# Synthesis of Diverse Natural Products and Complex Heterocycles with Donor/Donor Carbenoids

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $286,841

## Abstract

Project Summary/Abstract 
An urgent need exists for new methods to rapidly prepare complex organic molecules with the potential to 
become new drugs. There is a widening gap in both the accessibility of complex core structures that are 
difficult to exploit and in the availability of core structures that are not already the subject of numerous patents. 
This gap will be addressed by identifying new synthetic methods that achieve the dual goals of enabling 
efficient access to useful cores while also exploring previously inaccessible "chemical space." The long-term 
goal is to understand the reactivity of unstabilized carbenes and their immediate precursors. The objective of 
this application is to explore rhodium-catalyzed C–H insertion reactions of carbenes that are generated without 
the isolation of diazo compounds while also exploring new tandem cycloaddition/rearrangement processes. 
The central hypothesis is that appending two "donor" groups to a carbene precursor will open up new avenues 
of reactivity for organic chemistry. This hypothesis is supported by preliminary results regarding a) the unique 
ability of donor/donor carbenes to engage in highly enantioselective C–H insertion reactions and b) a 
remarkable cycloaddition/ rearrangement sequence that produces drug-like heterocyclic core structures absent 
from the patent literature! Small molecules comprise the vast majority of treatments for both acute and chronic 
diseases in both the developed and developing world. Research in this application will lay the groundwork to 
save lives and enable the next generation of pharmaceutical discovery by advancing three Specific Aims. 1) 
Synthesis of oxygen and sulfur heterocycles by catalytic C–H insertion. This aim will explore asymmetric 
carbene reactions under conditions that avoid isolation of dangerous intermediates, exhibit unprecedented 
functional group tolerance, and lead to core structures common to both drug discovery leads and natural 
products that modulate biological phenomena. 2) Assembly of densely-substituted indolines, indanes and 
tetrahydro-isoquinolines (THIQs) by catalytic C–H insertion. The insertion technology will become a platform 
for discovery in the assembly of nitrogen- and carbon-based polycyclic systems representing useful starting 
points for drug discovery. 3) Rapid construction of complex heterocycles from new one-pot dipolar 
cycloaddition-[1,5] shift sequence. Our one-pot system for the generation and immediate reaction of diazo 
intermediates will be used to construct complex spiro-heterocycles in a single step, yielding unexplored 
molecules for pharmaceutical and biomedical applications. The proposed approach is innovative because it is 
based on a new methodological platform that accesses previously inaccessible chemical reactivity. This 
research is significant because it will change the way synthetic chemists approach targets while at the same 
time opening up new vistas for discovery of useful mole...

## Key facts

- **NIH application ID:** 9846231
- **Project number:** 5R01GM124234-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Jared Thomas Shaw
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $286,841
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846231

## Citation

> US National Institutes of Health, RePORTER application 9846231, Synthesis of Diverse Natural Products and Complex Heterocycles with Donor/Donor Carbenoids (5R01GM124234-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9846231. Licensed CC0.

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