Unexpected Nucleophile Masking in Acyl Transfer to Sterically Crowded and Conformationally Restricted Galactosides

Yonatan Sukhran, Israel Alshanski, Ofer Filiba, Megan J. Mackintosh, Igor Schapiro*, Mattan Hurevich*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Design and synthesis of orthogonally protected monosaccharide building blocks are crucial for the preparation of well-defined oligosaccharides in a stereo- and regiocontrolled manner. Selective introduction of protecting groups to partially protected monosaccharides is nontrivial due to the often unpredictable electronic, steric, and conformational effects of the substituents. Abolished reactivity toward a commonly used Lewis base-catalyzed acylation of O-2 was observed in conformationally restricted 4,6-O-benzylidene-3-O-Nap galactoside. Investigation of analogous systems, crystallographic characterization, and quantum chemical calculations highlighted the overlooked conformational and steric considerations, the combination of which produces a unique passivity of the 2-OH nucleophile. Evaluating the role of electrophile counterion and auxiliary base in the acylation of the sterically crowded and conformationally restricted galactoside system revealed an alternative Brønsted base-driven reaction pathway via nucleophilic activation. Insights gained from this model system were utilized to access the target galactoside intermediate within the envisioned synthetic route. The acylation strategy described herein can be implemented in future syntheses of key monomeric building blocks with unique protecting group hierarchies.

Original languageAmerican English
Pages (from-to)9313-9320
Number of pages8
JournalJournal of Organic Chemistry
Volume88
Issue number13
DOIs
StatePublished - 7 Jul 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.

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