A new approach for the total synthesis of spilanthol and analogue with improved anesthetic activity

Author(s)

Alonso, Isabella G. ^[1] ; Yamane, Lais T. ^[2] ; de Freitas-Blanco, Veronica S. ^[2] ; Novaes, Luiz F. T. ^[1] ; Franz-Montan, Michelle ^[3] ; de Paula, Eneida ^[4] ; Rodrigues, Marili V. N. ^[2] ; Rodrigues, Rodney A. F. ^[2] ; Pastre, Julio C. ^[1]

Affiliation

^[1] Univ Estadual Campinas, Inst Chem, POB 6154, BR-13084971 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Chem Biol & Agr Res Ctr CPQBA, BR-13148218 Campinas, SP - Brazil

^[3] Univ Estadual Campinas, Piracicaba Dent Sch, BR-13414903 Piracicaba, SP - Brazil

^[4] Univ Estadual Campinas, Inst Biol, BR-13083862 Campinas, SP - Brazil

• Document type: Journal article
• Source: Tetrahedron; v. 74, n. 38, p. 5192-5199, SEP 20 2018.
• Web of Science Citations: 0

Abstract

A 5-step synthesis of spilanthol (affinin) is reported, where the route features complete control of alkene geometry during the assembling of the double bonds, with the use of a Sonogashira cross-coupling reaction, a Z-selective alkyne semi-reduction and a HWE olefination reaction as the key steps. A simplified analogue was also prepared in 4 steps. Both compounds were found to permeate dermatomed pig ear skin through an in vitro Franz-type diffusion cell. The simplified analogue presented a superior anesthetic effect in vivo, using the tail flick model, when compared to spilanthol and to the commercial standard EMLA (R). These results suggest that both spilanthol and its analogue could be useful as a topical anesthetic in clinical practice. (C) 2018 Elsevier Ltd. All rights reserved. (AU)

• FAPESP's process: 15/08199-6 - Application of Dioxiranes in continuous flow, synthesis of Actinoranone and decalin fragment of Azadirachtin
• Grantee: Luiz Fernando Toneto Novaes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/06461-2 - Extraction of espilantol in the context of green chemistry and its application in the treatment of oral mucositis
• Grantee: Verônica Santana de Freitas Blanco
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/25770-6 - New frontiers in cross-coupling reactions promoted by palladium: combining enantioselective catalysis, C-H activations, new materials and in flux reactions aiming at high efficiency and sustainability in synthetic processes
• Grantee: Carlos Roque Duarte Correia
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/16186-9 - Development and evaluation of topical formulations for oral mucositis treatment containing Spilanthol
• Grantee: Rodney Alexandre Ferreira Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/26378-2 - Development of methodologies and synthetic processes employing a new technological platform: micro and meso reactor assisted synthesis of natural products and derivatives with potential pharmacological activity
• Grantee: Júlio Cezar Pastre
• Support Opportunities: Research Grants - Young Investigators Grants