Alkyne‐Mediated Approach for Total Syntheses of Cladospolides A, B, C and iso‐Cladospolide B

Abstract

A general strategy for the stereoselective total syntheses of cladospolides A, B, and C and iso‐cladospolide B has been accomplished. The key steps provide easy access to the target molecules and include an alkyne‐zipper reaction, a Sharpless asymmetric epoxidation/dihydroxylation, and a Yamaguchi macrolactonization. The feasibility of the alkyne‐mediated approach to construct the required carbon framework as well as to create the diol functionality and the olefin geometry is successfully demonstrated.

Twelve‐membered macrolactones: privileged scaffolds for the development of new therapeutics

“…Table shows some representative examples of syntheses of the Clad family, paying specific attention to the key intermediates employed and the method of ring closure. According to the literature, there have been ten reports of total syntheses of CladA since 1987. Five of these syntheses have intercepted an intermediate of type 107 .…”

“…According to the literature, there have been ten reports of total syntheses of CladA since 1987. Five of these syntheses have intercepted an intermediate of type 107 . The first example was reported by Mori in 1987 and utilized a Sharpless asymmetric epoxidation to set the stereochemistry of the diol under kinetic resolution conditions.…”

“…This was the first example of a CladA synthesis that did not rely on the Yamaguchi esterification and also the first that implemented the RCM reaction to close the macrocyclic ring. Another interesting report came from Reddy in 2013 in which they applied the alkyne ‘zipper’ reaction en route to CladA‐C in a divergent manner.…”

“…Similarly, CladB and CladC have also received significant attention from synthetic chemists, both being the subject of several synthetic quests (Table ). The first reports of syntheses of CladB were in 2005 .…”

“…Moving through the early 2000s, many groups applied divergent approaches to synthesize multiple members of the Clad family. The previously mentioned report by Reddy utilized a divergent alkyne‐mediated strategy, employing 111 to access CladB/C. Prasad employed a strategy affording the tartaric acid derivative 112 to reveal 3‐ ent ‐CladC .…”