Asymmetric Photoaerobic Lactonization and Aza-Wacker Cyclization of Alkenes Enabled by Ternary Selenium-Sulfur Multicatalysis.

An adaptable, sulfur-accelerated photoaerobic selenium-π-acid ternary catalyst system for the enantioselective allylic redox functionalization of simple, nondirecting alkenes is reported. In contrast to related photoredox catalytic methods, which largely depend on olefinic substrates with heteroatomic directing groups to unfold high degrees of stereoinduction, the current protocol relies on chiral, spirocyclic selenium-π-acids that covalently bind to the alkene moiety. The performance of this ternary catalytic method is demonstrated in the asymmetric, photoaerobic lactonization and cycloamination of enoic acids and unsaturated sulfonamides, respectively, leading to an averaged enantiomeric ratio (er) of 92:8. Notably, this protocol provides for the first time an asymmetric, catalytic entryway to pharmaceutically relevant 3-pyrroline motifs, which was used as a platform to access a 3,4-dihydroxyproline derivative in only seven steps with a 92:8 er.

Mechanistic Insight into the Mode of Action of Acid ß-Glucosidase Enhancer Ambroxol.

Ambroxol (ABX) is a mucolytic agent used for the treatment of respiratory diseases. Bioactivity has been demonstrated as an enhancement effect on lysosomal acid ß-glucosidase (ß-Glu) activity in Gaucher disease (GD). The positive effects observed have been attributed to a mechanism of action similar to pharmacological chaperones (PCs), but an exact mechanistic description is still pending. The current study uses cell culture and in vitro assays to study the effects of ABX on ß-Glu activity, processing, and stability upon ligand binding. Structural analogues bromohexine, 4-hydroxybromohexine, and norbromohexine were screened for chaperone efficacy, and in silico docking was performed. The sugar mimetic isofagomine (IFG) strongly inhibits ß-Glu, while ABX exerts its inhibitory effect in the micromolar range. In GD patient fibroblasts, IFG and ABX increase mutant ß-Glu activity to identical levels. However, the characteristics of the banding patterns of Endoglycosidase-H (Endo-H)-digested enzyme and a substantially lower half-life of ABX-treated ß-Glu suggest different intracellular processing. In line with this observation, IFG efficiently stabilizes recombinant ß-Glu against thermal denaturation in vitro, whereas ABX exerts no significant effect. Additional ß-Glu enzyme activity testing using Bromohexine (BHX) and two related structures unexpectedly revealed that ABX alone can refunctionalize ß-Glu in cellula. Taken together, our data indicate that ABX has little in vitro ability to act as PC, so the mode of action requires further clarification.

Photo-Mediated Decarboxylative Giese-Type Reaction Using Organic Pyrimidopteridine Photoredox Catalysts.

The decarboxylative Giese-type reaction offers a versatile methodology for the radical alkylation of electron-deficient alkenes. Photo-mediated variants often require a pre-activation of carboxylic acids and/or employment of costly transition-metal photocatalysts. Herein, we present a metal-free photocatalyzed decarboxylative Giese-type addition to electron-deficient alkenes using pyrimidopteridine N-oxides as organic photoredox-active catalysts. This protocol comprises mono-, di-, and trisubstituted aliphatic, α-amino, and α-oxy acids as well as a variety of electron-deficient alkenes. Moreover, post-synthetic derivatization and applications are presented.