Aqueous semisynthesis of C-glycoside glycamines from agarose

Abstract

Agarose was herein employed as starting material to produce primary, secondary and tertiary C-glycoside glycamines, including mono- and disaccharide structures. The semisynthetic approach utilized was generally based on polysaccharide-controlled hydrolysis followed by reductive amination. All reactions were conducted in aqueous media and without the need of hydroxyl group protection. We were able to identify optimal conditions for the reductive amination of agar hydrolysis products and to overcome the major difficulties related to this kind of reaction, also extending it to reducing anhydrosugars. The excess of ammonium acetate, methyl- or dimethylamine, and the use of a diluted basic (pH 11) reaction media were identified as important aspects to achieve improved yields, as well as to decrease the amount of byproducts commonly related to reductive amination of carbohydrates. This strategy allowed the transposition of the 3,6-anhydro-α-L-galactopyranose unit (naturally present in the agarose structure) to all glycamines synthesized, constituting an amino-substituted C-threofuranoside moiety, which is closely related to (+)-muscarine.

Synthesis and Pharmacological Evaluation of Heterocyclic Carboxamides: Positive Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor with Weak Agonist Activity and Diverse Modulatory Profiles

“…Azaindole-3-carboxylic acid ( 8 ) (100 mg, 0.62 mmol) and amino-1-deoxy-3,6- l -anhydrogalactose ( 7f ) (77 mg, 0.74 mmol) were reacted according to general procedure A. The crude extract was purified by two FCC (eluent 1, EtOAc/MeOH 4:1; eluent 2, DCM/MeOH 100:1 to 10:1) to afford 9f as a colorless oil (18 mg, 29% yield).…”

1,4-d-Sorbitan: A Promising Biobased-Platform for the Synthesis of Chiral Amines

“…In 2018, a consortium of pharmaceutical industries cosigned a paper on the importance of developing new opportunities in organic synthesis to be compatible with the drug-discovery process, insisting on the nitrogen-containing molecules reported to display high-affinity binding interactions with proteins . Among the different methods for the obtention of nitrogen-containing sugars, reductive amination of glucose, galactose, isomaltulose, or agarose has been reported as one of the most efficient and promising.…”

“…This hypothesis was further confirmed by Zhao while reporting the acid-assisted enantioselective amination of 1,2-diol . The chiral scaffold of sorbitan appeared not to be sufficiently constrained to control the chiral information on C 1′ position during the final reduction step, as reported by Gonçalves et al for the reductive amination of chiral agarobiose . Following these first observations and in order to control the C 1′ stereocenter, we applied the reaction conditions developed by Zhao using [RuCl 2 ( p -cymene)] 2 in the presence of ( S )-Josiphos and benzoic acid at 120 °C .…”