New approaches to iminoglycoside mimics by way of organotin intermediates

Session: 
S7.1 Synthetic glycomimetic glycosidase inhibitors
Code: 
OL7.1.1
Location (hall): 
Glucose
Start/end time: 
Wednesday, July 3, 2019 - 11:45 to 12:00
Justyna
Jaszczyk

Justyna Jaszczyk1, Sizhe Li1, Cyril Nicolas1, Olivier Martin1

1ICOA, University of Orleans and CNRS, Orleans, France

Sugar analogs with nitrogen in the ring, or iminosugars, are now recognized as major carbohydrate mimics and are gaining increasing importance as potential or proven thera-peutic agents for a diversity of diseases such as lysosomal disease, diabetes, viral infections and others. In this context, our group has been actively investigating new iminosugar derivatives designed to exhibit higher efficiency and selectivity towards specific enzymes, and has focused on the synthesis of iminoglycosides mimics. Of particular interest are derivatives in which the ‘aglycone’ is linked to the anomeric carbon by a C-C-bond (imino-C-glycosides). Such compounds have been shown to demonstrate exquisite selectivity and potent activity as glycosidase inhibitors for example towards GCase, the enzyme involved in Gaucher disease.

In recent work, we have demonstrated that N-sulfinylglycosylamines constituted favorable precursors for the stereocontrolled synthesis of iminosugar-C-glycosides of defined ‘pseudoanomeric’ configuration [1][2]. In continuation of this work, we have investigated the addition of organotin reagent such as tributyltinlithium to various glycosylamines. These reactions were found to be very efficient and highly stereoselective, with control by the sulfinyl group,  leading to chain extended stannylated aminoalditols (Scheme 1). 

These intermediates could be exploited directly for organometallic coupling reactions or cyclized to give novel 1-C-stannyl iminosugar derivatives; pyrrolidines and piperidines derivatives were thus prepared, with a well-defined - or -configuration. These derivatives constitute remarkable precursors for the diversity-oriented synthesis of glycoside mimics: conditions of Pd-mediated Stille coupling of these organometallic derivatives of iminosugars with various ar(o)yl halides were optimized and applied to the synthesis of a small library of novel imino-C-glycosyl aromatic compounds. Details of these investigations will be illustrated in this presentation.

Scheme 1. Synthetic methodology

Acknowlegements

A grant from Labex SYNORG (ANR-11-LABX-0029) and a stipend from the French Ministry of Higher Education and Research are gratefully acknowledged.

References: 
  1. A Tuneable Approach for the Stereoselective Synthesis of 1-C-Diethylphosphono (difluoromethyl) Imino-sugars as Glycosyl Phosphate Mimics”, C. Cocaud, C. Nicolas, T. Poisson, X. Pannecoucke, C. Y. Legault, O.R. Martin, J.Org.Chem. 2017, 82, 2753-2763.
  2. Glycoside Mimics from Glycosylamines: Recent Progress  C. Nicolas, O.R. Martin Molecules 2018, 1612-1641 Special issue on Glycomimetics (P. Compain, Ed.).

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