Upgraded Production of a Hydroxylactone Anhydrosugar by Cellulose Pyrolysis and its Application in the Synthesis of Biologically Active Compounds

The fairly ignored (1R,5S)-anhydroisosaccharino-δ-lactone (LAC,1) is a product from catalytic pyrolysis of cellulose [1] and of renewable lignocellulosic biomass sources. Recently LAC production in a gram scale by cellulose pyrolysis has been upgraded and the compound has been quantified in bio-oils by FT-IR and 1HNMR analysis. The best results have been obtained at 500 °C by mesoporous Sn-MCM-41 catalyst (7.6 % from cellulose, 6.6 % after a regeneration cycle) and by the cheap and eco-friendly montmorillonite K10 (4.8 %).[2] Anhydro-sugar 1 represents a fine chemical with a high added value, due to its application as building block in the synthesis of enantiomerically pure molecules with potential biological activities. Its potential as a versatile chiral synthone was verified in the synthesis of the new tetrahydrofurane δ- amino acid 2, as an isoster of glycine-alanine dipeptide (H-Gly-Ala-OH), interesting for access to new peptidomimetics with conformationally restricted structures.[3] We also recognized structural similarity of amino acid 2 with natural L(+)-muscarine, notable in pharmacology because it faithfully reproduces some of the response to stimulations of the parasympathetic nervous system. Based on a renewed interest in the design of molecules exhibiting selectivity with regard to muscarinic receptors in the brain for application in the treatment of Alzheimer’s disease and other cognitive disorders, we have applied 1 in the synthesis of a series of muscarine-analogues (3). They have been investigated with respect to their binding affinity to human M1-M5 muscarinic acetylcholine receptors by R. Matucci and coworkers at University of Florence, Italy. A compound has emerged as the most active in the series with enough values comparable to natural (+)-muscarine and a moderate selectivity in favor of hM2 subtype receptor. It also exhibited the highest stability in the interaction with hM2 (3UON) subtype muscarinic receptor by using a docking calculation. Another application of LAC (1) is given by the synthesis of a series of potentially antiviral compounds, including analogues 4a related to nucleoside inhibitor rivabirine and 4b related to the drug vidarabine.