Asymmetric carbon coupling at boron The Matteson reaction produces carbon–carbon bonds by coupling halocarbons such as widely available dichloromethane with an alkyl substituent on boron. Sharma et al . report asymmetric catalysis of this reaction. Their catalyst, derived from a chiral thiourea, a boronic ester, and an alkyl lithium base, appears to accelerate a chloride abstraction step through its lithium center. The product, still bearing a chloride, can be further modified through stereospecific displacement to generate a wide variety of trisubstituted chiral centers. —JSY

Intramolecular alkoxylation of C–H bonds can rapidly introduce structural and functional group complexities into seemingly simple or inert precursors. The transformation is particularly important due to the ubiquitous presence of tetrahydrofuran (THF) motifs as fundamental building blocks in a wide range of pharmaceuticals, agrochemicals, and natural products. Despite the various synthetic methodologies known for generating functionalized THFs, most show limited functional group tolerance and lack demonstration for the preparation of spiro or fused bi- and tricyclic ether units prevalent in molecules for pharmacological purposes. Herein we report an intramolecular C–H alkoxylation to furnish oxacycles from easily prepared α-diazo-β-ketoesters using commercially available iron acetylacetonate (Fe­(acac)2) as a catalyst. The reaction is proposed to proceed through the formation of a vinylic carboradical arising from N2 extrusion, which mediates a proximal H–atom abstraction followed by a rapid C–O bond forming radical recombination step. The radical mechanism is probed using an isotopic labeling study (vinyl C–D incorporation), ring opening of a radical clock substrate, and Hammett analysis and is further corroborated by density functional theory (DFT) calculations. Heightened reactivity is observed for electron-rich C–H bonds (tertiary, ethereal), while greater catalyst loadings or elevated reaction temperatures are required to fully convert substrates with benzylic, secondary, and primary C–H bonds. The transformation is highly functional group tolerant and operates under mild reaction conditions to provide rapid access to complex structures such as spiro and fused bi-/tricyclic O-heterocycles from readily available precursors.

Our group’s discovery of lithium-isothiourea-boronate–catalyzed Matteson homologations is chronicled. Chiral thiourea dual–hydrogen bond donors were initially found to promote enantioselective dichloromethyl boronate rearrangements, albeit with poor reproducibility. Systematic investigations of the fate of the thiourea led to the discovery that lithium-isothiourea-boronate derivatives were being generated in situ as highly enantioselective catalytically active species. The optimal lithium-isothiourea-boronate catalyst displays significant generality in the rearrangement of primary alkyl migrating groups, affording synthetically valuable α-chloro boronic ester products with consistently high enantioselectivities. The catalyst is proposed to act as a structurally rigid chiral framework that precisely positions two lithium cations to enable a dual-lithium–mediated chloride abstraction.

Macrocyclic peptides have received increasing attention throughout the pharmaceutical industry as attractive scaffolds for the development of new therapeutics. Here, we describe the development of a new proline‐to‐cysteine (PTC) peptide cyclization reaction. Peptide sequences flanked by an N‐terminal proline and a C‐terminal cysteine were reacted with α,α′‐dibromo‐m‐xylene to furnish cyclic peptides bearing a tertiary amine embedded within the macrocycle backbone. Macrocyclization proceeded efficiently in solution and on‐resin with peptides of different sequence lengths (5‐10 amino acids) and amino acid compositions. This approach was also applied for peptide bicyclization. Liquid chromatography mass spectrometry (LC‐MS)/MS analysis of a fingerprint ion related to the PTC linkage that was present throughout the substrate scope expedited confirmation of the product cyclic topologies. Conformational studies by variable‐temperature NMR revealed PTC macrocycles can adopt a rigid structure and display an intramolecular hydrogen‐bonding pattern that differs significantly from their cysteine‐to‐cysteine linked counterparts, further highlighting the value of this alternative cyclization approach. Due to its compatibility with library‐based peptide display and selection technologies, the described approach could offer significant utility in drug discovery campaigns.