Dynamic stereomutation of vinylcyclopropanes with metalloradicals.

The ever increasing demands for greater sustainability and lower energy usage in chemical processes call for fundamentally new approaches and reactivity principles. In this context, the pronounced prevalence of odd-oxidation states in less precious metals bears untapped potential for fundamentally distinct reactivity modes via metalloradical catalysis. Contrary to the well-established reactivity paradigm that organic free radicals, upon addition to a vinylcyclopropane, lead to rapid ring opening under strain release-a transformation that serves widely as a mechanistic probe (radical clock) for the intermediacy of radicals-we herein show that a metal-based radical, that is, a Ni metalloradical, triggers reversible cis/trans isomerization instead of opening.

Machine Learning-Guided Development of Trialkylphosphine Ni Dimers and Applications in Site-Selective Catalysis.

Owing to the unknown correlation of a metal's ligand and its resulting preferred speciation in terms of oxidation state, geometry, and nuclearity, a rational design of multinuclear catalysts remains challenging. With the goal to accelerate the identification of suitable ligands that form trialkylphosphine-derived dihalogen-bridged Ni dimers, we herein employed an assumption-based machine learning approach. The workflow offers guidance in ligand space for a desired speciation without (or only minimal) prior experimental data points.

Ruthenium-Catalyzed Synthesis of Aryl and Alkenyl Halides from Fluorosulfonates.

Aryl and alkenyl halides are widely used as key intermediates in organic synthesis, particularly for the formation of organometallic reagents or as radical precursors. They are also found in pharmaceutical and agrochemical ingredients. In this work, the synthesis of aryl and alkenyl halides from the corresponding fluorosulfonates using commercially available ruthenium catalysts is reported.

Oxidative Rearrangement of MIDA (-Methyliminodiacetic Acid) Boronates: Mechanistic Insights and Synthetic Applications.

Herein we report that coordinative hemilability allows the MIDA (-methyliminodiacetic acid) nitrogen to behave as a nucleophile and intramolecularly intercept palladium π-allyl intermediates. A mechanistic investigation indicates that this rearrangement proceeds through an S2-like displacement at tetrasubstituted boron to furnish novel DABN boronates. Oxidative addition into the N-C bond of the DABN scaffold furnishes borylated π-allyl intermediates that can then be trapped with a variety of nucleophiles, including in a three-component coupling.

Reaction of Vinyl Aziridines with Arynes: Synthesis of Benzazepines and Branched Allyl Fluorides.

We report the cycloaddition between vinyl aziridines and arynes. Depending on the reaction conditions and the choice of the aryne precursor, the aziridinium intermediate can be trapped through two distinct mechanistic pathways. The first one proceeds through a formal [5+2] cycloaddition to furnish valuable multi-substituted benzazepines.

Conformationally stable peptide macrocycles assembled using the Petasis borono-Mannich reaction.

Macrocyclization of linear peptide precursors using the Petasis borono-Mannich reaction affords a diverse range of macrocycles with an endocyclic amine. Analysis of the corresponding macrocyclic structures underscores that the hydrogen bond between an endocyclic amine and the adjacent amide NH is a powerful control element for conformationally homogenous peptide macrocycles.

Author Correction: Amine hemilability enables boron to mechanistically resemble either hydride or proton.

During the revision of this Article prior to publication, a computational study was reported (Vallejos, M. M. & Pellegrinet, S.

Amine hemilability enables boron to mechanistically resemble either hydride or proton.

Tetracoordinate MIDA (N-methyliminodiacetic acid) boronates have found broad utility in chemical synthesis. Here, we describe mechanistic insights into the migratory aptitude of the MIDA boryl group in boron transfer processes, and show that the hemilability of the nitrogen atom on the MIDA ligand enables boron to mechanistically resemble either a hydride or a proton. The first case involves a 1,2-boryl shift, in which boron migrates as a nucleophile in its tetracoordinate form.

Modular Synthesis of β-Amino Boronate Peptidomimetics.

