Unified Total Synthesis of Hetiamacins A–D

A concise enantioselective total synthesis of hetiamacin A has been accomplished from a known l‐aspartic acid derivative by an eight‐step sequence that features ammonolytic opening of the γ‐lactone moiety of amicoumacin C followed by 1,3‐oxazinane ring formation in one pot. Hetiamacins B–D with putatively assigned stereochemistries have also been synthesized from amicoumacin C, each in three steps involving tetrahydro‐4(1H)‐pyrimidinone ring formation. The excellent NMR spectroscopic agreement of the synthetic materials with the corresponding natural products, coupled with biosynthetic considerations, has enabled the full stereochemical assignments of hetiamacins B–D. A concise total synthesis of hetiamacins A–D, members of the amicoumacin family of natural products that feature naturally rare heterocyclic ring systems, has been achieved using amicoumacin C as a common intermediate. This work is the first synthesis of hetiamacins B–D which has enabled their full stereochemical assignments.