Ghosez cyclization

What is Ghosez cyclization?

The Ghosez and colleagues were the first to report this reaction in 1988. It involves the synthesis of α,β-unsaturated δ-lactone and its corresponding dihydropyran, which is reduced from a lactone derivative. The reaction consists of the lithiation of methyl 3-(phenylsulfonyl)orthopropionate and the reaction of the resulting 1,3-dipole equivalent with an epoxide. Subsequent acid hydrolysis and base-induced elimination of phenylsulfinic acid produce the final product. This reaction is commonly referred to as the Ghosez cyclization or Ghosez lactonization.

Ghosez cyclization - general reaction scheme
Ghosez cyclization

R = alkyl, aryl

In Ghosez cyclization, the methyl 3-(phenylsulfonyl)orthopropionate acts as a 1,3-dipole equivalent and contains a carbanion center at C-3, which is stabilized by a phenylsulfonyl group. The molecule also has a cationic character at C-1 in the form of an ortho-ester. Upon treatment with a base, the carbanion is generated at C-3, which then attacks the epoxide ring through a SN2 reaction. The resulting alkoxide anion undergoes the second SN2 reaction by replacing a methoxide, leading to the formation of the cyclic orthoester. The δ-lactone is then formed through acidic hydrolysis of the cyclic orthoester, and the α,β-unsaturated δ-lactone is generated by the base-induced elimination of phenylsulfinic acid.

The Ghosez cyclization finds applications in organic synthesis, including the production of hydrindan, glycoside, and the natural product swinholide A.

References

Juan Carlos Carretero, Léon Ghosez (1988A practical route towards α,β-unsaturated δ-lactones based on a [3+3] strategy. Synthesis of (−)-argentilactone. Tetrahedron Letters, 29(17), 2059-2061
DOI: 10.1016/S0040-4039(00)87834-X

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