(+)‐Lentiginosine, a Potent and Selective Inhibitor of Amyloglucosidase: Synthetic Efforts and Disputes on Its Absolute Configuration

Abstract

(+)‐Lentiginosine is a powerful and selective inhibitor of amyloglucosidases and has become a reference compound in the field among derivatives related to imino sugars. The present review focuses on the several total syntheses of this alkaloid, which rely on either a chiral pool or on enantioselective approaches that have appeared since its isolation in 1990. A summary of biological assays and molecular dynamic studies which allowed the assignment of the correct absolute configuration of natural (+)‐lentiginosine is reported.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Synthesis of iminosugars via 1,3-dipolar cycloaddition reactions of nitrones to α,β-unsaturated sugar aldonolactones

“…There are numerous polyhydroxylated alkaloids containing methyl group attached to the iminosugar skeleton [4,7,[12][13][14][15]77]. Interesting biological properties of methyliminosugars encouraged us to propose a synthetic route to the methyl substituted pyrrolidines related to casuarine …”

“…The structural similarity of these compounds to monosaccharides, is reflected in the fact that they are also called iminosugars, and they have interesting biological activities, typically presented by the selective inhibition of glycosidases. Consequently, the iminosugars show antibacterial, antiviral, antitumor, or antidiabetic activities [4][5][6][7][8][9][10][11][12][13][14][15]. Therefore, the synthesis of iminosugars and their analogues a,b-unsaturated lactones Iminosugars Piperidines Pyrrolizidines Indolizidines A B S T R A C T 1,3-Dipolar cycloaddition reactions of nitrones to a,b-unsaturated g-and d-lactones are presented.…”

“…An apparent common structural feature of this group is a nitrogen-containing four-(azetidine), five-(pyrrolidine) or six-membered (piperidine) ring, or a related fused-ring system (pyrrolizidine, indolizidine, and quinolizidine) built up from the above monocycles, substituted with one or more hydroxyl groups (Fig. 2) [4][5][6][7][8][9][10][11][12][13][14][15][16]. The structural similarity of these compounds to monosaccharides, is reflected in the fact that they are also called iminosugars, and they have interesting biological activities, typically presented by the selective inhibition of glycosidases.…”

Synthesis of biotin and fluorescein labeled (–)-lentiginosine

“…Among the different iminosugars (+)-lentiginosine (1) (Figure 1), a natural alkaloid, 6 has attracted our interest for the simplified structure, with respect to other iminosugars, compared to the important glycosidase inhibitory activity, 7,8 and the more recently discovered activity as a good inhibitor of Hsp90 (Heat Shock Protein 90). 9 This interest was reinforced by the discovery that the non-natural enantiomer (-)-lentiginosine (2, Figure 1) is a potent proapoptotic agent against tumor cells with low toxicity towards normal cells.…”

Asymmetric Synthesis of (–)‐Lentiginosine by Double Aza‐Michael Reaction

“…[2] Due to the potential use of glycosidase inhibitors as antifungal agents, insecticides, antidiabetics and antiobesities, antivirals, and therapeutic agents for some genetic disorders, syntheses of these polyhydroxylated indolizidines have attracted the attention of chemists. [3,4] For example, lentiginosine, isolated from the plant Astragalus lentiginosus in 1990 and later found as the most powerful, competitive inhibitor of amyloglucosidases known so far, [5,6] has been the subject of a considerable number of synthetic studies. [7,8] Most of the reported syntheses utilized or constructed the five-membered pyrrolidines as the precursors to indolizidines.…”