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.
Sonsona I.G., Vicenzi A., Guidotti M., Bisag G.D., Fochi M., Herrera R.P., et al. (2022). Investigation of Squaramide Catalysts in the Aldol Reaction En Route to Funapide. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2022(1), 1-6 [10.1002/ejoc.202101254].
Investigation of Squaramide Catalysts in the Aldol Reaction En Route to Funapide
Vicenzi A.;Bisag G. D.;Fochi M.;Bernardi L.
2022
Abstract
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.File | Dimensione | Formato | |
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