# Dual Hydrogen-Bond Donor & Cation-π Catalysis: Enantioselective Cycloadditions of Strained Donor-Acceptor Ring Systems

> **NIH NIH F32** · HARVARD UNIVERSITY · 2020 · $65,310

## Abstract

Project Summary.
 The cycloaddition between a small-ring donor-acceptor compound and a dipolarophile produces
stereochemically rich heterocyclic and carbocyclic building blocks that are useful in the construction of
bioactive small molecules. Improved access to these building blocks will facilitate the construction of a wide
range of useful molecular scaffolds that could act as tool compounds to probe biological systems or as drug
candidates to treat disease. Current methods for these cycloadditions employ either Lewis acid or transition
metal catalysts to partially stabilize the zwitterionic transition state. This proposal aims to leverage a
bifunctional catalyst system that will more effectively stabilize both charge components of the transition state,
removing the requirement for strong anion and cation stabilizing groups on the substrate, thereby increasing
the substrate scope of this transformation. Specifically, current methods stabilize only one of the two charged
functional groups in the zwitterionic transition state of the donor-acceptor ring, relying on substrate
functionality to stabilize the opposing charge. In contrast, employing a hydrogen-bond donor (HBD)/cation-π
catalyst system will stabilize both charge components using optimized catalyst-substrate interactions. The
anionic component will be stabilized through a hydrogen-bond interaction between an HBD donor on the
catalyst and an enolate on the substrate, while the cationic component will be stabilized through a cation-π
interaction between an aryl ring on the catalyst and the cation of the zwitterionic intermediate. The use of
multiple noncovalent interactions with a chiral catalyst should produce a well-defined catalyst-substrate
construct, allowing for effective differentiation of enantiotopic transition states leading to enantioenriched
products.
 Successful realization of this strategy will broaden the substrate scope of these reactions, increasing
the chemical space accessible using this type of chemistry. Ideally, this method will become a universal tool for
diverse carbocyclic and heterocyclic frameworks, simplifying disconnections for biologically relevant
molecules. A variety of useful heterocycles and carbocycles can be generated from simple starting materials
with the proposed catalyst system, including furans, pyrans, substituted cyclopentane rings, and amino acid
derivatives. Many of these products are common structural motifs found in bioactive natural products such as
polyketides, terpenes, and nonribosomal peptides, and this method would facilitate access to these useful
molecules.

## Key facts

- **NIH application ID:** 9823884
- **Project number:** 5F32GM126636-03
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Adam Trotta
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2017-12-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9823884

## Citation

> US National Institutes of Health, RePORTER application 9823884, Dual Hydrogen-Bond Donor & Cation-π Catalysis: Enantioselective Cycloadditions of Strained Donor-Acceptor Ring Systems (5F32GM126636-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9823884. Licensed CC0.

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