Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute–specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box–containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute–AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients.

The mechanism of asymmetric α-hydroxylation of tetralone-derived β-ketoesters with guanidine-bisurea bifunctional organocatalyst in the presence of cumene hydroperoxide (CHP) was examined by means of DFT calculations to understand the origin of the stereocontrol in the reaction. The identified transition-state model was utilized to design an enantioselective synthesis of β- or γ-substituted tetralones by catalytic oxidative kinetic resolution reaction of tetralone-derived β-ketoesters. This kinetic resolution reaction proceeded with high selectivity, and selectivity factors (s value) of up to 99 were obtained. The potential utility of this oxidative kinetic resolution method for synthesis of natural products was confirmed by applying it to achieve an enantioselective synthesis of (+)-linoxepin (13) from β-substituted tetralone rac-7 in only six steps.

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We report the first enantioselective total syntheses of the hasubanan alkaloid (−)-metaphanine and the norhasubanan alkaloid (+)-stephadiamine. Key features of these syntheses include diastereoselective oxidative phenolic coupling reaction and subsequent regioselective intramolecular aza-Michael reaction, which efficiently construct the hasubanan skeleton with the all-carbon quaternary stereogenic center at C13. Based on our hypothesis regarding the biosynthetic pathway of (+)-stephadiamine, we found that (−)-metaphanine is easily converted to (+)-stephadiamine via aza-benzilic acid type rearrangement reaction.

Acyclic ketone-derived oxocarbenium ions are involved as intermediates in numerous reactions that provide valuable products,h owever,t hey have thus far eluded efforts aimed at asymmetric catalysis.W er eport that ar eadily accessible chiral carboxylic acid catalyst exerts control over asymmetric cyclizations of acyclic ketone-derived trisubstituted oxocarbenium ions,t herebyp roviding access to highly enantioenriched dihydropyran products containing atetrasubstituted stereogenic center.T he high acidity of the carboxylic acid catalyst, whiche xceeds that of the well-known chiral phosphoric acid catalyst TRIP,i sl argely derived from stabilization of the carboxylate conjugate base through intramolecular anion-binding to athiourea site.