Stereoselective synthesis of the C4−C16 polyketide fragment of portimines A and B is reported, enabled by our previously established method for the stereoselective synthesis of syn-α,α′-dihydroxyketones. The preparation of this advanced fragment provides insights useful for the total synthesis of portimines A and B. An asymmetric Evans aldol reaction was used to install the C10−C11 adjacent stereogenic centers before incorporation of indantrione, followed by epoxidation and epoxide opening to forge the challenging syn-α,α′-dihydroxyketone functionality.

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The NHC‐catalysed intermolecular Stetter reaction provides direct access to 1,4‐diketones, however current NHC catalysts for this specific transformation remain underdeveloped, significantly limiting the use of this reaction in target‐oriented synthesis. Here we report a novel N‐mesityl thiazolium NHC as a high‐performing catalyst for this reaction, enabling high yields and short reaction times for a range of sterically non‐trivial aliphatic aldehydes reacting with enone substrates. Quantification of the properties of novel and known NHC organocatalysts revealed that both steric and electronic properties play an important role in the success of the new N‐mesityl thiazolium NHC for this reaction. These developments will facilitate wider application of the Stetter reaction as a key carbon‐carbon bond forming reaction for coupling of complex fragments under mild conditions.