Ireland–Claisen rearrangement

Ireland–Claisen rearrangement is a chemical reaction that involves the stereocontrolled rearrangement of allyl esters to γ,δ-unsaturated carboxylic acids using a base. This reaction is a variant of the classic Claisen rearrangement, and it was first reported by Robert Ireland in 1972. The Ireland–Claisen rearrangement has become a valuable tool in organic synthesis, especially in the synthesis of complex natural products due to its ability to efficiently construct carbon-carbon bonds with high stereocontrol.

Mechanism

The Ireland–Claisen rearrangement proceeds through a six-membered cyclic transition state. Initially, the reaction involves the deprotonation of the allyl ester by a strong base, typically a lithium diisopropylamide (LDA) or other non-nucleophilic bases, to form an enolate. This enolate then undergoes a [6,3]-sigmatropic rearrangement, leading to the formation of an allylic carboxylate intermediate. Subsequent protonation yields the γ,δ-unsaturated carboxylic acid. The stereochemistry of the product is determined by the stereochemistry of the starting material and the mechanism of the rearrangement, which often allows for high levels of stereocontrol.

Applications

The Ireland–Claisen rearrangement has found extensive applications in the synthesis of complex organic molecules, including natural products and pharmaceuticals. Its ability to form carbon-carbon bonds while introducing functional groups in a stereocontrolled manner makes it a powerful tool in the arsenal of organic chemists. For example, it has been used in the synthesis of (-)-swainsonine, a potent inhibitor of glycoprotein processing enzymes, and in the construction of the C15-C21 fragment of the antitumor agent discodermolide.

Variants

Several variants of the Ireland–Claisen rearrangement have been developed to expand its utility and applicability. These include the asymmetric Ireland–Claisen rearrangement, which employs chiral auxiliaries or chiral bases to induce asymmetry in the product, and the intramolecular Ireland–Claisen rearrangement, which is used to construct cyclic compounds. Other notable variants include the silyl ketene acetal version, which allows for the use of less reactive esters, and the heteroatom-substituted Ireland–Claisen rearrangement, which introduces heteroatoms into the rearranged product.

Limitations

Despite its versatility, the Ireland–Claisen rearrangement has some limitations. The requirement for strong bases can lead to side reactions, especially in molecules with sensitive functional groups. Additionally, the reaction conditions may not be suitable for all substrates, limiting its applicability in certain cases.

Conclusion

The Ireland–Claisen rearrangement is a powerful and versatile tool in organic synthesis, offering chemists the ability to construct complex molecules with high levels of stereocontrol. Its variants and applications continue to expand, making it an indispensable reaction in the field of organic chemistry.

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Ireland–Claisen rearrangement

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  Ireland-Claisen Rearrangement Scheme