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Catalyst recognition of cis-1,2-diols enables site-selective functionalization of complex molecules

Nature Chemistry volume 5, pages 790–795 (2013)Cite this article

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Abstract

Carbohydrates and natural products serve essential roles in nature, and also provide core scaffolds for pharmaceutical agents and vaccines. However, the inherent complexity of these molecules imposes significant synthetic hurdles for their selective functionalization and derivatization. Nature has, in part, addressed these issues by employing enzymes that are able to orient and activate substrates within a chiral pocket, which increases dramatically both the rate and selectivity of organic transformations. In this article we show that similar proximity effects can be utilized in the context of synthetic catalysts to achieve general and predictable site-selective functionalization of complex molecules. Unlike enzymes, our catalysts apply a single reversible covalent bond to recognize and bind to specific functional group displays within substrates. By combining this unique binding selectivity and asymmetric catalysis, we are able to modify the less reactive axial positions within monosaccharides and natural products.

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Figure 1: The role of selectively modified polyols in naturally occurring compounds and approaches to their site-selective functionalization
Figure 2: The site-selective modification of both the C2 and C4 hydroxyls of Helicid.
Figure 3: Expansion of scaffolding-catalysed electrophile transfer beyond monosaccharides.

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Acknowledgements

This research was supported by the National Institutes of Health (RO1-GM087581), National Science Foundation Career Award (CHE-1150393) and Boston College. X.S. is an AstraZeneca Graduate Fellow and K.L.T. is an Alfred P. Sloan fellow. We thank P. Ozkal for early experimental assistance; E. Weerapana, J. Morken and A. Hoveyda for discussions; R. Jain, H. Pham and Novartis for providing spectra of α-acetyl digoxin.

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  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, 02467, Massachusetts, USA

    Xixi Sun, Hyelee Lee, Sunggi Lee & Kian L. Tan

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  1. Xixi Sun
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Contributions

K.L.T. and X.S. were involved in the design and discovery of the catalysts; X.S. was responsible for the data obtained with methyl-α-D-mannose, arabinose, galactose and digoxin; H.L. was responsible for the data obtained with methyl-α-L-rhamnose and mupirocin; S.L. was responsible for the data obtained with uridine; K.L.T. conceived and directed the investigation and wrote the manuscript.

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Correspondence to Kian L. Tan.

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Sun, X., Lee, H., Lee, S. et al. Catalyst recognition of cis-1,2-diols enables site-selective functionalization of complex molecules. Nature Chem 5, 790–795 (2013). https://doi.org/10.1038/nchem.1726

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