Intramolecular Aglycon Delivery (IAD): The Solution to 1,2-cis Stereocontrol for Oligosaccharide Synthesis?

Abstract

Intramolecular glycosylation of a glycosyl acceptor temporarily tethered to the 2-hydroxyl group of the glycosyl donor, commonly referred to as Intramolecular Aglycon Delivery (IAD), potentially provides a solution to the perennial problem of how to synthesise 1,2-cis glycosidic linkages with complete stereocontrol. This account summarises developments in this area, focussing on the development within our group of intramolecular glycosylation based on allyl protecting groups (allyl IAD). Optimisation, the current scope and limitations, and further potential developments of allyl IAD are discussed herein.

• 1 Introduction

• 2 Intramolecular Aglycon Delivery (IAD): Previous Approach­es

• 2.1 Synthesis of β-Mannosides

• 2.2 Synthesis of Other 1,2-cis Glycosides by IAD

• 3 NIS-mediated Hindsgaul IAD

• 4 Allyl IAD

• 4.1 Thioglycoside Donors

• 4.2 Glycosyl Fluoride Donors

• 4.3 Attempted Facile Synthesis of (1-4) Linked Disaccharides

• 4.4 Extension to Other Sugars and Protecting Group Patterns

• 4.5 Optimisation

• 4.6 Mechanistic Studies

• 4.7 Iterative Oligosaccharide Synthesis

• 5 Summary and Future Perspectives

Key words

carbohydrates - glycosylations - stereoselective - intramolecular aglycon delivery (IAD) - 1,2-cis-glycosides

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5

Our main interest in accessing tetrasaccharide 1 was in order to determine its solution conformation by a series of NMR experiments in a variety of different solvents. However, as an offshoot of any synthesis we undertook we also desired access to a variety of truncated and fluorescence labeled sub-structures for use in enzyme assays amongst other purposes.

37

Cumpstey, I.; Fairbanks, A. J. unpublished results.

38

In fact both of these glycosylation reactions have only been performed on a single occasion on a small scale and so the reaction yields remain somewhat unoptimised.