Discovery of an Azabicyclo[2.1.1]hexane Piperazinium Salt and Its Application in Medicinal Chemistry via a Rearrangement.

Herein we report the discovery of an azabicyclo[2.1.1]hexane piperazinium methanesulfonate salt from an unexpected rearrangement reaction in the preparation of ligand-directed degraders (LDDs).

Trends in Neosubstrate Degradation by Cereblon-Based Molecular Glues and the Development of Novel Multiparameter Optimization Scores.

Molecular glues enable the degradation of previously "undruggable" proteins via the recruitment of cereblon (CRBN) to the target. One major challenge in designing CRBN E3 ligase modulating compounds (CELMoDs) is the selectivity profile toward neosubstrates, proteins recruited by CRBN E3 ligase agents for degradation. Common neosubstrates include Aiolos, Ikaros, GSPT1, CK1α, and SALL4.

Chemoselective Electrosynthesis Using Rapid Alternating Polarity.

Challenges in the selective manipulation of functional groups (chemoselectivity) in organic synthesis have historically been overcome either by using reagents/catalysts that tunably interact with a substrate or through modification to shield undesired sites of reactivity (protecting groups). Although electrochemistry offers precise redox control to achieve unique chemoselectivity, this approach often becomes challenging in the presence of multiple redox-active functionalities. Historically, electrosynthesis has been performed almost solely by using direct current (DC).

Chemoselective, Scalable Nickel-Electrocatalytic O-Arylation of Alcohols.

The formation of aryl-alkyl ether bonds through cross coupling of alcohols with aryl halides represents a useful strategic departure from classical S 2 methods. Numerous tactics relying on Pd-, Cu-, and Ni-based catalytic systems have emerged over the past several years. Herein we disclose a Ni-catalyzed electrochemically driven protocol to achieve this useful transformation with a broad substrate scope in an operationally simple way.

Intermolecular Crossed [2 + 2] Cycloaddition Promoted by Visible-Light Triplet Photosensitization: Expedient Access to Polysubstituted 2-Oxaspiro[3.3]heptanes.

This paper describes an intermolecular cross-selective [2 + 2] photocycloaddition reaction of exocyclic arylidene oxetanes, azetidines, and cyclobutanes with simple electron-deficient alkenes. The reaction takes place under mild conditions using a commercially available Ir(III) photosensitizer upon blue light irradiation. This transformation provides access to a range of polysubstituted 2-oxaspiro[3.

Impact of Stereo- and Regiochemistry on Energetic Materials.

The synthesis, physical properties, and calculated performances of six stereo- and regioisomeric cyclobutane nitric ester materials are described. While the calculated performances of these isomers, as expected, were similar, their physical properties were found to be extremely different. By alteration of the stereo- and regiochemistry, complete tunability in the form of low- or high-melting solids, stand-alone melt-castable explosives, melt-castable explosive eutectic compounds, and liquid propellant materials was obtained.

A Radical Approach to Anionic Chemistry: Synthesis of Ketones, Alcohols, and Amines.

Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper historical context, this Article reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes (to produce alcohols).

Modular radical cross-coupling with sulfones enables access to sp-rich (fluoro)alkylated scaffolds.

Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron-induced variants of this reaction class have proven particularly useful in the formation of C(sp)-C(sp) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents.

Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles.

Helenalin is a pseudoguaianolide natural product that targets Cys38 within the DNA binding domain of NF-κB transcription factor p65 (RelA). Helenalin contains two Michael acceptors that covalently modify cysteines: a α-methylene-γ-butyrolactone and a cyclopentenone. We recently reported two simplified helenalin analogues that mimic the biological activity of helenalin and contain both electrophilic moieties.

Decarboxylative Alkynylation.

The development of a new decarboxylative cross-coupling method that affords terminal and substituted alkynes from various carboxylic acids is described using both nickel- and iron-based catalysts. The use of N-hydroxytetrachlorophthalimide (TCNHPI) esters is crucial to the success of the transformation, and the reaction is amenable to in situ carboxylic acid activation. Additionally, an inexpensive, commercially available alkyne source is employed in this formal homologation process that serves as a surrogate for other well-established alkyne syntheses.

Decarboxylative alkenylation.

Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids.

Fe-Catalyzed C-C Bond Construction from Olefins via Radicals.

This Article details the development of the iron-catalyzed conversion of olefins to radicals and their subsequent use in the construction of C-C bonds. Optimization of a reductive diene cyclization led to the development of an intermolecular cross-coupling of electronically-differentiated donor and acceptor olefins. Although the substitution on the donor olefins was initially limited to alkyl and aryl groups, additional efforts culminated in the expansion of the scope of the substitution to various heteroatom-based functionalities, providing a unified olefin reactivity.

Nickel-Catalyzed Barton Decarboxylation and Giese Reactions: A Practical Take on Classic Transforms.

Two named reactions of fundamental importance and paramount utility in organic synthesis have been reinvestigated, the Barton decarboxylation and Giese radical conjugate addition. N-hydroxyphthalimide (NHPI) based redox-active esters were found to be convenient starting materials for simple, thermal, Ni-catalyzed radical formation and subsequent trapping with either a hydrogen atom source (PhSiH ) or an electron-deficient olefin. These reactions feature operational simplicity, inexpensive reagents, and enhanced scope as evidenced by examples in the realm of peptide chemistry.

Radicals: Reactive Intermediates with Translational Potential.

This Perspective illustrates the defining characteristics of free radical chemistry, beginning with its rich and storied history. Studies from our laboratory are discussed along with recent developments emanating from others in this burgeoning area. The practicality and chemoselectivity of radical reactions enable rapid access to molecules of relevance to drug discovery, agrochemistry, material science, and other disciplines.

Nickel-Catalyzed Cross-Coupling of Redox-Active Esters with Boronic Acids.

A transformation analogous in simplicity and functional group tolerance to the venerable Suzuki cross-coupling between alkyl-carboxylic acids and boronic acids is described. This Ni-catalyzed reaction relies upon the activation of alkyl carboxylic acids as their redox-active ester derivatives, specifically N-hydroxy-tetrachlorophthalimide (TCNHPI), and proceeds in a practical and scalable fashion. The inexpensive nature of the reaction components (NiCl2 ⋅6 H2 O-$9.

A general alkyl-alkyl cross-coupling enabled by redox-active esters and alkylzinc reagents.

Alkyl carboxylic acids are ubiquitous in all facets of chemical science, from natural products to polymers, and represent an ideal starting material with which to forge new connections. This study demonstrates how the same activating principles used for decades to make simple C-N (amide) bonds from carboxylic acids with loss of water can be used to make C-C bonds through coupling with dialkylzinc reagents and loss of carbon dioxide. This disconnection strategy benefits from the use of a simple, inexpensive nickel catalyst and exhibits a remarkably broad scope across a range of substrates (>70 examples).

Practical Ni-Catalyzed Aryl-Alkyl Cross-Coupling of Secondary Redox-Active Esters.

A new transformation is presented that enables chemists to couple simple alkyl carboxylic acids with aryl zinc reagents under Ni-catalysis. The success of this reaction hinges on the unique use of redox-active esters that allow one to employ such derivatives as alkyl halides surrogates. The chemistry exhibits broad substrate scope and features a high degree of practicality.