Extended Data Fig. 4: Chematica’s synthetic plan for scabrolide A.

Scabrolide A is a polycyclic furanobutenolide-derived norcembranoid diterpenoid that belongs to a family of marine natural products isolated from Sinularia soft corals^63,64. The molecule poses a synthetic challenge owing to its compact, densely functionalized core: a fused 5–6–7 carbocyclic scaffold decorated with five adjacent stereocentres and one additional remote stereocentre on the seven-membered ring. A recent literature pathway⁵⁰ (to the enantiomer from ref. ⁶⁴) comprises 21 synthetic steps and relies on the intramolecular Diels–Alder cycloaddition and late-stage [2+2] photocycloaddition/fragmentation sequence. During computer planning of the enantiomer from ref. ⁶³, several constrains were imposed; for example, Chematica was asked to design an enantioselective strategy (using the REMOVE_DIAST variable to exclude reactions that lead to a single racemic diastereoisomer), and was not allowed to use SAMP or RAMP hydrazones (to minimize the use of chiral auxiliaries), or highly strained bridgehead intermediates. The route proposed by the software is longer (about 30 steps) and more conservative in the sense that it relies on only broadly applicable chemistries. When planning its route, Chematica did not know the highly scaffold-specific (though elegant) fragmentation–recombination–elimination sequence of steps used towards the end of the literature pathway. The synthesis proposed by the machine relies on an intramolecular aldol addition of 17 followed by FGI, which sets the scene for the closure of a six-membered ring via alkylation reaction to yield intermediate 20. Subsequent substrate-controlled, stereoselective addition installs the tertiary alcohol. Reduction (with double-bond migration) of intermediate 21 followed by reductive ozonolysis sets the scene for the construction of the second five-membered ring of scabrolide’s scaffold. The fourth and final, seven-membered ring is closed via Pd-mediated coupling. The starting material initially identified by the software (aldehyde 11) is not commercially available, but can be sourced in four steps from (±)-cis-bicyclo[3.2.0]hept-2-en-6-one. Looking for alternative endings of the pathways, that terminate in commercially available, achiral and inexpensive starting materials, we restarted the search from a node marked in the graph view (top) by a yellow asterisk (bicyclic intermediate 18). The alternative ending (blue reaction arrows in the bottom scheme) was found within about half an hour and commenced from readily available, protected hydroxyaldehyde and cyclopentanone. The initial ending, starting from the aldehyde 11, is marked by green arrows.