Spirocycles provide an exciting platform to develop and understand the reactivity and selectivity for a wide variety of catalysts while affording diverse strategies to access molecules with important applications. This review features recent examples in which a spirocenter is formed within the key step of a catalytic asymmetric process, in either an intramolecular or intermolecular fashion. Examples highlight notable spirocyclization strategies and compare the reactivity and selectivity for different classes of chiral organocatalysts and organometallic catalysts.

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Substituted 3-hydroxy-2-oxindoles are important core structures found in many natural products [1] and pharmaceutical lead compounds.[2] Despite the prevalence of bioactive oxindole structures, there is not currently a general asymmetric method for the addition of a broad range of unactivated electron-rich p nucleophiles to isatins (indole-2,3-diones). [3, 4] Although the development of an asymmetric reaction is the primary challenge, the addition of electron-rich arenes is further complicated by the competing formation of achiral 3,3-diaryl oxindole products (such as B, Scheme 1). [5,6] Herein, we compare the activity and selectivity of diverse Lewis acid catalysts and show that chiral scandium(III) and indium(III) complexes offer a general method to control both the reactivity of the direct monoaddition of indole and arene nucleophiles to isatins and the absolute configuration of the product. Reactions involving catalytic asymmetric addition to isatins have been reported previously; however, this direct method is the first catalytic asymmetric addition of indole nucleophiles to an isatin.We III , and Y III complexes) capable of activating 1,2-dicarbonyl electrophiles to classify the effects of the metal, ligand, and temperature for addition reactions of nucleophiles to isatins. We used the addition of N-methylindole (2) to 5-bromo-N-methylisatin (1 a) as a model reaction and evaluated three criteria: reactivity, selectivity for the monoaddition product 3, and enantioselectivity (Table 1). Metal complexes with slower reaction rates were observed to be active for the addition reaction with limited (or no) formation of the 3,3'-bisindolyl product 4; however, both the use of a low temperature and the presence of a chiral ligand also promoted the Scheme 1. Competing formation of monoaddition (A) and doubleaddition (B) oxindole products in the Lewis acid catalyzed addition of nucleophiles to isatin. TMS = trimethylsilyl.

The scandium(III)-catalyzed enantioselective Hosomi-Sakurai allylation of isatins with various substituted allylic silanes is described. A catalyst loading as low as 0.05 mol % is utilized at room temperature to afford the 3-allyl-3-hydroxy-2-oxindoles in excellent yields and enantioselectivity up to 99% ee, including a demonstration of a gram-scale reaction. The effects of additives and varying silyl groups were explored to demonstrate the scope and application.

Substituted 3-hydroxy-2-oxindoles are important core structures found in many natural products [1] and pharmaceutical lead compounds. [2] Despite the prevalence of bioactive oxindole structures, there is not currently a general asymmetric method for the addition of a broad range of unactivated electron-rich p nucleophiles to isatins (indole-2,3-diones). [3, 4] Although the development of an asymmetric reaction is the primary challenge, the addition of electron-rich arenes is further complicated by the competing formation of achiral 3,3-diaryl oxindole products (such as B, Scheme 1). [5,6] Herein, we compare the activity and selectivity of diverse Lewis acid catalysts and show that chiral scandium(III) and indium(III) complexes offer a general method to control both the reactivity of the direct monoaddition of indole and arene nucleophiles to isatins and the absolute configuration of the product. Reactions involving catalytic asymmetric addition to isatins have been reported previously; however, this direct method is the first catalytic asymmetric addition of indole nucleophiles to an isatin.We examined a series of Lewis acid catalysts (Pd II , Cu II , In III , Sc III , La III , and Y III complexes) capable of activating 1,2dicarbonyl electrophiles to classify the effects of the metal, ligand, and temperature for addition reactions of nucleophiles to isatins. We used the addition of N-methylindole (2) to 5bromo-N-methylisatin (1 a) as a model reaction and evaluated three criteria: reactivity, selectivity for the monoaddition product 3, and enantioselectivity (Table 1). Metal complexes with slower reaction rates were observed to be active for the addition reaction with limited (or no) formation of the 3,3'bisindolyl product 4; however, both the use of a low temperature and the presence of a chiral ligand also promoted the Scheme 1. Competing formation of monoaddition (A) and doubleaddition (B) oxindole products in the Lewis acid catalyzed addition of nucleophiles to isatin. TMS = trimethylsilyl. Table 1: Metal and ligand effects for the addition of N-methylindole. [a] M(OTf) n Ligand T [8C] t [h] Yield [%] [b] ee [%] [c] 3 a 4

Silyl‐inspirierter Spirocyclus: Die Titelreaktion ermöglichte erstmals die katalytische asymmetrische [3+2]‐Anellierung von Allylsilanen. Mit dem chiralen Katalysator ScCl2(SbF6)/L und TMSCl als Promotor wurden die Produkte bei Raumtemperatur in ausgezeichneter Enantioselektivität erhalten. Die Si‐C‐Bindung kann unter Bildung von hydroxysubstituierten Spirooxindolen oxidiert werden. TMS=Trimethylsilyl.

A concise synthesis of homocitric acid lactone was developed to accommodate systematic placement of carbon isotopes (specifically 13C) for detailed studies of this co-factor. This new route uses a chiral allylic alcohol, available in multi-gram quantities from enzymatic resolution, as a starting material, which transposes asymmetry through an Ireland-Claisen rearrangement.

Trimethyl silanes provide best results, whereas chloro‐, methoxy‐ or aryl‐substituted silanes give rise to lower yields and decreasing enantioselectivities.