Cobalt-Catalyzed N‑Alkylation of Amines with Alcohols

A well-defined nonprecious metal cobalt­(II) catalyst based on a pincer PNP ligand has been employed for the efficient N-alkylation of both aromatic and aliphatic amines with alcohols. A subtle change of reaction conditions (simply adding 4 Å molecular sieves) was observed to readily switch the resulting products (amines vs imines) with high chemoselectivity. A range of alcohols and amines including both aromatic and aliphatic substrates were efficiently converted to secondary amines in good-to-excellent yields when 2 mol % cobalt catalyst was used. Additional experiments indicate that a hydrogen-borrowing mechanism is responsible for the tandem acceptorless dehydrogenation/condensation/hydrogenation process

Cobalt-Catalyzed Synthesis of Aromatic, Aliphatic, and Cyclic Secondary Amines via a “Hydrogen-Borrowing” Strategy

The replacement of precious metals with inexpensive, less toxic, and earth-abundant elements in typical noble-metal-mediated organic transformations is a major goal in current synthetic chemistry and industries. The metal-catalyzed N-alkylation of amines with other amines through a “hydrogen-borrowing” principle represents a green and atom-economical reaction for the synthesis of secondary amines. However, catalysts developed thus far that are effective for this process remain quite scarce and are only limited to a few ruthenium and iridium complexes. In this work, we present a cobalt-catalyzed selective alkylation of amines with amines to synthesize a large variety of secondary amines. A range of amine substrates have been converted to the corresponding products through hetero- or homocoupling between amines. Cyclic <i>sec</i>-amines are also achieved from diamine precursors as rare examples

Cobalt-Catalyzed α‑Alkylation of Ketones with Primary Alcohols

An ionic cobalt–PNP complex is developed for the efficient α-alkylation of ketones with primary alcohols for the first time. A broad range of ketone and alcohol substrates were employed, leading to the isolation of alkylated ketones with yields up to 98%. The method was successfully applied to the greener synthesis of quinoline derivatives while using 2-aminobenzyl alcohol as an alkylating reagent

Bioactive and Marker Compounds from Two Edible Dark-Colored <i>Myrciaria</i> Fruits and the Synthesis of Jaboticabin

Jaboticaba (<i>Myrciaria cauliflora</i>) and false jaboticaba (<i>Myrciaria vexator</i>) fruits are two pleasant-tasting, dark-colored fruits, native to Brazil. They are rich sources of phenolic compounds, including anthocyanins, flavonoids, phenolic acids, and tannins, as well as less well known polyphenols such as depsides. These two fruits are very similar in morphology, but their taste profiles differ markedly. This study was focused on identifying the marker compounds between them using HPLC-PDA and LC-TOF-MS, combined with principal component analysis. As a result, cyanidin-3-<i>O</i>-glucoside was found as the major anthocyanin in <i>Myrciaria</i> fruits. Delphinidin-3-<i>O</i>-glucoside was found to be the marker compound for jaboticaba, while cyanidin-3-<i>O</i>-galactoside and cyanidin-3-<i>O</i>-arabinose were two marker compounds distinguishing false jaboticaba. In addition, two ellagitannins, iso-oenothein C and oenothein C, were isolated and identified from both of these fruits for the first time. Jaboticabin, a minor bioactive depside, occurred in both fruits and, because of its potential to treat chronic obstructive pulmonary disease, was successfully synthesized in the laboratory

Double Hetero-Michael Addition of <i>N</i>‑Substituted Hydroxylamines to Quinone Monoketals: Synthesis of Bridged Isoxazolidines

A general synthesis of bridged isoxazolidines from a double hetero-Michael addition of <i>N</i>-substituted hydroxylamines to quinone monoketals has been developed. The different addition order of <i>N</i>-benzylhydroxylamine and <i>N</i>-Boc hydroxylamine is also discussed. Moreover, the various functionalities in the isoxazolidine products allow facile derivatization

The Effect of Cage Shape on Nanoparticle-Based Drug Carriers: Anticancer Drug Release and Efficacy via Receptor Blockade Using Dextran-Coated Iron Oxide Nanocages

Although a range of nanoparticles have been developed as drug delivery systems in cancer therapeutics, this approach faces several important challenges concerning nanocarrier circulation, clearance, and penetration. The impact of reducing nanoparticle size on penetration through leaky blood vessels around tumor microenvironments via enhanced permeability and retention (EPR) effect has been extensively examined. Recent research has also investigated the effect of nanoparticle shape on circulation and target binding affinity. However, how nanoparticle shape affects drug release and therapeutic efficacy has not been previously explored. Here, we compared the drug release and efficacy of iron oxide nanoparticles possessing either a cage shape (IO-NCage) or a solid spherical shape (IO-NSP). Riluzole cytotoxicity against metastatic cancer cells was enhanced 3-fold with IO-NCage. The shape of nanoparticles (or nanocages) affected the drug release point and cellular internalization, which in turn influenced drug efficacy. Our study provides evidence that the shape of iron oxide nanoparticles has a significant impact on drug release and efficacy

Discovery of the Human Immunodeficiency Virus Type 1 (HIV-1) Attachment Inhibitor Temsavir and Its Phosphonooxymethyl Prodrug Fostemsavir

The optimization of the 4-methoxy-6-azaindole series of HIV-1 attachment inhibitors (AIs) that originated with <b>1</b> to deliver temsavir (<b>3</b>, BMS-626529) is described. The most beneficial increases in potency and pharmacokinetic (PK) properties were attained by incorporating N-linked, sp²-hybridized heteroaryl rings at the 7-position of the heterocyclic nucleus. Compounds that adhered to a coplanarity model afforded targeted antiviral potency, leading to the identification of <b>3</b> with characteristics that provided for targeted exposure and PK properties in three preclinical species. However, the physical properties of <b>3</b> limited plasma exposure at higher doses, both in preclinical studies and in clinical trials as the result of dissolution- and/or solubility-limited absorption, a deficiency addressed by the preparation of the phosphono­oxymethyl prodrug <b>4</b> (BMS-663068, fostemsavir). An extended-release formulation of <b>4</b> is currently in phase III clinical trials where it has shown promise as part of a drug combination therapy in highly treatment-experienced HIV-1 infected patients

Improving Metabolic Stability with Deuterium: The Discovery of BMT-052, a Pan-genotypic HCV NS5B Polymerase Inhibitor

Iterative structure–activity analyses in a class of highly functionalized furo­[2,3-<i>b</i>]­pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (<b>14</b>), a potential clinical candidate. The key challenge of poor metabolic stability was overcome by strategic incorporation of deuterium at potential metabolic soft spots. The preclinical profile and status of BMT-052 (<b>14</b>) is described