Investigation of squaramide catalysts in the Aldol reaction en route to Funapide

Sonsona, Isaac G. ; Vicenzi, Andrea ; Guidotti, Marco ; Bisag, Giorgiana Denisa ; Fochi, Mariafrancesca ; Perez Herrera, Raquel ; Bernardi, Luca

Resumen: Funapide is a 3, 3’-spirocyclic oxindole with promising analgesic activity. A reported pilot-plant scale synthesis of this chiral compound involves an asymmetric aldol reaction, catalyzed by a common bifunctional thiourea structure. In this work, we show that the swapping of the thiourea unit of the catalyst for a tailored squaramide group provides an equally active, but rewardingly more selective, catalyst for this aldol reaction (from 70.5 to 85 % ee). The reaction was studied first on a model oxindole compound. Then, the set of optimal conditions was applied to the target funapide intermediate. The applicability of these conditions seems limited to oxindoles bearing the 3-substituent of funapide. Exemplifying the characteristics of target-focused methodological development, this study highlights how a wide-range screening of catalysts and reaction conditions can provide non-negligible improvements in an industrially viable asymmetric transformation. © 2021 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH

Idioma: Inglés

DOI: 10.1002/ejoc.202101254

Año: 2022

Publicado en: European Journal of Organic Chemistry 11, 1 (2022), e202101254 [6 pp]
ISSN: 1434-193X

Factor impacto JCR: 2.8 (2022)

Categ. JCR: CHEMISTRY, ORGANIC rank: 16 / 52 = 0.308 (2022) - Q2 - T1

Factor impacto CITESCORE: 5.5 - Chemistry (Q2)

Factor impacto SCIMAGO: 0.682 - Physical and Theoretical Chemistry (Q2) - Organic Chemistry (Q2)

Financiación: info:eu-repo/grantAgreement/ES/AEI/FEDER/CTQ2017-88091-P
Financiación: info:eu-repo/grantAgreement/ES/AEI/PID2020-117455GB-I00
Financiación: info:eu-repo/grantAgreement/ES/DGA-FSE/E07-20R

Tipo y forma: Artículo (Versión definitiva)