Yamaguchi mixed-anhydride method

Keck reinvestigated the potential of the N,N -dicyclohexylcarbodiimide (DCC) dehydration coupUng reaction based on Steghch s procedure [32]. His group found that in the presence of DMAP and the DMAP-HCI salt, DCC-induced intramolecular 

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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. 

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

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... 

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). 

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). 

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 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). 

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