# Aza-Heck/C-C cleavage/cross coupling cascades of pinene derivatives for the synthesis of zoanthamine alkaloids

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $65,610

## Abstract

PROJECT SUMMARY/ABSTRACT
Nitrogen-containing heterocycles are of considerable interest in medicinal chemistry, often responsible for key
non-bonding interactions that contribute to a molecule’s overall pharmacological activity. The zoanthamine
alkaloids are an example of natural products that display a variety of biological activities mostly attributed to the
heterocyclic portion of their structures. Notable examples include norzoanthamine with potent anti-osteoporotic
properties, and zoanthenol, which is a selective collagen receptor antagonist for inhibiting platelet aggregation.
The difficulties in synthesizing these architecturally complex alkaloids are apparent in the relative dearth of total
syntheses: since their initial isolation in 1984, only two total syntheses have been reported for norzoanthamine
and one for zoanthenol, all of which are considerably lengthy (40+ steps). This project proposes a total synthesis
for zoanthenol using an aza-Heck/C–C cleavage/cross coupling cascade process to provide an overall
convergent approach to the natural product.
The proposed methodology builds upon precedent established by the Sarpong group in utilizing C–C
cleavage/cross coupling as a strategy for rapidly generating complexity from simple, hydroxylated pinenes. The
addition of an aza-Heck reaction to this overall sequence should provide an avenue for introducing N-
heterocycles onto natural product-like structures. Specific Aim I outlines key considerations for introducing an
aza-Heck reaction to the C–C cleavage/cross coupling sequence, and identifying O-acyl oximes as a versatile
precursor for N-heterocycle formation using transition metal catalysis. Specific Aim II then details a total synthesis
of the natural product zoanthenol using the cascade process developed in Specific Aim I as the key coupling
step. This approach should also enable preparations of related derivatives for potential structure-activity
relationship (SAR) studies to fully elucidate the unique bioactivities displayed by the zoanthamine alkaloids.

## Key facts

- **NIH application ID:** 10140751
- **Project number:** 1F32GM137490-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Christina Grace Na
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $65,610
- **Award type:** 1
- **Project period:** 2021-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140751

## Citation

> US National Institutes of Health, RePORTER application 10140751, Aza-Heck/C-C cleavage/cross coupling cascades of pinene derivatives for the synthesis of zoanthamine alkaloids (1F32GM137490-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10140751. Licensed CC0.

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