Yamaguchi method, 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... 

The second reaction is a macrolactonization which is performed with retention of configuration at C-15. Therefore the acid component has to be activated and the Yamaguchi-Yonemitsu macrolactonization method was chosen. For the detailed mechanism see the Key Chemistry of this chapter. Typical conditions are TCBC, EtsN, THF,... 

An alternative route by the Danishefsky group was developed [142e-g] (Scheme 84). The aldol reaction of ethyl ketone 580, prepared from P-keto ester 579, with aldehyde 581 stereoselectively afforded 582 (dr = 5.4 1). After Troc protection followed by hydrolysis of the enol ether, Suzuki coupling with 583 followed by TBS deprotection gave the desired (12Z)-olefin 584. The Noyori reduction of the P-keto ester 584 gave 3a-alcohol with high stereoselectivity, which was converted into hydroxy carboxylic acid 585. Macrolactonization of 585 was accomplished by the Yamaguchi method, and subsequent deprotection and DMDO oxidation efficiently afforded epothilone B (5b). 

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). 

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

Verbalactone 139 is a novel C2 symmetric macrocycUc dilactone, isolated from the roots of Verhascum undulatum possessing antibacterial activity [95]. It has 1,7-dioxacyclododecane moiety in its ring system and its first chemical total synthesis was reported by Sharma and Reddy [96] The two appropriately protected segments, acid 135 and alcohol 136, were prepared as shown in Scheme 6.23 and coupled by esterification and macrolactonization by the Yamaguchi method. 

The 15-hydroxy acids 10a and 10b (Scheme 2) were cyclized with the reliable Yamaguchi (2,4,6-trichlorobenzoylchloride, TEA, DMAP, toluene) [10, 11, 13, 16] and Keck methods (DCC, DMAP, DMAPxHCl, CHCI3) [23, 28]. Both delivered the macrolactones in good to excellent yields, the first (90 % 9b and 78 % 9c) being superior to the latter. 

After installation of the C1-C4 unit, the Yamaguchi macrolactonization [60] was subjected to the seco-acid derived from 113 to successfully yield the macrolactone 114, although Kang s group failed. Finally, the side chain was introduced to the macrolactone via Lee s method to provide (+)-lasonolide A. 

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]. 

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