Comprehensive Mechanistic Analysis of Palladium- and Nickel-Catalyzed α,ß-Dehydrogenation of Carbonyls via Organozinc Intermediates.

Introducing degrees of unsaturation into small molecules is a central transformation in organic synthesis. A strategically useful category of this reaction type is the conversion of alkanes into alkenes for substrates with an adjacent electron-withdrawing group. An efficient strategy for this conversion has been deprotonation to form a stabilized organozinc intermediate that can be subjected to α,ß-dehydrogenation through palladium or nickel catalysis. This general reactivity blueprint presents a window to uncover and understand the reactivity of Pd- and Ni-enolates. Within this context, it was determined that ß-hydride elimination is slow and proceeds via concerted syn-elimination. One interesting finding is that ß-hydride elimination can be preferred to a greater extent than C-C bond formation for Ni, more so than with Pd, which defies the generally assumed trends that ß-hydride elimination is more facile with Pd than Ni. The discussion of these findings is informed by KIE experiments, DFT calculations, stoichiometric reactions, and rate studies. Additionally, this report details an in-depth analysis of a methodological manifold for practical dehydrogenation and should enable its application to challenges in organic synthesis.

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. Unlike achieving potency and selectivity for traditional small molecule inhibitors, reducing the degradation of these neosubstrates is complicated by the ternary nature of the complex formed between the protein, CRBN, and CELMoD. The standard guiding principles of medicinal chemistry, such as enforcing hydrogen bond formation, are less predictive of degradation efficiency and selectivity. Disclosed is an analysis of our glutarimide CELMoD library to identify interpretable chemical features correlated to selectivity profiles and general cytotoxicity. Included is a simple multiparameter optimization function using only three parameters to predict whether molecules will have undesired neosubstrate activity.

Allyl-Nickel Catalysis Enables Carbonyl Dehydrogenation and Oxidative Cycloalkenylation of Ketones.

We herein disclose the first report of a first-row transition metal-catalyzed α,ß-dehydrogenation of carbonyl compounds using allyl-nickel catalysis. This development overcomes several limitations of previously reported allyl-palladium-catalyzed oxidation, and is further leveraged for the development of an oxidative cycloalkenylation reaction that provides access to bicycloalkenones with fused, bridged, and spirocyclic ring systems using unactivated ketone and alkene precursors.

Total Synthesis of (±)-Berkeleyone A.

A 13-step total synthesis of the fungal meroterpenoid berkeleyone A is reported. The molecular skeleton is formed using the first examples of two critical construction reactions: (1) an epoxide-initiated, ß-ketoester-terminated polycyclization, and (2) an isomerization-cyclization cascade to generate the remaining bicyclo[3.3.1]nonane framework. The resulting 6-step synthesis of the carbocyclic core of the berkeleyone natural products has been used to access protoaustinoid A and berkeleyone A, and will aid future biosynthetic investigations into the origin of related natural products.