Chemistry at Illinois University of Illinois at Urbana-Champaign

Martin D. Burke

associate Professor of Chemistry

Professor Burke completed his undergraduate studies at Johns Hopkins University in 1998 and his Ph.D. at Harvard University in 2003. After completing an M.D. at Harvard Medical School, he joined the faculty in the Department of Chemistry at the University of Illinois in June of 2005. His research interests are in the area of organic chemistry with a specific focus on the synthesis and study of small molecules with protein-like functions.

Research

Research in the Burke group focuses on the synthesis and study of small molecules with the capacity to perform protein-like functions. Ultimately, we envision such compounds serving as substitutes for missing or dysfunctional proteins, thereby operating as prostheses on the molecular scale. To enable these studies, we seek to develop new strategies and methods that make the process of complex small molecule synthesis as simple, efficient, and flexible as possible. We further aim to harness the power of this chemistry to illuminate the underpinnings of higher-order small molecule function in atomistic detail. Collectively, these efforts seek to make possible the development of molecular prosthetics as a general strategy for the understanding and betterment of human health. Specific examples of ongoing projects are described below:

Iterative Cross-Coupling (ICC): Towards a General Strategy for Complex Small Molecule Synthesis

To most effectively harness the potential impact of complex small molecules on both science and medicine, it is critical to maximize the simplicity, efficiency, and flexibility with which these types of compounds can be synthesized in the laboratory. In this regard, modern peptide synthesis, involving the iterative coupling of bifunctional amino acids represents a valuable benchmark. Amino acid building blocks are now commercially-available in suitably-protected form as stable, crystalline solids, and the process of peptide synthesis is routinely automated. As a result, this powerful discovery engine is accessible to a broad range of scientists. In sharp contrast, the laboratory synthesis of small molecules remains a relatively complex and non-systematized process. We are currently developing a simple and highly modular strategy for making small molecules which is analogous to peptide synthesis and involves iterative Suzuki-Miyaura cross-coupling of B-protected haloboronic acids. In this approach, building blocks are prepared (or in the future simply purchased) having all of the required functional groups preinstalled in the correct oxidation state and with the desired stereochemical relationships. These building blocks are then brought together via the recursive application of one mild reaction. Although certain small molecules are currently more amenable to this approach than others, the rapidly expanding scope of the Suzuki-Miyaura reaction, which increasingly includes sp3-sp3 couplings, suggests the potential for broad generality. Our long term goal is to create a general and automated process for the simple and flexible construction of a broad range of complex small molecules.

Towards the Total Synthesis of Amphotericin B via Iterative Cross-Coupling

The channel-forming natural product amphotericin B is a prominent example of the special utility that may be found in small molecules that perform higher-order functions. Specifically, in contrast to most antibiotics, microbial resistance to amphotericin B is extremely rare, and it is likely that the lack of a mutable protein target and lack of resistance are causatively linked. This relationship may prove to be general and merits intense inquiry. Moreover, in many ways amphotericin B represents a potential prototype for small molecules that replicate the functions of protein-based ion channels and thereby operate as prostheses on the molecular scale. However, despite more than five decades of research, the archetypal amphotericin B channel remains poorly understood at the molecular level precluding the rational pursuit of these objectives. An efficient, modular, and flexible total synthesis of this complex natural product stands to enable the first systematic dissection of the structure/function relationships that underlie its extraordinary ion channel activity. Taking advantage of the iterative cross-coupling strategy described above, we aim to synthesize amphotericin B using only the Suzuki-Miyaura reaction to bring together a collection of efficiently synthesized bifunctional building blocks.

Harnessing the Power of Synthesis to Probe the Structure and Function of the Amphotericin B Ion Channel

Molecular modeling studies predict that specific protic functional groups appended to the amphotericin B macrolide skeleton make important contributions to the self-assembly and/or ion transport properties of this prototypical small molecule-based ion channel. We aim to harness the power of organic synthesis to systematically test these hypothetical structure/function relationships. More specifically, we are employing a variety of approaches including total synthesis (described above), degradation of the natural product, and a hybrid semisynthetic approach to prepare a collection of amphotericin B derivatives that each lack one or more of the appended polar functional groups. We have found using multidimensional NMR techniques that the conformation of the macrolide skeleton is unaltered by these types of appendage deletions, greatly facilitating the interpretation of structure/function studies. Using the degradative synthetic approach, we have recently discovered that, in stark contrast to the leading model for channel self-assembly, oxidation at C(41) of the amphotericin B skeleton is not required for potent antifungal activity. Systematic evaluation of the complete collection of targeted derivatives in a battery of biological and biophysical assays stands to produce, for the first time, an atomistic understanding of the self-assembly and conducting properties of the potentially prototypical amphotericin B ion channel.

