Stereodivergent Synthesis of Lankacyclinol and Its C2/C18-Congeners Enabled by a Bioinspired Mannich Reaction.

Lankacidin-group antibiotics are complex polyketides typically with a synthetically challenging 17-membered carbocyclic ring. Herein we evolved an alternative palladium-catalyzed coupling-based strategy for constructing this structural moiety. After assembling the two advanced fragments under basic conditions in a biphasic system, of the four possible Mannich adducts, two separable adducts bearing identical C2-stereochemistries were formed in high combined yields, and the ratio of them can be altered by changing the reaction conditions from dichloromethane and 23 °C (18R/18S, 1.5:1) to toluene and 100 °C (18R/18S, 1:3.5). Subsequent base-promoted decarboxylation at lower temperatures unexpectedly favored the formation of the 2,18-anti product, which is less accessible via the reaction carried out on known macrocyclic substrates. All four biosynthetically related C2/C18-isomeric lankacyclinols can be smoothly yielded after Stille macrocyclization, followed by global desilylation. The antimycobacterial activity of the synthetic lankacyclinols and several macrolatonic congeners were preliminarily evaluated.