What Is Sharpless Olefin Synthesis?
The "Sharpless olefin synthesis" is a reliable method to convert saturated (often substituted) alcohol-derived substrates into alkenes via installation of an aryl–selenide followed by oxidation to a selenoxide and syn-elimination. This protocol—developed and systematized by K. B. Sharpless and co-workers—makes use of electron-deficient arylselenyl groups (notably o-nitrophenyl) to accelerate the key selenoxide elimination and allows olefin formation under mild, stereospecific conditions. The transformation is widely used for stereospecific dehydrations, making terminal and internal olefins, and for sequences where retaining or controlling alkene geometry is important.
- Reagents:
a) Aryl-selenium installation reagents (commonly o-nitrophenyl selenocyanate).
b) Trialkylphosphine activators (e.g., Bu3P) or other nucleophilic promoters for selenide formation.
c) Oxidants for selenide → selenoxide (typical: mCPBA; alternatives: H2O2, peracetic acid).
d) Common solvents: CH2Cl2, THF, Et2O; quench/reducing agents for workup (Na2S2O3, Na2SO3). - Reactants: Alcohols (primary or secondary) or derivatives that can be converted to alkyl–aryl selenides (i.e., substrates bearing a site for Se-installation).
- Products: Alkenes (olefins) — formation is typically stereospecific (resulting alkene geometry reflects the syn-elimination pathway).
- Related Reactions: Grieco–Sharpless (Grieco) elimination, Wittig reaction, Horner–Wadsworth–Emmons.
- Tips: The reaction temperature typically ranges from -78 °C to 0 °C, up to room temperature—many protocols utilize low temperatures to avoid over-oxidation; electron-withdrawing ortho-substituents can promote the elimination reaction even below zero degrees.
Fig 1. Sharpless olefin synthesis reaction and its mechanism. [1]
Mechanism of Sharpless Olefin Synthesis
- Formation of the alkyl aryl selenide. Commonly achieved by nucleophilic displacement on an activated selenium reagent (e.g., reaction of an alcohol with o-nitrophenyl selenocyanate in the presence of a phosphine such as Bu3P) to give the alkyl–Se–Ar species. The mild, one-step conversion from alcohol to selenide is a key practical advantage.
- Oxidation to selenoxide. Use a stoichiometric oxidant (mCPBA, H2O2, peracetic acid, or peroxynitrite variants). The selenide → selenoxide oxidation is usually rapid; choice of oxidant and temperature determines chemoselectivity (avoiding oxidation of sensitive functional groups).
- Selenoxide syn-elimination. The selenoxide undergoes a concerted syn elimination (a five-centered, intramolecular transition state) to deliver the alkene and release a selenium oxide or the corresponding selenenic/selenonic species. Electron-withdrawing substituents on the aryl ring (ortho-nitro in particular) accelerate elimination and lower the temperature required. The stereospecific, syn nature means cis/trans relationships in the starting material map predictably to the product geometry.
Application Examples of Sharpless Olefin Synthesis
The Sharpless olefin synthesis and related selenoxide eliminations have been used in complex molecule syntheses where mild, stereospecific formation of an alkene is required (e.g., late-stage dehydroxylations, geometry-preserving transformations in polyfunctional molecules). The method's mildness and predictable stereochemistry make it attractive for multi-step sequences and for substrates that cannot tolerate strong acids/bases or high temperatures.
- Example 1: Leo A. Paquette et al. described a scheme aimed at achieving the asymmetric synthesis of pestalotiopsin A. This involved the phenylselenation reaction of intermediate compound triol 40. [2]
- Example 2: Hiromasa Yokoe et al. reported a total synthesis route of (–)-xanthatin. This involved reacting compound 4 with o-nitrophenyl selenocyanate and tributylphosphine to obtain a selenide, which was then oxidized with hydrogen peroxide to yield the diene 13. [3]
Fig 2. Synthetic examples via Sharpless olefin synthesis reaction.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Fourth Edition, 2014, 555-556.
- Paquette, Leo A., et al. The Journal of Organic Chemistry 72.19 (2007): 7135-7147.
- Yokoe, Hiromasa, et al. Tetrahedron Letters 49.21 (2008): 3504-3506.
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