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A "chiral aldehyde" equivalent as a building block towards biologically active targets
Barry M Trost1, Matthew L Crawley
1Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA. bmtrost@stanford.edu
Chemistry (Weinheim an Der Bergstrasse, Germany)
|April 28, 2004
Summary
Chiral gamma-aryloxybutenolides serve as versatile chiral building blocks for complex molecule synthesis. This research enabled the creation of a novel drug candidate and the total synthesis of (+)-brefeldin A.
Area of Science:
- Organic Chemistry
- Asymmetric Synthesis
- Medicinal Chemistry
Background:
- Chiral gamma-aryloxybutenolides are valuable synthetic intermediates.
- Dynamic kinetic asymmetric transformation (DYKAT) provides efficient access to these chiral building blocks.
Purpose of the Study:
- To utilize chiral gamma-aryloxybutenolides as chiral aldehyde synthons.
- To develop efficient synthetic routes for complex molecules, including drug candidates and natural products.
Main Methods:
- Dynamic kinetic asymmetric transformation (DYKAT) for chiral building block synthesis.
- Intermolecular cycloadditions and Michael reactions.
- Palladium-catalyzed asymmetric allylic alkylation.
- Julia olefination and ruthenium-catalyzed hydrosilylation-protodesilylation.
Main Results:
- Demonstrated unprecedented selectivity in trimethylenemethane cycloadditions.
- Enabled efficient synthesis of a novel metabotropic glutamate receptor 1 antagonist.
- Achieved the total synthesis of (+)-brefeldin A in 18 steps with 6% overall yield.
- Established a synthetic route amenable to analogue synthesis.
Conclusions:
- Chiral gamma-aryloxybutenolides are powerful and versatile building blocks in organic synthesis.
- The developed methodologies facilitate the synthesis of biologically relevant molecules.
- The synthetic route to (+)-brefeldin A offers opportunities for further structural diversification.
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