BINOL Phosphate Research Articles

Discovery of GPR84 Fluorogenic Probes Based on a Novel Antagonist for GPR84 Bioimaging.

GPR84 is a promising therapeutic target and biomarker for a range of diseases. In this study, we reported the discovery of BINOL phosphate (BINOP) derivatives as GPR84 antagonists. By investigating the structure-activity relationship, we identified 15S as a novel GPR84 antagonist. 15S exhibits low nanomolar potency and high selectivity for GPR84, while its enantiomer 15R is less active. Next, we rationally designed and synthesized a series of GPR84 fluorogenic probes by conjugating Nile red and compound 15S. The leading hybrid, probe F8, not only retained GPR84 activity but also exhibited low nonspecific binding and a turn-on fluorescent signal in an apolar environment. F8 enabled visualization and detection of GPR84 in GPR84-overexpressing HEK293 cells and lipopolysaccharide-stimulated neutrophils. Furthermore, we demonstrated that F8 can detect upregulated GPR84 protein levels in mice models of inflammatory bowel disease and acute lung injury. Thus, compound F8 represents a promising tool for studying GPR84 functions.

Chiral Counteranion-Directed Catalytic Asymmetric Methylene Migration Reaction of Ene-Aldimines.

A catalytic asymmetric methylene migration reaction of ene-aldimines directed by chiral counteranions is developed, with the optimal catalyst identified as phenanthryl-substituted (R)-BINOL phosphate. Control experiments and density functional theory computations reveal the importance of the 2-hydroxy group of the ene-aldimine and attractive (e.g., OH···O, CH···O, CH···π, and π···π) interactions for high enantioselectivity (up to 74% ee). The results contribute to the design of asymmetric catalysis for the rearrangement of highly reactive iminium intermediates.

Computational Exploration of a Pd(II)-Catalyzed γ-C-H Arylation Where Stereoselectivity Arises from Attractive Aryl-Aryl Interactions.

The enantioselective Pd(II)-catalyzed γ-C-H arylation of picolinamides with a chiral BINOL phosphate ligand was explored using density functional theory (DFT). Enantioselectivity arises from attractive aryl-aryl interactions between the pseudoequatorial phenyl substituent of the substrate and the chiral BINOL phosphate ligand.

An Enantioselective Bidentate Auxiliary Directed Palladium‐Catalyzed Benzylic C−H Arylation of Amines Using a BINOL Phosphate Ligand

AbstractA new enantioselective palladium(II)‐catalyzed benzylic C−H arylation reaction of amines is enabled by the bidentate picolinamide (PA) directing group. This reaction provides the first example of enantioselective benzylic γ‐C−H arylations of alkyl amines, and proceeds with up to 97 % ee. The 2,2′‐dihydroxy‐1,1′‐binaphthyl (BINOL) phosphoric acid ligand, Cs2CO3, and solvent‐free conditions are essential for high enantioselectivity. Mechanistic studies suggest that multiple BINOL ligands are involved in the stereodetermining C−H palladation step.

An Enantioselective Bidentate Auxiliary Directed Palladium-Catalyzed Benzylic C-H Arylation of Amines Using a BINOL Phosphate Ligand.

A new enantioselective palladium(II)-catalyzed benzylic C-H arylation reaction of amines is enabled by the bidentate picolinamide (PA) directing group. This reaction provides the first example of enantioselective benzylic γ-C-H arylations of alkyl amines, and proceeds with up to 97 % ee. The 2,2'-dihydroxy-1,1'-binaphthyl (BINOL) phosphoric acid ligand, Cs2 CO3 , and solvent-free conditions are essential for high enantioselectivity. Mechanistic studies suggest that multiple BINOL ligands are involved in the stereodetermining C-H palladation step.

Carboxylic Acid Modified BINOL Phosphate Catalysis

Key words hetero-Diels–Alder reaction - Brønsted acid catalysis - tetrahydro-pyridazines - amidodienes

Dynamic Inversion of Stereoselective Phosphate Binding to a Bisurea Receptor Controlled by Light and Heat

AbstractA chiral bisurea anion receptor, derived from a first‐generation molecular motor, can undergo photochemical and thermal isomerization operating as a reconfigurable system. The two possible cis configurations in the isomerization cycle are opposite in helicity, as is shown by CD spectroscopy. 1H NMR titrations demonstrate that the P and M helical cis isomers hold opposite enantioselectivity in the binding of binol phosphate, while anion complexation by the intermediate trans isomer is not selective. The difference in the binding affinity of the enantiomers was rationalized by DFT calculations, revealing very distinct binding modes. Thus, the enantiopreferred substrate binding in this receptor can be inverted in a dynamic fashion using light and heat.

Dynamic Inversion of Stereoselective Phosphate Binding to a Bisurea Receptor Controlled by Light and Heat.

