ABSTRACT
Online HPLC reaction progress monitoring provides detailed data-rich profiles; however, extracting kinetic information requires ultraviolet-visible response factors to determine concentrations from peak areas. If the reaction's overall mass balance is known and some analytical trend for all relevant species can be recorded, it is possible to estimate the absolute response factors of all species using a system of linear equations. We delineate a method using the Microsoft Solver plug-in to convert time course profiles to reagent concentrations without analytical standards.
ABSTRACT
Background: In 1948, the synthesis and Plasmodium lophurae activity of 2-hydroxy-1,4-naphthoquinones containing 3-alkyldiarylether side chains was reported. Method/results: The synthesis of five related compounds, designed to be more metabolically stable, was pursued. The compounds were synthesized using a radical alkylation reaction with naphthoquinones. One compound had a lower IC50 value against various strains of Plasmodium falciparum and assay data indicate that it binds to the Qo site of cytochrome bc1. With a low yield for the radical alkylation of the most active compound, a reductive alkylation method with used to improve reaction yields. Conclusion: Further synthetic knowledge was obtained, and the assay data indicate that there are sensitivity differences between avian and human malarial parasites for these molecules.
Malaria is a disease caused by a parasite that affects millions of people each year and results in many deaths. In 1948, 300 structurally related compounds were made and tested for antimalarial activity with the goal of finding a drug to treat the disease. From this work, promising compounds were identified and this work has served as a starting point for further investigations. Based on recent discoveries, this study made variations of promising 1948 compounds to investigate whether antimalarial activity could be improved. These compounds were made using two different methods. One derivative was found to be more potent than the original compound but was not the one expected based on the 1948 work.
Subject(s)
Antimalarials , Naphthoquinones , Humans , Plasmodium falciparum , Antimalarials/chemistryABSTRACT
Ring walking is an important mechanistic phenomenon leveraged in many catalytic C-C bond forming reactions. However, ring walking has been scarcely studied under Buchwald-Hartwig amination conditions despite the importance of such transformations. An in-depth mechanistic study of the Buchwald-Hartwig amination is presented focussing on ligand effects on ring walking behavior. The ability of palladium catalysts to promote or inhibit ring walking is strongly influenced by the chelating nature of the ligand. In stark contrast, the resting state of the catalyst had no impact on ring walking behavior. Furthermore, the complexity of the targeted system enabled the differentiation between catalysts which undergo ring walking versus diffusion-controlled coupling. The insights gained in this study were leveraged to achieve desymmetrization of a tetrabrominated precursor. A small library of asymmetric 2,2',7,7'-tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9'spirobifluorene (SpiroOMeTAD) derivatives were successfully synthesized using this strategy highlighting the ease with which libraries of these compounds can be accessed for screening.
Subject(s)
Palladium , Amination , Catalysis , Ligands , Palladium/chemistryABSTRACT
A new general de novo synthesis of pharmaceutically important N-(hetero)aryl piperidines is reported. This protocol uses a robustly diastereoselective reductive amination/aza-Michael reaction sequence to achieve rapid construction of complex polysubstituted ring systems starting from widely available heterocyclic amine nucleophiles and carbonyl electrophiles. Notably, the diastereoselectivity of this process is enhanced by the presence of water, and DFT calculations support a stereochemical model involving a facially selective protonation of a water-coordinated enol intermediate.
