Extended Data Fig. 6: Chematica-designed, enantioselective synthesis of a marine steroid, aplykurodinone-1.

Prior syntheses⁶⁷ of this target, featuring six contiguous stereocentres, either relied on the late-stage introduction of the side chain via Michael addition to cyclopentenone (which suffers from low selectivity), or started⁶⁷ from chiral building blocks (in the latter case, in 11 steps but from much more advanced, chiral substrates). Chematica used 17 steps to reach achiral and commercially available substrates: crotonyl chloride, allyl bromide and bromochloropropane 2. This synthesis commences with the installation of two contiguous stereocentres via stereoselective vic-difunctionalization of unsaturated amide and subsequent hydroboration and bisoxidation, followed by McMurry coupling to give cyclopentene 7. From there on, oxidation of the less hindered allylic position, methylation of cyclopentenone, reoxidation and formation of imine (elegantly ensuring that a single regioisomer would form in the Diels–Alder reaction) with aminodiene 10 (available in four steps from ethyl sorbate) derives triene 11, which is then used in an intramolecular Diels–Alder cycloaddition that forms the desired 6–5 ring system of aplykurodinone-1. Hydrolysis of the imine linker and conversion of the primary amine to the carboxylic acid via oxidation and hydrolysis yields 15, which is then subjected to iodolactonization followed by dehalogenation to form the entire 5–6–5 ring system. The synthesis is completed by elaborating the remaining alkyl chloride to the desired alkene.