Chiral Anion Phase-Transfer Catalysis Research Articles

Asymmetric Bromoaminocyclization and Desymmetrization of Cyclohexa-1,4-dienes through Anion Phase-Transfer Catalysis.

The catalytic enantioselective desymmetrizing bromoaminocyclization of prochiral cyclohexa-1,4-dienes has been achieved by using chiral anion phase-transfer catalysis, providing a range of enantioenriched cis-3a-arylhydroindoles bearing an all-carbon quaternary stereocenter in good yields (up to 78%) and excellent enantioselectivities (up to 97% ee). Furthermore, the potential application of this methodology to natural product total synthesis was demonstrated by the asymmetric synthesis of (+)-Mesembrane.

Catalytic Dynamic Kinetic Resolutions in Tandem to Construct Two-Axis Terphenyl Atropisomers.

The defined structure of molecules bearing multiple stereogenic axes is of increasing relevance to materials science, pharmaceuticals, and catalysis. However, catalytic enantioselective approaches to control multiple stereogenic axes remain synthetically challenging. We report the catalytic synthesis of two-axis terphenyl atropisomers, with complementary strategies to both chlorinated and brominated variants, formed with high diastereo- and enantioselectivity. The chemistry proceeds through a sequence of two distinct dynamic kinetic resolutions: first, an atroposelective ring opening of Bringmann-type lactones produces a product with one established axis of chirality, and second, a stereoselective arene halogenation delivers the product with the second axis of chirality established. In order to achieve these results, a class of Brønsted basic guanidinylated peptides, which catalyze an efficient atroposelective chlorination, is reported for the first time. In addition, a complementary bromination is reported, which also establishes the second stereogenic axis. These bromo-terphenyls are accessible following the discovery that chiral anion phase transfer catalysis by C2-symmetric phosphoric acids allows catalyst control in the second stereochemistry-determining event. Accordingly, we established the fully catalyst-controlled stereodivergent synthesis of all possible chlorinated stereoisomers while also demonstrating diastereodivergence in the brominated variants, with significant levels of enantioselectivity in all cases.

Synthesis of Difluoromethylated Tetrasubstituted Stereocenters by Chiral Anion Phase-Transfer Catalysis

Synthesis of Difluoromethylated Tetrasubstituted Stereocenters by Chiral Anion Phase-Transfer Catalysis

Counterion-Induced Asymmetric Control in Ring-Opening of Azetidiniums: Facile Access to Chiral Amines.

Counterion-induced stereocontrol is a powerful tool in organic synthesis. However, such enantiocontrol on tetrahedral ammonium cations remains challenging. Described here is the first example of using chiral anion phase-transfer catalysis to achieve intermolecular ring-opening of azetidiniums with excellent enantioselectivity (up to 97 % ee). Precise control over the formation and reaction of the chiral ion pair as well as inhibition of the background reaction by the biphasic system is key to the success of the reaction.

Mechanistic Investigations of the Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Benzyl Acrylates.

A mechanistic study of the Pd-catalyzed enantioselective 1,1-diarylation of benzyl acrylates that is facilitated by a chiral anion phase transfer (CAPT) process is presented. Kinetic analysis, labeling, competition, and nonlinear effect experiments confirm the hypothesized general mechanism and reveal the role of the phosphate counterion in the CAPT catalysis. The phosphate was found to be involved in the phase transfer step and in the stereoinduction process, as expected, but also in the unproductive reaction that provides the traditional Heck byproduct. Multivariate correlations revealed the CAPT catalyst's structural features, affecting the production of this undesired byproduct, as well as weak interactions responsible for enantioselectivity. Such putative interactions include π-stacking and a CH···O electrostatic attraction between the substrate benzyl moiety and the phosphate. Analysis of the computed density functional theory transition structures for the stereodetermining step of the reaction supports the multivariate model obtained. The presented work provides the first comprehensive study of the combined use of CAPT and transition metal catalysis, setting the foundation for future applications.

Molecular Recognition in Asymmetric Counteranion Catalysis: Understanding Chiral Phosphate-Mediated Desymmetrization.

