# Rapid Synthesis of Topologically Complex Molecules with Tungsten Dearomatization Agents

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $348,613

## Abstract

Project Summary/Abstract
 The development of a new pharmaceutical agent often requires screening thousands of compounds. Such
compounds are typically derived from high-throughput syntheses, which tend to focus on simple transformations.
For this reason, so called “flat” compounds, made from aromatic rings coupled together, predominate medchem
libraries. However, molecules in these libraries stand in contrast to most naturally occurring, biologically active
compounds, which have well-defined three-dimensional structures, rich in carbon stereocenters, adapted for
specific and selective interactions with receptors. Since more complex molecules are better able to optimally fill
space in their binding sites, molecular complexity strongly correlates with clinical success. Thus, a limited scope
of synthetic methods used in discovery chemistry has led to an overpopulation of certain types of molecular
shapes and properties to the exclusion of others. The challenge is to generate new classes of compounds with
both diversity and complexity in a manner that is accessible to medicinal chemists. Such methodologies would
open new, more prolific chemical space for exploration in both traditional SAR studies and the generation of
fragment libraries. This proposal describes an approach to building cyclohexanes with multiple stereocenters
derived from simple benzene precursors. The otherwise inert benzene scaffold is chemically enabled through its
dihapto-coordination to a tungsten complexing agent. In the proposed study, we will assess the ability of
{WTp(NO)(PMe3)} to activate electrophilic addition and nucleophilic addition reactions with a high degree of
regio- and stereochemical control.
Aim 1 focuses on the conversion of the 2-benzene complex to chiral 2-1,3-cyclohexadiene complexes. Aim 2
explores the conversion of these 2-1,3-cyclohexadienes to highly functionalized 2-cyclohexene complexes.
Aim 3 is concerned with elaboration of these cyclohexene complexes into a wide variety of cyclohexanes,
decorated with amine, alcohol, and carboxylate functionalities. Aim 4 evaluates the effects of a single substituent
on an 2-benzene substrate. And finally, whereas the first four sections of this proposal explore the potential of
creating molecular diversity using nucleophiles, Aim 5 focuses on the strategic use of carbon electrophiles. This
dearomatization methodology will open more fertile chemical space-- fragment libraries that feature a diverse
range of complex three-dimensional architectures with many of the functional groups common to proven
pharmaceuticals. This approach not only increases the chances for finding new lead-like compounds for
pharmaceutical development with increased affinity for a targeted binding site, but more importantly, increased
specificity for that site.

## Key facts

- **NIH application ID:** 10119303
- **Project number:** 5R01GM132205-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Walter Dean Harman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $348,613
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119303

## Citation

> US National Institutes of Health, RePORTER application 10119303, Rapid Synthesis of Topologically Complex Molecules with Tungsten Dearomatization Agents (5R01GM132205-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10119303. Licensed CC0.

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