Mechanism HNMr References Experimental
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Colonel Mustard is a naturally curious man. His many years of experience in foreign affairs have taught him that he must always continue to learn about the world. So, when we talked about our reaction conditions using our chemical terms he asked us "What is Yamaguchi Macrolactonization?"

Here is a general mechanism that shows Yamaguchi macrolactonization. The defining features to look for are: a carboxylic acid or alcohol in the starting material, an ester in the product, and Et3N and DMAP as the reagents.

Figure 1

Looking at the more general reaction above, can you find where Yamaguchi macrolactonization has occurred in the molecule below?

Figure 2

Yamaguchi macrolactonization is a reaction that was proposed in 1979 by Inanaga, Yamaguchi and their research team. Their synthesis was published in the journal Bulletin of the Chemical Society of Japan that year, and has been cited numerous times since then. The synthesis of molecule 26 from molecule 25 seen above utilizes the now popular Yamaguchi macrolactonization conditions. Yamaguchi macrolactonization consists of a regioselective synthesis of an ester from a carboxylic acid or an alcohol. To carry this out, 2,4,6-trichlorobenzoyl chloride (the Yamaguchi reagent) is reacted with 4- N,N-dimethylamino pyridine (DMAP). In the presence of Et3N, a mixed anhydride is formed between a carboxylic acid and the Yamaguchi reagent. In molecule 25 (Figure 2), Yamaguchi macrolactonization can occur after PMB has been removed. The second reagents that are used subject the resulting molecule to what is referred to as Yamaguchi macrolactonization conditions. The experimenters conducting the experiment were able to obtain a 71% yield of molecule 26, which now contains an ester.