Figure 6.

A challenge for Machine Learning: Minor structural changes in starting materials can dramatically influence the reaction outcomes. (a) Replacement of two O-protecting groups (orange OMe to green OBn and OMOM) in the intermediate in Danishefsky’s synthesis of (+/−)-FR-900482 changes the lability of ether groups and prohibits rearrangement of an epoxide to an aldehyde³⁷. (b) Minute changes in temperature alter reaction mechanism and result in different products³⁸. (c) Small changes in electron density modify reactivity of N-pivaloyl and N-Boc protected anilines. The upper substrate reacts into an intermediate that is impossible to isolate and thus leads to a product that is markedly different than the one obtained from the lower substrate differing in only one atom (oxygen)³⁹. (d) Presence of the epoxide ring in the tricyclic moiety allows for close proximity of the terminal iodides enabling double Pd-mediated coupling. In contrast, when the epoxide is replaced by a double bond, the iodides are further apart and no cyclization is observed⁴⁰.