Catalytic,Enantioselective α‐Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation

A palladium(II)‐catalyzed enantioselective α‐alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL‐derived phosphoric acid as the source of stereoinduction, and a cleavable bidentate directing group appended to the alkene to control the regioselectivity and stabilize the nucleopalladated alkylpalladium(II) intermediate in the catalytic cycle. A wide range of azlactones were found to be compatible under the optimal reaction conditions to afford products bearing α,α‐disubstituted α‐amino‐acid derivatives with high yields and high enantioselectivity.     

Intermolecular Heck Coupling with Hindered Alkenes Directed by Potassium Carboxylates

Pd⁰‐catalyzed Mizoroki–Heck reactions traditionally exhibit poor reactivity with polysubstituted, unbiased alkenes. Intermolecular reactions with simple, all‐carbon tetrasubstituted alkenes are unprecedented. Herein we report that pendant carboxylic acids, combined with bulky monophospine ligands on palladium, can direct the arylation of tri‐ and tetrasubstituted olefins. Quaternary carbons are established at high Fsp³ attached‐ring junctures and the carboxylate directing group can be removed after coupling. Carboxylate directivity prevents over‐arylation of the new, less substituted alkene, which can be diversified in subsequent reactions.     

Palladium(0)‐Catalyzed Directed syn‐1,2‐Carboboration and ‐Silylation: Alkene Scope,Applications in Dearomatization,and Stereocontrol by a Chiral Auxiliary

We report the development of palladium(0)‐catalyzed syn‐selective 1,2‐carboboration and ‐silylation reactions of alkenes containing cleavable directing groups. With B₂pin₂ or PhMe₂Si‐Bpin as nucleophiles and aryl/alkenyl triflates as electrophiles, a broad range of mono‐, di‐, tri‐ and tetrasubstituted alkenes are compatible in these transformations. We further describe a directed dearomative 1,2‐carboboration of electron‐rich heteroarenes by employing this approach. Through use of a removable chiral directing group, we demonstrate the viability of achieving stereoinduction in Heck‐type alkene 1,2‐difunctionalization. This work introduces new avenues to access highly functionalized boronates and silanes with precise regio‐ and stereocontrol.     

Direct Borylation of Primary C?H Bonds in Functionalized Molecules by Palladium Catalysis

Organoborane compounds are among the most commonly employed intermediates in organic synthesis and serve as crucial precursors to alcohols, amines, and various functionalized molecules. A simple palladium‐based system catalyzes the conversion of primary C(sp³) H bonds in functionalized complex organic molecules into alkyl boronate esters. Amino acids, amino alcohols, alkyl amines, and a series of bioactive molecules can be functionalized with the use of readily available and removable directing groups in the presence of commercially available additives, simple ligands, and oxygen (O₂) as the terminal oxidant. This approach represents an economic and environmentally friendly method that could find broad applications.     

Ligand‐Enabled Alkynylation of C(sp3)−H Bonds with Palladium(II) Catalysts

The palladium(II)‐catalyzed β‐ and γ‐alkynylation of amide C(sp³)−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(sp³)−H bonds of various carbocyclic rings were also successfully alkynylated.     

Amino Acid‐Specific,Ribonucleotide‐Promoted Peptide Formation in the Absence of Enzymes

Nucleic acids and polypeptides are at the heart of life. It is interesting to ask whether the monomers of these biopolymers possess intrinsic reactivity that favors oligomerization in the absence of enzymes. We have recently observed that covalently linked peptido RNA chains form when mixtures of monomers react in salt‐rich condensation buffer. Here, we report the results of a screen of the 20 proteinogenic amino acids and four ribonucleotides. None of the amino acids prevent phosphodiester formation, so all of them are compatible with genetic encoding through RNA chain growth. A reactivity landscape was found, in which peptide formation strongly depends on the structure of the amino acid, but less on the nucleobase. For example, proline gives ribonucleotide‐bound peptides most readily, tyrosine favors pyrophosphate and phosphodiester formation, and histidine gives phosphorimidazolides as dominant products. When proline and aspartic acid were allowed to compete for incorporation, only proline was found at the N‐terminus of peptido chains. The reactivity described here links two fundamental classes of biomolecules through reactions that occur without enzymes, but with amino acid specificity.     

Ligand‐Enabled β‐C–H Arylation of α‐Amino Acids Without Installing Exogenous Directing Groups

Herein we report acid‐directed β‐C(sp³)‐H arylation of α‐amino acids enabled by pyridine‐type ligands. This reaction does not require the installation of an exogenous directing group, is scalable, and enables the preparation of Fmoc‐protected unnatural amino acids in three steps. The pyridine‐type ligands are crucial for the development of this new C(sp³)‐H arylation.