Photoacid-catalyzed acetalization of carbonyls with alcohols.

In this report, we demonstrate that visible light photoactivation of 6-bromo-2-naphthol facilitates the photoacid-catalyzed acetalization of carbonyls with alcohols. We also demonstrate that 2-naphthol when coupled to a photosensitizer provides acetals from electron-deficient aldehydes. In addition, the S1 excited state pKa for 6-bromo-2-naphthol in water was determined and shown to have increased excited-state acidity relative to 2-naphthol.

Photoacid-Catalyzed Friedel-Crafts Arylation of Carbonyls.

In this report, we demonstrate that visible-light-induced thiourea photoacids catalyze C-C bond-forming reactions. Upon photoirradiation, Schreiner's thiourea [(N,N'-bis[3,5-bis(trifluoromethyl)phenyl]-thiourea] catalyzes the double Friedel-Crafts addition of indoles to aldehydes and isatins to form the corresponding triarylmethanes and 3,3'-diarylindolin-2-ones. This protocol is amenable to a wide range of aldehyde and isatin electrophiles, as well as a variety of electronically diverse indoles. Mechanistic studies show that light is required for reaction initiation.

Catalyst-controlled oligomerization for the collective synthesis of polypyrroloindoline natural products.

In nature, many organisms generate large families of natural product metabolites that have related molecular structures as a means to increase functional diversity and gain an evolutionary advantage against competing systems within the same environment. One pathway commonly employed by living systems to generate these large classes of structurally related families is oligomerization, wherein a series of enzymatically catalysed reactions is employed to generate secondary metabolites by iteratively appending monomers to a growing serial oligomer chain. The polypyrroloindolines are an interesting class of oligomeric natural products that consist of multiple cyclotryptamine subunits. Herein we describe an iterative application of asymmetric copper catalysis towards the synthesis of six distinct oligomeric polypyrroloindoline natural products: hodgkinsine, hodgkinsine B, idiospermuline, quadrigemine H and isopsychotridine B and C. Given the customizable nature of the small-molecule catalysts employed, we demonstrate that this strategy is further amenable to the construction of quadrigemine H-type alkaloids not isolated previously from natural sources.

Titanium(IV)-catalyzed stereoselective synthesis of spirooxindole-1-pyrrolines.

A stereoselective cyclization between alkylidene oxindoles and 5-methoxyoxazoles has been developed using catalytic titanium(IV) chloride (as low as 5 mol %) to afford spiro[3,3'-oxindole-1-pyrrolines] in excellent yield (up to 99%) and diastereoselectivity (up to 99:1). Using a chiral scandium(III)-indapybox/BArF complex affords enantioenriched spirooxindole-1-pyrrolines where a ligand-induced reversal of diastereoselectivity is observed. This methodology is further demonstrated for the synthesis of pyrrolines from malonate alkylidene and coumarin derivatives.

Catalytic enantioselective carboannulation with allylsilanes.

The first catalytic asymmetric carboannulation with allylsilanes is presented. The enantioselective [3+2] annulation is catalyzed using a scandium(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 center are derived from alkylidene oxindole, coumarin, and malonate substrates with high stereoselectivity. The enantioselective 1,4-conjugate addition and enantioselective lactone formation (by trapping of the ß-silyl carbocation) is also described.

Strategies for the enantioselective synthesis of spirooxindoles.

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.

Catalytic stereoselective synthesis of diverse oxindoles and spirooxindoles from isatins.

A strategy for the efficient two-step synthesis of triazole derivatives of oxindoles and spirooxindoles is presented. Using a common set of N-propargylated isatins, a series of mechanistically distinct stereoselective reactions with different combinations of nucleophiles and catalysts provide access to diverse hydroxy-oxindoles, spiroindolones, and spirocyclic oxazoline structures. The resulting N-propargylated oxindoles are then converted to triazoles using copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. Overall, this strategy affords a 64-member pilot-scale library of diverse oxindoles and spirooxindoles.

Enantioselective Pictet-Spengler Reactions of Isatins for the Synthesis of Spiroindolones.

The condensation cyclization between isatins and 5-methoxy tryptamine catalyzed by chiral phosphoric acids provides spirooxindole tetrahydro-ß-carboline products in excellent yields (up to 99%) and enantioselectivity (up to 98:2 er). A comparison of catalysts provides insight for the substrate scope and factors responsible for efficient catalytic activity and selectivity in the spirocyclization. Chiral phosphoric acids with different 3,3'-substitution on the binaphthyl system and opposite axial chirality afford the spiroindolone product with the same absolute configuration.

Titanium-catalyzed stereoselective synthesis of spirooxindole oxazolines.

A regio- and stereoselective cyclization between isatins and 5-methoxyoxazoles has been developed using catalytic titanium(IV) chloride (10 or 20 mol %) to afford spiro[3,3'-oxindoleoxazolines] in excellent yield (up to 99%) and diastereoselectivity (dr >99:1). Substitution at the 4-position of the oxazole controls nucleophilic attack to provide either the 2-oxazoline or 3-oxazoline spirocycle with excellent (>99:1) regiocontrol.

Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery.

This review describes recent methods for the enantioselective synthesis of oxindoles and spirooxindoles, with a particular focus on scaffolds with applications in drug discovery. The synthetic challenge of the spiro-motif and the important biological activity of spirooxindoles continue to encourage the development of creative methods to access these important structures. Unique spirocycles often result from creative synthetic methods that would not typically be identified using classical synthetic disconnections. To establish the importance of asymmetric synthesis in the context of oxindole structures, recent examples are highlighted in which stereospecific binding and differential biological activity have been demonstrated based on the configuration at the 3-position. This review is organized by type of catalyst and synthetic strategy in order to compare traditional organometallic and Lewis acid methods with more recent organocatalytic methods. A section describing multicomponent and cascade reaction strategies is also included.