Corey method, macrolactonization

The first total synthesis of erythronolide B (1) by Corey stands as an event of great historical significance in synthetic chemistry it provides a powerful illustration of the utility of Corey s methods of macrolactonization and it demonstrates, in a particularly insightful way, the value of using readily accessible six-membered ring templates for the assembly of contiguous arrays of stereo-genic centers. 

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

Corey, E. J., Brunelle, D. J. New Reagents for Conversion of Hydroxy-Acids to Macrolactones by Double Activation Method. Tetrahedron Lett. 1976, 17, 3409-3412. 

The first total syntheses of racemic zearalenone (rac-479) were reported in the 1960s by the Merck and Syntex research groups (364, 365). In their multistep synthesis routes of the seco acid, the double bond was introduced by a Wittig reaction, but the required ( )-configured double bond was not formed selectively and the yields of the following lactonization were very low. The yields of macrolactonization were improved remarkably by Corey (360) and Masamune (361) using new activation methods for carboxylic acids (366). In aU the syntheses of zearalenone, the macrolide was formed by lactonization, but numerous possibilities are evident for the cyclization step. Figure 9.4 illustrates some different approaches to the synthesis of zearalenone (367). 

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]. 

In 1980, Venkataraman and Wagle [43] reported cyanuric chloride (Scheme 6.2) in the synthesis of macrolactones from the corresponding seco-acids, whose mechanism is closely related to the Corey-Nicolaou method. 

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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