# Unlocking Access to Cyclopropanones as Divergent Reactive Intermediates in Synthesis

> **NIH NIH R35** · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2022 · $363,102

## Abstract

ABSTRACT
 Strained cyclic compounds are often used as key intermediates in the synthesis of bio-active drugs
and natural products through strain-releasing reactions such as ring-expansion and ring-opening
processes. While small ring ketones such as cyclobutanones have found widespread applicability in
these transformations, the analogous use of cyclopropanone derivatives as substrates has seriously
lagged behind, as these compounds have long been considered unsustainable synthetic intermediates
due to their extreme strain and kinetic instability. This work proposes the use of 1-sulfonylcyclopropanols
as a general class of stable cyclopropanone surrogates in organic synthesis, unlocking access to myriad
previously inaccessible synthetic disconnections via strain-releasing reactions. These include (1)
rearrangements initiated by the addition of nucleophiles, (2) transition metal-catalyzed C–C activation
and deconstruction strategies, and (3) application of cyclopropanone derivatives as 1,1-cyclopropyl
linchpins. We have already developed an efficient enantioselective route to these compounds and have
obtained significant preliminary data in each of these types of reactions, leading to a variety of chiral
synthons difficult to access by other methods. Both the electronic and steric nature of the sulfonyl moiety
in these surrogates, which is acting here as a base-labile protecting group and conferring crystallinity to
these compounds, is found to have a crucial impact on their rate of equilibration to cyclopropanone,
highlighting their tunable reactivity and the potential for their widespread applicability as synthetic
intermediates. During the funding period and using the mechanistic knowledge acquired, this technology
leading to enantioenriched 1-sulfonylcyclopropanols will be extended to the formation of 1-
sulfonylcyclopropylamine and hydrazines as modular precursors of chiral cyclopropanimines and
hydrazones, respectively, and will allow novel access to chiral amine-containing scaffolds as well as
strained chiral carbene equivalents. We firmly believe that the stability, ease of synthesis and modular
character of these reagents will serve as a general solution to harvest the untapped versatility of
cyclopropanones and its analogues as highly reactive building blocks in synthesis. Thus, this work will
significantly expand the scope of disconnections available to chemists in the realm of strained ring
activation and functionalization, evolving these severely strained derivatives from chemical curiosities to
versatile synthetic intermediates, greatly contributing to streamline the production of biologically relevant
organic molecules.

## Key facts

- **NIH application ID:** 10451631
- **Project number:** 5R35GM142965-02
- **Recipient organization:** NORTH CAROLINA STATE UNIVERSITY RALEIGH
- **Principal Investigator:** Vincent Lindsay
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $363,102
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451631

## Citation

> US National Institutes of Health, RePORTER application 10451631, Unlocking Access to Cyclopropanones as Divergent Reactive Intermediates in Synthesis (5R35GM142965-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10451631. Licensed CC0.

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