A biomimetic synthetic strategy has resulted in a two-step total synthesis of (�)-ulodione A and the prediction of two potential natural products, (�)-ulodiones C and D. This work was guided by computational investigations into the selectivity of a proposed biosynthetic Diels-Alder dimerization, which was then utilized in the chemical synthesis. This work highlights how biosynthetic considerations can both guide the design of efficient synthetic strategies and lead to the anticipation of new natural products.

The stereoselective synthesis of chiral molecules in enantioenriched form – i.e., asymmetric synthesis – underpins many fields of pure and applied science. Enantioconvergent reactions are preeminent in contemporary asymmetric synthesis as they convert both enantiomers of a racemic starting material into a single enantioenriched product, thus avoiding the maximum 50% yield associated with resolutions. All currently known enantioconvergent processes necessitate the loss or partial-loss of the racemic substrate’s configuration, thus limiting the potential substrate scope to molecules that contain labile stereogenic units. Here we present a new approach to enantioconvergent reactions that can proceed with full retention of the racemic substrate’s configuration. This uniquely stereo-economic approach is possible if the two enantiomers of a racemic starting material are joined together to form one enantiomer of a non-meso product. Experimental validation of this concept is presented using two distinct strategies; (1) a direct unsymmetrical coupling approach and (2) a multi-component approach, which exhibits statistical-amplification of enantiopurity. Our results demonstrate that stereoretentive-enantioconvergent reactions can be achieved using a wide variety of synthetic tactics, including stoichiometric chiral reagents, chiral auxiliaries, and chiral catalysts. Thus, the established dogma that enantioconvergent reactions require substrates that contain labile stereogenic units is shown to be incorrect. We anticipate the concept of stereoretention in enantioconvergent reactions will lead to the development of novel methodologies that can utilize a hitherto unexplored range of racemic substrates.

A biomimetic synthetic strategy has resulted in a 2-step total synthesis of (±)-ulodione A and the prediction of two potential natural products, (±)-ulodiones C and D. This work was guided by computational investigations into the selectivity of a proposed biosynthetic Diels–Alder dimerization, which was then utilized in the chemical synthesis. This work highlights how biosynthetic considerations can both guide the design of efficient synthetic strategies and lead to the anticipation of new natural products.

A biomimetic synthetic strategy has resulted in a two-step total synthesis of (�)-ulodione A and the prediction of two potential natural products, (�)-ulodiones C and D. This work was guided by computational investigations into the selectivity of a proposed biosynthetic Diels-Alder dimerization, which was then utilized in the chemical synthesis. This work highlights how biosynthetic considerations can both guide the design of efficient synthetic strategies and lead to the anticipation of new natural products.