The glycosidic bond (-O-CR2-O-) is prevalent in natural products since glycosidase enzymes (glycoside hydrolases) are widespread in all domains of life to generate (and break) ketals with an extremely high selectivity, at neutral pH in water, by the combined action of several amino acid residues in the enzyme electrostatic pocket. This situation contrasts to that observed in classical synthetic chemistry, which occurs under much harder conditions, by using formal acids (i.e. protons and Lewis metal cations) or bases (i.e. inorganic bases and amines), which are clearly incompatible with the outstanding structural richness and sensitive functionality of ketals in Nature, and severely hampers the absolute configuration determination of natural products by simple chemical degradation.
For the last several years, we have been working in tandem to exploit the confined space of a well-known type of porous materials, so-called Metal-Organic Framework (MOFs), to mimic nature and to snapshot, as much as possible, processes taking place within their functional empty space, taking advantage of cutting-edge crystallographic methods. In this context, MOFs may bear resemblance to enzymes with their active catalytic species in an electrostatic confined space, as it has observed before for microporous pure silicates, showing that densely-packaged and interacting Si-OH groups, called silanol nests, naturally generate an acid site for catalysis.1
This concept has intrigued us for long. So, having in our hands the appropriate MOF –possessing functional channels densely decorated with –CH2OH L-serine residues and intrinsic ability to accommodate relatively large organic molecules such as natural products2– we started to work in this exciting project, focused on exploiting the concept of confined water activation for acid catalysis.
This MOF allows, in a single operation, ketal deprotection and structural determination of sugars3 and flavonoids4 of known and unknown absolute configurations. It selectively breaks the ketal groups of the natural products and also incorporates the resulting chiral fragments inside the still crystalline MOF network allowing us to snapshot the structure using Single Crystal X-Ray Crystallography (Figure 1).
In this work, we expand the concept of “alcohol nests” from inorganic porous solid to crystallizing MOFs laying the foundation to design extremely-mild metal-free solid-catalysed processes without formal acid protons. The appropriate confined and densely-packaged methyl alcohol groups and the micropore size, perfect to accommodate fitting natural products has voted it as an excellent catalyst for ketal deprotection in a flavonoid -extracted by fragrant bergamot-of unknown absolute structure containing different acid sensitive functional groups via Single-Crystal X-Ray Diffraction (SCXRD).
Let us stress that the experiments were run blind among us, thus the SCXRD and chemical synthesis gave the same absolute configuration without cross-contamination between our Spanish and Italian groups, and so did the experimental and computational reaction mechanism experiments.
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- Wang, Y., Carder, H. M. & Wendlandt, A. E. Synthesis of rare sugar isomers through site-selective epimerization. Nature 578, 403–408 (2020).
- Di Donna, L. et al. Statin-like Principles of Bergamot Fruit ( Citrus bergamia ): Isolation of 3-Hydroxymethylglutaryl Flavonoid Glycosides. J. Nat. Prod. 72, 1352–1354 (2009).