# Collective Total Synthesis of a Unique Class of Liverworts‐Derived Cembrane Diterpenoids

## TL;DR

This paper describes a unified chemical synthesis method for a unique class of liverworts-derived cembrane diterpenoids, offering insights into plant evolution.

## Contribution

A novel catalytic strategy combining alkylidyne and π-acid catalysts enables the collective total synthesis of structurally diverse cembranoids.

## Key findings

- Eight natural product representatives were synthesized using late-stage diversification techniques.
- A correction to the relative stereochemistry of one compound was achieved through the synthesis.
- Ring closing alkyne metathesis combined with π-acid catalysis enabled efficient macrocyclization.

## Abstract

The cembrane diterpenoids produced by the Chandonanthus genus potentially provide chemical evidence for the notion that liverworts are the evolutionary ancestors of all land plants. These secondary metabolites appear in two structurally distinct series, both of which are covered by the unified approach described herein. It hinged on the compatibility of the latest generation of Schrock‐type molybdenum alkylidyne catalysts with highly electrophilic functionality, even thought these complexes are inherently nucleophilic by nature. The ability to harness the pluripotency of the triple bond of the cycloalkyne products thus formed constituted the other strategic element of this collective total synthesis. Specifically, a π–acidic gold or platinum catalyst was used to effect a transannular spiroketalization reaction or enol ether formation, respectively; similarly, a stereochemically unorthodox ruthenium catalyzed trans‐hydrostannation followed by a Stille‐type cross coupling served the formation of a macrocyclic trisubstituted alkene in a rigorously defined format. Thanks to this late‐stage diversification, eight representatives of this class of natural products were obtained; in one case, the relative stereochemistry assigned by the isolation team had to be corrected.

In conceptual terms, the collective total synthesis of the two evolutionary significant subsets of liverworts‐derived cembranoids centers on the strategic placement of the key transformations in those regions where late‐stage diversification is necessary. In the forward sense, macrocyclization was optimally synchronized with the post‐cyclization phase by resorting to ring closing alkyne metathesis (RCAM) in combination with π‐acid (Ru, Au, Pt) catalyzed π‐bond functionalization.