Yong Wang

Dedicated to Prof. Erick M. Carreira on the occasion of his 60^th birthday. Targeted protein degradation (TPD) has emerged as an important strategy to target disease-relevant proteins that were previously considered difficult to drug or even undruggable. Cereblon (CRBN) plays an outsized role in TPD as a preferred degradation-inducing effector protein for several reasons, including its anticipated broad protein substrate scope and its ligandability with drug-like small molecules. Notably, CRBN-based molecular glue degraders (MGDs) and proteolysis targeting chimeras (PROTACs) have shown success in clinical trials and, in some cases, as approved drugs. Thus, the interest in CRBN ligands within the pharmaceutical industry and academia has increased dramatically in recent years, highlighting the need for robust synthetic approaches towards them. This short review summarizes tactics and strategies to synthesize CRBN ligands, including the most recent developments in the field. Particular emphasis is put on the construction and direct functionalization of key CRBN binding motifs such as glutarimides and dihydrouracils. 1 Introduction 2 Cereblon Ligands with Glutarimide Binding Motif 3 Cereblon Ligands with Dihydrouracil Binding Motif 4 Cereblon Ligands with Other Binding Motifs 5 Conclusions and Outlook Received: 30 March 2024 Accepted after revision: 25 June 2024 Article published online: 16 July 2024 © 2024. Thieme. All rights reserved Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

The stereoselective synthesis of complex targets requires the precise orchestration of chemical transformations that simultaneously establish the connectivity and spatial orientation of desired bonds. In this work, we describe a complementary paradigm for the synthesis of chiral molecules and their isomers, which tunes the three-dimensional structure of a molecule at a late stage. Key to the success of this strategy is the development of a mild and highly general photocatalytic method composed of decatungstate polyanion and disulfide cocatalysts, which enable the interconversion of unactivated tertiary stereogenic centers that were previously configurationally fixed. We showcase the versatility of this method—and the implementation of stereoediting logic—by the rapid construction of chiral scaffolds that would be challenging to access using existing tools and by the late-stage stereoediting of complex targets.

The targeted introduction of substituents in order to tailor a molecule's pharmacologic, physicochemical, and metabolic properties has long been of interest to medicinal chemists. The all-cis tetrafluorocyclohexyl motif-dubbed Janus face, due to its electrostatically polarized cyclohexyl ring-represents one such example where chemists might incorporate a metabolically stable, polar, lipocompatible motif. To better understand its potential utility, we have synthesized three series of matched molecular pairs (MMPs) where each MMP differs only in the cyclohexane unit, i.e., with a tetrafluorocyclohexyl or a standard cyclohexyl motif. With the introduction of the facially polarized all-cis tetrafluorocyclohexyl ring, the resulting compounds have significantly modified physicochemical properties (e.g., kinetic solubility, lipophilicity and permeability) and metabolic stabilities. These results further speak to the promise of this substituent as a tactic to improve the drug-like properties of molecules.

Radical-mediated transformations have emerged as powerful methods for the synthesis of rare and unnatural branched, deoxygenated, and isomeric sugars. Here, we describe a radical-mediated axial-to-equatorial alcohol epimerization method to transform abundant glycans into rare isomers. The method delivers highly predictable and selective reaction outcomes that are complementary to other sugar isomerization methods. The synthetic utility of isomer interconversion is showcased through expedient glycan synthesis, including one-step glycodiversification. Mechanistic studies reveal that both site- and diastereoselectivities are achieved by highly selective H atom abstraction of equatorially disposed α-hydroxy C–H bonds.

α-Alkynyldiazomethanes, generated in situ from the corresponding sulfonyl hydrazones in the presence of a base, can serve as effective metalloradicophiles in Co(II)-based metalloradical catalysis (MRC) for asymmetric cyclopropanation of alkenes. With D₂-symmetric chiral amidoporphyrin 2,6-DiMeO-QingPhyrin as the optimal supporting ligand, the Co(II)-based metalloradical system can efficiently activate different α-alkynyldiazomethanes at room temperature for highly asymmetric cyclopropanation of a broad range of alkenes. This catalytic radical process provides a general synthetic tool for stereoselective construction of alkynyl cyclopropanes in high yields with high both diastereoselectivity and enantioselectivity. Combined computational and experimental studies offer several lines of evidence in support of the underlying stepwise radical mechanism for the Co(II)-catalyzed olefin cyclopropanation involving a unique α-metalloradical intermediate that is associated with two resonance forms of α-Co(III)-propargyl radical and γ-Co(III)-allenyl radical. The resulting enantioenriched alkynyl cyclopropanes, as showcased with several stereospecific transformations, may serve as valuable chiral building blocks for stereoselective organic synthesis.

A new C–C bond formation strategy based on enantioselective radical alkylation of C(sp ³ )–H bonds via Co( ii )-based metalloradical catalysis has been demonstrated for stereoselective synthesis of chiral indolines.

For the first time, α-formyldiazoacetates have been successfully applied for the asymmetric cyclopropanation of alkenes via Co(II)-based metalloradical catalysis. The cobalt(II) complex of the D₂-symmetric chiral amidoporphyrin [Co(3,5-Di^tBu-ChenPhyrin)] is an effective metalloradical catalyst that can activate α-formyldiazoacetates to cyclopropanate both aromatic and aliphatic olefins with varied electronic properties, affording the synthetically useful 1,1-cyclopropaneformylesters in high yields with both high diastereo- and enantioselectivity.