# Biocatalytic Enantioselective Synthesis of Non-Biaryl and Hetero-Biaryl Atropisomers and Testing of their Antimalarial Properties

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $66,790

## Abstract

Project Summary/Abstract
 Atropisomerism, or stereoisomerism arising as a consequence of hindered bond rotation, has
traditionally been avoided as a design strategy in drug design. As a result of this, catalytic methods for
atroposelective synthesis are underdeveloped, despite the growing evidence that atropisomerism can be
strategically applied to improve the potency and selectivity of a potential drug by increasing its binding
specificity to a biological target. In particular, the synthesis of non-biaryl and hetero-biaryl atropisomers
containing chiral C–O and C–N axes often relies on the functionalization of a substrate with the C–X bond
already installed, thus limiting the utility of these methods in designing convergent syntheses. Here, I propose
the development of a biocatalytic approach for the atroposelective synthesis of diarylethers, C,N-coupled
naphthylisoquinoline alkaloids, and N-aryl indoles. These classes of compounds were chosen based on the
current limitations for their syntheses and their potential therapeutic properties, with the proposed research
aiming to address both points. To achieve this goal, we will take a three stage approach consisting of
screening wild-type enzymes, biocatalyst engineering, and combinatorial synthesis and biological testing of
compound libraries.
 In the first stage, monomers will be screened against a library of wild-type P450 enzymes. This library
was constructed using a bioinformatics approach to identify P450 enzymes with sequence similarity to those
with known reactivity. In this stage, reactions will be analyzed for evidence of reactivity and detection of the
target product. Upon identification of a suitable starting point for engineering, directed evolution of the
enzyme will be conducted to improve formation of the target product. Finally, once a suitable P450 variant is
identified, a library of compounds will be constructed through combinatorial synthesis in 96 well plates. These
compounds will then undergo biological testing to evaluate their antimalarial potential by analyzing their
impact on transmission and viability. The research proposed above will be facilitated by high-thoroughput
experimentation and reaction analysis, in conjunction with high-thoroughput platform for biological testing.
We anticipate that that this research will streamline the synthesis of molecule classes previously challenging
to access. This will accelerate preparation and evaluation of potential therapeutic compounds, expediting the
identification of antimalarial drug targets.

## Key facts

- **NIH application ID:** 10534903
- **Project number:** 1F32GM147938-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Casey Bard Roos
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $66,790
- **Award type:** 1
- **Project period:** 2022-08-15 → 2025-08-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534903

## Citation

> US National Institutes of Health, RePORTER application 10534903, Biocatalytic Enantioselective Synthesis of Non-Biaryl and Hetero-Biaryl Atropisomers and Testing of their Antimalarial Properties (1F32GM147938-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10534903. Licensed CC0.

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