The Diels-Alder reaction is arguably one of the most studied reactions in organic chemistry and one of the most utilized for its ability to accomplish complex scaffolds. This work showcases the first diastereodivergent Diels-Alder/Lactonization (DAL) organocascade utilizing a chiral isothiourea organocatalyst to deliver complex frameworks found in bioactive compounds. The joint experimental and computational study details the mechanism, origins of enantioselectivity and diastereoselectivity, and the role of the base in this reaction, providing a comprehensive model that explains experimental outcomes. Computed transition state structures (TSSs) revealed that conformational control induced by an S...O interaction directs facial selectivity of attack by the diene, thereby imposing enantioselectivity. Computed TSSs and experimental NMR analysis showed that catalyst-base synergy leads to stereoelectronic effects that can selectively stabilize the <i>exo </i>Diels-Alder TSS, leading to resulting cylcoadducts with similar energies. Furthermore, tuning the stereoelectronics was found to induce stereodivergent pathways. An evaluation of computed energies and experimental temperature studies revealed a rare instance of entropy-controlled diastereoselectivity. Finally, the scope and utility of this reaction has been tested on a new Diels-Alder/Lactamization reaction involving furans.

Theoretical insights into the mechanism and selectivity of the Diels-Alder/lactonization (DAL) organocascasde catalyzed by a chiral isothiourea

251st National Meeting (2016)

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