Creating New Strategies and Methods for 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. 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.
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.
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). The 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.
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.