# Expanding Access to Molecular Complexity through Natural Product Synthesis

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $328,000

## Abstract

The development of modern medicines relies on the ability to access compounds that are potent, selective,
and ideally curative. To achieve these goals, chemists have sought to prepare evermore complex structures in
search of nuanced activity and selectivity profiles, advances dependent on the availability of tools and strategies
to synthesize such compounds in an economical and scalable fashion. Complex natural products have
traditionally inspired the development of such tools, often acting as key milestones in the advancement of organic
synthesis and as vital medicines in their own right. However, at the apex of complexity, their structures continue
to test the limits of current capabilities: highly intricate targets are prepared only through enormous effort in terms
of man-years and number of synthetic operations, often only in a target-specific manner.
 Here, we propose to utilize such compounds as vehicles for the discovery of complexity-generating tools and
tactics. We outline approaches to several families of natural products built upon two distinct complexity-building
strategies: dearomative transformations of readily available aromatic compounds and desymmetrization of
simple symmetrical precursors. In the former case, aromatic feedstocks – available as petroleum byproducts or
from renewable biomass – represent a versatile synthesis platform given well-established, predictable modes
for their functionalization. We seek to deploy these materials in complexity-building dearomative reactions,
disrupting their otherwise stable aromatic systems and transforming their flat sp2-scaffolds into sp3-rich
compounds containing multiple stereogenic centers. Specifically, we propose to utilize the regiodivergent
oxidative coupling of simple bisphenolic compounds to access the structural complexity inherent to the
quassinoids, a family of potent anticancer terpenoids. Our synthesis platform will leverage the built-in oxidation
of the aromatic systems to encode for much of the sp3-skeletal oxidation in these highly oxidized terpenoids,
providing a unique means to access these targets and analogues, and illuminate their biological mode of action.
 In a symmetry-breaking transformation, we will develop new photochemistry of pyridinium ions to provide
convenient access to highly functionalized cyclopentane building blocks, in particular via enantioselective
desymmetrization of symmetrical allylic cation intermediates. We will apply these intermediates to the
asymmetric synthesis of pactamycin-type aminocyclopentitols, highly potent antiparasitic agents. We will also
develop a related approach to two subclasses of the Lycopodium alkaloids, which include central nervous
system-active compounds, built upon two sequential photochemical dearomatizations of a simple quinoline.
 Overall, such discoveries will open up new areas of complex chemical space from simple aromatic or
symmetrical precursors, providing natural products and designed analogues for interrogati...

## Key facts

- **NIH application ID:** 10939707
- **Project number:** 1R35GM155273-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Myles Warwick Smith
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $328,000
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939707

## Citation

> US National Institutes of Health, RePORTER application 10939707, Expanding Access to Molecular Complexity through Natural Product Synthesis (1R35GM155273-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10939707. Licensed CC0.

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