Charles K. Zercher

Professor
Associate Dean College of Engineering & Physical Sciences

Department of Chemistry
University of New Hampshire
Durham, NH 03824-3598 U.S.A.
Office: 603-862-2697
Lab: 603-862-0187
Fax: 603-862-4278
chuck.zercher@unh.edu

Group members:(front) Dr. Zercher, Jen Mazzone, Carley Spencer, Alex Jacobine.
(back) Ian Taschner, Tim Henderson.


Chuck Zercher earned a BA in Chemistry at Messiah College in Grantham, PA. His graduate education initiated with studies in Medicinal Chemistry at the State University of New York at Buffalo leading to an MS degree in 1985. He received a PhD in Chemistry at the University of Notre Dame 1989 where he studied under the direction of Marvin Miller. Following post-doctoral studies in the laboratory of Paul Wender at Stanford University, Chuck joined the faculty at the University of New Hampshire. He was awarded the University of New Hampshire's Outstanding Assistant Professor Award in 1996 and was promoted to Professor in 2003. His teaching interests include synthetic methods and strategies, organic spectroscopy, and introductory organic chemistry.

Research Interests

Synthetic organic chemistry; The development of novel and efficient synthetic methods to produce natural and unnatural products

General Research Goals

Our research interest focuses on the development of novel and efficient synthetic methods. Although many natural and unnatural products are under current investigation by organic chemists for reasons that range from chemotherapeutic research to host-guest interactions, the synthetic methods which allow the stereocontrolled preparation of complex functionality are often underdeveloped for the task at hand. It is our goal to contribute to the development of novel synthetic methods and strategies, thereby facilitating the preparation of these complex synthetic targets.

Zinc-mediated Chain Extension

One of the reactions under investigation is an efficient zinc-mediated chain extension, which was discovered in our research group a few years ago. Exposure of a β-keto ester (1) to the Furukawa-modified Simmons-Smith reagent results in the insertion of a methylene unit between the two carbonyls. While all of the mechanistic details are not known, it appears that an intermediate cyclopropoxide (2) is generated, which fragments to provide a zinc enolate equivalent (3). Simple protonation of the enolate provides the chain extended material (4). The chain extension reaction proceeds efficiently with β-keto ester, amide, or phosphonate substrates.

We have elaborated on the fundamental chain extension reaction through the stereo-controlled addition of other electrophiles, like aldehydes, ketones, iminium ions, halogens, and electrophilic carbenoids. The result is a reaction that converts easily accessible β-dicarbonyl functionality into heavily functionalized γ-dicarbonyl systems. We are applying the chain extension reaction to a variety of synthetic targets, including amino acids isosteres, ribonucleoside analogues, and natural products.

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Ketal-derived Oxonium Ylide Formation and Rearrangement

Another research project underway in our groups involves the investigation of ketal-derived oxonium ylide formation and rearrangement. We are particularly interested in substrates in which an α-diazo-β-keto ester or an α-diazo ketone functionality is tethered to a functionalized ketal. When these substrates are exposed to catalytic Rh(II) or Cu(I), decomposition of the diazo functionality is followed by oxonium ylide formation through attack of a ketal oxygen. The oxonium ylides that are generated are extremely reactive and undergo immediate rearrangement. A variety of rearrangement pathways are available to the ylide, although the substitution pattern of the ketal is the major determining feature. Nicely functionalized bicyclic and tricyclic ketal skeletons are available through the rearrangement of these ylides.

These bicyclic and tricyclic ketals form the fundamental core of a number of natural products, including the zaragozic acids, tirandamycin, and Bu-2313. We have initiated efforts to apply this methodology to the synthesis of these complex natural products. Rearrangement of the bicyclic ketal skeleton into a spirolactone provides an attractive entry into the hyperolactone family of natural products.

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Publications

Syntheses of Papyracillic Acids: Application of the Tandem Chain Extension-Acylation Reaction, Mazzone, J. A.; Zercher, C. K. J. Org. Chem. 2012, 77, 9171-9178,

A Combined DFT and NMR Investigation of the Zinc Organometallic Intermediate Proposed in the Syn-Selective Tandem Chain Extension-Aldol Reaction of β‑Keto Esters, Aiken, K. A.; Eger, W. A.; Williams, C. M.; Spencer, C. M.; Zercher, C. K. J. Org. Chem. 2012, 77, 5942-5955.

Tandem Chain Extension-Mannich Reaction: An Approach to b-Proline Derivatives, Jacobine, A. M.; Puchlopek, A. L. A.; Zercher, C. K.; Briggs, J. B.; Jasinski, J. P.; Butcher, R. J. Tetrahedron 2012, 68, 7799–7805.

Small Organic Solutes in Sticky Droplets from Orb Webs of the Spider Zygiella atrica (Araneae; Araneidae): b-Alaninamide is a Novel and Abundant Component, Townley, M. A.; Pu, Q.; Zercher, C. K.; Neefus, C. D.; Tillinghast, E. K. Chem. Biodiv. 2012, 10, 2159–2174.

