Catalyst-Controlled Regiodivergent Oxidation of Unsymmetrical Diols.

In this work we use aminoxyl-peptide conjugates to catalyze the regiodivergent oxidation of unsymmetrical diols. Through structural tuning of both the aminoxyl catalytic core and the chiral peptide backbone, we achieved catalyst control that either reinforces or overrides the intrinsic steric bias, leading to oxidation of either the less hindered or the more hindered alcohol in high selectivity.

Dihydropyrazinoquinazolinones via S2 Sulfamidate Ring-Opening and a Sequential Quinazolinone-Amidine Rearrangement Strategy (SQuAReS).

A synthesis of dihydropyrazino-[2,1-]-quinazolinones is described using a 2-alkylaminoquinazolinone-mediated ring opening of a-/chiral sulfamidates, followed by a tandem quinazolinone-amidine rearrangement termed SQuAReS. This approach takes advantage of sulfamidates whose regioselective ring opening, after hydrolysis, appends an optimally distanced nucleophilic amine to a quinazolinone such that subsequent domino rearrangements are favored, integrating unique substitution patterns on a privileged core. This three-step protocol integrated five telescoped transformations and generated 20 pyrazinoquinazolinones in up to 74% yield with high enantiomeric fidelity and diastereoselectivity.

Characterization of Glucokinases from Pathogenic Free-Living Amoebae.

Infection with pathogenic free-living amoebae, including Naegleria fowleri, spp., and Balamuthia mandrillaris, can lead to life-threatening illnesses, primarily because of catastrophic central nervous system involvement. Efficacious treatment options for these infections are lacking, and the mortality rate due to infection is high.

Atroposelective Desymmetrization of Resorcinol-Bearing Quinazolinones via Cu-Catalyzed C-O Bond Formation.

Enantioselective Cu-catalyzed C-O cross coupling reactions yielding atropisomeric resorcinol-bearing quinazolinones have been developed. Utilizing a new guanidinylated dimeric peptidic ligand, a set of products were generated in good yields with excellent stereocontrol. The transformation was readily scalable, and a range of product derivatizations were performed.

Dual-Stage Picolinic Acid-Derived Inhibitors of .

causes a prevalent human infection for which only the acute stage has an FDA-approved therapy. To find inhibitors of both the acute stage parasites and the persistent cyst stage that causes a chronic infection, we repurposed a compound library containing known inhibitors of parasitic hexokinase, the first step in the glycolysis pathway, along with a larger collection of new structural derivatives. The focused screen of 22 compounds showed a 77% hit rate (>50% multistage inhibition) and revealed a series of aminobenzamide-linked picolinic acids with submicromolar potency against both parasite forms.

Enzymatic and Structural Characterization of the Glucokinase.

Infection with the free-living amoeba leads to life-threatening primary amoebic meningoencephalitis. Efficacious treatment options for these infections are limited, and the mortality rate is very high (∼98%). Parasite metabolism may provide suitable targets for therapeutic design.