Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.

G protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue, and cellular level. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized.

Merging C(sp)-H activation with DNA-encoding.

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C-H bonds provides a unique avenue for creating diversity and complexity from simple starting materials.

Ligand-Enabled, Palladium-Catalyzed β-C(sp)-H Arylation of Weinreb Amides.

We report the development of Pd(II)-catalyzed C(sp)-H arylation of Weinreb amides. This work demonstrates the first example of using Weinreb amide as a directing group for transition metal-catalyzed C(sp)-H activation. Both the inductive effect and the potential bidentate coordination mode of the Weinreb amides pose a unique challenge for this reaction development.

Pd -Catalyzed Enantioselective C(sp )-H Activation/Cross-Coupling Reactions of Free Carboxylic Acids.

Pd -catalyzed enantioselective C(sp )-H cross-coupling of free carboxylic acids with organoborons has been realized using either mono-protected amino acid (MPAA) ligands or mono-protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl- and vinyl-boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α-chiral tertiary and quaternary stereocenters.

Pd(II)-Catalyzed Enantioselective C(sp)-H Arylation of Free Carboxylic Acids.

A monoprotected aminoethyl amine chiral ligand based on an ethylenediamine backbone was developed to achieve Pd-catalyzed enantioselective C(sp)-H arylation of cyclopropanecarboxylic and 2-aminoisobutyric acids without using exogenous directing groups. This new chiral catalyst affords new disconnection for preparing diverse chiral carboxylic acids from simple starting materials that are complementary to the various ring forming approaches.

Enantioselective C-H Arylation and Vinylation of Cyclobutyl Carboxylic Amides.

Chiral mono--protected aminomethyl oxazoline (MPAO) ligands are found to promote enantioselective C-H arylation and vinylation of the cyclobutyl carboxylic acid derivatives Pd(II)/Pd(IV) redox catalysis. This ligand scaffold overcame two important limitations of the previous MPAHA (mono--protected α-amino--methylhydroxamic acid) ligands-enabled asymmetric C-H activation/C-C coupling reactions of cyclic carboxylic amides through Pd(II)/Pd(0) catalysis: substrates containing α-hydrogen atoms are not compatible; vinylation has not been developed. Sequential C-H arylation and vinylation of cyclobutanes are also accomplished to construct three consecutive chiral centers on the crowded cyclobutane rings, rendering this reaction highly versatile for the preparation of chiral cyclobutanes.

Formation of α-chiral centers by asymmetric β-C(sp3)-H arylation, alkenylation, and alkynylation.

The enzymatic β-C-H hydroxylation of the feedstock chemical isobutyric acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transition metal-catalyzed enantioselective β-C-H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge.

Ligand-Enabled Alkynylation of C(sp )-H Bonds with Palladium(II) Catalysts.

The palladium(II)-catalyzed β- and γ-alkynylation of amide C(sp )-H bonds is enabled by pyridine-based ligands. This alkynylation reaction is compatible with substrates containing α-tertiary or α-quaternary carbon centers. The β-methylene C(sp )-H bonds of various carbocyclic rings were also successfully alkynylated.

Ligand-Promoted meta-C-H Amination and Alkynylation.

Using a modified norbornene (methyl bicyclo[2.2.1]hept-2-ene-2-carboxylate) as a transient mediator, meta-C-H amination and meta-C-H alkynylation of aniline and phenol substrates have been developed for the first time.

Ligand-Promoted Meta-C-H Arylation of Anilines, Phenols, and Heterocycles.

Here we report the development of a versatile 3-acetylamino-2-hydroxypyridine class of ligands that promote meta-C-H arylation of anilines, heterocyclic aromatic amines, phenols, and 2-benzyl heterocycles using norbornene as a transient mediator. More than 120 examples are presented, demonstrating this ligand scaffold enables a wide substrate and coupling partner scope. Meta-C-H arylation with heterocyclic aryl iodides as coupling partners is also realized for the first time using this ligand.

Ligand-Enabled Meta-C-H Alkylation and Arylation Using a Modified Norbornene.

2-Carbomethoxynorbornene is identified as a more effective transient mediator to promote a Pd(II)-catalyzed meta-C(sp(2))-H alkylation of amides with various alkyl iodides as well as arylation with previously incompatible aryl iodides. The use of a tailor-made quinoline ligand is also crucial for this reaction to proceed.

Development of modifiable bidentate amino oxazoline directing group for pd-catalyzed arylation of secondary C-H bonds.

A novel bidentate α-amino oxazolinyl directing group has been developed. Different from previous directing groups, this newly designed directing group was easily prepared from amino acids and modified in structure. This auxiliary preferentially effects functionalization at secondary C(sp(3) )-H bonds, rather than at aryl C(sp(2) )-H bonds.

Direct arylation of primary and secondary sp3 C-H bonds with diarylhyperiodonium salts via Pd catalysis.

Palladium-catalyzed primary and secondary sp(3) C-H bond arylation is reported. The method using diarylhyperiodonium salts as arylation reagents shows good functional group tolerance and proceeds under mild reaction conditions. The KIE experiments show that the C-H bond activation is the rate-determining step.