Macrolactonization Mukaiyama

Mukaiyama macrolactonization —4. deconjugation of double bond spiroketahzahon g glycosidation (NIS, deiodination)... 

Ley et al. [22] recently applied this method to the total synthesis of the antibiotic ( + )-milbemycin jSi(ii). Thus, hydroxy acid 31 was cyclized to macrolactone 32 in good yield (more than 49%) by slow addition (over 9 h) of a solution of 31 and triethylamine in acetonitrile to a refluxing solution of 28 in acetonitrile (Scheme 11). Another recent application of the Mukaiyama method is due to White and Bolton [23],... 

Mukaiyama and coworkers [24] found that 2-chloro-3-methoxymethyl-l-me-tbylpyridinium iodide is also suitable for effecting macrolactonization. Furthermore [25], the cyclization mediated by the 2-chloropyridinium salts described above sometimes gives no satisfactory yields. It is mainly due to the decomposition of the pyridinium salts under the cyclization conditions by the attack of triethylamine to either the 1-methyl group or the 2-position of the pyridinium ring to form 2-chloropyridine or 2-ammoniopyridinium salts. To solve this... 

A variety of specialized reagents have been developed for macrolactonization reactions. Two of the more important are the Corey-Nicolaou reagent, 2,2 -dipyridyl disulfide (232)10 jjjg Mukaiyama reagent, which is 2-chloro-l-methylpyridinium iodide (233). A number of related reagents have been developed, including imidazole disulfide 234 [2,2 -dithio-(4-ferf-butyl-l-isopropylimidazole)]l 2 and imidazole 235 [N-(trimethylsilyl)imidazole].l 3 All of these reagents are effective for the cyclization of co-hydroxy acids, as shown in Table 6.1. For comparison, available cyclization results with DEAD and 234 are included. In this table, a hydroxy acid is converted to a lactone (219). 

Impact of the Mukaiyama aldol reaction in total synthesis 13AG(E)9097. Macrolactonizations in the total synthesis of natural products 13CRV (PR)1. 

The synthetic strategy is based on Yamaguchi macrolactonization, metal alkynylide addition at C17, Mukaiyama-aldol Prins reaction of vinyl ether 219 with aldehyde 218 forming 2,6-d5-tetrahydropyran, Hosomi-Sakurai reaction giving 2,6-tran5-tetrahydropyran, asymmetric center formation via Myers alkylation at C12 and Noyori reduction at C15 and C3 (Scheme 47). 

Mukaiyama developed l-alkyl-2-halopyridinium salts, which are useful reagents for the preparation of carboxylic esters and lactones in the presence of tertiary amines [22]. After generation of activated onium salts from the corresponding co-hydroxycarboxylic acids, spontaneous lactonization smoothly proceeds to produce various macrolactones. Bartlett first used this lactonization method for the... 

Accordingly, deprotection of the TBS in 174 and transesterification of the salicylic acid acetonide with 2-(trimethylsilyl)ethanol gave deactivated monomeric salicylate ester 175. Ester 175 was stable to strong base, whereas 174 (Scheme 6.31) was decomposing under basic conditions therefore, 175 acted as pronucleophile for acylation with 174 to afford 176 as dimeric ester. Protection of dimeric ester 176 followed by desilylation provided the seco-acid, which on macrolactonization using the modified Mukaiyama salt and deprotection furnished 44-membered C2-symmetrical marinomycin A 177. 

Chapter Synthesis of 12- to 16-Membered-Ring Lactones is dedicated to the synthesis of 12- to 16-membered ring lactones. In this chapter, M. Kalesse and M. Cordes present an overview of the macrocyclization of seco-acids as well as new effective procedures to access 12- to 16-membered ring lactones such as ringclosing metatheses of alkynes and olefins. The authors also report the use of ketene sources and benzodioxinones to produce macrocyclic lactones. Nitrile oxide-olefin cycloaddition, intramolecular C-H oxidative macrolactonization, and Yamaguchi and Mukaiyama macrocyclization as well as macrolactonization via thioester or using phosphorus reagents are described. 

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