A robust and tunable halogen bond organocatalyzed 2-deoxyglycosylation involving quantum tunneling

Chunfa Xu,Julia Weigen,V U Bhaskara Rao,Charles C J Loh

doi:10.1038/s41467-020-18595-2

Chunfa Xu, Julia Weigen + Show 2 more

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https://doi.org/10.1038/s41467-020-18595-2

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Abstract

The development of noncovalent halogen bonding (XB) catalysis is rapidly gaining traction, as isolated reports documented better performance than the well-established hydrogen bonding thiourea catalysis. However, convincing cases allowing XB activation to be competitive in challenging bond formations are lacking. Herein, we report a robust XB catalyzed 2-deoxyglycosylation, featuring a biomimetic reaction network indicative of dynamic XB activation. Benchmarking studies uncovered an improved substrate tolerance compared to thiourea-catalyzed protocols. Kinetic investigations reveal an autoinductive sigmoidal kinetic profile, supporting an in situ amplification of a XB dependent active catalytic species. Kinetic isotopic effect measurements further support quantum tunneling in the rate determining step. Furthermore, we demonstrate XB catalysis tunability via a halogen swapping strategy, facilitating 2-deoxyribosylations of D-ribals. This protocol showcases the clear emergence of XB catalysis as a versatile activation mode in noncovalent organocatalysis, and as an important addition to the catalytic toolbox of chemical glycosylations.

Highlights

The development of noncovalent halogen bonding (XB) catalysis is rapidly gaining traction, as isolated reports documented better performance than the well-established hydrogen bonding thiourea catalysis
A conceivable configurational advantage pertaining to XB catalysis would involve the ease of σ-hole tunability via halogen swapping to accommodate challenging substrates—an advantage not well adoptable in thiourea catalysis due to strict requirements of hydrogen atoms for dual hydrogen bonds (HB) activation
We initiated our investigation on a model glycosylation by selecting the D-glucal substrates 1a–1b as our glycosyl donor, and 2a as the Limited prior reports of competitiveness of XB over thiourea catalysis a

Summary

Introduction

The development of noncovalent halogen bonding (XB) catalysis is rapidly gaining traction, as isolated reports documented better performance than the well-established hydrogen bonding thiourea catalysis. We demonstrate XB catalysis tunability via a halogen swapping strategy, facilitating 2-deoxyribosylations of D-ribals This protocol showcases the clear emergence of XB catalysis as a versatile activation mode in noncovalent organocatalysis, and as an important addition to the catalytic toolbox of chemical glycosylations. A conceivable configurational advantage pertaining to XB catalysis would involve the ease of σ-hole tunability via halogen swapping to accommodate challenging substrates—an advantage not well adoptable in thiourea catalysis due to strict requirements of hydrogen atoms for dual HB activation. This property is not yet successfully exploited. An extension of the same activation concept was exemplified by Toy et al, wherein they demonstrated substantially improved effectiveness of a bidentate XB catalyst over thiourea catalysis in a bis-Friedel–Crafts-type reaction of indoles on ketones[41]

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