Yamaguchi method

The Yamaguchi process , also called Yamaguchi cyclization or Yamaguchi esterification , is a name reaction from organic chemistry. It is used to produce macrolides (including macrolactones ) from easily accessible hydroxycarboxylic acids . Macrolides have a wide range of uses, for example as macrolide antibiotics or antimycotics . The reaction of the hydroxycarboxylic acid with 2,4,6-trichlorobenzoyl chloride leads, in the presence of a stoichiometric amount of DMAP, to an intermediate stage which, with elimination of 2,4,6-trichlorobenzoic acid, carries out the ring closure intramolecularly to the end product; the procedure was discovered by Masaru Yamaguchi and co-workers.

mechanism

The acid group is deprotonated by triethylamine . In a nucleophilic substitution reaction, the activated ω-hydroxycarboxylic acid now attacks the carboxylic acid chloride of 2,4,6-trichlorobenzoic acid chloride . In the reaction, a mixed anhydride is formed via the tetrahedral intermediate . The chloride released in this way is bound as triethylamine hydrochloride.

The addition of DMAP to the sterically unhindered carbonyl group of the anhydride causes the elimination of 2,4,6-trichlorobenzoic acid as a by-product. The hydroxyl group of the starting material acts nucleophilically on the strongly positive carbon of the original acid group of the compound. The ring closure to the lactone ( lactonization ) takes place with cleavage of the catalytically used DMAP.

application

Macrolactonization is an important step in the synthesis of many natural substances or artificial macrolides that can be used as medicinal substances . A practical example is the synthesis of the cancer drug epothilone A find.

literature

J. Mulzer , Angew. Chem. 1991 , 103 , 1484, DOI: 10.1002 / anie.19911031108 .
D. Sawada, M. Shibasaki, Angew. Chem. 2000 , 112 , 215, doi : 10.1002 / (SICI) 1521-3757 (20000103) 112: 1 <215 :: AID-ANGE215> 3.0.CO; 2-A .
I. Dhimitruka, J. Santa Lucia, Jr, Org. Lett. , 2006 , 8 , 47-50, doi : 10.1021 / ol0524048 .
Nicolaou, KC; Sarabia, F .; Finlay, MRV; Ninkovic, S .; King, NP; Vourloumis, D .; He, Y., Chem. Eur. J. , 1997 3 , 1971-1986, DOI: 10.1002 / chem . 19970031212 .

Lee, JY; Kim, BH, Tetrahedron , 1996 , 52 , 571-588, DOI: 10.1016 / 0040-4020 (95) 00913-2 .

Kürti, László and Czakó, Barbara: Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press, Burlington-San Diego-London 2005, 1st edition; ISBN 0-12-369483-3 .

Individual evidence

↑ Inanaga, J .; Hirata, K .; Saeki, H .; Katsuki, T .; Yamaguchi, M. "A Rapid Esterification by Means of Mixed Anhydride and Its Application to Large-Ring Lactonization". Bull. Chem. Soc. Jpn. 1979 , 52 , 1989-1993. doi: 10.1246 / bcsj.52.1989 .
↑ Kawanami, Y .; Dainobu, Y .; Inanaga, J .; Katsuki, T .; Yamaguchi, M. "Synthesis of Thiol Esters by Carboxylic Trichlorobenzoic Anhydrides". Bull. Chem. Soc. Jpn. 1981 , 54 , 943-944. doi: 10.1246 / bcsj.54.943 .

[1] Inanaga, J .; Hirata, K .; Saeki, H .; Katsuki, T .; Yamaguchi, M. "A Rapid Esterification by Means of Mixed Anhydride and Its Application to Large-Ring Lactonization". Bull. Chem. Soc. Jpn. 1979 , 52 , 1989-1993. doi: 10.1246 / bcsj.52.1989 .

[2] Kawanami, Y .; Dainobu, Y .; Inanaga, J .; Katsuki, T .; Yamaguchi, M. "Synthesis of Thiol Esters by Carboxylic Trichlorobenzoic Anhydrides". Bull. Chem. Soc. Jpn. 1981 , 54 , 943-944. doi: 10.1246 / bcsj.54.943 .