Protocol to synthesize the auxin analog 5-Ph-IAA for conditional protein depletion in C. elegans using the AID2 system.

The auxin-inducible degron (AID) system is a broadly used tool for spatiotemporal and reversible control of protein depletion in multiple experimental model systems. AID2 technology relies on a synthetic ligand, 5-phenyl-indole-3-acetic acid (5-Ph-IAA), for improved specificity and efficiency of protein degradation. Here, we provide a protocol for cost-effective 5-Ph-IAA synthesis utilizing the Suzuki coupling of 5-chloroindole and phenylboronic acid.

Strategies for Nucleophilic C(sp)-(Radio)Fluorination.

This Perspective surveys the progress and current limitations of nucleophilic fluorination methodologies. Despite the long and rich history of C(sp)-F bond construction in chemical research, the inherent challenges associated with this transformation have largely constrained nucleophilic fluorination to a privileged reaction platform. In recent years, the Doyle group─along with many others─has pursued the study and development of this transformation with the intent of generating deeper mechanistic understanding, developing user-friendly fluorination reagents, and contributing to the invention of synthetic methods capable of enabling radiofluorination.

A general strategy for C(sp)-H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor.

Photoredox catalysis has provided many approaches to C(sp)-H functionalization that enable selective oxidation and C(sp)-C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp)-H functionalization strategy with nucleophiles.

Nickel/Photoredox-Catalyzed Methylation of (Hetero)aryl Chlorides Using Trimethyl Orthoformate as a Methyl Radical Source.

Methylation of organohalides represents a valuable transformation, but typically requires harsh reaction conditions or reagents. We report a radical approach for the methylation of (hetero)aryl chlorides using nickel/photoredox catalysis wherein trimethyl orthoformate, a common laboratory solvent, serves as a methyl source. This method permits methylation of (hetero)aryl chlorides and acyl chlorides at an early and late stage with broad functional group compatibility.

Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1.

Spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody-drug conjugates and other targeted delivery approaches. Unfortunately, it is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive. As a result, the design and synthesis of more acid-stable and linker functional group-equipped analogs that retain the low picomolar potency of the parent natural product requires more efficient and step-economical synthetic access.

Direct, Mild, and General n-BuNBr-Catalyzed Aldehyde Allylsilylation with Allyl Chlorides.

A direct, mild, and general method for the enantioselective allylsilylation of aldehydes with allyl chlorides is reported. The reactions are effectively catalyzed by 5 mol % of n-BuNBr, and this rate acceleration allows the use of complex allyl donors in fragment-coupling reactions and of electron-deficient allyl donors. The results are (1) significant progress toward a "universal" asymmetric aldehyde allylation reaction that can reliably and highly stereoselectively couple any allyl chloride_aldehyde combination and (2) the discovery of a novel mode of nucleophilic catalysis for aldehyde allylsilylation reactions.