Developing a sacrificial protective group to deliver the 1,2 cis glycoside

• Main Author: Grey, L. G.
• Published: Nottingham Trent University 2016
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.734408

The purpose of this study was to investigate whether the stereochemistry of a newly formed glycoside bond could be controlled through the novel use of an appropriately functionalised sacrificial neighbouring protecting group. This methodology would complement existing chemistries but with the added advantage that it would not require a two-step intramolecular delivery system, but instead involve a single-step synthesis of a cis glycoside bond from a neighbouring acetal or ketal group, armed with the same leaving group as the anomeric position. Scheme 1. Proposed approach to a novel neighbouring group direction. The first goal of the study was the synthesis of a 3,4,6-tri-O-protected, 2-O-unprotected glycoside donor to which the desired neighbouring group system could be attached. We investigated multiple synthetic routes and approaches to achieve our target donor, which ultimately resulted in an efficient four-step synthesis of ethyl, 3,4,6-tri-O-benzyl thioglucopyranoside, and its n-pentenyl ether analogue. Scheme 2. Summary of Section 2.1. We found that attaching a mixed thioacetal, thio ketal acetal, or a ketal to our donor proved to be difficult. Acetals are renowned for their instability, especially glycosidic acetals, and this was confirmed in this study. Thioacetal derivatives were also explored, but were unfortunately found to be too unstable for further study. We found that n-pentenyl ethers were considerably more stable. After multiple attempts, a para-methoxy benzyl mixed acetal was found to be very unstable. Scheme 3. Summary of Section 2.2. Finally, we identified that an isopropylidene mixed ketal, which is expected to be more stable, would allow us to test our theory. Unfortunately, though, within the time constraints of the project there was not enough time to carry out this final investigation.