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Density functional theory (DFT) is used for analyzing the regioselectivity of Rh(I)-catalyzed (5+2) cycloadditions between vinylcyclopropanes (VCPs) and alkynes. VCPs with substitution at the internal position of the alkene have reacted with variable regioselectivity, indicating a refined model in which electron-withdrawing substituents on the alkyne have decreased or reversed sterically controlled selectivity by stabilizing the transition state in which the substituent is proximal to the forming C-C bond.

Four diastereomers of the biosynthetic substrate for module 2 of the rifamycin polyketide synthase (PKS) in form of their N-acetylcysteamine (SNAC) thioesther are synthesized. Only one diastereomer was turned over in vivo into rifamycin B, thus establishing the obscured absolute and relative configuration of the native biosynthetic intermediates.

The first studies on the regioselectivity of Rh(l)-catalyzed (5 + 2) cycloadditions between vinylcyclopropanes (VCPs) and alkynes have been conducted experimentally and analyzed using density functional theory (DFT). The previously unexplored regiochemical consequences for this catalytic, intermolecular cycloaddition were determined by studying the reactions of several substituted VCPs with a range of unsymmetrical alkynes. Experimental trends were identified, and a predictive model was established. VCPs with terminal substitution on the alkene reacted with high regioselectivity (>20:1), as predicted by a theoretical model in which bulkier alkyne substituents prefer to be distal to the forming C-C bond to avoid steric repulsions. VCPs with substitution at the internal position of the alkene reacted with variable regioselectivity (ranging from >20:1 to a reversed 1:2.3), suggesting a refined model in which electron-withdrawing substituents on the alkyne decrease or reverse sterically controlled selectivity by stabilizing the transition state in which the substituent is proximal to the forming C-C bond. [ABSTRACT FROM AUTHOR]

Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2- a ]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28 . It turned out that BAY 1165747 (BAY-747, 28 ) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 ( 28 ) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.

ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.

[reaction: see text] A highly convergent asymmetric synthesis of the masked southern segment of the antimitotic agent disorazole A(1) involves a Sonogashira coupling between a C1'-C10' enyne and a suitably protected C11'-C19' vinyl iodide. The central E,Z,Z-triene moiety is masked as a more stable ynediene.