# Novel Synthetic Strategies for Drug Synthesis via Radical-Mediated Chemistry

> **NIH NIH F31** · OHIO STATE UNIVERSITY · 2020 · $33,781

## Abstract

The average time for a pharmaceutical to go from its inception to FDA approval takes 10-15 years! 
Furthermore, in the early stages of drug discovery, upwards of ~10,000-15,000 compounds 
are synthesized by medicinal chemists. Of that, only ~250 compounds may make it into pre-clinical 
trials and only an average of ~5 make it to clinical trials! As medicinal chemists build drug 
libraries, they take compounds that show efficacy towards a desired target and make modifications 
to try and improve performance. The ability to streamline the synthesis of these various drug 
analogues is of great value.

A large portion of commercial drugs contain heteroarenes. Thus, developing ways to 
selectively functionalize the C-H bonds on a given heteroarene is of great importance. One way of 
functionalizing these moieties is through Minisci-type reactions, that is, a radical substitution 
to an aromatic compound. One aim of the proposed research is a method for heteroarene alkylation 
via a ketyl radical intermediate. Ketyl radicals are the product of a single electron reduction of 
a carbonyl. The overall strategy of this Minisci-type reaction is to first convert 
aliphatic aldehydes to their corresponding, α-acetoxy iodides using acetyl iodide. In this form, 
non-bonding oxygen electrons are able to donate into the C-I antibonding orbital, making 
this C-I bond weaker. Mn2(CO)10 catalyst is initiated by visible light irradiation and then 
abstracts the iodide via an atom transfer mechanism to afford ketyl radicals. The ketyl radicals 
are further coupled with heteroarenes, and then reduced via a single electron transfer to afford 
the final product.

The other aim of the proposed research is an environmentally benign, electrocatalytic aza-pinacol 
coupling. The resulting product of an aza-pinacol coupling is a β-amino alcohol, a motif that is 
ubiquitous in pharmaceuticals and biologically relevant natural products. The overall 
strategy of this proposal is to use the cathode in an electrochemical cell to reduce 
added α-acetoxy iodide. Residual iodide from the reduction can then be oxidized at the anode, 
affording iodine that can be removed by a sodium thiosulfate work-up. The ketyl radical is then 
coupled to the imine affording a nitrogen radical. An electron-withdrawing protecting group 
on the nitrogen could also aid in the single electron reduction of the nitrogen radical by 
the cathode by stabilizing the resulting nitrogen anion. Lastly, acid is added to protonate the 
nitrogen and affords the β-amino alcohol. Should the proposed aims be achieved, the findings will 
help accelerate the delivery of clinical drug candidates. The following research will be 
conducted at the facilities at The Ohio State University within the Sponsor’s laboratory 
space.

## Key facts

- **NIH application ID:** 9991627
- **Project number:** 5F31GM134573-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Joy Rutherford
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,781
- **Award type:** 5
- **Project period:** 2019-08-16 → 2021-08-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991627

## Citation

> US National Institutes of Health, RePORTER application 9991627, Novel Synthetic Strategies for Drug Synthesis via Radical-Mediated Chemistry (5F31GM134573-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9991627. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*