Organics, Volume 6, Issue 3 (September 2025) – 3 articles

Density functional theory calculations were performed to elucidate the mechanistic details and origins of the selectivity of the nickel-catalyzed hydroboration of vinylarenes using B₂pin₂/MeOH. The catalytic cycles involved four sequential elementary steps: hydronickelation, anion exchange, transmetalation, and reductive elimination. Kinetic analyses identified hydronickelation as the rate-determining step with an activation barrier of 19.8 kcal/mol, while transmetalation proceeded through a stepwise mechanism characterized by two distinct transition states. Comprehensive analyses of the relevant transition structures and energetics demonstrated that the observed R-enantioselectivity (94% ee) originated from favorable nonbonding interactions. Lastly, our calculations suggested that the Markovnikov regioselectivity was predominantly governed by steric factors rather than electronic effects. Full article

Hydroxymethyl 1,3-diol motifs are common structural motifs in natural products, particularly in polypropionates with important therapeutic potential. However, general and complementary methods for their regio- and diastereoselective synthesis remain limited. In this study, we expanded a second-generation epoxide-based methodology involving the regioselective cleavage of TIPS-monoprotected cis- and trans-2,3-epoxy alcohols using alkenyl Grignard reagents. Regioselective ring opening of cis-epoxides provided anti-1,3-diols, while trans-epoxides afforded the corresponding syn-1,3-diols. The use of cis-propenylmagnesium bromide and vinyl Grignard reagents enabled direct access to cis- and terminal homoallylic 1,3-diols, respectively, with moderate to good yields (46–88%) and excellent regioselectivities (95:5). In contrast, reactions with trans-propenyl Grignard reagent led to partial alkene isomerization, limiting their synthetic utility. To address this, a complementary two-step approach employing propynyl alanate addition followed by sodium/ammonia reduction was incorporated, providing access to trans-homoallylic 1,3-diols with high diastereoselectivity. All 1,3-diols were characterized by NMR spectroscopy, confirming regioselective epoxide opening. These combined strategies offer a practical and modular platform for the synthesis of syn- and anti-hydroxymethylated 1,3-diols and their application to the construction of polypropionate-type fragments, supporting future efforts in the total synthesis of polyketide natural products. Full article

Vancomycin, a cornerstone antibiotic against severe Gram-positive infections, is increasingly challenged by resistance in Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin Enterococcus spp. (VRE), necessitating the development of novel therapeutic strategies. This review examines how structural modifications to vancomycin can enhance its antibacterial activity and explores the critical role of computational approaches in designing the next generation of analogs. By analyzing the existing literature, we highlight how strategic alterations, such as the introduction of lipophilic side chains, substitutions on the sugar moieties, and modifications to the aglycone core, have yielded derivatives with improved antibacterial potency. Notably, certain analogs (e.g., Vanc-83, Dipi-Van-Zn) have demonstrated expanded activity against Gram-negative bacteria and exhibited enhanced pharmacokinetic profiles, including prolonged half-lives and improved tissue penetration, crucial for effective treatment. Semisynthetic glycopeptides like telavancin, dalbavancin, and oritavancin exemplify successful translation of structural modifications, offering sustained plasma concentrations and simplified dosing regimens that improve patient compliance. Complementing these experimental efforts, computational methods, including molecular docking and molecular dynamics simulations, provide valuable insights into drug–target interactions, guiding the rational design of more effective analogs. Furthermore, physiologically based pharmacokinetic modeling aids in predicting the in vivo behavior and optimizing the pharmacokinetic properties of these novel compounds. This review highlights a critical path forward in the fight against multidrug-resistant infections. By meticulously examining the previously carried out structural refinement of vancomycin, guided by computational predictions and validated through rigorous experimental testing, we underscore its immense potential. Full article