Amino Acid-Derived Ionic Chiral Catalysts Enable Desymmetrizing Cross-Coupling to Remote Acyclic Quaternary Stereocenters

Abstract

Synthetic application of asymmetric catalysis relies on strategic alignment of bond construction to creation of chirality of a target molecule. Remote desymmetrization offers distinctive advantages of spatial decoupling of catalytic transformation and generation of a stereogenic element. However, such spatial separation presents substantial difficulties for the chiral catalyst to discriminate distant enantiotopic sites through a reaction three or more bonds away from a prochirality center. Here, we report a strategy that establishes acyclic quaternary carbon stereocenters through cross-coupling reactions at distal positions of aryl substituents. The new class of amino acid-derived ionic chiral catalysts enables desymmetrizing (enantiotopic-group-selective) Suzuki–Miyaura reaction, Sonogashira reaction, and Buchwald–Hartwig amination between diverse diarylmethane scaffolds and aryl, alkynyl, and amino coupling partners, providing rapid access to enantioenriched molecules that project substituents to widely spaced positions in the three-dimensional space. Experimental and computational investigations reveal electrostatic steering of substrates by the C-terminus of chiral ligands through ionic interactions. Cooperative ion-dipole interactions between the catalyst’s amide group and potassium cation aid in the preorganization that transmits asymmetry to the product. This study demonstrates that it is practical to achieve precise long-range stereocontrol through engineering the spatial arrangements of the ionic catalysts’ substrate-recognizing groups and metal centers.

An Asymmetric Aromatic Finkelstein Reaction: A Platform for Remote Diarylmethane Desymmetrization

“…Diarylmethanes have been successfully utilized in several methodology and drug discovery campaigns. [25][26][27][28][29][30][31][32][33] In particular, a series of reports from our lab established a high degree of compatibility with small-peptide catalysis over a broad range of mechanistically distinct transformations. [20][21][22][23][34][35] A series of experiments was therefore undertaken to identify key parameters that govern mechanism and structure to elucidate the privileged role of diarylmethanes in peptide catalysis.…”

“…[17][18][19] [20][21][22][23] The generation of stereocenters removed from the center of reaction remains a major challenge in contemporary asymmetric catalysis. [24][25][26] In this field, peptide-based catalysts have found particular utility, stimulating the present study of their capacity to mediate remote aryl bromide to aryl iodide substitution. We further hypothesized that leveraging the enhanced reactivity of the C-I bond towards venerable cross-coupling reactions would allow for translation of the installed stereoinformation into chemoselective transition metal-catalyzed transformations (Figure 1C).…”

sSPhos: A General Ligand for Enantioselective Arylative Phenol Dearomatization via Electrostatically-Directed Palladium Catalysis

“…Originally reported by Anderson and Buchwald as a water-soluble ligand for cross-coupling, we initially utilized ( rac )-sSPhos for control of site selectivity in the cross-coupling of polyhalogenated arenes. Therein, we introduced the concept of electrostatically directed palladium catalysis, whereby an anionic ligand interacts with an anionic substrate via a bridging alkali metal cation through electrostatic interactions (Figure C, left). , We subsequently found enantiopure sSPhos to be highly proficient in controlling enantioselectivity in Suzuki–Miyaura couplings to form 2,2′-biphenols, an outcome we tentatively attributed to an organizing network of hydrogen bonds between the ligand sulfonate group and the phenolic hydroxyls on the coupling partners (Figure C, right) . On the basis of these precedents, we hypothesized that enantiopure sSPhos might be an effective ligand for enantiocontrol in the Buchwald arylative dearomatization reaction.…”

An Asymmetric Aromatic Finkelstein Reaction: A Platform for Remote Diarylmethane Desymmetrization

“…Motivated by recent observations applying guanidinylated peptide-based ligands in asymmetric copper-based cross-couplings, we sought to establish a synthetic platform that would allow for the development of an enantioselective aromatic Finkelstein reaction for remote desymmetrization of diarylmethanes. − The generation of stereocenters removed from the center of reaction remains a major challenge in contemporary asymmetric catalysis. − In this field, peptide-based catalysts have found particular utility, stimulating the present study of their capacity to mediate remote aryl bromide to aryl iodide substitution. We further hypothesized that leveraging the enhanced reactivity of the C–I bond toward venerable cross-coupling reactions would allow for translation of the installed stereoinformation into chemoselective transition-metal-catalyzed transformations (Figure C) .…”

“…Having established the synthetic potential of the asymmetric aromatic Finkelstein reaction as a platform for chiral diarylmethane synthesis, we explored the mechanistic and structural requirements to achieve high selectivity. Diarylmethanes have been successfully utilized in several methodology and drug discovery campaigns. − In particular, our lab has established a high degree of compatibility with small-peptide catalysis over a broad range of mechanistically distinct transformations. − ,, A series of experiments was therefore undertaken to identify parameters that govern the privileged role of diarylmethanes in peptide catalysis.…”