y.-F.; Hsung, R. P. In Asymmetric Synthesis II: Methods and Applications. Christmann, M., Bräse, S., Eds. Wiley-VCH, Verlag & Co. KGaA: Weinheim, Germany, Chapter 30, 2012.
  • "Alpha-Aryl-Substituted Allenamides in an Imino Nazarov Cyclization Catalyzed by Au(I)." Ma, Z.-X.; He, S.; Song, W.; Hsung, R. P. Organic Lett. 2012, 14, 5736–5739.
  • "Gassman's Cation [2 + 2] Cycloadditions Using Temporary Tethers." Deng, J.; Hsung, R. P.; Ko, C. Organic Lett. 2012, 14, 5562–5565.
  • "An Intramolecular [2 + 2] Cycloaddition of Ketenimines via Palladium-Catalyzed Rearrangements of N-Allyl-Ynamides." DeKorver, K. A.; Hsung, R. P.; Song, W.-Z.; Walton, M. C.; Wang, X.-N. Organic Lett. 2012, 14, 3214–3217.
  • "Total Syntheses of Chelidonine and Norchelidonine Via an Enamide-Benzyne-[2 + 2] Cycloaddition Cascade." Ma, Z.-X.; Feltenberger, J. B.; Hsung, R. P. Organic Lett. 2012, 14, 2742–2745.
  • "Carbocyclization Cascades of Allyl Ketenimines Via Aza-Claisen Rearrangements of N-Phosphoryl-N-Allyl-Ynamides. "DeKorver, K. A.; Wang, X.-N.; Walton, M. C.; Hsung, R. P. Organic Lett. 2012, 14, 1768–1771.
  • "A Tandem 1,3-H-Shift-6pi-Electron Pericyclic Ring-Closure-Intramolecular Diels-Alder Cycloadditions Approach to BCD-Ring of Atropurpuran." Hayashi, R.; Ma, Z.-X.; Hsung, R. P. Organic Lett. 2012, 13, 252–255.
  • "Challenges in Constructing the Architecturally Distinctive ABD-Tricycle via An Intramolecular Oxa-[3+ 3] Annulation Strategy." Buchanan, G. S.; Cole, K. P.; Li, G.; Tang, Y.; You, L.; Hsung, R. P. Tetrahedron 2011, 67, 10105–10118. [Tetrahedron-Symposium-In-Print Dedicated to Professor Gilbert Stork's 90th Birthday]
  • "Stereoselectivities and Regioselectivities of (4+3) Cycloadditions Between Allenamide-Derived Chiral Oxazolidinone-Stabilized Oxyallyls and Furans: Experiment and Theory." Antoline, J. E.; Krenske, E. H.; Lohse, A. G.; Hsung, R. P.; Houk, K. N. J. Am. Chem. Soc. 2011, 133, 14443–14451.
  • "Introducing the New Class of N-Phosphoryl Ynamides via Cu(I)-Catalyzed Amidations of Alkynyl Bromides." DeKorver, K. A.; Walton, M. C.; North, T. D.; Hsung, R. P. Organic Lett. 2011, 13, 4862–4865.
  • "Asymmetric Aza-[3 + 3] Annulation in the Synthesis of Quinolizidine Alkaloids: An Unexpected Reversal of Regiochemistry." Buchanan, G. S.; Dai, H.; Hsung, R. P.; Gerasyuto, A. I.; Schienebeck, C. M. Organic Lett. 2011, 13, 4402–4405.
  • "Oppolzer-Type Intramolecular Diels-Alder Cycloadditions via Isomerizations of Allenamides." Feltenberger, J. B.; Hsung, R. P. Organic Lett. 2011, 13, 3114–3117.
  • "Total Synthesis of Phomactin A. Lessons Learned from Respecting a Challenging Structural Topology." Buchanan, G. S.; Cole, K. P.; Tang, Y.; Hsung, R. P. J. Org. Chem. 2011, 76, 7027–7039.
  • "(+)-Arisugacin A: Computational Evidence of a Dual Binding Site Covalent Inhibitor of Acetylcholinesterase." Al-Rashid, Z. F.; Hsung, R. P. Bioorg. Med. Chem. Lett. 2011, 21, 2687–2691. [Symposium-In-Print in Recognition of the Journal's 20 Years of Service to Medicinal Chemistry Community]
  • "Resveratrol Metabolites Do Not Elicit Early Pro-Apoptotic Mechanisms in Neuroblastoma Cells." Kenealey, J. D.; Subramanian, L.; Van Ginkel, P. R.; Darjatmoko, S.; Lindstrom, M. J.; Somoza,V.; Ghosh, S. K.; Song, Z.; Hsung, R. P.; Kwon, G. S.; Eliceiri, K.; Albert, D. M.; Polans, A. S. J. Agric. Food. Chem.2011, 59, 4979–4986.
  • "Stereoselectivity in Oxyallyl-Furan 4+3 Cycloadditions: Control of Intermediate Conformations and Dispersive Stabilization in Cycloadditions Involving Oxazolidinone Auxiliaries." Krenske, E. H.; Houk, K. N.; Lohse, A. G.; Antoline, J. E.; Hsung, R. P. Chem. Science 2010, 1, 387–392.
  • "Ynamides: A Modern Functional Group In the New Millennium." DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung R. P. Chem. Rev. 2010, 110, 5064–5106.