Development of New Enantioselective Reactions using Generality as the Guiding Principle

Abstract

Despite the continuous development of new organic reaction methods, only a small fraction achieve widespread adoption. This generality problem is particularly acute in asymmetric catalysis, where the expensive and time-consuming optimization of chiral ligands for diverse substrates hinders broad applicability. Current approaches to enhancing generality rely heavily on high-throughput experimentation (HTE), often with limited underlying design principles. This work addresses these challenges by introducing a modular catalyst paradigm that significantly improves generality through the use of easily synthesized aryl sulfonamide cocatalysts, optimized via HTE. We successfully implemented this approach in two enantioselective reactions: diketone addition to nitroalkenes and azide addition to nitroalkenes. In both cases, achiral aryl sulfonamides act as cocatalysts, enhancing the generality of the reactions when paired with various chiral ligands. Mechanistic studies revealed that aryl triflamides enhance the performance of chiral catalysts by subtly perturbating the topology of each catalyst-substrate complex. These insights led to a deeper understanding of the origin of generality: the ability of chiral catalysts to recognize and leverage only the minimal essential parts of substrates required for catalysis (termed "minimal catalaphore"). This approach affords maximum flexibility to accommodate diverse substrate structures. Guided by this principle, we developed an amidine amide (AmA) catalyst that demonstrates superior generality for enantioselective nitroalkene reduction over 70 different substrates. The reaction mechanism was studied using density functional theory (DFT) calculations to quantify the minimal catalaphore concept. Finally, the application of generality was demonstrated in the synthesis of a peptidomimetics-based proteasome inhibitor that both a nonconical α-amino acid and a β-amino acid were enantioselective synthesized using AmA catalysts.