Hantzsch-Type Three-Component Approach to a New Family of Carbon-Linked Glycosyl Amino Acids. Synthesis of C-Glycosylmethyl Pyridylalanines^,

Abstract

C-Glycosylmethyl pyridylalanines reported in this paper constitute a novel family of glycosyl amino acids that contain a pyridine ring linking the carbohydrate and amino acid residues. These amino acids may serve to prepare nonnatural glycopeptides displaying firmly bound carbohydrate fragments through a rigid and highly stable tether. A viable route to these new hybrid molecules has been opened via thermally induced Hantzsch-type cyclocondensation using an aldehyde-ketoester-enamino ester system. To one of these reagents was attached a C-glycosyl residue, while to another was bound an amino acid fragment. In a one-pot optimized methodology, the dihydropyridine was not isolated while its purification was carried out by removal of unreacted material and side products using polymer-supported scavengers. Then the dihydropyridine (mixture of diastereoisomers) was oxidized by a polymer-bound oxidant to give the target pyridine bearing the two bioactive residues. In this way a range of eight compounds (58-68% yield) was prepared in which the elements of diversity were (i) the gluco and galacto configurations of the pyranose ring, (ii) the alpha- and beta-configurations at the anomeric center, and (iii) the positions of the carbohydrate and amino acid sectors in the pyridine ring. The orthogonal functional group protection in these amino acids allowed their easy incorporation into oligopeptides via sequential amino and carboxylic group coupling.

Selected Research Topics of the Dondoni Group over the Last Two Decades (2000–2020)

“…8 More recently pyridine-linked glycosyl alanines were prepared via Hantzsch three-component cyclocondensation. 9 The latter reaction was carried under MW irradiation to reduce the reaction time while the workup was simplified using polymer-supported reagents. The insertion of these amino acids in small peptides was demonstrated as well ( Figure 5).…”

Asymmetric Domino Reactions Based on the Use of Chiral Substrates

“…138 The scope of this methodology was later extended by the same authors to the synthesis of a variety of enantiopure C-glycosylmethyl pyridylalanines, starting from the corresponding chiral aldehydes. 139 A group of eight novel C-glycosylmethyl pyridine amino acids were achieved in 55-68% yields with total preservation of the stereocentre integrity and functional group protection. Furthermore, the same authors developed, in 2009, the first organocatalysed three-component Hantzsch reaction between a chiral C-glycosyl aldehyde, a b-diketone, and an enamine, to provide the corresponding enantiopure substituted 1,4-dihydropyridine C-glycoconjugate in 50% yield and excellent diastereoselectivity of 498% de, as shown in Scheme 1.90.…”

A Journey into Recent Microwave‐Assisted Carbohydrate Chemistry

“…Because of their potential use as probes in glycobiology and leads in carbohydrate-based drug discovery, synthetic glycopeptides, in which the native O-or N-glycosidic linkages are replaced by C-or S-linkages, have attracted increasing attention by researchers in industry and academia in recent years. This modification is considered to provide substantial resistance to chemical and enzymatic deglycosylation, while retaining the original biological properties of the peptide [23]. Papinia and co-workers [24] demonstrated that the use of MWI allowed the rapid and high-yielding preparation of N-glycosylamino acids orthogonally protected for SPPS (solid-phase peptide synthesis).…”

“…Dondoni et al [23] further validated the exceptional efficacy of Hantzsch pyridine synthesis by assembling in a one-pot procedure, without added catalysts and under the simple application of MWI, three densely functionalized substrates, such as a carbohydrate, a pyridine, and an amino acid. They reported the synthesis of a novel family of heterocycle-linked C-glycosylamino acids in which the flat and rigid pyridine ring holds the two chiral bioactive entities (Figure 21.4).…”