Yamaguchi mixed anhydride

Use of 2,4,6-trichlorobenzoyl chloride, Et3N, and DMAP, known as the Yamaguchi method,128 is frequently used to effect macrolactonization. The reaction is believed to involve formation of the mixed anhydride with the aroyl chloride, which then forms an acyl pyridinium ion on reaction with DMAP.129... 

To complete the synthesis of 1, the acid 3 derived from 20 was converted to the mixed anhydride (Yamaguchi coupling), then esterified with 2. Exposure to , < 8-crown-b gave the all-E tetraene, which was deprotected to give the aglycone 4. 

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. 

Macrocycles are often not easy to form, especially when they include many substituents. The applied procedure to synthesize macrolactones was introduced by Yamaguchi and co-workers and has since been used extensively.21 First the acid is transformed into the mixed anhydride 26. Refluxing the anhydride in toluene will yield the desired macrocycle. The attack of the alcohol at the trichlorobenzoic acid carbonyl moiety is not favored because of steric hindrance by the chlorine substituents ortho to the acid. Therefore the ring is closed selectively. Usually in macrocyclizations high dilution conditions are applied, too, in order to avoid intermolecular reactions. 

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... 

A variety of synthetic methods have been introduced for macrolacto-nizations. The most popular method seems to be the Yamaguchi-Yonemitsu reaction using 2,4,6-trichlorobenzoyl chloride (TCBC) for acid activation by the formation of mixed anhydrides. 

The formation of mixed anhydrides, which in some cases may be isolated, is an established method. For instance, racemic zearalenone (352) has been obtained by treating the seco-acid (351) with trifluo-roacetic anhydride (equation 126). Similarly, antimycin A3 has been prepared. A more modem procedure makes use of Yamaguchi s 2,4,6-benzoyl chloride esterification. For example, a synthesis of methynolide is based on the lactonization of the alkynic seco-acid (353) to (354 equation 127). 

The stereocontrolled total synthesis of (-)-macrolactin A, a 24-membered macrolide, was achieved by J.P. Marino and co-workers/ The key macrocyclization step was carried out using the Yonemitsu modification of the Yamaguchi macroiactonization. In this procedure, the mixed anhydride is added to the highly dilute solution of DMAP rapidly (in one portion) at room temperature. The final step of the total synthesis was the removal of the protecting groups under acidic condition. 

Inanaga, J., Hirata, K., Saeki, H., Katsuki, T., Yamaguchi, M. A rapid esterification by mixed anhydride and its application to large-ring lactonization. Bull. Chem. Soc. Jpn. 1979, 52,1989-1993. 

Yamaguchi and co-workers then screened a number of acid chlorides for the formation of the mixed anhydride with two features in mind (1) the component should be a good leaving group, and (2) the carbonyl group of the component should be sterically hindered from nucleophilic attack.5,6 Eventually, 2,4,6-trichlorobenzoyl chloride was deemed to be the best in terms of rate of reaction and yield. 

Yamaguchi s methynolide synthesis is based on the coupling of the C1-C7 (13) and Cg-Cii (14) segments, both of which are prepared from the resolved compounds, and the macrolactonization using the mixed anhydride prepared by use of 2,4,6-trichlorobenzoyl chloride and dimethylaminopyridine (Yamaguchi method). 

Inanaga J, Hirata K, Saeki H, Katsuki T, Yamaguchi M (1979) A Rapid Esterification by Mixed Anhydride and its Application to Large-Ring Lactonization. Bull Chem Soc Jpn 52 1989... 

Extension of the traditional Yamaguchi/Corey-Nicolaou/Keck macrolactonization protocols (see Scheme 2.1) [5] to catalytic variants can address some of the drawbacks of classical methods. Mixed anhydrides can undergo cyclization with Lewis adds such as Sc,1i, Zr, and Hf [125,126].Trostetol. reported the use of ethoxyacetylene as a stoichiometric activating agent, installed via Ru catalysis [127], later applied to the synthesis of apicularen A (Scheme 2.67) [128]. 

Yamaguchi investigated the utility of a mixed anhydride composed of the 2,4,6-trichlorobenzoate moiety, which was generated from 2,4,6-trichlorobenzoyl chloride with EtjN (triethyl amine) [26]. Thermodynamic activation of the bulky mixed anhydride in the presence of DMAP (4-dimethylaminopyridine) afforded the corresponding lactones in good yields. Yamaguchi then used this methodology to synthesize methynolide (18), as depicted in Scheme 5.4 [27], and over 340 examples of the application of this procedure showed the usefulness of the protocol [17]. 

Wills first accomphshed the total synthesis of 6a using the Yamaguchi lactonization to form the medium-sized lactone of 6a (Scheme 5.31) [80]. Lactonization of 87 was achieved by employing Yamaguchi s mixed-anhydride method to form the corresponding lactone 88 [26]. Although the preparation of the nine-membered lactone moiety can be difficulL smooth lactonization was accomphshed because the cis double bond provides both enthalpic and entropic assistances to this process, in contrast with cychzation of a saturated ring. 

Yamaguchi et al. [45] developed most efficient method through mixed anydride under basic conditions using 2,4,6-trichlorobenzoyl chloride and Et3N (triethyl amine), and the resultant mixed anhydride affords the corresponding lactone in the presence of 4-dime thylaminopyridine (DMAP) (Scheme 6.4). 

Scheme 6.4 Mixed anhydride method of Yamaguchi for macrolactonization...

Yonemitsu et al. [46] modified the Yamaguchi conditions in which the mixed anhydride is not isolated and DMAP is directly introduced at room temperature from the beginning. Shiina et al. [47] described the use of 2-methyl-6-nitrobenzoic anhydride (MNBA) as an alternative to 2,4,6-trichlorobenzoyl chloride. Pivaloyl chloride [48], trifluoroacetic anhydride [49], AC2O [50], and B0C2O [51] are also employed for the lactonization via mixed anhydride under basic conditions. Furthermore, Yamamoto et al. [52] described the use of Sc(OTf)3 as a Lewis acid. 

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