# Iron-Catalyzed Synthesis and Derivatization of 1,1'-Bicyclobutyls

> **NIH NIH F32** · PRINCETON UNIVERSITY · 2021 · $15,015

## Abstract

Project Summary/Abstract: The strong correlation between the number of aromatic rings in a drug candidate
and the candidate’s likely attrition during development has led to the pursuit of replacements for phenyl moieties,
giving rise to medicinal compounds containing alicycles. However, current small ring bioisosteres for phenyl
groups are not amenable to facile derivatization, hindering their incorporation into drug candidates. Further, with
the known bioisosteres utilized as alicyclic bridges in molecules, only a limited portion of spatial length is covered
compared to that encompassed by phenyl and biphenyl units. As such, designing C(sp3)-enriched molecules
with innovative structural properties is limited not only by the difficulty in synthesizing alicyclic isosteres, but also
by the abridged spatial diversity achieved when employing these molecules in bioactive compounds. Thus, an
easily accessible alicyclic compound that provides structural diversity in both 3-dimensional vectoral space and
length would reveal new opportunities for molecular design.
 An alicyclic motif fulfilling spatial and vectoral requirements necessary for a phenylene bioisostere is 1,1’-
bicyclobutyl; however, this species is currently absent from the synthetic literature. Preliminary results from the
Chirik laboratory indicate that this architecture can be synthesized in one step from feedstock dienes and alkenes
by (PDI)Fe-catalyzed [2+2] cascade cyclization (PDI = pyridinediimine). Herein, this proposal focuses on the
expedient, modular synthesis of new 1,1’-bicyclobutyl isosteres as well as their derivatization relevant to
incorporation into druglike molecules. Aim 1 details procedures to control chain length during the oligomerization
process to selectively produce 1,1’-bicyclobutyl structures. Further, increases to reaction chemoselectivity and
rate will be examined by installing hemilabile groups on the (PDI)Fe backbone. The potential for controlled
derivatization of the resultant vinyl 1,1’-bicyclobutyls is explored in Aim 2, in which vinylcyclobutanes will be
exploited as model systems en-route to functionalization of 1,1-bicyclobutyls. Here, (PDI)Fe-catalyzed
hydrofunctionalization at the vinyl position provides a one-pot methodology for the construction and derivatization
of cyclobutane cores; complementary functionalization at the opposite terminus of the cyclobutane structure will
be conducted through expansion of the scope of alkene oligomerization partner to include synthetically useful
boranes. In Aim 3, the core atoms in the framework of the bicyclobutyl will be altered through the [2+2]
oligomerization of dienes and aldimines or nitriles mediated by (PDI)Fe catalysts. The regioselectivity of the
oxidative cyclization event prevents opportunities for installing a nitrogen atom at either the 2’ or 3’ position of
the core, providing otherwise inaccessible modularity in the vectoral disposition of the structure. The synthetic
protocols established in this...

## Key facts

- **NIH application ID:** 10129196
- **Project number:** 5F32GM134610-02
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Megan Mohadjer Beromi
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $15,015
- **Award type:** 5
- **Project period:** 2020-04-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129196

## Citation

> US National Institutes of Health, RePORTER application 10129196, Iron-Catalyzed Synthesis and Derivatization of 1,1'-Bicyclobutyls (5F32GM134610-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129196. Licensed CC0.

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