Multi‐Step Synthesis and Biological Evaluation of Analogues of Insulin Secretagogue (2S,3R,4S)‐4‐Hydroxyisoleucine

Abstract

A series of stereochemically defined analogues of (2S,3R,4S)‐4‐hydroxyisoleucine and related α‐hydroxy acids have been prepared by multi‐step routes from D‐glucose, whereas ketolization between TBDMS‐protected hydroxypropanone and ethyl isocyanoacetate led to racemic analogues. Bioassays showed that of eight newly synthesized compounds, two of them presented an interesting statistical trend to increase glucose‐induced insulin secretion when tested in isolated rat pancreatic islets in the presence of 8.3 mM glucose and at a concentration of 200 μM, which has previously been shown to be effective for (2S,3R,4S)‐4‐hydroxyisoleucine.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Unprecedented Synthesis of 4‐Ylidene (3 S)‐3‐hydroxy‐1‐aryl (alkyl)‐pyrrolidine‐2,5‐diones Based on 1,3‐Dipolar Cycloaddition of a Sugar‐derived Nitrone to N‐Substituted Maleimides

“…Diacetone glucose, a commercially available precursor amenable to suitable modifications was used as starting material. Methylation of the 3‐OH group, regioselective acid‐catalyzed hydrolysis of the isopropylidene acetal at the 5‐ and 6‐positions, and oxidative cleavage of the 5,6‐diol in the presence of sodium periodate delivered the 3‐ O ‐methyl sugar aldehyde 1 . This latter was treated with N ‐benzylhydroxylamine hydrochloride in a mixture of EtOH/H 2 O at room temperature to afford the unprecedented 3‐ O ‐methyl sugar nitrone 2 in good yield (Scheme ).…”

Multifunctional isoxazolidine derivatives as α-amylase and α-glucosidase inhibitors

“…In turn, the isoxazolidine functional group, obtained by 1,3-dipolar cycloaddition between a nitrone and an alkene, plays a crucial role in several chemical transformations due to the lability of the N-O bond [12]. In this context, our research team has been interested for some years in the study of the 1,3-dipolar cycloaddition reaction between chiral nitrones and dipolarophiles to access natural organic compounds such as 4-hydroxyisoleucine [13], 4-hydroxy-L-ornithine [14], and other non-naturally occurring compounds such as 4-hydroxyproline derivatives [15], (αS,3R,4S)-3-glycinyl-4-hydroxypyrrolidine [16] and 4-ylidene (3S)-3-hydroxy-1-aryl (alkyl)pyrrolidine-2,5-diones [17]. Additionally, the prediction of possible interactions between chemical compounds and the target proteins remains a very important task in research and development process.…”