2,2 -Dipyridyl Disulfide macrolactonization

Macrolactonization of CD-hydroxyl-acid using 2,2 -dipyridyl disulfide. Also known as Corey-Nicolaou double activation method. 

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). 

Macrolactonization. When a carboxylic acid is treated with 2,2 -dipyridyl disulfide in the presence of Triphenylphosphine, the corresponding 2-pyridinethiol ester is formed. Corey and Nicolaou have developed an efficient method for the synthesis of macrocyclic lactones based on these 2-pyridinethiol esters. When an m-hydroxy thiolester is heated in refluxing xylene under high dilution conditions (10 M, typically accomplished with syringe pump techniques), macrolactonization occurs, liberating triphenylphosphine oxide and pyridinethione. The reaction is quite general and is believed to proceed by a double activation mechanism in which the basic 2-pyridinethiol ester simultaneously activates both the hydroxy and the carboxylic acid moieties with a single proton transfer. It has been shown that the cyclization rate is not affected by the presence of acids, bases, or any of the possible reaction contaminants. ... 

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