Total Synthesis of (–)‐Cordycicadin D and 3,4‐trans‐Cordycicadins A and B: Entry to the 3,4‐trans‐Fused Cordycicadin Framework

: Lost in post‐translation. Cordycicadins A–D are four C20 polyketides, all containing a g‐lactone fused to a 10‐membered lactone. The proposed biosynthetic pathway for the cordycicadins anticipates the formation of two more natural products which are unknown. We report the total synthesis of (–)‐cordycicadin D and the two anticipated natural products 3,4‐trans‐cordycicadins A and B. The targets were convergently assembled, in a biomimetic fashion, via an efficient ketene trapping‐intramolecular Michael addition sequence that delivered the requisite 3,4‐trans‐fused framework with high diastereoselectivity, enabled by the synthesis of complex dioxenones that serve as in situ ketene precursors. Recognition of the embedded polyketide symmetry enabled the use of a divergent‐convergent synthetic strategy, based on the use of two products from an early‐stage enzymatic resolution. The synthetic routes afforded (–)‐cordycicadin D in 14 steps and 3,4‐trans‐cordycicadins A and B in 13 steps (longest linear sequence). This work confirms the structure of (–)‐cordycicadin D and the observed instability of the anticipated natural product 3,4‐trans‐cordycicadin B during purification may explain why it is yet to be isolated.