Accessing 2-substituted piperidine iminosugars by organometallic addition/intramolecular reductive amination: aldehyde vs. nitrone route

Year: 2017

Authors: Mirabella S., Fibbi G., Matassini C., Faggi C., Goti A., Cardona F.

Autors Affiliation: Univ Firenze, Dept Chem Ugo Schiff, Via Lastruccia 3-13, I-50019 Sesto Fiorentino, FI, Italy; CNR INO, Via N Carrara 1, Sesto Fiorentino, FI, Italy.

Abstract: A dual synthetic strategy to afford 2-substituted trihydroxypiperidines is disclosed. The procedure involved Grignard addition either to a carbohydrate-derived aldehyde or to a nitrone derived thereof, and took advantage of an efficient ring-closure reductive amination strategy in the final cyclization step. An opposite diastereofacial preference was demonstrated in the nucleophilic attack to the two electrophiles, which would finally produce the same piperidine diastereoisomer as the major product. However, use of a suitable Lewis acid in the Grignard addition to the nitrone allowed reversing the selectivity, giving access to 2-substituted piperidines with the opposite configuration at C-2.

Journal/Review: ORGANIC & BIOMOLECULAR CHEMISTRY

Volume: 15 (43)      Pages from: 9121  to: 9126

More Information: This work was supported by grants from the Italian Ministry of Health and Regione Toscana (Ricerca Finalizzata-2011-02347694) and MIUR-Italy (PRIN 2010-2011, 2010L9SH3K 006). C. M. thanks Fondazione Donegani/Accademia dei Lincei for a postdoctoral fellowship. We also thank Macarena Martinez-Bailen for the preparation of compounds 16a,b and 17a,b.
KeyWords: Pharmacological Chaperone Therapy; Lysosomal Beta-galactosidase; Nucleophilic Additions; Gaucher-disease; Storage Disorders; Highly Potent; Inhibitors; Design; G(m1)-gangliosidosis; Glucocerebrosidase
DOI: 10.1039/c7ob01848g

ImpactFactor: 3.423
Citations: 10
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