Mechanistic analysis of Riboswitch Ligand interactions provides insights into pharmacological control over gene expression.

Riboswitches are structured RNA elements that regulate gene expression upon binding to small molecule ligands. Understanding the mechanisms by which small molecules impact riboswitch activity is key to developing potent, selective ligands for these and other RNA targets. We report the structure-informed design of chemically diverse synthetic ligands for PreQ riboswitches.

Mechanistic Analysis of Riboswitch Ligand Interactions Provides Insights into Pharmacological Control over Gene Expression.

Riboswitches are structured RNA elements that regulate gene expression upon binding to small molecule ligands. Understanding the mechanisms by which small molecules impact riboswitch activity is key to developing potent, selective ligands for these and other RNA targets. We report the structure-informed design of chemically diverse synthetic ligands for PreQ riboswitches.

A chemical probe based on the PreQ metabolite enables transcriptome-wide mapping of binding sites.

The role of metabolite-responsive riboswitches in regulating gene expression in bacteria is well known and makes them useful systems for the study of RNA-small molecule interactions. Here, we study the PreQ riboswitch system, assessing sixteen diverse PreQ-derived probes for their ability to selectively modify the class-I PreQ riboswitch aptamer covalently. For the most active probe (11), a diazirine-based photocrosslinking analog of PreQ, X-ray crystallography and gel-based competition assays demonstrated the mode of binding of the ligand to the aptamer, and functional assays demonstrated that the probe retains activity against the full riboswitch.

Fluorofunctionalization of C═C Bonds with Selectfluor: Synthesis of β-Fluoropiperazines through a Substrate-Guided Reactivity Switch.

The halofunctionalization of alkene substrates remains an essential tool for synthetic chemists. Herein, we report regioselective ammoniofluorination of unactivated alkenes through photochemical means. A one-pot transformation of the ammonium fluoride products into pharmaceutically relevant β-fluoropiperazines is highlighted.

Catalyzed and Promoted Aliphatic Fluorination.

In the last six years, the direct functionalization of aliphatic C-H (and C-C) bonds through user-friendly, radical-based fluorination reactions has emerged as an exciting research area in fluorine chemistry. Considering the historical narratives about the challenges of developing practical radical fluorination in organic frameworks, notable advancements in controlling both reactivity and selectivity have been achieved during this time. As one of the participants in the field, herein, we a provide brief account of research efforts in our laboratory from the initial discovery of radical monofluorination on unactivated C-H bonds in 2012 to more useful strategies to install fluorine on biologically relevant molecules through directed fluorination methods.

Sensitized Aliphatic Fluorination Directed by Terpenoidal Enones: A "Visible Light" Approach.

In our continued effort to address the challenges of selective sp C-H fluorination on complex molecules, we report a sensitized aliphatic fluorination directed by terpenoidal enones using catalytic benzil and visible light (white LEDs). This sensitized approach is mild, simple to set up, and an economical alternative to our previous protocol based on direct excitation using UV light in a specialized apparatus. Additionally, the amenability of this protocol to photochemical flow conditions and preliminary evidence for electron-transfer processes are highlighted.

Ketones as directing groups in photocatalytic sp C-H fluorination.

The ubiquitous ketone carbonyl group generally deactivates substrates toward radical-based fluorinations, especially sites closest to it. Herein, ketones are used instead to direct aliphatic fluorination using Selectfluor, catalytic benzil, and visible light. Selective β- and γ-fluorination are demonstrated on rigid mono-, di-, tri-, and tetracyclic (steroidal) substrates employing both cyclic and exocyclic aliphatic ketones as directing groups.

Multiple Enone-Directed Reactivity Modes Lead to the Selective Photochemical Fluorination of Polycyclic Terpenoid Derivatives.

In the realm of aliphatic fluorination, the problem of reactivity has been very successfully addressed in recent years. In contrast, the associated problem of selectivity, that is, directing fluorination to specific sites in complex molecules, remains a great, fundamental challenge. In this report, we show that the enone functional group, upon photoexcitation, provides a solution.

Unstrained C-C bond activation and directed fluorination through photocatalytically-generated radical cations.

Expanding the repertoire of controlled radical fluorination techniques, we present a photosensitized unstrained C-C bond activation/directed monofluorination method using Selectfluor and 9-fluorenone. The reaction is amenable to the opening of multiple 1-acetal-2-aryl substituted rings to yield ω-fluoro carboxylic acids, esters, alcohols, and ketones with relative ease. Initial mechanistic insight suggests radical ion intermediates.

Site-Selective Approach to β-Fluorination: Photocatalyzed Ring Opening of Cyclopropanols.

To expand upon the recent pioneering reports of catalyzed sp(3) C-H fluorination methods, the next rational step is to focus on directing "radical-based fluorination" more effectively. One potential solution entails selective C-C bond activation as a prelude to selective fluorination. Herein, we report the tandem photocatalyzed ring-opening/fluorination reactions of cyclopropanols by 1,2,4,5-tetracyanobenzene (TCB) and Selectfluor to afford a process tantamount to site-selective β-fluorination of carbonyl-containing compounds.