Publications

E.M. Woerly, J. Roy, M.D. Burke, “Synthesis of Most Polyene Natural Products Using Just Twelve Building Blocks and One Coupling Reaction”Nature Chemistry 2014, accepted in principle.

T.M.Anderson, M.C. Clay, A.G. Cioffi, K.A. Diaz, G.S. Hisao, M.D. Tuttle, A.J. Nieuwkoop, G. Comellas, S. Wang, B.E. Uno, E.L. Wildeman, N. Maryum, T. Gonen, C.M. Rienstra, M.D. Burke “Amphotericin forms an extramembranous and fungicidal sterol sponge.”Nature Chemical Biology,2014 ,in press.

B.C. Wilcock, M.M.Endo, B.E. Uno, M.D. Burke, “The C2’-OH of Amphotericin Plays a Major Role in Binding the Primary Sterol of Human But Not Yeast Cells”J. Am. Chem. Soc.2013,135,8488-8491.

B. C. Wilcock, B.E. Uno, G.L. Bromann, M.J. Clark, T.M. Anderson, M.D. Burke, "Electronic Tuning of Site-Selectivity"Nature Chemistry 2012, 4, 996-1003.

K.C. Gray, D.S. Palacios, I. Dailey, M. Endo, B.E. Uno, B.C. Wilcock, M.D. Burke, “Amphotericin Primarily Kills Yeast by Simply Binding Ergosterol.” Proc. Natl. Acad. Sci. 2012, 109, 2234-2239.

G.R. Dick, E.M. Woerly, M.D. Burke, “A General Solution to the 2-Pyridyl Problem” Angew. Chem. Int. Ed. 2012, 51, 2667-2672.

┬áJ. Li, M.D. Burke, “Pinene-Derived Iminodiacetic Acid (PIDA): A Powerful Ligand for Stereoselective Synthesis and Iterative Cross-Coupling of C(sp3)Boronate Building Blocks” J. Am. Chem. Soc. 2011, 131, 13774-13777.

S. Fujii, S.Y. Chang, M.D. Burke, "Total Synthesis of Synechoxanthin through Iterative Cross-Coupling" Angew. Chem. Int. Ed. 2011, Early View DOI: 10.1002/anie.201102688.

D.S. Palacios, I. Dailey, D.M. Siebert, B.C. Wilcock, M.D. Burke "Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities" Proc. Natl. Acad. Sci. U.S.A. 2011, Early Edition

M.D. Burke, D.S. Palacios, "The Prospect of Molecular Prosthetics" submitted.

E.M. Woerly, A.H. Cherney, E.K. Davis, M.D. Burke, "Stereoretentive Suzuki-Miyaura Coupling of Haloallenes Enables Fully Stereocontrolled Access to (-)-Peridinin" J. Am. Chem. Soc. 2010, 132, 6941-6943.

S.J. Lee, T.M. Anderson, M.D. Burke, "A Simple and General Platform for Generating Stereochemically Complex Polyene Frameworks via Iterative Cross-Coupling." Angew. Chem. Int. Ed. 2010, asap.

G.R. Dick, D.M. Knapp, E.P. Gillis, M.D. Burke, "A General Method for Synthesis of 2-Heterocyclic N-Methyliminodiacetic Acid Boronates" Organic Letters 2010, 12, 2314-2317.

I. Dailey, M.D. Burke. "N-(Carboxymethyl)-N-methyl-glycine" EROS, 2010, In Press.

J.R. Struble, S.J. Lee, M.D. Burke "Ethynyl MIDA Boronate, A Readily-Accessible and Highly Versatile Building Block for Small Molecule Synthesis." Invited Contribution to Tetrahedron:Special Issue in Honor of Professor Brian Stoltz' Tetrahedron Young Investigator Award 2010, 66, 4710-4718.

