Molecular glues are an intriguing therapeutic modality that harness small-molecules to induce interactions between proteins that typically do not interact. However, such molecules are rare and have been discovered fortuitously, thus limiting their potential as a general strategy for therapeutic intervention. We postulated that natural products bearing one or more electrophilic sites may be an unexplored source of new molecular glues, potentially acting through multi-covalent attachment. Using chemoproteomic platforms, we show that members of the manumycin family of polyketides, which bear multiple potentially reactive sites, target C374 of the putative E3 ligase UBR7 in breast cancer cells and engage in molecular glue interactions with the neo-substrate tumor-suppressor TP53, leading to p53 transcriptional activation and cell death. Our results reveal a novel anti-cancer mechanism of this natural product family and highlight the potential for combining chemoproteomics and multi-covalent natural products for the discovery of new molecular glues.

The dearomatization of aromatic compounds is an important synthetic strategy used in accessing complex three‐dimensional structures from simple aromatic precursors. This minireview aims to provide an overview of recent advancements in this area, with a specific focus on visible‐light‐mediated dearomative transformations. Compared to the conventional high‐energy ultraviolet (UV) light‐promoted processes, not only these new approaches offer milder reaction conditions to accommodate wider variety of substrates with sensitive functionalities, but also enable the use of photocatalysts and other promoters, significantly expanding the reaction space. Application of these transformations to the synthesis of bioactive compounds are also discussed.

A dearomative reduction of simple arenes has been developed which employs a visible-light-mediated cycloaddition of arenes with an N-N-arenophile and in situ diimide reduction. Subsequent cycloreversion or fragmentation of the arenophile moiety affords 1,3-cyclohexadienes or 1,4-diaminocyclohex-2-enes, compounds that are not synthetically accessible using existing dearomatization reactions. Importantly, this strategy also provides numerous opportunities for further derivatization as well as site-selective functionalization of polynuclear arenes.

We developed poly(dimethyl)silane-supported Pd catalysts that are readily prepared from Pd(OAc) 2 ,p oly(dimethyl)silane, and Al 2 O 3 .T he immobilization was achieved for the first time with as upport that does not contain benzene rings. The Pd catalyst thus prepared was found to have higher hydrogenation activity than Pd/C. Furthermore,t he catalystw as used in continuous-flow hydrogenation with various substrates, including simple liquid substrates (neat) and dissolved solid substrates. Vegetable oils, squalenes, and phosphatidylcholine were successfully hydrogenated on gram to kilogram scales.Catalytic hydrogenation is one of the most important methods for organic synthesis in both academia and industry. [1] It is widely used for the synthesis of natural products,b iologically important compounds, active pharmaceutical ingredients, and many intermediate compounds. The hydrogenation of fats, phospholipids,a nd squalenesi sp erformed to prevent oxidation of their unsaturated bonds, which causes coloration or odor. [2] The hydrogenated products thus prepared are used as emulsifiers, compoundinga gents, and so on. Hydrogenation of lecithin is an important process for the preparation of emulsifiers. Catalytic hydrogenation by using Pd/C has been used in ab atch system for this process;h owever,arelativelyh igh loading of Pd/C is required and subsequentr emoval of Pd by filtration is time consuming.M oreover,t he recovered Pd has low activity.T oa ddress thesei ssues, alternative catalyst systems have been investigated, and among the variousc atalysts tested, polysilane-supported Pd (Pd/PSi) was found to have high activity.W ed eveloped this methodology further, and herein, we describe ac ontinuous-flow hydrogenation process by using an ovel Pd/PSisystem as the catalyst.We previously prepared poly(methylphenyl)silane-supported Pd (Pd/MPPSi)a nd used it as ac atalyst for severalr eactions. [3] Poly(methylphenyl)silane was chosen as an analogue of polystyrene, because in microencapsulated [4] and polymer-incarcerated [5] catalysts with polystyrenes as polymer backbones, it is assumed that the benzene rings of the backbone are important for the immobilization of the metal catalysts through electronic interactions (p electrons). This reasoning led us to assumet hat benzene rings would also be important for immobilization of polysilane-supported catalysts, and poly(methylphenyl)silane was chosen accordingly.H owever,t he availability of poly(methylphenyl)silane is relatively limited. In contrast, poly(dimethyl)silane is readily available; [6] therefore, we examined the use of poly(dimethyl)silane in place of polystyrenes or poly(methylphenyl)silane as ab ackbone fors upported catalysts.We began our study by exploring the preparation of ap oly(dimethyl)silane-supported palladium/alumina hybrid catalyst [Pd/(DMPSi-Al 2 O 3 )] according to the method shown in Scheme 1. This methodw as based on ap rocedure that was used previously to preparet he Pd/MPPSi catalyst. [3] Unexpectedly,t he Pd loading of the catalyst (56.6...

Herein we report a dearomative syn-1,4-diamination protocol using simple nonactivated arenes and amines. This one-pot method utilizes arene–arenophile para-cycloadducts, formed via visible-lightmediated [4+2]-photocycloaddition that undergoes formal allylic substitution with amine nucleophiles under Pdcatalysis. The products are obtained with exclusive syn-1,4-selectivity; the method permits enantioselective desymmetrization of naphthalene, as well as elaborations of amine-containing drug molecules. Furthermore, the resulting unsaturated products are amenable to numerous options for diversification. Overall, this novel dearomative functionalization strategy offers rapid and straightforward access to complex building blocks, which are difficult to prepare otherwise, from simple arenes.