Yamaguchi Macrolactonization

Yamaguchi Macrolactonization

Overall Score4.5
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  • General Characteristics

In the method developed by Yamaguchi, hydroxycarboxylic acids (“seco-acids”) are converted into reactive acid anhydrides using 2,4,6-trichlorobenzoyl chloride and the intramolecular esterification is promoted by DMAP under high dilution conditions. This reaction often requires refluxing temperatures depending on the size of the ring being formed.

  • General References

・Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989. DOI: 10.1246/bcsj.52.1989
・Kawanami, Y.; Dainobu, Y.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1981, 54, 943. DOI: 10.1246/bcsj.54.943

  • Reaction Mechanism

The acid anhydrides react regioselectively due to the steric hindrance by the ortho-substitution on the benzoyl group (Ref: Org. Lett.2006, 8, 47.).


  • Examples

The Yamaguchi conditions are compatible with a wide range of substrates and are used frequently even today. An example shown below is the esterification between two large fragments in the total synthesis of cryptophycin-24.[1]


  • Experimental Procedure

  • Experimental Tips

  • References

[1] Eggen, M.; Mossman, C. J. et al. J. Org. Chem. 2000, 65, 7792. DOI: 10.1021/jo000767+

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