Structural optimization of pyrrolopyrimidine BTK inhibitors based on molecular simulation.

Context: BTK is a critical regulator involved in the proliferation, differentiation, and apoptosis of B cells. BTK inhibitors can effectively alleviate various diseases such as tumors, leukemia, and asthma. During this study, a range of novel BTK inhibitors were designed using 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation.

Catalytic Cross-Metathesis Reactions That Afford - and -Trisubstituted Alkenyl Bromides: Scope, Applications, and Mechanistic Insights.

Stereochemically defined trisubstituted alkenes with a bromide and a methyl group at a terminus can be readily and stereoretentively derivatized through catalytic cross-coupling, affording unsaturated fragments found in many bioactive natural products. A direct method for generating such entities would be by stereocontrolled catalytic cross-metathesis (CM). Such methods are scarce however.

-Trisubstituted α,β-Unsaturated Esters and Acid Fluorides through Stereocontrolled Catalytic Cross-Metathesis.

Catalytic cross-metathesis (CM) reactions that can generate trisubstituted alkenes in high stereoisomeric purity are important but remain limited in scope. Here, CM reactions are introduced that generate -trisubstituted α-methyl, α,β-unsaturated, alkyl and aryl esters, thiol esters, and acid fluorides. Transformations are promoted by a Mo bis-aryloxide, a monoaryloxide pyrrolide, or a monoaryloxide chloride complex; air-stable and commercially available paraffin tablets containing a Mo complex may also be used.

E- and Z-trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing.

Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance.

Stereodefined alkenes with a fluoro-chloro terminus as a uniquely enabling compound class.

Trisubstituted alkenyl fluorides are important compounds for drug discovery, agrochemical development and materials science. Despite notable progress, however, many stereochemically defined trisubstituted fluoroalkenes either cannot be prepared efficiently or can only be accessed in one isomeric form. Here we outline a general solution to this problem by first unveiling a practical, widely applicable and catalytic strategy for stereodivergent synthesis of olefins bearing a fluoro-chloro terminus.

Impact of Ethylene on Efficiency and Stereocontrol in Olefin Metathesis: When to Add It, When to Remove It, and When to Avoid It.

Ethylene is the byproduct of olefin metathesis reactions that involve one or more terminal alkenes. Its volatility is one reason why many cross-metathesis or ring-closing metathesis processes, which are reversible transformations, are efficient. However, because ethylene can be converted to a methylidene complex, which is a highly reactive but relatively unstable species, its concentration can impact olefin metathesis in other ways.

Delayed catalyst function enables direct enantioselective conversion of nitriles to NH-amines.

Accessing enantiomerically enriched amines often demands oxidation-state adjustments, protection and deprotection processes, and purification procedures that increase cost and waste, limiting applicability. When diastereomers can be formed, one isomer is attainable. Here, we show that nitriles, largely viewed as insufficiently reactive, can be transformed directly to multifunctional unprotected homoallylic amines by enantioselective addition of a carbon-based nucleophile and diastereodivergent reduction of the resulting ketimine.

E- and Z-, di- and tri-substituted alkenyl nitriles through catalytic cross-metathesis.

Nitriles are found in many bioactive compounds, and are among the most versatile functional groups in organic chemistry. Despite many notable recent advances, however, there are no approaches that may be used for the preparation of di- or tri-substituted alkenyl nitriles. Related approaches that are broad in scope and can deliver the desired products in high stereoisomeric purity are especially scarce.

Traceless Protection for More Broadly Applicable Olefin Metathesis.

An operationally simple in situ protection/deprotection strategy that significantly expands the scope of kinetically controlled catalytic Z- and E-selective olefin metathesis is introduced. Prior to the addition of a sensitive Mo- or Ru-based complex, treatment of a hydroxy- or a carboxylic-acid-containing olefin with commercially available HB(pin) or readily accessible HB(trip) (pin=pinacolato, trip=2,4,6-tri(isopropyl)phenyl) for 15 min is sufficient for efficient generation of a desired product. Routine workup leads to quantitative deprotection.

Palladium-Catalyzed C-H Arylation of Indoles at the C7 Position.

In the past decade, direct C-H arylation of indoles has been developed with high selectivity at the C2 and C3 positions via transition-metal-catalyzed cross-coupling reactions. Here we show that C-H activation can be directed to the C7 position with high selectivity in Pd-catalyzed coupling of indoles with arylboronic acids. The key to this high regioselectivity is the appropriate choice of a phosphinoyl directing group and a pyridine-type ligand in the presence of Pd(OAc)2 catalyst.