Nicolaou macrolactonization

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

Dithiane as a nucleophile, serving as a masked carbonyl equivalent. This is an example of umpolung. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 66, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 73, Springer International Publishing Switzerland 2014 

2 -dipyridyl disulfide (1.5 equiv) PPhs (1.5 equiv), benzene, r.t., 5h 

The modified Corey-Nicoiaou macroiactonization was applied for the construction of the BCD ring system of brevetoxin A by K.C. Nicolaou and co-workers. The dihydroxy dicarboxylic acid substrate was subjected to a one-pot bis-lactonization. After the formation of the bis-2-pyridinethiol ester, the lactonization was conducted at low substrate concentration (0.013 M) in toluene at reflux temperature. 

The first totai synthesis of the ichthyotoxic marine naturai product (-)-apiyoiide A was accomplished by Y. Stenstrom and co-workers. The compound has a 16-membered lactone ring, four (Z)-double bonds, as well as a stereogenic center. Numerous macroiactonization protocols were tested, but most of them gave the diolide (dimer) except for the Corey-Nicoiaou procedure. 

Andrus and T.-L. Shi achieved the total synthesis of the 10-membered lactone (-)-tuckolide (decarestrictine D), which potentially inhibits cholesterol biosynthesis. The lactonization was only successful under the Corey-Nicoiaou conditions. Interestingly, the unsubstituted 9-hydroxynonanoic acid did not lactonize under these conditions. 

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Related reactions Corey-Nicolaou macrolactonization, Yamaguchi macrolactonization ... 

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