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Synthesis of Carbasugars Expedited

Carbasugars (also known as cyclitols), all-carbon bioisosteres of natural sugars, are an extremely useful class of compounds that can be applied as chemical tools to probe biological systems such as the α-galactose mimic (+)-MK7607, or as therapeutics, as exemplified by the FDA approved antiviral drug oseltamivir (Tamiflu®) (Figure 1).1 

 Despite their vast biological importance, their general preparation can involve lengthy sequences that oftentimes limits the exploration of chemical space within this class of compounds. A more concise protocol for accessing carbasugars could be realized via the desymmetrization of aromatic ring systems to afford arene cis-dihydrodiols, which have found wide application in biological systems (Figure 2), however this has only been accomplished asymmetrically by using traditional 

 enzymatic methods. Liang et al.2 report a creative two-step, one pot procedure for the highly enantioselective preparation of arene cis-dihydrodiols. This process involves a ytterbium (Yb)-catalyzed asymmetric inverse-electron-demand Diels–Alder (IEDDA) reaction with 2-pyrone substrates 1, to afford stable endo adducts 3, which upon heating undergo a retro-Diels–Alder reaction with CO2 extrusion to afford cis-dihydrodiols 4. Importantly, this synthetic method has a broad substrate scope and can be performed on a multigram scale, showcasing its robust applicability. To further demonstrate its synthetic utility, this method was applied to the synthesis of carbasugars (+)-MK7607 and its epimeric analogue, 1-epi-(+)-MK7607. (Figure 3). 

 Critically, this is the most concise reported total synthesis route for these compounds, and it is expected that this technology will streamline the preparation of unique carbasugars by medicinal chemists for a variety of biological applications
References
1.         Kobayashi, Y., Carbasugars: Synthesis and Functions. In Glycoscience: Chemistry and Chemical Biology, Fraser-Reid, B. O.; Tatsuta, K.; Thiem, J., Eds. Springer Berlin Heidelberg: Berlin, Heidelberg, 2008; pp 1913-1997.
2.         Liang, X. W.; Zhao, Y.; Si, X. G.; Xu, M. M.; Tan, J. H.; Zhang, Z. M.; Zheng, C. G.; Zheng, C.; Cai, Q., Enantioselective Synthesis of Arene cis-Dihydrodiols from 2-Pyrones. Angew Chem Int Ed Engl 2019, 58 (41), 14562-14567.


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