Oxindoles and spirooxindoles are important synthetic targets that are often considered to be prevalidated with respect to their biological activity and applications for pharmaceutical lead discovery. This review features efficient strategies for the enantioselective synthesis of spirocyclic oxindoles, focusing on reports in 2010 and 2011. Although enantioselective synthesis remains an ongoing challenge, exciting recent advances in this area feature spirooxindoles with greater complexity, up to eight stereogenic centers, more practical synthetic methods, and new catalytic activation strategies. Developments in catalyst systems and reaction conditions have shown that many reactions can be optimized to control selectivity and provide access to isomeric products, which are important for biological testing. This review is organized based on two primary disconnection strategies, and then further subdivided into the type and ring size of the spirocycle that is generated. Strategies are also compared for the synthesis of non-spirocyclic 3,3'-disubstituted oxindoles.

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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The first catalytic asymmetric carboannulation with allylsilanes is presented. The enantioselective [3+2] annulation is catalyzed using a Sc(III)-indapybox complex with tetrakis-[3,5-bis(trifluoromethyl)phenyl]-borate (BArF) to enhance catalytic activity and control stereoselectivity. Functionalized cyclopentanes containing a quaternary carbon are derived from alkylidene oxindole, coumarin, and malonate substrates with high stereoselectivity. The enantioselective 1,4-conjugate addition and enantioselective lactone formation (via trapping of the β-silyl carbocation) is also described.

A short and efficient synthesis of a series of isoprenecarboxylic acid esters (ICAEs) and their corresponding polymers is presented. The base-catalyzed eliminative ring-opening of anhydromevalonolactone (3) provides isoprenecarboxylic acid (6-H), which was further transformed to the ICAEs. Reversible addition-fragmentation chain-transfer (RAFT) polymerization was used to synthesize high molecular weight (>100 kg mol−1) poly(isoprenecarboxylates) with dispersities (Đ) of ca. 1.5. The glass transition temperatures (Tg) and entanglement molecular weights (Me) of the poly(isoprenecarboxylates) were determined and showed similar trends to the Tg and Me values for analogous poly(acrylate esters). These new glucose-derived materials could provide a sustainable alternative to poly(acrylates).

The first catalytic asymmetric carboannulation with allylsilanes is presented. The enantioselective [3+2] annulation is catalyzed using a Sc(III)-indapybox complex with tetrakis-[3,5-bis(trifluoromethyl)phenyl]-borate (BArF) to enhance catalytic activity and control stereoselectivity. Functionalized cyclopentanes containing a quaternary carbon are derived from alkylidene oxindole, coumarin, and malonate substrates with high stereoselectivity. The enantioselective 1,4-conjugate addition and enantioselective lactone formation (via trapping of the β-silyl carbocation) is also described.Keywords asymmetric catalysis; cyclopentane; NaBArF; scandium; conjugate addition Lewis acid-catalyzed conjugate addition and cyclization reactions of unsaturated carbonyl compounds are important routes for the synthesis of complex heterocycles and carbocycles. Despite significant advances in asymmetric catalysis, [1,2] many conjugate addition and cyclization reactions using unsaturated carbonyl compounds still lack catalytic asymmetric variants. First reported by Knölker in 1990, [3] the cyclopentane annulation of air-and moisture-stable allylsilane nucleophiles with unsaturated carbonyl compounds is a transformation where a catalytic asymmetric variant has eluded development. [4][5][6] The challenge associated with controlling additions to unsaturated carbonyl compounds is highlighted by the fact that only one method has been reported for a catalytic enantioselective conjugate addition reaction using allylsilanes ( Figure 1A). [7] Herein, we report the first catalytic asymmetric annulation of allylsilanes with unsaturated carbonyl compounds ( Figure 1B) to access cyclopentanes possessing up to three stereocenters, including a quaternary carbon spirocenter.The reaction of alkylidene oxindole 1 with allylsilane 2a [8] offers a platform to study the reactivity and selectivity for the annulation reaction (Table 1). The selective formation of a cyclic product (e.g. 4) or an allylation (Hosomi-Sakurai) product (e.g. 5) is determined based on control of the β-silyl-stabilized carbocation intermediate (e.g. 3). [9,10] Selective formation of spirocyclopentane 4, resulting from rearrangement of the β-silyl carbocation intermediate, HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript is a critical component of the successful development of this methodology. Our initial studies with chiral tin(IV), [11] copper(II), [7] and scandium(III)[5a,12] complexes afforded only low selectivity and/or low reactivity for the synthesis of spirocyclopentane 4a (e.g. entries 1-4). [13] To identify a more effective catalyst, we investigated Sc(III)-pybox complexes with NaBArF [BArF = B(3,5-C 6 H 3 (CF 3 ) 2 ) 4 ] ( Table 1, entries 5-9). [14] A significant activating effect was observed for both ScCl 3 -and Sc(OTf) 3 -derived complexes, affording spirocyclopentane 4a [15] with high yield and up to 97:3 enantioselectivity (entries 5 and 6).Using other counterions such as NaSbF 6 and KPF 6 , or additives such as...

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 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.