The mechanistic study of the gold-catalyzed cycloisomerization of alcohols or amine tethered-vinylidenecyclopropanes has been performed using high-level DFT calculations to find the reasons for the observed selectivity of the products. Two possible pathways were observed, in the first product, during the cyclization process, the vinylidenecyclopropane moiety converts to methylidenecyclopropane-containing product (P1) via an ionic (non-carbene) intermediate, and in the second product, converts to cyclobutene-containing product (P2) via a carbene intermediates. In all six examined derivatives (containing different alkyl groups at C1 allenic carbon) P2 was the major product by both thermodynamic (the more stability of P1 than P2) and kinetic (the smaller barrier for producing P2 versus P1) criteria in both gas phase and solvent (THF, using PCM model) media. However, in the derivatives with low-strain allenic group (R), I1 (which leads to P1) is more stable than I3 intermediates (which leads to P2) by 0.6-4.2 kcal/mol in the gas phase and 1.0-3.1 kcal/mol in the solvent and the derivatives with high-strain allenic group, I3 is more stable than I1 by 2.1-2.5 kcal/mol in the gas phase and 3.5-4.2 kcal/mol in the solvent. Therefore, both gas phase and solvent data show that because of the different hindrance between the alkyl group and gold cation complex, the selectivity of the reaction is yielded by the favorability of I1 or I3 intermediates. Interestingly, another evidence was provided by atomic charges in the reactants using NBO calculations. These calculations showed that when the atomic charge of C1 allenic carbon was higher than C3, the gold cation prefers to produce I1, leading to P1, and when the atomic charge of C3 allenic carbon was higher than C1, the gold cation prefers to produce I2, leading to P2.

Hydroxybenzylamines are prevalent in drugs and bioactive molecules, including various antimalarial and anticancer drugs. alpha-tertiary alkylation of amines impacts drug-target interactions significantly through their influence on basicity and lipophilicity. Traditional N-alkylation methods, especially for alpha-tertiary amines, suffer from limitations due to high energy barriers from steric hindrance. In this work, we leverage visible light irradiation to enable the organoboronic acid addition to sterically hindered ketimines in the excited state. Notably, it overcomes the limitations of the well-explored Petasis reaction, which is restricted to aldimines due to the high energy barrier associated with ketimines (51.3 kcal/mol). This three-component coupling of aliphatic amines, o-phenolic ketones, and organoboronic acids delivers diverse alpha-tertiary o-hydroxybenzylamines (77 examples, yields up to 82%) with broad functional group tolerance. The light-driven 1,3-boronate rearrangement introduces quaternary carbon centers adjacent to the amine moiety to enable late-stage functionalization of complex bioactive molecules. This versatile tool for complex amine synthesis holds significant potential for accelerating advancements in drug discovery, chemical biology, and materials science research. Traditional N-alkylation methods, especially for alpha-tertiary amines, suffer from limitations due to high energy barriers from steric hindrance. In this work, the authors leverage visible light irradiation to enable organoboronic acid addition to sterically hindered ketimines using a three-component coupling of aliphatic amines, ortho-phenolic ketones, and organoboronic acids.

Halogenases are spurring a growing interest in the fields of biosynthesis and biocatalysis. Although various halogenases have been identified in numerous natural product biosynthetic pathways, the mechanisms for multiple halogenations and site-selectivity remain largely unclear. In this study, we biochemically characterized FasV, a flavin-dependent halogenase (FDH) that catalyzes five successive chlorinations in the biosynthesis of the naphthacene-containing aromatic polyketide naphthacemycin. This multiple halogenation reaction was elucidated to occur in an orderly fashion, as evidenced by enzyme kinetics, time-course assays, and computational simulations. Crystallographic analyses and mutagenesis studies revealed previously unrecognized amino acid residues, including T53, L81, F93, and I212, that are crucial for controlling regioselectivity and substrate specificity. Based on this, a I212T mutant was generated to exclusively catalyze selective monohalogenation. We propose a novel dual-activation mechanism and demonstrate that the larger binding pocket of FasV makes it a valuable biocatalyst for other substrates with diverse structures. Therefore, this study provides new insight into multi-site polyhalogenases and highlights the potential for engineering FasV-like FDHs for biocatalytic applications.

The transition metal-catalysed dicarbofunctionalisation of unactivated alkenes normally requires exogenous strong coordinated directing groups, thus reducing the overall reaction efficiency. Here, we report a ligand-enabled Ni(II)-catalysed dicarbofunctionalisation of unactivated alkenes with aryl/alkenyl boronic acids and alkyl halides as the coupling partners with a diverse range of native functional groups as the directing group. This dicarbofunctionalisation protocol provides an efficient and direct route towards vicinal 1,2-disubstituted alkanes using primary, secondary, tertiary amides, sulfonamides, as well as secondary and tertiary amines under redox-neutral conditions that are challenging to access through conventional methods. The key to the success of this reaction is the use of a bulky beta-diketone ligand, which could enable the insertion of alkene to aryl-Ni(II) species, stabilize the alkyl-Ni(II) species and inhibit the homolytic alkyl-Ni(II) cleavage, supporting by both experimental and computational studies. This dicarbofunctionalisation reaction features the use of native directing group, a broad substrate scope, and excellent scalability. The dicarbofunctionalisation of unactivated alkenes normally requires the use of exogenous strong coordinated directing groups. Here, the authors report a Ni(II)-catalysed dicarbofunctionalisation of unactivated alkenes with aryl/alkenyl boronic acids and alkyl halides as the coupling partners with a diverse range of native functional groups as the directing group.