Landscape of Lankacidin Biomimetic Synthesis: Structural Revisions and Biogenetic Implications

In
this report, a unified biomimetic approach to all known macrocyclic
lankacidins is presented. By taking advantage of the thermolysis of N,O-acetal to generate the requisite N-acyl-1-azahexatriene species, we eventually realized the
biomimetic Mannich macrocyclization, from which all of the macrocyclic
lankacidins can be conquered by orchestrated desilylation. The reassignments
of the reported structures of isolankacidinol (7 to 10) and the discovery of a recently isolated “lankacyclinol”
found to be in fact 2,18-bis-epi-lankacyclinol (72) unraveled the previously underappreciated chemical diversity
exhibited by the enzymatic macrocyclization. In addition, the facile
elimination/decarboxylation/protonation process for the depletion
of C1 under basic conditions resembling a physiological environment
may implicate more undiscovered natural products with variable C2/C18
stereochemistries (i.e., 62, 73, and 75). The notable aspect provided by a biomimetic strategy
is significantly reducing the step count compared with the two previous
entries to macrocyclic lankacidins.