# Total synthesis of bioactive natural products

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA BARBARA · 2021 · $446,559

## Abstract

Abstract
The proposed research program combines three research topics: 1) development and application of methods
for efficient asymmetric synthesis using readily available chiral lithium amides as recoverable stereodirecting
reagents, 2) total synthesis of complex bioactive molecules, and 3) investigating effects of Cyclic Imine (CI)
toxins on various aspects cholinergic transmission by defining their interaction with nicotinic acetylcholine
receptors (nAChRs). Total synthesis of complex natural products, in particular CI toxins, has served as a
unifying platform for our diverse research interests. Within the first two areas, we will extend the utility of chiral
lithium reagents for asymmetric alkylation reactions with momoanionic and dianionic intermediates. This
methodology forms the basis of synthesis strategies directed at the enantioselective preparation of
duocarmycin alkaloids and a morphine and related alkaloids by a shortest synthetic sequence to date. In the
third area, we bring in our expertise in scalable synthesis of CI toxins to produce subtype-selective probes and
radiotracers for the study of nAChRs. CI toxins are an emerging group of marine toxins with global distribution
and uncertain human health risks. We will carry out comprehensive functional studies on the interaction of CI
toxins with selected subtypes of individual nAChRs using electrophysiology, radioligand-displacement, and
other functional studies. Using radiolabeled CI toxins produced by total synthesis, we will investigate in vivo
biodistribution of these marine toxins and their effect of developmental biology using chick embryo as a model.
In this sense, synthetic CI toxins will serve as unique tools that promise to enrich our knowledge of this
important class of ionotropic receptors, including, in long term, additional insight into metabolic turnover and
broader impact of nAChRs on neurodegenerative disorders.

## Key facts

- **NIH application ID:** 10222713
- **Project number:** 5R01GM077379-13
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA BARBARA
- **Principal Investigator:** DENIS SERVENT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $446,559
- **Award type:** 5
- **Project period:** 2008-06-10 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222713

## Citation

> US National Institutes of Health, RePORTER application 10222713, Total synthesis of bioactive natural products (5R01GM077379-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10222713. Licensed CC0.

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