Exploiting the sp character of bicyclo[1.1.1]pentyl radicals in the transition-metal-free multi-component difunctionalization of [1.1.1]propellane.

Strained bicyclic substructures are increasingly relevant in medicinal chemistry discovery research because of their role as bioisosteres. Over the last decade, the successful use of bicyclo[1.1.

Enabling Metallophotoredox Catalysis in Parallel Solution-Phase Synthesis Using Disintegrating Reagent Tablets.

Compressed tablets containing a mixture of a photocatalyst, a nickel catalyst, an inorganic base, and an inert excipient are employed as a fast, safe, and user-friendly chemical delivery system for two different metallophotoredox-catalyzed reactions. This delivery method simplifies the preparation of compound libraries using photoredox chemistry in a parallel setting. The reagent tablets were successfully applied to late-stage functionalization of drug-like intermediates.

Photocatalysis in the Life Science Industry.

In the pursuit of new pharmaceuticals and agrochemicals, chemists in the life science industry require access to mild and robust synthetic methodologies to systematically modify chemical structures, explore novel chemical space, and enable efficient synthesis. In this context, photocatalysis has emerged as a powerful technology for the synthesis of complex and often highly functionalized molecules. This Review aims to summarize the published contributions to the field from the life science industry, including research from industrial-academic partnerships.

Nickel-Catalyzed Decarboxylative Cross-Coupling of Bicyclo[1.1.1]pentyl Radicals Enabled by Electron Donor-Acceptor Complex Photoactivation.

The use of bicyclo[1.1.1]pentanes (BCPs) as -disubstituted aryl bioisosteres has gained considerable momentum in drug development programs.

Reagent and Catalyst Capsules: A Chemical Delivery System for Reaction Screening and Parallel Synthesis.

Commercially available hydroxypropyl methylcellulose capsules are employed as a fast, safe, and user-friendly chemical delivery system containing all reagents (catalyst, ligand, and base) for three important transition-metal-catalyzed reactions: Buchwald-Hartwig, Suzuki-Miyaura, and metallophotoredox C-N cross-coupling reactions. This encapsulation methodology simplifies the screening of reaction conditions and the preparation of compound libraries using parallel synthesis in organic solvents or aqueous media. These reagents-containing HPMC capsules are easy to prepare, come in different sizes, and can be stored on the bench under noninert conditions.

The Evolution of the Total Synthesis of Rocaglamide.

The complex flavagline, (-)-rocaglamide, possesses a synthetically intriguing tricyclic scaffold with five contiguous stereocenters and also exhibits potent anticancer, anti-inflammatory and insecticidal activity. This full account details distinct approaches to (±)- and (-)-rocaglamide utilizing Brønsted acid catalyzed and asymmetric Pd -catalyzed Nazarov chemistry developed in our laboratory, respectively. The successful asymmetric synthesis revealed unforeseen mechanistic complexity that required adjusting our strategy to overcome an unanticipated racemization process, an unusual reversible ring-cleavage step and a very facile trialkylsilyl group migration.

A family of low molecular-weight, organic catalysts for reductive C-C bond formation.

Hydrazines form a new family of low molecular-weight reducing agents for diazonium salts. Using only small amounts of hydrazine catalyst, the coupling of diazonium salts to a variety of reactive partners has been achieved, without the requirement for either metal adjuvants or irradiation with visible or ultraviolet light. The generality of the concept proposed herein as well as its advantages in the preparative scale is outlined and discussed.

Catalytic enantioselective Nazarov cyclization: construction of vicinal all-carbon-atom quaternary stereocenters.

The diastereoselective asymmetric synthesis of vicinal all-carbon-atom quaternary stereocenters is a challenging problem in organic synthesis for which only few solutions have been described. A catalytic asymmetric Nazarov cyclization of fully substituted dienones that provides cyclopentenone derivatives with vicinal quaternary stereocenters in high optical purity and as single diastereoisomers is now reported.

Diastereospecific nazarov cyclization of fully substituted dienones: generation of vicinal all-carbon-atom quaternary stereocenters.

No vacancy: Fully substituted dienones that are highly polarized by a vinylogous carbonate group were found to undergo a remarkably rapid and diastereospecific Nazarov cyclization that led to cyclopentenones with vicinal all-carbon-atom quaternary centers (see example; SEM=2-(trimethylsilyl)ethoxymethyl, Tf=trifluoromethanesulfonyl).

Neutral Nazarov-type cyclization catalyzed by palladium(0).

[Image: see text] The first Pd(0)-catalyzed Nazarov-type cyclization of diketoesters proceeds in 70% to 95% yield under strictly neutral conditions. Aryl substitution is not required so the reaction succeeds with aliphatic substrates. The mechanism appears to be novel.

Discovery of novel cyanamide-based inhibitors of cathepsin C.

The discovery of potent and selective cyanamide-based inhibitors of the cysteine protease cathepsin C is detailed. Optimization of the template with regard to plasma stability led to the identification of compound 17, a potent cathepsin C inhibitor with excellent selectivity over other cathepsins and potent in vivo activity in a cigarette smoke mouse model.

Enamine-iminium ion Nazarov cyclization of alpha-ketoenones.

The mono-triflate salts of some chiral nonracemic 1,2-diamines react with alpha-ketoenones in a stoichiometric reaction to form products of the Nazarov cyclization in high enantiomeric ratios. The mechanism appears to involve rearrangement of an enamine-iminium ion.