Synthesis and Glycosidase Inhibition Studies of 5-Methyl-Substituted Tetrahydroxyindolizidines and -pyrrolizidines Related to Natural Hyacinthacines B

Year: 2013

Authors: Martella D., Cardona F., Parmeggiani C., Franco F., Tamayo J.A., Robina I., Moreno-Clavijo E., Moreno-Vargas A.J., Goti A.

Autors Affiliation: Univ Florence, Dipartimento Chim Ugo Schiff, I-50019 Sesto Fiorentino, FI, Italy; Univ Granada, Fac Farm, Dept Quim Farmaceut & Organ, E-18071 Granada, Spain; Univ Florence, CNR INO, I-50019 Sesto Fiorentino, FI, Italy; Univ Florence, European Lab Nonlinear Spect LENS, I-50019 Sesto Fiorentino, FI, Italy; Univ Seville, Fac Quim, Dept Quim Organ, Seville 41012, Spain.

Abstract: The synthesis of three tetrahydroxyindolizidines and one tetrahydroxypyrrolizidine related to natural hyacinthacines B and their biological evaluation as glycosidase inhibitors is reported. The target molecules were obtained through highly stereoselective cycloadditions between sugriched allylic and homoallylic alcohols. This allowed the installation of a methyl group at C5 – a common feature of many natural hyacinthacines – with high control over the stereoselectivity. The new compounds inhibit amyloglucosidase from Aspergillus niger and β-glucosidase from almonds. Compound 1 is a competitive inhibitor of amyloglucosidase and shows a fair selectivity towards this enzyme. The presence of C5-Me substitution in indolizidines 2 and 3 slightly diminishes the inhibitory activity towards amyloglucosidase whereas it improves the inhibitory properties towards β-glucosidase. Cycloaddition between a carbohydrate-derived nitrone and suitable chemoenzymatically prepared enantioenriched allylic and homoallylic alcohols allowed the straightforward synthesis of three tetrahydroxyindolizidines and one tetrahydroxypyrrolizidine related to natural hyacinthacines B. They inhibit amyloglucosidase from Aspergillus niger and β-glucosidase from almonds.

Journal/Review: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY

Volume: 2013 (19)      Pages from: 4047  to: 4056

More Information: The authors thank the Ministero dell’Universita e della Ricerca (MIUR) (PRIN 2010-11, 2010L9SH3K_006) and Ente CRF for financial support. The authors also thank the Spanish Ministerio de Ciencia e Innovacion (MICINN) (CTQ2008-01565/BQU) and Ministerio de Economia y Competitividad (MEC) (CTQ2012-31247) and the Junta de Andalucia (FQM 345) for fina ncial support. The Erasmus programme is acknowledged for a mobility grant to D. M. Maurizio Passaponti and Brunella Innocenti (University of Firenze) are acknowledged for technical support. The authors thank Martina Bonciani for parts of the synthetic work.
KeyWords: Total synthesis; Azasugars; Alkaloids; Enzyme catalysis; Inhibitors; Cycloaddition
DOI: 10.1002/ejoc.201300103

ImpactFactor: 3.154
Citations: 31
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