D.M. Knapp, E.P. Gillis, M.D. Burke. "A General Solution for Unstable Boronic Acids: Slow- Release Cross-Coupling from Air-Stable MIDA Boronates" J. Am. Chem. Soc. 2009, 131, 6961-6963.

M.D. Burke. "Flexible Tetracycline Synthesis Yields Promising Antibiotics" Nature Chemical Biology, News and Views 2009, 5, 77-79.

D.S. Palacios, M.D. Burke. "The Prospect of Molecular Prosthetics: Small Molecules with Protein-Like Functions" Angew. Chem. Int. Ed., 2009, Invited Review.

E.P. Gillis, M.D. Burke. "Iterative Cross-Coupling with MIDA Boronates: Towards a General Platform for Small-Molecule Synthesis" Aldrichimica Acta, 2009, 42, 17-27.

E.P. Gillis, M.D. Burke. "Multistep Synthesis of Complex Boronic Acids from Simple MIDA Boronates" J. Am. Chem. Soc. 2008, 130, 14084-14085.

S.G. Ballmer, E.P. Gillis, M.D. Burke. "B-Protected Haloboronic Acids for Iterative Cross- Coupling" Org. Syn. 2009, 86, 344-359.

B.E. Uno, E.P. Gillis, M.D. Burke. "Vinyl MIDA Boronate, A Readily-Accessible and Highly Versatile Building Block for Small Molecule Synthesis." 2008, ASAP, Invited Contribution to Tetrahedron: Special Issue in Honor of Professor Justin Dubois' Tetrahedron Young Investigator Award.

E.P. Gillis, M.D. Burke. "Multistep Synthesis of Complex Boronic Acids from Simple MIDA Boronates" J. Am. Chem. Soc. 2008, 130, 14084-14085

S.J. Lee, K.C. Gray, J.S. Paek, M.D. Burke. "Simple, Efficient, and Modular Syntheses of Polyene Natural Products via Iterative Cross-Coupling" J. Am. Chem. Soc. 2008, 130, 466-468.

D.S. Palacios, T.M. Anderson, M.D. Burke "A Post-PKS Oxidation of the Amphotericin B Skeleton Predicted to be Critical for Channel Formation is Not Required for Potent Antifungal Activity" J. Am. Chem. Soc. 2007, 129, 13804-13805.

E.P. Gillis and M.D. Burke. "A Simple and Modular Strategy for Small Molecule Synthesis: Iterative Suzuki-Miyaura Coupling of B-Protected Haloboronic Acid Building Blocks." J. Am. Chem. Soc. 2007, 129, 6716-6717.

Awards

  • 2014 Thieme-IUPAC Prize in Synthetic Organic Chemistry
  • 2014 Hirata Memorial Lectureship Award, Japan
  • 2014 International Organic Chemistry Foundation Lectureship Award, Japan
  • 2013 Elias J. Corey Award for Outstanding Contribution in Organic Synthesis by a Young Investigator, American Chemical Society
  • 2012 Novartis Chemistry Lectureship: Basel, Horsham, Shanghai, Singapore, San Francisco, and Cambridge
  • Arthur C. Cope Scholar Award, American Chemical Society, 2011
  • Bristol-Myers Squibb Lectureship at Harvard University, 2010
  • Frontiers in Chemistry Lectureship at The Scripps Research Institute, 2010
  • Novartis Lectureship at The University of California Berkeley, 2010
  • Howard Hughes Medical Institute Early Career Scientist, 2009
  • Alfred P. Sloan Foundation Research Fellowship
  • Bristol-Myers Squibb Unrestricted Grant in Synthetic Organic Chemistry, 2009
  • Eli Lilly Grantee Award, 2009
  • AstraZeneca Excellence in Chemistry Award, 2009
  • Howard Hughes Medical Institute Early Career Scientist Award, 2009
  • Amgen Young Investigator Award, 2009
  • Sloan Research Fellowship from the Alfred P. Sloan Foundation, 2009
  • Thieme Chemistry Journals Award, 2009
  • Arnold and Mabel Beckman Foundation Young Investigator Award, 2008
  • Teacher Ranked as Excellent, UIUC Center for Teaching Excellence, 2008
  • National Science Foundation CAREER Award, 2008
  • Teacher Ranked as Excellent, UIUC Center for Teaching Excellence, 2007
  • Teacher Ranked as Excellent, UIUC Center for Teaching Excellence, 2006
  • ACS Petroleum Research Foundation Type G Award, 2005
  • Camille and Henry Dreyfus New Faculty Award, 2005
  • Henry Asbury Christian Award, HMS, 2005
  • NIH Medical Scientist Training Program Fellowship, 2003
  • Howard Hughes Medical Institute Predoctoral Fellowship, 2000
  • Hunterian Research Award, JHMI, 1998

