Emerging Capabilities of Nonclassical Noncovalent Interactions and Asymmetric Catalysis in Stereoselective Glycosylations and Carbohydrate Functionalizations

Abstract

ConspectusDeriving inspiration from frontier catalytic paradigms has emerged as a major force to tackle long-standing stereoselectivity issues in carbohydrate synthesis. In particular, there is a strong momentum in the harnessing of nonclassical σ-hole based noncovalent interactions (NCIs) in chemical glycosylations and the use of asymmetric catalysis to surmount the formidable site-selectivity challenge in the functionalization of carbohydrate polyols.In this Account, we describe our pioneering contributions to advancing these two major directions. First, we introduce our early work whereby halogen bonding (XB) interactions could be harnessed catalytically on sugars. We realized that the polyoxygenated motifs embedded in different regions of the carbohydrate scaffold offered multiple anchoring points where the XB-catalyst could iteratively interact via halogen···O interactions. As a consequence, a counterintuitive multistage XB-activation concept was discovered. In our XB-catalyzed strain-release glycosylation, we intriguingly observed substantial elevation of anomeric selectivity over a wide array of glycosyl substrates as compared with thiourea catalysis. In XB-catalyzed 2-deoxyglycosylations, the multistaged XB-activation phenomena was also operative. Apart from the broader tolerance of glycosyl donors/acceptors compared to thiourea catalysis, we demonstrated the halogen tunability concept, where a halogen swap on the catalyst enabled tolerance of sensitive pentose-based donors.Next, we discovered that the two σ-holes per chalcogen property of phosphonochalcogenide (PCH) catalysts imparted unique benefits in glycoside activation. This opened up an unknown bifurcated chalcogen bonding (ChB) activation concept that paved a stereoselective entry into 7-ring sugars through either an internal nucleophilic substitution (S_Ni) type mechanism or an intramolecular aglycone transposition strategy. C- and N-glycosylations of indoles with glycals were realized through conformational distortion by a network of ChB and π-interactions. The exclusively α-selective O- and S-iminoglycosylation of iminoglycals was further developed through an unprecedented multistep ChB-activation manifold.Second, our investigations revealed that multiple stereoselectivity challenges in site-selective carbohydrate functionalizations can be concomitantly tackled by an asymmetric catalytic system. Departing from the classical use of asymmetric catalysis to create chiral centers on achiral substrates, we advanced stereochemical complexity generation on sugars by simultaneously addressing the site-, diastereo-, and enantioselectivity challenges when carbohydrate polyols react with prochiral electrophiles. Additionally, rarely observed dynamic kinetic resolution type glycosylations on reducing sugars were unravelled when chiral Rh(I) and chiral copper catalytic systems were employed. We also discovered that the multiple stereoselectivity control by chiral Pd/organoboron-catalyzed site-selective functionalization of carbohydrate polyols can be attributed to the vital stereocontrolling role of NCIs such as CH-π interactions and hydrogen bonding.

1

Summary of our two strategic lines to tackle different stereoselectivity challenges in carbohydrate synthesis.

1. Development of Our Seminal XB-Catalyzed Strain-Release Glycosylation

2. (A) Control Experiment That Unveiled the Multistaged Nature of XB Catalytic Activation; (B) Proposed Mechanism Based on NMR Titration and In-Situ ¹H NMR Monitoring

3. Development of a XB-Catalyzed 2-Deoxyglycosylation That Accommodates a Broad Array of Glycosyl Donors and Acceptors

4. Differing Reactivity of the XB Donor Catalyst versus Classical Thiourea/Thiouracil Catalysis

5. Tunability of XB Catalysis Exemplified by the “Halogen Swap” Strategy on Ribals

6. Participation of XB Activation in Multiple Elementary Steps of 2-Deoxyglycosylations

7. Exploring the Differences in Electrophilic Axes of XB and ChB Catalysts to Bring about Differentiated Glycosylation Outcomes

8. Seminal Report for the Debut of the ChB-Catalyzed Glycosylation

9. Computational and Experimental Studies That Contributed to the Mechanistic Proposal of the Septanosylation

10. ChB-Catalyzed C- and N-Septanosylation Using Silylated Nucleophiles

11. Mechanistic Switch to an Aglycone Transposition Using Silylated Nucleophiles

12. ChB-Catalyzed C,N-Indolyl Glycosylation with Glycals

13. NMR Titration and DFT Modeling That Evidence Glycal Conformational Distortion

14. Proposed Mechanism for the ChB-Catalyzed 2-Deoxyglycosylation of Glycals with Indoles

15. Facile ChB-Catalyzed Iminoglycosylation of Iminoglycals

16. Experiments That Led to the Hypothesis of Multielementary Step ChB Activation

17. DFT-Computed Intermediates That Are Proposed in the ChB-Catalyzed Iminoglycosylation

18. Proposed Mechanism of Multistep ChB-Catalyzed Iminoglycosylation

19. Synergistic Chiral Rh­(I)/Organoboron Catalyzed Site-Selective Functionalization of Carbohydrate Polyols to Access Arylhydronapthalene Glycosides

20. Working Mechanistic Hypothesis of the Synergistic Rh­(I)/Organoboron Catalysis

21. Synergistic Pd/Organoboron-Catalyzed Site-Selective Functionalization of Carbohydrate Polyols with Alkoxyallenes.

22. Experiments That Evidence the Participation of HB and CH−π Interactions in the Stereocontrol

23. DFT-Modeled Reaction Path and Proposed Mechanism for the Pd/Organoboron Catalysis

24. Site-Selective and Enantioconvergent Etherification through Chiral Copper Radical Catalysis

25. Radical Probe Control Experiments Evidence a Radical Pathway

26. Site-Selective and Enantioconvergent Etherification through Chiral Copper Radical Catalysis