Thiourea-catalysed ring opening of episulfonium ions with indole derivatives by means of stabilizing non-covalent interactions

Small organic and metal-containing molecules (molecular mass <1,000) can catalyse synthetically useful reactions with the high levels of stereoselectivity typically associated with macromolecular enzymatic catalysts. Whereas enzymes are generally understood to accelerate reactions and impart selectivity as they stabilize specific transition structures through networks of cooperative interactions, enantioselectivity with chiral, small-molecule catalysts is rationalized typically by the steric destabilization of all but one dominant pathway. However, it is increasingly apparent that stabilizing effects also play an important role in small-molecule catalysis, although the mechanistic characterization of such systems is rare. Here, we show that arylpyrrolidino amido thiourea catalysts catalyse the enantioselective nucleophilic ring opening of episulfonium ions by indoles. Evidence is provided for the selective transition-state stabilization of the major pathway by the thiourea catalyst in the rate- and selectivity-determining step. Enantioselectivity is achieved through a network of attractive anion binding, cation-π and hydrogen-bond interactions between the catalyst and the reacting components in the transition-structure assembly.Chemistry and Chemical Biolog

Asymmetric Ion-Pairing Catalysis

Chemistry and Chemical Biolog

Transition-State Charge Stabilization through Multiple Non-covalent Interactions in the Guanidinium-Catalyzed Enantioselective Claisen Rearrangement

The mechanism by which chiral arylpyrrole-substituted guanidinium ions promote the Claisen rearrangement of O-allyl α-ketoesters and induce enantioselectivity was investigated by experimental and computational methods. In addition to stabilization of the developing negative charge on the oxallyl fragment of the rearrangement transition state by hydrogen-bond donation, evidence was obtained for a secondary attractive interaction between the π-system of a catalyst aromatic substituent and the cationic allyl fragment. Across a series of substituted arylpyrrole derivatives, enantioselectivity was observed to vary predictably according to this proposal. This mechanistic analysis led to the development of a new p-dimethylaminophenyl-substituted catalyst, which afforded improvements in enantioselectivity relative to the parent phenyl catalyst for a representative set of substrates.Chemistry and Chemical Biolog

Chiral Sulfinamidourea and Strong Brønsted Acid–Cocatalyzed Enantioselective Povarov Reaction to Access Tetrahydroquinolines

This protocol describes a method for the laboratory synthesis of enantiomerically enriched, chiral tetrahydroisoquinolines through the application of a chiral sulfinamido urea catalyst for the Povarov reaction. Tetrahydroisoquinolines are bicyclic organic frameworks present in a wide assortment of natural and synthetic biologically important compounds including ​martinelline, ​scoulerine and ​tubocurarine. The methodology involves the [4+2] cycloaddition of a N-arylimines with electron-rich olefins such as vinyl lactams and dihydropyrroles in the presence of a two-catalyst system consisting of an achiral strong Brønsted acid (​o-nitrobenzenesulfonic acid), together with the chiral sulfinamido urea derivative 1. The anion-binding properties of the ​urea lead to the association of the ion pair that results from protonation of the imine substrate. Cycloaddition is followed by spontaneous proton loss with re-aromatization to provide the tetrahydroisoquinoline products in highly enantio-enriched form.Chemistry and Chemical Biolog

Structural Analysis of Spiro β-Lactone Proteasome Inhibitors

Spiro β-lactone-based proteasome inhibitors were discovered in the context of an asymmetric catalytic total synthesis of the natural product (+)-lactacystin (1). Lactone 4 was found to be a potent inhibitor of the 26S proteasome, while its C-6 epimer (5) displayed weak activity. Crystallographic studies of the two analogues covalently bound to the 20S proteasome permitted characterization of the important stabilizing interactions between each inhibitor and the proteasome’s key catalytic N-terminal threonine residue. This structural data support the hypothesis that the discrepancy in potency between 4 and 5 may be due to differences in the hydrolytic stabilities of the resulting acyl enzyme complexes.Chemistry and Chemical Biolog

Thiourea-Catalyzed Enantioselective Iso-Pictet-Spengler Reactions

A one-pot condensation of isotryptamines and aldehydes that affords enantiomerically enriched 4-substituted tetrahydro-$\gamma$-carbolines is reported. The reaction is induced by a chiral thiourea/benzoic acid dual catalyst system. Purification of the N-Boc-protected products by trituration or crystallization provides the optically pure tetrahydro-$\gamma$-carboline derivatives in a scalable and highly practical procedure.Chemistry and Chemical Biolog

Dual Catalysis in Enantioselective Oxidopyrylium-Based [5+2] Cycloadditions

A new method is reported for effecting catalytic enantioselective intramolecular [5+2] cycloadditions based on oxidopyrylium intermediates. The dual catalyst system consists of a chiral primary aminothiourea and a second achiral thiourea. Experimental evidence points to a new type of cooperative catalysis with each species being necessary to generate a reactive pyrylium ion pair which undergoes subsequent cycloaddition with high enantioselectivity.Chemistry and Chemical Biolog

Enantioselective Thiourea-Catalyzed Additions to Oxocarbenium Ions

Asymmetric, catalytic reactions of oxocarbenium ions are reported. Simple, chiral urea and thiourea derivatives are shown to catalyze the enantioselective substitution of silyl ketene acetals onto 1-chloroisochromans. A mechanism involving anion binding by the chiral catalyst to generate a reactive oxocarbenium ion is invoked. Catalysts bearing tertiary benzylic amide groups afforded highest enantioselectivities, with the optimal structure being derived from enantioenriched 2-arylpyrrolidine derivatives

Chiral Sulfinamide/Achiral Sulfonic Acid Cocatalyzed Enantioselective Protonation of Enol Silanes

The application of chiral sulfinamides and achiral sulfonic acids as a co-catalyst system for enantioselective protonation reactions is described. Structurally simple, easily accessible sulfinamides were found to induce moderate-to-high eeʼs in the formation of 2-aryl-substituted cycloalkanones from the corresponding trimethylsilyl enol ethers.Chemistry and Chemical Biolog

Enantioselective Acylation of Silyl Ketene Acetals through Fluoride Anion-Binding Catalysis

A highly-enantioselective acylation of silyl ketene acetals with acyl fluorides has been developed to generate useful $\alpha$, $\alpha$-disubstituted butyrolactone products. This reaction is promoted by a new thiourea catalyst and 4-pyrrolidinopyridine and represents the first example of enantioselective thiourea anion-binding catalysis with fluoride.Chemistry and Chemical Biolog