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

Abstract

Arylative phenol dearomatization affords complex, cyclohexanone-based scaffolds from simple starting materials, and asymmetric versions allow access to valuable enantioenriched structures. However, bespoke chiral ligands must typically be identified for each new scaffold variation. We have addressed this limitation by applying the concept of electrostatically-directed palladium catalysis whereby the chiral sulfonated ligand sSPhos engages in electrostatic interactions with a phenolate substrate via its associated alkali metal cation. This approach allows access to highly enantioenriched spirocyclohexadienones, a process originally reported by Buchwald and co-workers in a predominantly racemic manner. In addition, sSPhos is proficient at forming two other distinct scaffolds, which had previously required fundamentally different chiral ligands, as well as a novel oxygen-linked scaffold. We envisage that the broad generality displayed by sSPhos will facilitate the expansion of this important reaction type and highlight the potential of this unusual design principle, which harnesses attractive electrostatic interactions.

Organocatalytic Dearomative Spirocyclization Reaction of Enone-Tethered α-and β-Naphthols and Dearomatization Reaction of In Situ Generated Nitro-Olefin-Tethered α-Naphthols

“…In recent years, transition metal catalyzed dearomatization of phenol and naphthol derivatives has been explored widely for the preparation of different spirocarbocyclic molecules . Pioneering examples of transition metal-catalyzed dearomative spirocyclizations were recognized by the groups of Hamada, You, Buchwald, and Feringa through an intramolecular design by using tethered phenol ,, and naphthol. ,,,, Also, intermolecular approaches were developed by the groups of Luan, Gulías and Mascareñas, Lam, You, Xu, and Jia and the methods mainly involve Ru II -, Rh III -, and Pd-catalyzed dearomatizing [3 + 2] spiroannulations of phenol-derived biaryls with alkynes. In contrast metal-free approaches are less.…”

Application of sSPhos as a Chiral Ligand for Palladium-Catalyzed Asymmetric Allylic Alkylation

“… 8 Having developed a method for obtaining sSPhos in enantiopure form via resolution using quinidine ( Figure 1 A, right), we subsequently used sSPhos in enantiopure form to control enantioselectivity in Suzuki–Miyaura cross-coupling reactions to form 2,2′-biphenols, as well as in arylative dearomatization reactions to afford a range of scaffolds ( Figure 1 B, center and right). 9 In all cases, we believe that attractive noncovalent interactions involving the ligand sulfonate group are required for selectivity. We propose either electrostatic interactions or hydrogen bonding interactions depending on the specific reaction and conditions.…”

“…Use of ( R )-sSPhos-Np gave 3a in a very high 90% ee, supporting our sterics-based hypothesis for the control of enantioselectivity (Figure C, right). This stands in contrast to our previous reports of cross-coupling and arylative dearomatization, where sulfonate ester variants of ( R )-sSPhos gave negligible ee, providing support in those cases for attractive noncovalent interactions …”

“…We first used sSPhos in racemic form for the control of site selectivity in cross-coupling reactions (Figure B, left) . Having developed a method for obtaining sSPhos in enantiopure form via resolution using quinidine (Figure A, right), we subsequently used sSPhos in enantiopure form to control enantioselectivity in Suzuki–Miyaura cross-coupling reactions to form 2,2′-biphenols, as well as in arylative dearomatization reactions to afford a range of scaffolds (Figure B, center and right) . In all cases, we believe that attractive noncovalent interactions involving the ligand sulfonate group are required for selectivity.…”

“…This stands in contrast to our previous reports of cross-coupling and arylative dearomatization, where sulfonate ester variants of ( R )-sSPhos gave negligible ee, providing support in those cases for attractive noncovalent interactions. 9 …”