Keck macrolactonization

Macrolactonization of co-hydroxyl acids using a combination of DCC, DMAP and DMAP-HCl. 

DCC ( 1 equiv) or EDCI ( 1 equiv) DMAP ( 1 equiv), DMAP-HCI ( 1 equiv) 

The total synthesis of a novel fungicidal natural product, (-)-hectochlorin, was accomplished by J.R.P. Cetusic and co-workers. The final step in their synthetic route was the Keck macrolactonization under the original conditions developed by Keck et al. The substrate hydroxy acid was dissolved in ethanol-free CHCI3 and was slowly added to a chloroform solution of DCC, DMAP and DMAP-HCI at reflux temperature. 

The Keck macroiactonization was used by R.J.K. Taylor et al. to close the 10-membered ring of (+)-apicularen A. The lactonization was attempted using both the Yamaguchi and Mitsunobu procedures and neither gave even a trace of the cyclic product. However, when the Keck conditions were applied, the desired lactone was isolated in moderate yield. 

The total synthesis of the microtubule stabilizing antitumor drug epothilone B was achieved by J. Mulzer et al. who cyclized the 16-membered macrocycle using the Keck macroiactonization.  

EDC-HCI (2 equiv), DMAP (3 equiv) DMAP-HCI (2 equiv) CHCI3, reflux, 17h 69% 

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Related reactions Keck macrolactonization, Yamaguchi macrolactonization ... 

This reaction was first reported by Keck in 1985. It is a carbodiimide (e.g., DCC ) promoted esterification to form a macrolactone in the presence of a nitrogenous base (e.g., DMAP," jV,A-dimethylalanine ). This reaction has been used in the preparation of a variety of macrolactones, thus is known as the Keck macrolactonization... 

Other reference related to the Keck macrolactonization are cited in the literature. ... 

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]. 

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