The Paradox\nof Antimalarial Terpenoid Isonitrile Biosynthesis\nExplained. Proposal of Cyanoformate as an NC Delivery Vector

Marine sponge diterpenoid isonitriles\nare exceptional\nnitrogenous\nnatural products that exhibit antiplasmodial activity. Their biosynthesis\npresents a biosynthetic puzzle: how do the elements of NC engage terpenyl\ncarbocations in isoprenoid secondary metabolism, and what is the biosynthetic\nprecursor of the NC group? Cyanoformic acid (NC-COOH, <b>B1</b>) is proposed as a plausible delivery vehicle of NC that resolves\na paradox in the commonly held proposition that an inorganic cyanide\nanion, CN<sup>–</sup>, terminates terpenoid isonitrile (TI)\nbiosynthesis. DFT calculations of NC-COOH and its conjugate base,\ncyanoformate, NC-COO<sup>–</sup> (<b>B2</b>), support\nhigh nucleophilicity at N and explain bond-forming constitutionality:\nattack at N and formation of an isonitrile over its nitrile isomer.\nTI biogenesis is compared to the cyanoformamide-containing ceratamines\nthat arise from oxidation of a terminal <i>N</i>-Gly amide\nprecursor. A unifying model links C-NC vs C-CN bond formation and\nplaces Gly at the center of both biosynthetic schemes.