Chromium(III)-Catalyzed C(sp2)-H Alkynylation, Allylation, and Naphthalenation of Secondary Amides with Trimethylaluminum as Base.

Among base metals used for C-H activation reactions, chromium(III) is rather unexplored despite its natural abundance and low toxicity. We report herein chromium(III)-catalyzed C(sp2)-H functionalization of an ortho-position of aromatic and α,ß-unsaturated secondary amides using readily available AlMe3 as a base and using bromoalkynes, allyl bromide, and 1,4-dihydro-1,4-epoxynaphthalene as electrophiles. This redox-neutral reaction taking place at 70-90 °C, requires as low as 1-2 mol % of CrCl3 or Cr(acac)3 as a catalyst without any added ligand, and tolerates functional groups such as aryl iodide, boronate, and thiophene groups. Stoichiometric and kinetics studies as well as kinetic isotope effects suggest that the catalytic cycle consists of a series of thermally stable but reactive intermediates bearing two molecules of the amide substrate on one chromium atom and also that one of these chromate(III) complexes takes part in the alkynylation, allylation, and naphthalenation reactions. The proposed mechanism accounts for the effective suppression of methyl group delivery from AlMe3 for ortho-C-H methylation.

Diphospha-Ureas from the Phosphaketene Ph3 GePCO.

The phosphaketene Ph3 GePCO is shown to react with the phosphide KP(tBu)2 to generate the anion [Ph3 GePC(O)P(tBu)2 ]- 1. This species reacts with CH3 I or ClGePh3 to give the dissymmetric diphospha-ureas (tBu)2 PC(O)P(GePh3 )(CH3 ) 2 and (Ph3 Ge)2 PC(O)P(tBu)2 3 respectively. Sequential treatment of 2 with a base and CH3 I affords a route to (tBu)2 PC(O)P(CH3 )2 5. These species are products of the first modular diphospha-urea synthesis. The subsequent thermal and photochemical reactivity of these species was also probed and described.

Discovery of CRBN-dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While Cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-01 derivatives that target casein kinase 1 alpha (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and a rationale for the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

Avenue to phosphaalkenes from Ph3GePCO.

Reactions of Ph3GePCO with KP(t-Bu)2 and Ph3SiCl, or direct reaction with Ph3SiP(t-Bu)2 provides the (Z)- and (E)-isomers of the phosphaalkene (t-Bu2)PC(OSiPh3)P(GePh3) 2, respectively. These isomers interconvert thermally and photochemically, while 2 also undergoes silyl and phosphide exchange with silylphosphines, consistent with a mechanism involving the reversible silylphosphination of Ph3GePCO.