Burke Laboratories @ UIUC

Creating New Strategies and Methods for Small Molecule Synthesis

Three Facets of ResearchTo 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. A major bottleneck in understanding small molecule function lies in accessing structural derivatives of complex molecules for structure-activity relationship (SAR) studies. We are currently pursuing several complementary strategies that stand to accelerate the synthesis of complex small molecules with the ultimate aim of shifting the rate-limiting step in small molecule science from synthesis to function.
A) Synthesis via Iterative Cross-Coupling (ICC)


Iterative Cross-CouplingModern peptide synthesis, involving the iterative coupling of bifunctional amino acids represents an inspiring benchmark for a general and modular synthesis strategy that has dramatically accelerated functional discoveries in peptide science. In sharp contrast, the laboratory synthesis of small molecules remains a relatively complex and non-systematized process. We have developed 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 enabled by the N-methyliminodiacetic acid (MIDA) ligand that can reversibly attenuate the reactivity of boronic acids. Contrary to many other boron surrogates, MIDA boronates are air-stable, crystalline, and monomeric solids which can be purified by silica gel chromatography, making these boronates attractive for the realization of a universal platform.

MIDA Boronates are air-stable, crystalline, solids stable to silica gel chromatography

MIDA boronate building blocks having all of the required functional groups preinstalled in the correct oxidation state and with the desired stereochemical relationships are brought together via the recursive application of one mild reaction. The rapidly expanding scope of the Suzuki-Miyaura reaction, which increasingly includes stereospecific couplings of sp3 boronates, suggests the potential for broad generality of this strategy. 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, thereby making this powerful discovery engine widely accessible, even to the non-chemist. A broad range of natural products and pharmaceuticals have now been prepared using this approach. To broaden the generality of ICC, we are actively pursuing the synthesis of versatile boronate building blocks and strategies for enabling challenging cross-couplings for complex molecule synthesis.

B) Advanced Building Block Synthesis


MIDA Boronates are inert under many conditionsWe continue to discover that the MIDA ligand not only masks the reactivity of boron toward cross-coupling, but these boronates are surprisingly inert to a host of reaction conditions including treatment with nucleophiles, electrophiles, oxidants, reductants, acids, and several bases. This versatility has allowed us to prepare complex boron-containing building blocks from simple MIDA boronates which represent common motifs in natural products including 2-pyridyl, vinyl, (Z)-olefin, (E)-olefin, and ethynyl motifs. Currently more than 130 MIDA boronates are commercial from Sigma Aldrich (www.sigmaldrich.com/mida).

Common MIDA Boronates

Frontier challenges in cross-coupling reaction include the synthesis and stereospecific cross-couplings of sp3 boron-containing building blocks. Our group recently made advances into the stereoselective synthesis of sp3 boronates enabled by a chiral version of the MIDA ligand, termed pinene-derived iminodiacetic acid (PIDA). PIDA Boronates as chiral auxiliariesThe air-stable epoxy PIDA boronate can be transformed into the first reported stereo-defined a-boryl aldehyde via a novel boron migration. This versatile intermediate can be transformed into a variety of other sp3 boronate building blocks, including a B-protected haloboronic acid that is sp3-hybridized at both termini. We demonstrated that this bifunctional building block can undergo a sp3-sp2 ICC cycle to generate a chiral, non-racemic pharmaceutical in a concise, modular manner.
C)  Slow Release Cross-Coupling


Slow Release Cross-CouplingMany complex boronic acid building blocks are sensitive to decomposition through protodeboronation, polymerization, and oxidation. As such, strategies are needed to cross-couple these notoriously unstable organoboranes with high fidelity. 2-heterocyclic, vinyl and cyclopropyl derivatives, which represent substructures commonly found in natural products, pharmaceuticals and materials, are inherently unstable. This significantly limits their benchtop stability and utility as effective cross-coupling partners.

Our group has developed general solutions for these issues by using the corresponding MIDA boronates as bench-stable surrogates for these unstable boranes in slow-release cross-coupling. Using this strategy, we demonstrated that the corresponding MIDA boronates are excellent cross-coupling partners, even in traditionally challenging Suzuki-Miyaura cross-couplings. The use of K3PO4 in THF:H2O at elevated temperatures allows for the controlled release of the masked boronic acid, thus minimizing in situ decomposition caused by the Pd catalyst, base, and/or heat.

We further developed a general methodology to specially address the issue of extremely tough cross-couplings between 2-pyridyl boranes, which are notoriously susceptible to protodeboronation. With this improved catalyst system, even electronically deactivated aryl chlorides can be employed, as well as bromides, iodides and triflates. We envision that the synthesis and cross-couplings of robust MIDA boronates via in situ release of the boronic acids will lead to expanding utility of these versatile and important building blocks in both complex natural product and pharmaceutical synthesis settings.Cross-Coupling of the 2-Pyridyl Motif

It is our ultimate goal to harness the remarkable simplicity of these methods and robust nature of the B-protected haloboronic acid building blocks to develop a fully-automated small molecule synthesis process analogous to modern peptide coupling. Achieving this goal has the potential to make this powerful discovery engine maximally accessible, even to the non-chemist. Achieving this goal will broadly enable the more effective study and widespread utilization of these extraordinary classes of compounds.

Recent Burke Group publications in this area

1. 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.

2. 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, 133, 13774-13777.

3. S. Fujii, S.Y. Chang, M.D. Burke. "Total Synthesis of Synechoxanthin through Iterative Cross-Coupling"Angew. Chem. Int. Ed. 2011, 50, 7862-7864.

4. S.J. Lee, T.M. Anderson, M.D. Burke. "A Simple and General Platform for Generating Stereochemically Complex Polyene Frameworks by Iterative Cross-Coupling" Angew. Chem. Int. Ed. 2010, 47, 8860-8863

5. 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.

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

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

8. 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.

9. E.P. Gillis, 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.

    This paper 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. It was also highlighted in SynFacts 2007, 10, 1007.