# Simplified Approaches to Medium-Sized Heterocycles for the Synthesis of Bioactive Small Molecules

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $301,208

## Abstract

PROJECT SUMMARY
 The goal of this proposal is to develop simplified approaches to the construction of diverse medium-
sized oxygen and nitrogen heterocycles that can be applied to the synthesis and complexity-building
diversification of bioactive small molecules. Medium-ring heterocycles are ubiquitous in naturally occurring
bioactive molecules, however these scaffolds remain largely absent from pharmaceutical drug scaffolds due to
challenges associated with their synthesis. In order to address rising concerns regarding the lack of chemical
space explored by current therapeutic molecules, we propose methods that enable the use of readily available
alcohols and amines as functional handles for the facile synthesis of medium-sized heterocycles. Preliminary
work in our laboratory has discovered a novel electrophilic heteroatom rearrangement of benzylic alcohols
facilitated by a unique class of (poly)cationic hypervalent iodine reagents that allows direct access to diverse
medium-ring ethers. The first aim of this proposal is the continued development of this novel transformation to
include secondary and tertiary alcohols as well as amine substrates, providing a general platform for medium-
ring heterocycle synthesis. The second aim is the further development of our enabling (poly)cationic λ3-
iodanes, both through detailed reactivity studies as well as novel derivative syntheses, in order to facilitate their
adoption as broadly utilized synthetic reagents. We will also employ these reagents as a novel manifold for the
synthesis of chiral hypervalent iodine scaffolds. The third aim of this proposal will utilize our methodology as an
enabling platform for complex medium-sized ether analogues of the promising chemotherapeutic lead
podophyllotoxin, a compound that has seen little clinical development to date due to limited tolerance for
traditional medicinal chemistry diversification. The work is significant because the development of simplified
approaches to medium-ring heterocycles will expand the chemical space available for drug discovery by
providing previously inaccessible analogues and facilitating more rapid syntheses of complex bioactive natural
products. Furthermore, the development of promising (poly)cationic λ3-iodanes will provide the synthetic
community with a powerful new toolkit of synthetic reagents.

## Key facts

- **NIH application ID:** 9897570
- **Project number:** 5R01GM123098-04
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Sarah Elizabeth Wengryniuk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $301,208
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897570

## Citation

> US National Institutes of Health, RePORTER application 9897570, Simplified Approaches to Medium-Sized Heterocycles for the Synthesis of Bioactive Small Molecules (5R01GM123098-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9897570. Licensed CC0.

---

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