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

Abstract

Keywords: Total synthesis / Azasugars / Alkaloids / Enzyme catalysis / Inhibitors / CycloadditionThe 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

Cycloadditions of Sugar‐Derived ­Nitrones Targeting Polyhydroxylated Indolizidines

“…This ratio drastically increases when the reaction is carried out with vinyladenine (only the exo‐anti adduct was recovered) or with vinyluracil or vinylthymine (10:1 in favour of the exo‐anti ) 19. The cycloaddition of nitrone 1 with 3‐buten‐1‐ol, an unactivated dipolarophile, was recently reported by our group; this gave a similar result, with exclusive formation of the exo‐anti product, even though heating was necessary for the reaction to take place 7g. There are several other reports of cycloaddition reactions between the same nitrone and different dipolarophiles in which the exo‐anti adduct was the only isolated product 20.…”

“…Cycloadditions with 3‐buten‐1‐ol as dipolarophile showed excellent exo selectivity with all nitrones 1 – 3 , and the adducts are synthetically useful for the preparation of tetrahydroxyindolizidines. Indolizidines derived from D ‐ arabino nitrone 1 have previously been reported, and were shown to have good inhibitory activities against amyloglucosidase from Aspergillus niger 7g. Application of the same synthetic strategy to cycloadducts 14a , b and 18a , b gave four additional diasteromeric indolizidines, as reported below.…”

“…The results were compared with those obtained for compound 24 , derived from nitrone 1 (Figure 10). 7g…”

Human Acid β‐Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease

“…[38] Compounds 40-51 (Scheme 7) were synthesized from 4 either by nitrone cycloadditionc hemistry, [39] ap owerful strategy that allows the stereoselective installation of up to three stereocenters not present in the starting sugar, [40] or by the lithio allene addition strategy. [41] These approaches also allowed the synthesis of the unnatural derivatives7 -deoxyuniflorine (46), [42] pyrrolizidine 47, [43] and the two glucosyl pyrrolizidines 50 [44] and 51. [39c] Pyrrolizidines 52-55 (Scheme 8), which have the d-ribo configuration at one of the two five-membered rings of the pyrro- ChemBioChem 2015, 16,2054 -2064 www.chembiochem.org lizidine nucleus, were synthesized from 10 by nitrone cycloaddition chemistry.…”

A Glycal Approach to the Synthesis of Steviamine Analogues

“…As a result of these intriguing structural features, as well as the biological activities and their significance, there has been considerable interest in the last three years in the synthesis of steviamine and its analogues (Figure 1). 3,13–17 For obvious reasons, carbohydrates, in particular pentose sugars, have been the preferred choice of starting material for most of the reported syntheses of steviamine and its analogues. The single strategy using hexose sugars was reported by Vankar and coworkers,18 who, in their synthesis, introduced an additional carbon at the C‐2 position of glycals by formylation, and then removed the C‐1 carbon of the sugar at a later stage.…”