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 language | American English |
|---|---|
| Pages (from-to) | 9313-9320 |
| Number of pages | 8 |
| Journal | Journal of Organic Chemistry |
| Volume | 88 |
| Issue number | 13 |
| DOIs | |
| State | Published - 7 Jul 2023 |
Bibliographical note
Funding Information:The authors wish to acknowledge the Fritz Haber Center for Molecular Dynamics at the Hebrew University of Jerusalem for access to the high-performance computing facility. The authors wish to thank Dr. Benny Bogoslavsky for solving the X-ray structure (CCDC 2173185). M.J.M. wishes to thank the Zuckerman STEM Leadership Program for its support. M.H. thanks the Israel Science Foundation grant no. 1805/22 for the support. M.H., Y.S. and I.A. received funding from the European Innovation Council (EIC) under the European Union’s Horizon Europe research and innovation program (no. 101046369). O.F. and I.S. acknowledge support by the German Research Foundation (Deutsche Forschungsgemeinschaft) through SFB 1078, project C6. I.S. thanks the Israel Science Foundation grant no. 3131/20 for the support.
Funding Information:
The authors wish to acknowledge the Fritz Haber Center for Molecular Dynamics at the Hebrew University of Jerusalem for access to the high-performance computing facility. The authors wish to thank Dr. Benny Bogoslavsky for solving the X-ray structure (CCDC 2173185 ). M.J.M. wishes to thank the Zuckerman STEM Leadership Program for its support. M.H. thanks the Israel Science Foundation grant no. 1805/22 for the support. M.H., Y.S. and I.A. received funding from the European Innovation Council (EIC) under the European Union’s Horizon Europe research and innovation program (no. 101046369). O.F. and I.S. acknowledge support by the German Research Foundation (Deutsche Forschungsgemeinschaft) through SFB 1078, project C6. I.S. thanks the Israel Science Foundation grant no. 3131/20 for the support.
Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.