A chiral bisurea anion receptor, derived from a first-generation molecular motor, can undergo photochemical and thermal isomerization operating as a reconfigurable system. The two possible cis configurations in the isomerization cycle are opposite in helicity, as is shown by CD spectroscopy. (1)H NMR titrations demonstrate that the P and M helical cis isomers hold opposite enantioselectivity in the binding of binol phosphate, while anion complexation by the intermediate trans isomer is not selective. The difference in the binding affinity of the enantiomers was rationalized by DFT calculations, revealing very distinct binding modes. Thus, the enantiopreferred substrate binding in this receptor can be inverted in a dynamic fashion using light and heat.

An Approach to Highly Hindered BINOL Phosphates

The synthesis of 3-3′-substituted BINOL-derived chiral phosphoric acid catalysts is still largely limited by the limitations of current cross-coupling methodologies. For this reason, despite the importance of sterically demanding catalysts in Bronsted acid catalysis, highly hindered congeners are still unprecedented. Exploiting the aryne addition reaction as key step, we report herein the development of a novel synthetic route to access this unexplored class of catalysts.

ChemInform Abstract: Lithium BINOL Phosphate Catalyzed Desymmetrization of meso‐Epoxides with Aromatic Thiols.

A highly enantioselective method for desymmetrization of meso-epoxides using thiols is reported. This is the first example of epoxide activation achieved using metal BINOL phosphates. The reaction has a broad scope in terms of epoxide substrates and aromatic thiol nucleophiles. The resulting β-hydroxyl sulfides are obtained in excellent yield and enantioselectivity.

Lithium BINOL phosphate catalyzed desymmetrization of meso-epoxides with aromatic thiols.

A highly enantioselective method for desymmetrization of meso-epoxides using thiols is reported. This is the first example of epoxide activation achieved using metal BINOL phosphates. The reaction has a broad scope in terms of epoxide substrates and aromatic thiol nucleophiles. The resulting β-hydroxyl sulfides are obtained in excellent yield and enantioselectivity.

A New Approach towards the Asymmetric Fluorination of Alkenes Using Anionic Phase‐Transfer Catalysts

Chiral anions can do it: Asymmetric phase-transfer catalysis is no longer limited to cationic catalysts. Lipophilic BINOL phosphate anions are superior catalysts for the asymmetric electrophilic fluorination of alkenes under phase-transfer conditions (see picture). Now complex fluorinated compounds can be synthesized selectively from simple alkene starting materials.

Phosphate ligands in the gold(i)-catalysed activation of enynes

Gold(I) forms neutral complexes with binol phosphates that are unreactive in the catalytic cyclisation of enynes. Reaction in protic solvents or activation by silver(I) restores the catalytic activity.

Catalytic Asymmetric Peroxidation of Imines

Antilla and co-workers report the chiral phosphoric acid 1 catalyzed peroxidation of imines. In the presence of chiral 3,3′-bis-(9-­anthracenyl)-substituted BINOL phosphate 1, the addition of tert-butyl hydroperoxide to various aromatic imines proceeded smoothly to give the desired α-amino peroxides in generally high yields and enantioselectivities. The proposed transition state involves the dual activation of the imine and the hydroperoxide reagent via hydrogen bonding.

Chiral BINOL-derived phosphoric acids: privileged Brønsted acid organocatalysts for C–C bond formation reactions

BINOL-derived phosphoric acids have emerged during the last five years as powerful chiral Brønsted acid catalysts in many enantioselective processes. The most successful transformations carried out with chiral BINOL phosphates include C-C bond formation reactions. The recent advances have been reviewed in this article with a focus being placed on hydrocyanations, aldol-type, Mannich, Friedel-Crafts, aza-ene-type, Diels-Alder, as well as cascade and multi-component reactions.

The Catalytic Acylcyanation of Imines

The catalytic acylcyanation of aldimines with acylcyanides and a direct three-component variant involving the generation of an imine in situ have been developed. Furthermore, a highly enantioselective version has been established, culminating in the first organocatalytic asymmetric three-component Strecker reaction. Jacobsen thiourea catalysts were found to catalyze the reaction with excellent enantioselectivities, whereas binol phosphates (binol = 1,1'-bi-2,2'-naphthol) proved to be catalytically active but only modestly enantioselective. A large number of different substrates could be used in the processes described, thus illustrating the potential of our reaction for the generation of diversity within the attractive alpha-amino carbonyl framework. Furthermore, a novel cyclic amidine was obtained from the reaction of acetyl cyanide with ketimines.

A Highly Enantioselective Brønsted Acid Catalyst for the Strecker Reaction

An amenable route to amino acids: An optimized new chiral binol phosphate catalyst (see scheme; Ar=9-phenanthryl) for the hydrocyanation of imines provides a convenient strategy for the enantioselective synthesis of α-amino acids and diamines.

Enantioselective Brønsted Acid Catalyzed Transfer Hydrogenation: Organocatalytic Reduction of Imines

The first enantioselective Brønsted acid catalyzed reduction of imines has been developed. This new organocatalytic transfer hydrogenation of ketimines with Hantzsch dihydropyridine as the hydrogen source offers a mild method to various chiral amines with high enantioselectivity. The stereochemistry of the chiral amines can be rationalized by a stereochemical model derived from an X-ray crystal structure of a chiral BINOL phosphate catalyst. [reaction: see text]