On the proposed structures and stereocontrolled synthesis of the cephalosporolides

Abstract

SummaryThe synthesis of four candidate stereoisomers of cephalosporolide H is described, made possible by a zinc-chelation strategy for controlling the stereochemistry of oxygenated 5,5-spiroketals. The same strategy likewise enables the first stereocontrolled synthesis of cephalosporolide E, which is typically isolated and prepared admixed with its spiroketal epimer, cephalosporolide F.

Recent Developments in Total Syntheses of Cephalosporolides, Penisporolides, and Ascospiroketals

“…The final Brønsted acid‐catalyzed lactonization (A ring formation) furnished cephalosporolides E/F as a separable 3:2 mixture of diastereomers. In 2012, Dudley et al . reported the total synthesis of cephalosporolide E ( dr 5/1, Scheme b) using the AuCl‐catalyzed cycloisomerization of the protected alkyne triol 61 to construct the oxygenated [5,5]‐spiroketal 62 , which protocol was developed by his group in 2011 .…”

“…Interestingly, the equilibrium of the [5,5]‐spiroketals could be controlled by the zinc‐chelated stereoselective isomerization. The same strategy was further extended to the total syntheses of proposed cephalosporolide H and its stereoisomers (Scheme ) . In 2014, Ramana et al .…”

Total Synthesis of Marine Natural Products: Cephalosporolides

“…Dudley's [53] synthesis of cephalosporolide E 4 was based on a gold-catalyzed cycloisomerization reaction. This marked the first diastereoselective method for synthesis of 4.…”

Synthesis of 5,6- and 6,6-Spirocyclic Compounds

“…Beginning with studies toward Au(I)-or Au(III)-catalyzed synthesis of bridged acetals [92], these catalysts were soon applied to the synthesis of spiroacetals [93,94]. This method has been widely embraced by the synthetic community and used in the syntheses of a variety of complex spiroacetal natural products, including the cephalosporolides [95], okadaic acid [96], and ushikulide A [97].…”

“…179 to ushikulide A, 177) and protection of the alcohol as a benzoyl ether was required to prevent elimination. In their work toward the cephalosporolides 5a-b and 181, Dudley and Tlais [95,107] used a gold(I)-catalyzed intramolecular hydroalkoxylation strategy to form the 5,5-spiroacetal (Scheme 43). Treatment of alkyne 182 with a high catalyst loading of AuCl afforded a mixture of spiroacetals 183a and 183b in good yield.…”