We describe the total syntheses of natural pseurotins A and F2, inhibitors of chitin synthase, both of which possess an unusual 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione ring system. The total syntheses of these spiro-hetereocyclic natural products feature: 1) a stereoselective preparation of two segments, i.e., a 2,3-dihydroxylated heptenal derivative and a highly functionalized γ-lactone, each from D-glucose, 2) the connection of the two segments via an aldol-type carbon-carbon bond formation, 3) spirocyclic ring formation from the aldol adduct through convenient 3(2H)-furanone formation, 4) the transformation of a spirocyclic γ-lactone into a γ-lactam hemiaminal derivative, and 5) conversion of the benzyl substituent in the γ-lactam ring into a benzoyl group via a cyclic enamide followed by m-CPBA oxidation in the final stage of the total synthesis. In the initial stage, the quaternary spiro-carbon center in the target molecules was efficiently constructed by a stereochemically exclusive vinyl Grignard addition to the D-glucose-derived 3-ulose. Furthermore, the preparation of the γ-lactone included a stereo- and regioselective Cu(I)-mediated benzyl Grignard addition to aldehyde. We have also completed the total synthesis of a structurally related novel angiogenesis inhibitor, azaspirene, using the analogous reaction sequence.
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