Highlights

Highlights

“The C2’-OH of Amphotericin Plays a Major Role in Binding the Primary Sterol of Human But Not Yeast Cells” J. Am. Chem. Soc. 2013, 135, 8488-8491.

  • Highlighted in Chemical and Eng. News, “A Less Toxic Antifungal Agent2013, 91, 10.

"Electronic Tuning of Site-Selectivity" Nature Chemistry 2012, 4, 996-1003.

  • Highlighted in Nature Chemistry, “Remodelling by diversity and design” 2012, 4, 963-964.

K.C. Gray, D.S. Palacios, I. Dailey, M.M. Endo, B.E. Uno, B.C. Wilcock, M.D. Burke. "Amphotericin primarily kills yeast by simply binding ergosterol" Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 2234-2239.

  • Highlighted in Nature Chemical Biology, "Channel Closure." 2012, 8, 222.
  • Highlighted in Proc. Natl. Acad. Sci. U.S.A. "50 Year Antimicrobial's Mechanism of Action." 2012, 109, 222.
  • Highlighted in Microbe Magazine "Amphotericin binds ergosterol instead of forming ion channels." 2012, 109, 222.

J. Li, M.D. Burke, “Pinene-Derived Iminodiacetic Acid (PIDA): A Powerful Ligand for Stereoselective Synthesis and Iterative Cross-Coupling of C(sp3)Boronate Building Blocks” J. Am. Chem. Soc. 2011, 131, 13774-13777.

  • Highlighted as News of the Week: "Prefab Synthesis Moves Ahead" by Chemical and Engineering News; August 29, 2011, p. 5

D.S. Palacios, I. Dailey, D.M. Siebert, B.C. Wilcock, M.D. Burke "Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities" Proc. Natl. Acad. Sci. U.S.A. 2011, Early Edition.

  • Highlighted in Chemical and Engineering News: "Amphotericin B Mystery Solved: Decades-long Question about Antifungal Agent's Mechanism is Answered." 2011, 89, 51.
  • Highlighted in Chemistry World "Chemical Mystery of Antifungal Compound Solved" March 9, 2011.

Burke's research featured in C&E News article: "New Way to Protect Unstable Boron Reagents: Masked boronates make 2-pyridyl coupling possible" by Stu Borman. Read the article in C&E News here.

E.P. Gillis, M.D. Burke. "Multistep Synthesis of Complex Boronic Acids from Simple MIDA Boronates" J. Am. Chem. Soc. 2008, 130, 14084-14085.

  • Highlighted in Chemistry World: "Organic synthesis set for auto-pilot" November 2008.

Chemistry World recently highlighted the Burke groups' research into automated organic synthesis in an article, "Organic Synthesis Set for Auto-Pilot". Read the Chemistry World article here.

Technology Review has selected Marty Burke as one of the "World's Top Innovators Under 35". Read the Technology Review article here.

Marty Burke has been selected as a "Scientist to Watch" by The Scientist magazine (July 2008, Vol 22, No. 7, pg 63). Read The Scientist article here.

Publication Highlights

The power of Iterative Cross-Coupling (ICC) to simplify the process of complex small molecule synthesis is highlighted in the April 2008 issue of SynForm.

Dr. Burke's research into iterative cross coupling chemistry was recently highlighted in "Off-the-Shelf Small Molecules on the way" by Patrick Walter, Chemistry & Industry, 2008.

