Expeditious synthesis of polyacetylenic water hemlock toxins and their effects on the major GABAA receptor isoform.

Martin Berger,Margot Ernst,Konstantina Bampali,Nuno Maulide,Yong Chen

doi:10.1039/c7cc09801d

Martin Berger, Margot Ernst + Show 3 more

Open Access

https://doi.org/10.1039/c7cc09801d

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Abstract

Classical synthetic approaches to highly unsaturated polyene/yne natural products rely on iterative cross-coupling of linear fragments. Herein, we present an expeditious and unified approach to the unsaturated backbone of polyacetylenes via domino cuprate addition/4π-electrocyclic ring opening of a stereodefined cyclobutene intermediate. This sets the stage for a detailed biological assessment of the role of Virol A and Cicutoxin as inhibitors of GABA induced chloride currents, providing further insight into the interaction of these highly potent toxins towards the GABAA receptor, including the structure-activity relationship of the derivatives.

Highlights

Classical synthetic approaches to highly unsaturated polyene/yne natural products rely on iterative cross-coupling of linear fragments
We present an expeditious and unified approach to the unsaturated backbone of polyacetylenes via domino cuprate addition/ 4p-electrocyclic ring opening of a stereodefined cyclobutene intermediate. This sets the stage for a detailed biological assessment of the role of Virol A and Cicutoxin as inhibitors of GABA induced chloride currents, providing further insight into the interaction of these highly potent toxins towards the GABAA receptor, including the structure–activity relationship of the derivatives
The highly conjugated backbone of these compounds imparts on them considerable light- and air-sensitivity. This notwithstanding, the isolation of Cicutoxin (2) was reported as early as 19153 and its structural determination along with the first racemic total synthesis waited until 1953.4,5 The stereochemical assignment of Cicutoxin (2) and Virol A (1) along with their relative toxicity was first reported much later in 1999,6 followed by the first asymmetric total synthesis of Virol A (1) by Uwai in the same year

Summary

Introduction

Classical synthetic approaches to highly unsaturated polyene/yne natural products rely on iterative cross-coupling of linear fragments. Expeditious synthesis of polyacetylenic water hemlock toxins and their effects on the major GABAA receptor isoform† We present an expeditious and unified approach to the unsaturated backbone of polyacetylenes via domino cuprate addition/ 4p-electrocyclic ring opening of a stereodefined cyclobutene intermediate.

Results

Conclusion