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trans‐Hydrogenation: Application to a Concise and Scalable Synthesis of Brefeldin A

Abstract

The important biochemical probe molecule brefeldin A (1) has served as an inspirational target in the past, but none of the many routes has actually delivered more than just a few milligrams of product, where documented. The approach described herein is clearly more efficient; it hinges upon the first implementation of ruthenium‐catalyzed trans‐hydrogenation in natural products total synthesis. Because this unorthodox reaction is selective for the triple bond and does not touch the transannular alkene or the lactone site of the cycloalkyne, it outperforms the classical Birch‐type reduction that could not be applied at such a late stage. Other key steps en route to 1 comprise an iron‐catalyzed reductive formation of a non‐terminal alkyne, an asymmetric propiolate carbonyl addition mediated by a bulky amino alcohol, and a macrocyclization by ring‐closing alkyne metathesis catalyzed by a molybdenum alkylidyne.

The focal point: The recently disclosed ruthenium‐catalyzed trans‐hydrogenation of internal alkynes to E‐alkenes is noteworthy for its unorthodox stereochemical course, as well as its compatibility with other reducible or sensitive sites. This favorable profile allowed this emerging methodology to be implemented in a concise total synthesis of brefeldin A at a stage at which a conventional Birch‐type trans‐reduction would no longer be applicable.

Authors:   Michael Fuchs, Alois Fürstner
Journal:   Angewandte Chemie International Edition
Volume:   54
edition:   13
Year:   2015
Pages:   3978
DOI:   10.1002/anie.201411618
Publication date:   04-Feb-2015
Facts, background information, dossiers
  • synthesis
  • reductions
  • molybdenum
  • Metathesis
  • Formation
  • Addition
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