Tandem Chain Extension-Aldol Reaction Used for Synthesis of Stabilized Ketomethylene Prodrugs Targeting hPEPT1, Thorn, K.; Nielsen, C. U.; Jakobsen, P.; Steffansen, B.; Zercher, C. K.; Begtrup, M., Bioorg. & Med. Chem. Lett. 201121, 4597-4601.

A Mechanistic Investigation into the Zinc Carbenoid-mediated Homologation Reaction by DFT methods: Is a Classical Donor-Acceptor Cyclopropane Intermediate Involved? Eger, W.; Zercher, C. K.; Williams, C. M. J. Org. Chem. 2010, 75, 7322-7331.

Stereoselective Formation of a Functionalized Dipeptide Isostere by Zinc Carbenoid-mediated Chain Extension, Lin, W.; Theberge, C. R., Henderson, T. J.; Zercher, C.K., Jasinski, J. P., Butcher, R. J. J. Org. Chem. 2009, 74, 645-651.

Stereoselective Formation of a Functionalized Dipeptide Isostere by Zinc Carbenoid-mediated Chain Extension, Lin, W.; Theberge, C. R.; Henderson, T. J.; Zercher, C. K.; Jasinski, J. P., Butcher, R. J. J. Org. Chem. 2009, 74, 645-651.

Tandem Chain Extension-Iodomethylation Reactions: Formation of α-Functionalized γ-Keto Carbonyls, Pu, Q.; Wilson, E.; Zercher, C. K. Tetrahedron 2008, 64, 8405-8051.

Formation of γ-Lactones through CAN-Mediated Oxidative Cleavage of Hemiketals, Jacobine, A.M.; Lin, W.; Walls, B.; Zercher, C. K. J. Org. Chem. 2008, 73, 7409-7412.

Formation of Substituted γ-Keto Esters via Zinc Carbenoid-Mediated Chain Extension, Lin, W.; McGinness, R.J.; Wilson, E.; Zercher, C. K. Synthesis 2007, 2404-2408.

Formal Synthesis of (+)-Brefeldin A: Application of a Zinc-mediated Ring Expansion Reaction, Lin, W.; Zercher, C. K. J. Org Chem. 2007, 72, 4390-4395.

Stereocontrolled Formation of Ketomethylene Isosteres through Tandem Chain Extension Reactions, Lin, W.; Tryder, N.; Su, F.; Zercher, C. K., Jasinski, J. P., Butcher, R. J. J. Org. Chem. 2006, 71, 8140-8145.

Chain Extension of Amino Acid Skeletons: Preparation of Ketomethylene Isosteres, Theberge, C.R.; Zercher, C. K. Tetrahedron 2003, 59, 1521-1527.

Zinc Carbenoid-mediated Chain Extension: Preparation of α,β-Unsaturated-γ-Keto Esters and Amides, Ronsheim, M. D.; Zercher, C. K. J. Org. Chem. 2003, 68, 4535-4538.

Ring Expansions of β-Keto Lactones with Zinc Carbenoids: Synthesis of (+)-Patulolide A, Ronsheim, M. D.; Zercher, C. K. J. Org. Chem. 2003, 68, 1878-1885.

Formation of γ-Keto Esters from β-Keto Esters: Methyl 5,5-Dimethyl-4-Oxo-Hexanoate, Ronsheim, M. D.; Hilgenkamp, R.; Zercher, C. K. Org. Synth. 2002, 79, 146-153.

Zinc Carbenoid-mediated Chain Extension of β-Keto Amides, Hilgenkamp, R.; Zercher, C. K. Tetrahedron 2001, 57, 8793-8800.

Tandem Chain Extension-Homoenolate Formation: The Formation of α-Methylated-γ-Keto Esters, Hilgenkamp, R., Zercher, C. K. Org. Lett. 2001, 3, 3037-3040.

Tandem Chain Extension-Aldol Reaction: Syn Selectivity with a Zinc Enolate, Lai, S-J.; Zercher, C. K.; Jasinski, J. P.; Reid, S. N.; Staples, R. J. Org. Lett. 2001, 3, 4169-4171.

Preparation of γ-Keto Phosphonates via a Zinc-carbenoid Chain Extension Reaction, Verbicky, C. A.; Zercher, C. K. J. Org. Chem. 2000, 65, 5615-5622.

Olefin Cross-Metathesis in the Preparation of Polycyclopropanes: Formal Synthesis of FR-900848, Verbicky, C. A.; Zercher, C. K. Tetrahedron Lett. 2000, 41, 8723-8727.

Preparation of 1,4-Dioxenes from α-Diazo-β-Keto Esters, Hilgenkamp, R.; Brogan, J. B.; Zercher, C. K. Heterocycles 1999, 51, 1073-1078.

Preparation of the Zaragozic Acid Core through Rearrangement of an Oxonium Ylide, Brogan, J. B.; Zercher, C. K. Tetrahedron Lett.1998, 39, 1691-1694.

Facile Zinc-mediated Conversion of β-Keto Esters to γ-Keto Esters, Brogan, J. B.; Zercher, C. K.; J. Org. Chem. 1997, 62, 6444-6446.