We describe the first theoretical study of a landmark example of chiral anion phase-transfer catalysis: the enantioselective ring-opening of meso-aziridinium and episulfonium cations promoted by asymmetric counteranion-directed catalysis (ACDC). The mechanism of ion-pairing, ring-opening, and catalyst deactivation have been studied in the condensed phase with both classical and quantum methods using explicitly and implicitly solvated models. We find that the stability of chiral ion-pairs, a prerequisite for asymmetric catalysis, is dominated by electrostatic interactions at long range and by CH···O interactions at short range. The decisive role of solvent upon ion-pair formation and of nonbonding interactions upon enantioselectivity are quantified by complementary computational approaches. The major enantiomer is favored by a smaller distortion of the substrate, demonstrated by a distortion/interaction analysis. Our computational results rationalize the stereoselectivity for several experimental results and demonstrate a combined classical/quantum approach to perform realistic modeling of chiral counterion catalysis in solution.

ChemInform Abstract: Recent Advances in Asymmetric Fluorination and Fluoroalkylation Reactions via Organocatalysis

AbstractReview: [41 refs.

Asymmetric fluorination of α-branched cyclohexanones enabled by a combination of chiral anion phase-transfer catalysis and enamine catalysis using protected amino acids.

We report a study involving the successful merger of two separate chiral catalytic cycles: a chiral anion phase-transfer catalysis cycle to activate Selectfluor and an enamine activation cycle, using a protected amino acid as organocatalyst. We have demonstrated the viability of this approach with the direct asymmetric fluorination of α-substituted cyclohexanones to generate quaternary fluorine-containing stereocenters. With these two chiral catalytic cycles operating together in a matched sense, high enantioselectivites can be achieved, and we envisage that this dual catalysis method has the potential to be more broadly applicable, given the breadth of enamine catalysis. It also represents a rare example of chiral enamine catalysis operating successfully on α-branched ketones, substrates commonly inert to this activation mode.

A combination of directing groups and chiral anion phase-transfer catalysis for enantioselective fluorination of alkenes.

We report a catalytic enantioselective electrophilic fluorination of alkenes to form tertiary and quaternary C(sp3)-F bonds and generate β-amino- and β-aryl-allylic fluorides. The reaction takes advantage of the ability of chiral phosphate anions to serve as solid-liquid phase transfer catalysts and hydrogen bond with directing groups on the substrate. A variety of heterocyclic, carbocyclic, and acyclic alkenes react with good to excellent yields and high enantioselectivities. Further, we demonstrate a one-pot, tandem dihalogenation-cyclization reaction, using the same catalytic system twice in series, with an analogous electrophilic brominating reagent in the second step.

ChemInform Abstract: Chiral Anion Phase‐Transfer Catalysis Applied to the Direct Enantioselective Fluorinative Dearomatization of Phenols.

AbstractThis reaction yields quaternary fluorine‐substituted stereocenters with good enantioselectivities, which are interesting building blocks for synthetic and medicinal chemistry.

Enantioselective Fluoroamination: 1,4‐Addition to Conjugated Dienes Using Anionic Phase‐Transfer Catalysis

Chiral-anion phase-transfer catalysis (PTC) has been applied towards the enantioselective fluorocyclization reactions of 1,3-dienes. The method affords unprecedented fluorinated benz[f]isoquinoline and octahydroisoquinoline products in high yields and up to 96 % ee. New fluorinated amine reagents outperformed Selectfluor in the desired transformation.

Chiral Anion Phase-Transfer Catalysis Applied to the Direct Enantioselective Fluorinative Dearomatization of Phenols

Chiral anion phase-transfer catalysis has enabled the direct and highly enantioselective fluorinative dearomatization of phenols catalyzed by a BINOL-derived phosphate. The process efficiently transforms simple, readily available phenols into fluorinated chiral small molecules bearing reactive functionality under ambient reaction conditions with high enantioselectivity. The close relationship of the products with well-studied o-quinols provides numerous avenues for synthetic elaboration and exciting opportunities for bioisosteric replacement of hydroxyl with fluorine in natural products.

Enantioselective Halocyclization Using Reagents Tailored for Chiral Anion Phase-Transfer Catalysis

A chiral anion phase-transfer system for enantioselective halogenation is described. Highly insoluble, ionic reagents were developed as electrophilic bromine and iodine sources, and application of this system to o-anilidostyrenes afforded halogenated 4H-3,1-benzoxazines with excellent yield and enantioselectivity.