Herein, we describe the synthesis of novel β-amino boronate peptidomimetics from amphoteric α-borylaldehydes in the Ugi multicomponent reaction. A mild deprotection method provided the free and stable boronic acid forms of the target molecules, which display notable stability toward protodeborylation. Despite the presence of Lewis acidic boron, there is no evidence for hydrolysis of the adjacent amide via a 5- or 6-membered ring intermediate.

Achieving Skeletal Diversity in Peptide Macrocycles through The Use of Heterocyclic Grafts.

Despite their therapeutic potential, peptide macrocycles often suffer from drawbacks such as low membrane permeability, proteolytic instability, and conformational lability. As a result, there have been significant efforts to "depeptidize" amino acid-rich macrocycles through the incorporation of heterocyclic grafts into their backbones. In this concept article, we summarize selected recent methodologies that can be used to introduce heterocycles into cyclic peptides.

3-Cyanoallyl boronates are versatile building blocks in the synthesis of polysubstituted thiophenes.

We report the preparation of hitherto unprecedented 3-cyanoallyl boronates using condensation of the parent α-boryl aldehyde and nitriles. The resulting allyl boronates have been used to generate a wide range of borylated thiophenes, which represent a valuable class of heterocycles in modern drug discovery. Subsequent Suzuki-Miyaura cross-coupling enabled the synthesis of pharmaceutically important 3,5-disubstituted aminothiophenes.

Amphoteric Borylketenimines: Versatile Intermediates in the Synthesis of Borylated Heterocycles.

We report the first synthesis of amphoteric borylketenimines from ethynyl N-methyliminodiacetic acid (MIDA) boronate and sulfonyl azides via copper catalysis. In situ trapping of these intermediates with various nucleophiles provided access to novel borylated azetidimines, iminocoumarins, amides, iminooxetanes, and amidines. The described strategy based on borylketenimines offers high levels of chemo- and regioselectivity, enabling the synthesis of unprecedented borylated molecules.

A Linchpin Synthesis of 6-Hydroxyceramides from Aziridine Aldehydes.

A chemoselective N-oxidation/Meisenheimer rearrangement protocol was developed to generate vinylaziridine scaffolds from aziridine aldehydes. A subsequent Lewis acid-mediated aziridine ring opening with carboxylic acid nucleophiles followed by N-O bond cleavage furnishes a human skin 6-hydroxyceramide natural product in short order. The utility of this methodology is demonstrated by the preparation of a number of unnatural 6-hydroxyceramide analogues.

Synthesis of Chiral Piperazinones Using Amphoteric Aziridine Aldehyde Dimers and Functionalized Isocyanides.

We have evaluated a range of functionalized isocyanides in the aziridine aldehyde-driven multicomponent synthesis of piperazinones. High diasteroselectivity for each isocyanide was observed. A theoretical evaluation of the reaction course corroborates the experimental data.

Comparison of orthogonal chromatographic and lectin-affinity microarray methods for glycan profiling of a therapeutic monoclonal antibody.

The N-linked glycosylation of four lots of a marketed human therapeutic monoclonal antibody (mAb) was assessed by three orthogonal chromatographic methods and a commercial lectin microarray. For chromatography, the N-glycans were removed enzymatically from the mAbs using PNGase F. Native glycans were determined by HPAEC-PAD using a panel of 21 N-glycan standards and a multi-stage linear gradient eluent profile for sequential analyses of typical neutral and sialylated glycans in one chromatographic run.

Indole Functionalization via Photoredox Gold Catalysis.

The use of photoredox catalyst [Au2(dppm)2]Cl2 to initiate free-radical cyclizations onto indoles is reported. Excitation of the dimeric Au(I) photocatalyst for the reduction of unactivated bromoalkanes and bromoarenes is used for the generation of carbon-centered radicals. Previous to this work, reduction processes leading to indole functionalization utilizing photoredox catalysts were limited to activated benzylic or α-carbonyl-positioned bromoalkanes.