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MIDA boronates are hydrolysed fast and slow by two different mechanisms

Nature Chemistry volume 8, pages 1067–1075 (2016)Cite this article

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Abstract

MIDA boronates (N-methylimidodiacetic boronic acid esters) serve as an increasingly general platform for small-molecule construction based on building blocks, largely because of the dramatic and general rate differences with which they are hydrolysed under various basic conditions. Yet the mechanistic underpinnings of these rate differences have remained unclear, which has hindered efforts to address the current limitations of this chemistry. Here we show that there are two distinct mechanisms for this hydrolysis: one is base mediated and the other neutral. The former can proceed more than three orders of magnitude faster than the latter, and involves a rate-limiting attack by a hydroxide at a MIDA carbonyl carbon. The alternative ‘neutral’ hydrolysis does not require an exogenous acid or base and involves rate-limiting B–N bond cleavage by a small water cluster, (H2O)n. The two mechanisms can operate in parallel, and their relative rates are readily quantified by 18O incorporation. Whether hydrolysis is ‘fast’ or ‘slow’ is dictated by the pH, the water activity and the mass-transfer rates between phases. These findings stand to enable, in a rational way, an even more effective and widespread utilization of MIDA boronates in synthesis.

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Figure 1: Hydrolytic deprotection and coupling of MIDA boronates.
Figure 2: Distinction of limiting pathways for basic (fast, A), neutral (slow, F) and acidic (G) hydrolysis of 1a.
Figure 3: Kinetics of fast and slow hydrolysis of MIDA boronate 1a.
Figure 4: KIEs for Ar-B(MIDA) (1a) hydrolysis.
Figure 5: Fast-release hydrolysis (kOH).
Figure 6: Slow-release hydrolysis (k0).

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Acknowledgements

G.C.L.-J. is a European Research Council (ERC) Advanced Investigator. The research leading to these results has received funding from the ERC under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement No. 340163, and the US National Institutes of Health. G.C.L.-J. and J.A.G. thank CONACYT and The University of Edinburgh for generous support. M.D.B. acknowledges financial support from the US National Institutes of Health (GM118185). P.H.-Y.C. is the Bert and Emelyn Christensen Professor of Oregon State University and acknowledges financial support from the Stone family and the US National Science Foundation (NSF, CHE-1352663). K.N.H. is the Saul Winstein Chair in Organic Chemistry at the University of California Los Angeles and acknowledges financial support from the US NSF (CHE-1059084). O.M.O. acknowledges Tartar research support. O.M.O. and P.H.-Y.C. also acknowledge computing infrastructure in part provided by the NSF Phase-2 CCI, Center for Sustainable Materials Chemistry (NSF CHE-1102637).

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Authors and Affiliations

  1. EaStCHEM, School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK

    Jorge A. Gonzalez & Guy C. Lloyd-Jones

  2. Department of Chemistry, Oregon State University, Corvallis, 97331, Oregon, USA

    O. Maduka Ogba, Nicholas Rosson & Paul H.-Y. Cheong

  3. Department of Chemistry, University of Illinois, 454 RAL, Box 52-5 600 South Mathews Avenue, Urbana, 61801, Illinois, USA

    Gregory F. Morehouse & Martin D. Burke

  4. Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles, 90095-1569, California, USA

    Kendall N. Houk

  5. School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK

    Andrew G. Leach

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Contributions

Experimental work was conducted by J.A.G. and G.F.M. Computational work was conducted by O.M.O., N.R., P.H.-Y.C. and A.G.L. G.C.L.-J., M.D.B., P.H.-Y.C., A.G.L. and K.N.H. wrote the manuscript.

Corresponding authors

Correspondence to Paul H.-Y. Cheong, Martin D. Burke or Guy C. Lloyd-Jones.

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Competing interests

The University of Illinois has filed patent applications related to MIDA boronate chemistry, and these have been licensed to REVOLUTION Medicines, a company for which M.D.B. is a founder and consultant.

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Gonzalez, J., Ogba, O., Morehouse, G. et al. MIDA boronates are hydrolysed fast and slow by two different mechanisms. Nature Chem 8, 1067–1075 (2016). https://doi.org/10.1038/nchem.2571

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