Yamada coupling

What is Yamada coupling?

The condensation reaction between a carboxylic acid and an amine to form an amide using diethylphosphoryl cyanide (DEPC) as the coupling reagent is commonly known as the Yamada coupling. This reaction, first reported by Yamada et al. in 1973, has some advantages over other peptide condensation reagents such as dicyclohexylcarbodiimide (DCC) and diphenylphosphoryl azide (DPPA) (see list of acronyms).

Yamada coupling - general reaction scheme
Yamada coupling

The Yamada coupling has been widely used for the condensation of amino acids to form peptides. For instance, N-cyclohexylbenzamide cannot be synthesized from benzoic acid and cyclohexylamine using DCC, but it is prepared efficiently using DEPC. The coupling of [4(S)-amino-2,2-difluoro-3(R)-hydroxy-6-methyl-heptanosyl]-l-leucyll-phenylalaninamide trifluoroacetate and N-Boc-l-phenylalanyl-l-phenylalanine gives a low yield of [4(S)-[[N-(tert-butyloxycarbonyl)-l-phenyl-alanyl]-l-phenylalanyl]amino]-2,2-difluoro-3(R)-hydroxy-6-methylheptanoyl]-l-leucyl-l-phenylalaninamide when DCC/HOBt is used, but the same reaction proceeds readily with DEPC. The coupling using diphenylphosphoryl azide as the coupling reagent results in a significant amount of side products due to the Curtius Rearrangement. The Yamada coupling has the advantage that no racemization of amino acids occurs during the coupling.

The Yamada coupling is typically carried out in DMF or dichloromethane (DCM) in the presence of a tertiary amine such as triethylamine (TEA) or diisopropylethylamine (DIEA). Compared to DMF, DCM results in much less epimerization of the amino acids. However, the N-Fmoc protecting group may get lost over time in the presence of DEPC, and DEPC may also react with the disulfide bond within peptides. Furthermore, for peptides containing serine with an unprotected hydroxyl group, the coupling using DEPC is inferior to TBTU.

References

Yamada, S.-i.; Kasai, Y. and Shioiri, T.S., Tetrahedron Lett., 1973, 1595

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