Ligand-Accelerated Catalysis in Scandium(III)-Catalyzed Asymmetric Spiroannulation Reactions

Abstract

A mechanism for the scandium-catalyzed asymmetric allylsilane annulation reaction is proposed and supported by reaction heat flow calorimetry, NMR, and in situ infrared spectroscopy. The nature of a scandium­(III)–PyBox/BArF catalyst is probed using reaction calorimetric analysis, which reveals a complex interplay between in-solution and precipitated catalyst species. The scandium­(III)–PyBox/BArF catalyst is minimally soluble until the addition of a bidentate electrophile. The optimal reaction rate is dependent on precomplexation of the catalyst, order of complexation of the catalyst components, and delayed addition of nucleophile. The formation of the active catalyst proceeds through a bimolecular combination of scandium­(III) with a BArF anion, followed by complexation with PyBox ligand, where the ligand-dependent rate and selectivity are observed. Notably, ligand-accelerated catalysis is observed, attributed to the ligand reducing off-cycle oligomerization of allylsilane. The role of BArF is discussed with a specific focus on the source of counterion in the reaction rate and enantioselectivity. We also report the formation of a mechanistically relevant fused tetrahydropyranindole produced upon the reaction of an allylsilane with alkylidene oxindole. In situ infrared spectroscopy demonstrates ligand-dependent acceleration where sterically demanding ligands perform with a faster relative reaction rate.

Recent Developments in Enantioselective Scandium-Catalyzed Transformations

“…Later in 2022, Franz and Hein employed related chiral ligand 60 in combination with the same precatalyst Sc(OTf)3 to promote the enantioselective formal [3 + 2] cycloaddition between alkylideneoxindole 90a and allylsilane 94 (Scheme 23) [67]. Employed at respectively 11 and 10 mol% of catalyst loadings in dichloromethane in the presence of NaBArF as an additive, the annulation resulted in the formation of novel tetrahydropyranoindole 95 with complete conversion, excellent diastereoselectivity (90% de) and good enantioselectivity (84% ee).…”

“…Employed at respectively 11 and 10 mol% of catalyst loadings in dichloromethane in the presence of NaBArF as an additive, the annulation resulted in the formation of novel tetrahydropyranoindole 95 with complete conversion, excellent diastereoselectivity (90% de) and good enantioselectivity (84% ee). Later in 2022, Franz and Hein employed related chiral ligand 60 in combination with the same precatalyst Sc(OTf) 3 to promote the enantioselective formal [3 + 2] cycloaddition between alkylideneoxindole 90a and allylsilane 94 (Scheme 23) [67]. Employed at respectively 11 and 10 mol% of catalyst loadings in dichloromethane in the presence of NaBArF as an additive, the annulation resulted in the formation of novel tetrahydropyranoindole 95 with complete conversion, excellent diastereoselectivity (90% de) and good enantioselectivity (84% ee).…”

“…The latter further reacted with scandium-activated chalcones 97 to give the corresponding chiral 1,5-Scheme 23. Formal [3 + 2] cycloaddition of an alkylideneoxindole with an allylsilane [67].…”