"Simple, Efficient, and Modular Syntheses of Polyene Natural Products via Iterative Cross-Coupling&quot by S.J. Lee, K.C. Gray, J.S. Paek, and M.D. Burke was highlighted in Chemistry World magazine: Richard Van Noorden, "Off-the-peg organic synthesis goes commercial" Chemistry World Online 2007. http://www.rsc.org/chemistryworld/News/2007/December/20120701.asp

"A Post-PKS Oxidation of the Amphotericin B Skeleton Predicted to be Critical for Channel Formation is Not Required for Potent Antifungal Activity" by D.S. Palacios, T.M. Anderson, and M.D. Burke was featured in the Jan 1, 2008 issue of Nature Chemical Biology: Sergey Kozmin, "Chemical 'knockout' challenges the amphotericin B channel model" http://www.nature.com/nchembio/journal/v4/n1/full/nchembio0108-19.html

"A Simple and Modular Strategy for Small Molecule Synthesis: Iterative Suzuki-Miyaura Coupling of B-Protected Haloboronic Acid Building Blocks," by E.P. Gillis and M.D. Burke was highlighted in the June 18th 2007 issue of Chemical and Engineering News: S. Borman, "Masks unveil new synthetic routes" Chem. Eng. News 2007, 85, 63-64 http://pubs.acs.org/isubscribe/journals/cen/85/i25/html/8525sci1.html. It was also highlighted recently in SynFacts 2007, 10, 1007.

Patents

9. M.D. Burke et al, “Amphotericin B Derivatives with Improved Therapeutic Index” Provisional Application Filed Fall 2014.

8. M.D. Burke, B.C. Wilcock, M.M. Endo, B.E. Uno, “Amphotericin B Derivative with Reduced Toxicity” Provisional Application filed May 2013.

7. M.D. Burke, B.C. Wilcock "Electronic Tuning of Site Selectivity" Provisional Application filed October 12, 2012.

6. M.D. Burke, J.Q. Li, E.P. Gillis, PCT/US2012/035247 “Automated Synthesis of Small Molecules Using Chiral Nonracemic Boronates”

5. Burke et al PCT/US2011/045064 “Apparatus and Methods for the Automated Synthesis of Small Molecules”

4. M.D. Burke, J. Li, E.P. Gillis "Chiral Ligands for Making Boronates in Nonracemic Form" Provisional Application April 27, 2011.

  • Licensed to Sigma-Aldrich (Milwaukee, WI).
3. M.D. Burke, G.R. Dick, E.P. Gillis, J.A. Klubnick, D.M. Knapp, B.E. Uno, "Methods for Forming Protected OrganoBoronic Acids" U.S. Utilility Patent Application No.: 13/030,83. Claims Granted 7/23/2013.

  • Licensed to Sigma-Aldrich (Milwaukee, WI).

2. M.D. Burke, D.M. Knapp, E.P. Gillis, “Slow-Release of Unstable Boronic Acids from Air-Stable MIDA Boronates” Claims Granted 9/6/2012 (US09/58421).

  • Licensed to Sigma-Aldrich (Milwaukee, WI).

1. M.D. Burke, E.P. Gillis, S.J. Lee, D.M. Knapp, K.C. Gray, “System for Controlling the Reactivity of Boronic Acids” U.S. Patent # 8,013,203 Issued Sept. 6, 2011.

  • Licensed to Sigma-Aldrich (Milwaukee, WI), Boropharm (Ann Arbor, MI), and Allychem (Dalian, China) leading to the commercialization of more than 175 MIDA boronates to date, which are now being widely utilized to promote the discovery of new medicines by more than 70 different pharmaceutical companies throughout the world, including the U.S., Canada, United Kingdom, Germany, Spain, France, Switzerland, Denmark,Belgium, Sweden, Netherlands, China, Japan, Singapore, India, and Australia. Moreover, several MIDA boronates are already commercially available on the multi-kilogram scale, and one is already being used on the process scale toprepare a new drug candidate currently being evaluated in clinical trials in humans. The launch of this commercial platform was highlighted by CNN, Forbes, Tech.com, Chemical and Engineering News, Chemistry World, Genetic Engineering and BiotechnologyNews, Bio-Medicine, Pharmasia, and Merck Medicus.

A complete list of commercially available MIDA boronates can be found at: www.sigmaaldrich.com/mida

See also: http://www.sigmaaldrich.com/chemistry/chemical-synthesis/learning-center/chemfiles.html

Photo of Martin D. Burke