Tyrosol and hydroxytyrosol carbonates and carbamates as novel antiradical and antimicrobial agents: a chemo-enzymatic flow synthesis

Most chemical and pharmaceutical industries aim at developing new synthetic strategies towards the concepts of eco-sustainability described by the twelve principles of green chemistry, reducing pollution, waste and hazardous effects on workers’ health. Food-derived phenolic compounds have recently been described as object of interest by nutraceutical, cosmetic and phamaceutical companies for their antioxidant, metal chelator, free radical scavenger, antimicrobial and antiinflammatory properties.1,2 However, their relevance as active ingredients is still limited due to metabolic/chemical instability, solubility and bioavailability issues. Carbonate and carbamate chemical moieties play an important role in modern drug discovery and medicinal chemistry; thus, the development of environmentally friendly processes, exploiting no-toxic and biodegradable chemicals, is necessary. In this context, we developed a chemo- enzymatic continuous flow synthesis of tyrosol (Ty) and hydroxytyrosol (HTy) carbonates and carbamates. Starting from these natural molecules, a series of lipophilic derivatives were synthetized, increasing or leaving unaltered the antiradical and antimicrobial properties of the parent compounds. Candida antarctica lipase B (CaLB) was adopted as commercially available immobilized biocatalyst, suitably packed in a glass column reactor, and used in an unconventional organic medium as tert-amyl alcohol. A reproducible, efficient, safe, phosgene-free procedure to obtain carbonates has been set-up, followed by the nucleophilic attack using appropriate amines to obtain the desired carbamates (Scheme 1).3,4 Moreover, a telescoped two-step process was developed to reduce manual handling, time and costs. Acknowledgment: The project was realized within the MUSA – Multilayered Urban Sustainability Action – project, funded by the European Union – NextGenerationEU, under the National Recovery and Resilience Plan (NRRP) Mission 4 Component 2 Investment Line 1.5: Strenght- ening of research structures and creation of R&D “innovation ecosystems”, set up of “territorial leaders in R&D”. 1. Kumar, N.; Goel, N. Biotechnol. Rep. 2019, 24, e00370. 2. Cozier, A.; Jaganath, I.B.; Clifford, M.N. Nat. Prod. Rep. 2009, 26, 1001-1043. 3. Vicinanza, S.; Annunziata, F.; Pecora, D.; Pinto. A.; Tamborini, L. RCS Adv. 2023, 13, 22901-22904. 4. Vicinanza, S.; Mombelli L.; Annunziata F.; Donzella S., Contente M.L.; Borsari C.; Conti P.; Meroni G.; Molinari F.; Martino P.A.; Pinto A.; Tamborini L. Sustain. Chem. Pharm. 2024, 39, 101542.