An α-chloroaldehyde-based formal synthesis of eribulin

Anissa Kaghad, Dimitrios Panagopoulos, Guillermo Caballero-García, Huimin Zhai and Robert Britton ()
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Anissa Kaghad: Simon Fraser University
Dimitrios Panagopoulos: Simon Fraser University
Guillermo Caballero-García: Simon Fraser University
Huimin Zhai: Simon Fraser University
Robert Britton: Simon Fraser University

Nature Communications, 2023, vol. 14, issue 1, 1-8

Abstract: Abstract Eribulin (Halaven) is the most structurally complex non-peptidic drug made by total synthesis and has challenged preconceptions of synthetic feasibility in drug discovery and development. However, despite decades of research, the synthesis and manufacture of eribulin remains a daunting task. Here, we report syntheses of the most complex fragment of eribulin (C14–C35) used in two distinct industrial routes to this important anticancer drug. Our convergent strategy relies on a doubly diastereoselective Corey–Chaykovsky reaction to affect the union of two tetrahydrofuran-containing subunits. Notably, this process relies exclusively on enantiomerically enriched α-chloroaldehydes as building blocks for constructing the three densely functionalized oxygen heterocycles found in the C14–C35 fragment and all associated stereocenters. Overall, eribulin can now be produced in a total of 52 steps, which is a significant reduction from that reported in both academic and industrial syntheses.

Date: 2023
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DOI: 10.1038/s41467-023-37346-7

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