Yamaguchi reagent – Reagent of the month June

2,4,6-trichlorobenzoyl chloride (TCBCl), also known as Yamaguchi reagent (Figure 1) is a reagent that is employed in an esterification process devised by Masaru Yamaguchi et al. in 1979 and is also effective in macrolactonization reactions. (https://doi.org/10.1246%2Fbcsj.52.1989).

Figure 1: Structure of the Yamaguchi reagent. — **Figure 1:** Structure of the Yamaguchi reagent.

Preparation

Yamaguchi reagent is commercially available, but it can also be made from slightly less expensive 2,4,6-trichlorobenzoic acid by utilizing chlorinating agents such as SOCl₂ (Figure 2).

Yamaguchi esterification

In the original protocol for esterifications, the carboxylic acid is first treated with TCBCl and triethylamine (TEA), and after isolation of the mixed anhydride, the alcohol is added along with 4-dimethylaminopyridine (DMAP).

For lactonizations, the hydroxy acid is first deprotonated with TEA, and then treated with TCBCl, and after the removal of TEA.HCl from the mixture, the formed mixed anhydride is heated in toluene with DMAP under high dilution conditions to favour the intramolecular nucleophilic attack resulting in cyclization.

Figure 3: The Yamaguchi esterification and macrolactonization reactions. — **Figure 3:** The Yamaguchi esterification and macrolactonization reactions.

Application of Yamaguchi reagent in synthesis

This approach was employed in a number of total syntheses of natural products containing a macrolactone motif and proven to be effective even for macrolactonizations.

Macrolides are one type of natural chemical. They are a family of natural compounds that comprise a macrolactone ring with deoxy sugar sidechains attached. Some macrolides have antibacterial activity, such as Erythromycin or Kitasamycin, whereas others have cytostatic activity, such as Neopeltolide (Figure 4).

Figure 4: Three examples of the macrolides. Macrolactone ring is highlighted in red in the structures. — **Figure 4:** Three examples of the macrolides. Macrolactone ring is highlighted in red in the structures.

Finally, the Yamaguchi lactonization step from the 2008 total synthesis of Neopeltolide by Maier et al. (https://doi.org/10.1021/ol8001255) is illustrated as one of many applications of Yamaguchi esterification/lactonization in total syntheses.

Figure 5: Part of the 2008 total synthesis of (+)-Neopeltolide – a cytostatic macrolide isolated from a deep-water sponge. Yamaguchi macrolactonization was a key step in this total synthesis. — **Figure 5:** Part of the 2008 total synthesis of (+)-Neopeltolide – a cytostatic macrolide isolated from a deep-water sponge. Yamaguchi macrolactonization was a key step in this total synthesis.

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