Esterification Yamaguchi

Esterification using 2,4,6-trichlorobenzoyl chloride (the Yamaguchi reagent). 

Steric hindrance of the chloro substituents blocks attack of the other carbonyl of the mixed anhydride intermediate. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 295, Springer International Publishing Switzerland 2014 

Yamaguchi esterification. In Name Reactions for Functional Group Transformations, Li, J. J., Ed. Wiley Hoboken, NJ, 2007, pp 545-550. (Review). 

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Yamaguchi esterification of A-ring fragment 59 and C-ring fragment 60 delivers compound 65, the substrate for silyl-Prins macrocyclization, a transformation that proceeds in 65 % isolated yield under remarkably mild conditions. Notably, after the point of convergence, only five additional steps are required to access bryostatin 9 (Scheme 5.7). 

With both building blocks 21 and 28 secured, the total synthesis of lb was completed as depicted in Scheme 5. Intermolecular Yamaguchi esterification to give 29 and subsequent acidic desilylation, which required reinstatement of the... 

The Yamaguchi Esterification allows the mild synthesis of highly functionalized esters. After formation of a mixed anhydride between the Yamaguchi Reagent (2,4,6-trichlorobenzoyl chloride) and the carboxylic acid, the volatiles are removed and the reaction of the anhydride with an alcohol in presence of a stoichiometric amount of DMAP generates the desired ester. 

A mild method for forming ter/-butyl esters is the Yamaguchi esterification, which involves reaction of a carboxyl group with 2A6-trichlorobenzoyl chloride and triethylamine in THE The resultant mixed anhydride intermediate reacts with rm-butyl alcohol in the presence of DMAP to give the ferf-butyl ester in good yield.96... 

The Yamaguchi esterification (activation of an acid with trichlorobenzoyl chloride) is typically used to make macrolides, indicating its reliability. Unfortunately, these examples are typically done on very small scale, so a different example is shown. 

The Yamaguchi esterification utilises 2,4,6-trichlorobenzoyl chloride, also known as the Yamaguchi reagent, to form esters from carboxylic acids and alcohols. 

In a similar fashion, Dhimitruka and SantaLucia argue that the use of 2,4,6-trichlorobenzoyl chloride is not always necessary and that other inexpensive acid chlorides can be employed.15 This is attractive especially when dealing with scale-up reactions. The authors also postulate the formation of a symmetric aliphatic anhydride to explain the regioselectivity of the Yamaguchi esterification. The mechanism assumes that aliphatic carboxylates are better nucleophiles than aromatic carboxylates and... 

Due to the prevalence of many macrolide natural products, Yamaguchi s esterification has been used extensively in the total syntheses of such compounds. Increasingly, Yamaguchi s method has succeeded where other notable esterification conditions have failed. A recent example involves the coupling of two monomers to form the clavosolide A dimer.17 The Corey-Nicolaou protocol mentioned previously gave only a 30% conversion whereas the Yamaguchi esterification resulted in a clean reaction with a 66% yield. 

I. Dhimitruka, J. Santa Lucia Jr, Investigation of the Yamaguchi esterification mechanism. Synthesis of a lux-s enzyme inhibitor using an improved esterification method, Org. Lett. 2006, 8, 47-50. 

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