Catalytic Asymmetric Total Synthesis of Macrocyclic Marine Natural Product (–)-Haliclonin A?

Article abstract of DOI:10.1002/cjoc.202000291

We describe the full details of our total synthesis of haliclonin A, a macrocyclic natural product suggested to originate from a common biosynthetic intermediate as sarain A. Central to our synthetic route is the strategic employment of nitromethane for several purposes: (1) as an umpolung surrogate of an aminomethyl group; (2) as an ideal nucleophile for the highly enantioselective catalytic asymmetric conjugate addition to forge the challenging all-carbon quaternary stereogenic center that was used to induce the formations of all other chiral centers of the molecule; and (3) as a C₁N₁ building block to form the 3-azabicyclo[3.3.1]nonane framework. The realization of this strategy relied on the development of a novel organocatalytic asymmetric conjugate addition of nitromethane to 3-alkenyl cyclohex-2-enone, and the first Pd-promoted intramolecular coupling of a thiocarbamate moiety onto an electron-deficient alkene (enone) to form the 3-azabicyclo[3,3,1]nonane core. The synthesis also features a SmI₂-mediated intermolecular reductive coupling of an enone with an aldehyde, ring-closing alkene and alkyne metathesis reactions to build the two aza-macrocycles, and an unprecedented direct transformation of enol into enone.