# Cyclization Cascades to Access Bioactive Diterpenoids

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $397,147

## Abstract

Project Summary
 Polycyclic terpenoid natural products are endowed with a broad range of medicinally relevant biological
activities. Taxol and artemisinin are two premier examples of life-saving terpenoids; the former is used clinically
to treat several cancers, while the latter is a critical antimalarial agent used worldwide. Chemical synthesis
approaches to natural products provide opportunities to make compounds that might be scarcely available
from nature, to generate analogues that are only available by total synthesis, and to make probe molecules for
increased understanding of the underlying biology. A balance of innovative strategy and new chemical
methodology promises efficient syntheses of small molecules that can provide answers to important biological
questions that are not easily solved by other means.
 As part of our laboratory's long-term goal to enhance efficiency in the synthesis of complex natural
products to facilitate important studies in biology, the objective of the proposed research is to develop concise
and creative synthesis designs and empowering methodological advances to permit access to many bioactive
diterpenoid natural products. The rationale for this work is that synthetic chemistry is critical to the development
of natural product “hit molecules” into legitimate preclinical lead compounds by analogue production, by
identification of structure-activity relationships, by the synthesis of chemical probe molecules for mechanism of
action studies, and more. An efficient total synthesis of targeted natural products provides a platform from
which to address each of these key areas of research. Our specific aims include (1) the synthesis of the
lissoclimide family of cytotoxic translation inhibitors, to aid in refining our understanding of the molecular basis
of protein synthesis inhibition using biological and biochemical assays, as well as the tools of structural biology;
(2) the application of methodology developed for the lissoclimides to develop efficient syntheses of a range of
other complex, polycyclic diterpenoids; and (3) the development of new radical bicyclization strategies for the
synthesis of two architecturally complex anti-infective natural products.
 The proposed research is significant because chemical synthesis will provide access to a broad range of
biologically important secondary metabolites and analogues with which to interrogate key processes; at the
same time, the underlying synthesis designs and methodologies will lead to vertical advancement of the field of
organic chemistry. These contributions are innovative by virtue of the chemistry-driven, multi-faceted
investigations into the mechanism of ribosome inhibition by the lissoclimides, the development of new
stereocontrolled polyene cyclization strategies to access particularly challenging diterpenoid natural products,
and the elaboration of new radical bicyclization strategies to make complex polycyclic architectures relevant to
bioactive natura...

## Key facts

- **NIH application ID:** 9997705
- **Project number:** 5R01GM129264-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Christopher D Vanderwal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,147
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997705

## Citation

> US National Institutes of Health, RePORTER application 9997705, Cyclization Cascades to Access Bioactive Diterpenoids (5R01GM129264-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997705. Licensed CC0.

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