Synthetic Approaches to Macrocyclic Lactones

Synthetic Approaches to Macrocyclic Lactones. There are many examples of biologically important, naturally occurring lactones. A variety of cyclization techniques have been developed, but all are based on the idea that the carbonyl end of an cu-substituted acid is activated to facilitate attack by or at the other functionalized end. Trifluoroacetic anhydride, for example, was used to convert 220 to 222 in 31% yield.xhe initially formed mixed anhydride (221) activated the carbonyl to attack by the hydroxyl moiety, leading to 222 in the Taub et al. synthesis of zearalenone. An alternative synthetic route required a macrocyclization reaction but it involved Friedel-Crafts acylation (sec. 12.4.D). Cyclization has also been observed using a mixture of trifluoroacetic acid and trifluoroacetic anhydride.  

Mercuric trifluoroacetate [Hg(OCOCF3)2] is an effective reagent for the cyclization of hydroxy thio-esters. 5 This cyclization procedure was used by Masamune et al. for the conversion of 225 to 227 (in 90% yield) in a synthesis of zearalenone dimethyl ether. Masamune developed this procedure to complete the total synthesis of methymycin, where one step involved treatment of a thioester with mercuric salts. 2,96 Mercury(II) has an affinity for bivalent sulfur and it binds the thioester unit as well as the terminal hydroxyl 

The thioester moiety in 225 (see 229) is formed by reaction of the phosphonate ester of the appropriate acid (see generic structure 228) with the thallium salt of 2-methyl-2-propanethiol [TlSC(Me)3], which is a mild and general procedure for the preparation of thioesters. 

Diethyl azodicarboxylate (Et02C-N=N-C02Et, DEAD) is a key reagent in the Mitsunobu reaction (sec. 2.7.A.ii) and has also been used for macrolactonization. Reaction of 230 with DEAD gave 15% of 231 in White s synthesis of the antibiotic vermiculine.  

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). 

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