Chemo-enzymatic sustainable flow synthesis of biologically active nature-inspired carbonates and carbamates

Food-derived phenolic compounds are well known for their antioxidant and antimicrobial effects. 1 Because of their hydrophilic nature and their intrinsic instability and bioavailability issues, their use as active ingredients is limited. Lipophilization of phenolic derivatives is a valid strategy to obtain amphiphilic compounds that can be used as multifunctional additives in the pharmaceutical, nutraceutical, and cosmetic fields. 2 In particular, the synthesis of carbonates and carbamates is an attractive strategy to increase the lipophilicity of phenolic derivatives. However, their classic synthesis requires the employment of toxic acylating agents, unsafe solvents and drastic experimental conditions. In this context, we developed a reproducible, green, and scalable chemo-enzymatic flow process (Scheme 1) for the obtainment of a series of lipophilic carbonate and carbamate derivatives of natural tyrosol (Ty) and hydroxytyrosol (HTy). 3,4 Immobilized CaLB was used in a packed bed reactor for the selective carbonation of the primary alcohol of Ty and HTy in green solvents as dimethylcarbonate or tert-amyl alcohol. Then, two selected carbonates were reacted in flow with the appropriate amine to obtain the desired carbamates. A telescoped two-step process was set up allowing to reduce the manual handling, time, and costs of the process. All compounds were tested as antimicrobials and radical scavengers and they showed similar or even better activity compared to the parent compounds, with a significant increase in their lipophilicity Acknowledgements: 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: Strengthening of research structures and creation of R&D “innovation ecosystems”, set up of “territorial leaders in R&D”. References: 1 N. Kumar, N. Goel, Biotechnology Reports, 2019, 24, e00370. 2 S.I. Arzola-Rodriguez, L.N. Muñoz-Castellanos, C. Lopez-Camarillo, E. Salas, Biomolecules, 2022, 12, 1897. 3 S. Vicinanza, F. Annunziata, D. Pecora, A. Pinto, L. Tamborini, RSC Advances, 2023, 13, 22901. 4 S. Vicinanza et al., Sustainable Chemistry and Pharmacy, 2024, 39, 101542.