Fig. 3: Example of algorithmically-discovered one-pot sequences and the corresponding mechanistic network expanded to Level 4.

a Screenshot of Level 1 network propagated from cyclohexenone, trimethylsilylpropyne, n-butyllithium and azidotriflate substrates to n = 4 generations, G₄. The network encompasses all mutually-compatible sequences possible under different types of conditions. Node sizes are proportional to complexity increase per mechanistic step, ΔC/n (cf. Methods). Colors of the halos define MCR/one-pot sequences with or without warnings. Nodes whose interiors are colored green correspond to scaffolds not described in the literature. Within this network, two sequences (traced in blue and orange) up to G₄ are predicted to be one-pot without warnings and leading to unknown scaffolds 1 and 2 offering marked increase in ΔC/n (largest green nodes). A path to another complex scaffold in G₃ is also marked (in green). This product is predicted to form from the 1,2-adduct of nBuLi/cyclohexanone/azide cyclizing onto the double bond, and was detected by ESI-MS in the reaction mixture (structure highlighted in green in the L4 network in panel b). b Screenshot of the network branched-out from the blue pathway in a and analyzed at Level 4 (for networks analyzed at Levels 2 and 3, see Supplementary Fig. S158; interactive network expandable to Level 4 is deposited at https://mcrchampionship.allchemy.net). This Level 4 network encompasses various by- and side-products (gray and red nodes, respectively) and their further reactions (products marked in orange) between themselves and with the “parent” pathway. Larger orange nodes are likely structural assignments of peaks observed in the ESI-MS of the crude-reaction mixture. Interestingly, although the peaks corresponding to some predicted byproducts (e.g., A, B; structures drawn here with pink highlights) were not manifest in the ESI-MS spectra, their formation is corroborated by further products (A’, A”, B’; structures drawn with orange highlights) that can only be derived from these undetected species. For more structural assignments, see Supplementary Fig. S158. Also, the key cross-reactivity mandating sequential addition of reagents rather than MCR (i.e., reaction of alkyllithium with enone during metalation of alkyne) is highlighted by brighter pink connections at the bottom of the network. c General scheme and intermediates of the blue and orange one-pot pathways (leading to scaffolds 1 and 2, as in a) along with reaction conditions. In the substrates, the available nucleophilic and electrophilic sites are marked yellow and green, respectively, while the dark blue circle and the dotted arcs denote linkers between the azide and (pseudo)halides and a cyclic or acyclic fragment of the enone, respectively. The regioselectivity of addition (1,2- vs 1,4-) of propargyllithium reagent is controlled by the addition of HMPA as co-solvent. d Specific derivatives 1a, 1b and 2a–2g synthesized according to the general protocol along with the corresponding isolated yields. Note that the yields are low, as indeed predicted by the algorithm (see main text). Compounds 1a and 1b were isolated as single diastereoisomers. THF tetrahydrofuran, HMPA hexamethylphosphoramide, MW microwave, OTf triflate, TMS trimethylsilyl, TIPS triisopropylsilyl.