Crbn-based molecular Glues: Breakthroughs and perspectives.

CRBN is a substrate receptor for the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex. It has been observed that CRBN can be exploited by small molecules to facilitate the recruitment and ubiquitination of non-natural CRL4 substrates, resulting in the degradation of neosubstrate through the ubiquitin-proteasome system. This phenomenon, known as molecular glue-induced protein degradation, has emerged as an innovative therapeutic approach in contrast to traditional small-molecule drugs. One key advantage of molecular glues, in comparison to conventional small-molecule drugs adhering to Lipinski's Rule of Five, is their ability to operate without the necessity for specific binding pockets on target proteins. This unique characteristic empowers molecular glues to interact with conventionally intractable protein targets, such as transcription factors and scaffold proteins. The ability to induce the degradation of these previously elusive targets by hijacking the ubiquitin-proteasome system presents a promising avenue for the treatment of recalcitrant diseases. Nevertheless, the rational design of molecular glues remains a formidable challenge due to the limited understanding of their mechanisms and actions. This review offers an overview of recent advances and breakthroughs in the field of CRBN-based molecular glues, while also exploring the prospects for a systematic approach to designing these compounds.

Gold-catalyzed Dearomatization Reactions.

The advent of homogenous gold catalysis has revolutionized the way of approaching organic synthesis providing new and desirable solutions for challenging chemical manipulations of unactivated unsaturated hydrocarbons. In the realm of aromatic compounds, dearomatization protocols have been emerging as valuable synthetic tools to densely functionalized polycyclic 3D-molecular scaffolds, starting from readily available 2D-aromatic congeners. Gold catalysis contributed substantially in expanding this scenario enabling the condensation of numerous electron-rich arenes with hydrocarbons, resulting in the partial or total dearomatization of the aryl fragment. An overview of the most recent findings in the field, organized by type of electrophilic partners, is hereby presented.

Gold-Catalyzed Dearomatization of 2-Naphthols with Alkynes.

The site-selective dearomatization of naphthols is realized in a straightforward manner through a gold(I)-catalyzed [3,3]-sigmatropic rearrangement/allene functionalization cascade sequence. The method employs readily available naphthylpropargyl ethers as starting materials. A range of densely functionalized dihydrofurylnaphthalen-2(1H)-ones are obtained in high yields (up to 98 %) and extremely mild reaction conditions (reagent grade solvent, air, 10 minute reaction time). A complete theoretical elucidation of the reaction machinery is also proposed, providing a rationale for important issues such as regio- and chemoselectivity.

Site-selective synthesis of 1,3-dioxin-3-ones via a gold(i) catalyzed cascade reaction.

A novel gold(i)-catalyzed protocol for the synthesis of 4H-1,3-dioxin-3-ones is presented. The protocol exploits a metal induced cascade sequence involving a [3,3]-sigmatropic rearrangement followed by regioselective O-annulation reactions. A wide range of oxygen-based heterocyclic scaffolds (21 examples) were achieved in excellent yield (up to 80%) and a detailed computational investigation as well as deuterium-labelling investigations enabled all the plausible reaction pathways to be mapped and the rationalization of the recorded regioselectivity.

PPh3AuTFA Catalyzed in the Dearomatization of 2-Naphthols with Allenamides.

A new catalytic methodology for the direct dearomatization of substituted 2-naphthols via intermolecular condensation with allenamides is presented. PPh3AuTFA (5 mol %) promotes the formal allylating dearomative protocol under mild conditions, large scope (24 examples), and high regioselectivity and stereoselectivity. The synergistic catalytic role played by the [PPh3Au]+ (π-acid) and TFA- (Lewis base) is highlighted.

Graphene Oxide Promotes Site-Selective Allylic Alkylation of Thiophenes with Alcohols.

The graphene oxide (GO) assisted allylic alkylation of thiophenes with alcohols is presented. Mild reaction conditions and a low GO loading enabled the isolation of a range of densely functionalized thienyl and bithienyl compounds in moderate to high yields (up to 90%). The cooperative action of the Brønsted acidity, epoxide moieties, and π-surface of the 2D-promoter is highlighted as crucial in the reaction course of the present Friedel-Crafts-type protocol.

Hollow-shell-structured nanospheres: a recoverable heterogeneous catalyst for rhodium-catalyzed tandem reduction/lactonization of ethyl 2-acylarylcarboxylates to chiral phthalides.

Chiral organorhodium-functionalized hollow-shell-structured nanospheres were prepared by immobilization of a chiral N-sulfonylated diamine-based organorhodium complex within an ethylene-bridged organosilicate shell. Structural analysis and characterization reveal its well-defined single-site rhodium active center, and transmission electron microscopy images reveal a uniform dispersion of hollow-shell-structured nanospheres. As a heterogenous catalyst, it exhibits excellent catalytic activity and enantioselectivity in synthesis of chiral phthalides by a tandem reduction/lactonization of ethyl 2-acylarylcarboxylates in aqueous medium. The high catalytic performance is attributed to the synergistic effect of the high hydrophobicity and the confined chiral organorhodium catalytic nature. The organorhodium-functionalized nanospheres could be conveniently recovered and reused at least 10 times without loss of catalytic activity. This feature makes it an attractive catalyst in environmentally friendly organic reactions. The results of this study offer a new approach to immobilize chiral organometal functionalities within the hollow-shell-structured nanospheres to prepare materials with high activity in heterogeneous asymmetric catalysis.