Chiral succinimide moieties are prevalent in biologically active natural products and pharmaceuticals, including antiepileptic drugs like phensuximide, methsuximide, and ethosuximide, as well as compounds with antibacterial, antifungal, analgesic, anticonvulsant, and antitumor effects. While methods exist for synthesizing 3-substituted succinimides, efficient methods for 3,4-disubstituted succinimides are limited. This study focuses on developing an efficient method for constructing 3-hydroxy-4-substituted-succinimides, versatile synthons readily convertible into chiral pyrrolidones and lactams. The authors aim to achieve this using asymmetric transfer hydrogenation (ATH), a powerful technique for reducing α-functional ketones. However, traditional ATH methods face challenges when applied to 3-hydroxy-4-substituted maleimides due to their enol form predominance and low reducing activity under alkaline conditions. Therefore, the research focuses on overcoming these challenges to develop a reliable and stereoselective synthetic route.

Existing methods for synthesizing chiral succinimides include enantioselective cycloaddition reactions and hydrogenation reactions using maleimides as substrates. Asymmetric catalytic addition of nucleophilic reagents to maleimides has also been explored. However, these methods mostly focus on 3-substituted succinimides, with few efficient methods for the synthesis of 3,4-disubstituted succinimides. Previous work by Baiker et al. demonstrated enantioselective hydrogenation of pyrrolidine-2,3,5-triones using Pt-cinchonidine systems, yielding 3,4-disubstituted succinimides with a single stereocenter. This inspired the current research to explore the use of dynamic kinetic resolution (DKR)-ATH for the reduction of 3-hydroxy-4-substituted maleimides. DKR-ATH is known for its efficiency in achieving high enantiomeric purity in the reduction of α-functional ketones but requires a base to facilitate the process. The challenge lies in the low reactivity of 3-hydroxy-4-substituted maleimides under alkaline conditions.

The researchers developed a stereodivergent enantio- and diastereoselective ATH of maleimide derivatives catalyzed by a tethered rhodium catalyst. Initially, they optimized reaction conditions using model substrate 1a, testing various commercially available TsDPEN-derived Ru, Rh, and Ir complexes, solvents, and formic acid/triethylamine ratios. They found that tethered Rh catalysts, particularly (S,S)-cat.6, provided excellent conversion, enantioselectivity, and diastereoselectivity. The solvent EtOAc proved optimal, and adjusting the formic acid/triethylamine ratio allowed selective access to either *anti*- (using a 5:2 ratio) or *syn*- (using a 2:0.02 ratio) products. The optimized methodology was then applied to a broad range of substrates with various N-protecting groups and C4 substituents. Both anti- and syn-selective transformations were achieved with high yields (94-98% for anti, 93-98% for syn), excellent enantioselectivities (88-99% ee), and diastereoselectivities (90:10 to >99:1 dr). Furthermore, N-unprotected substrates were also successfully tested, with selective reduction of either the enol or both the enol and imide groups attainable by controlling catalyst loading. Gram-scale reactions were also performed to demonstrate the scalability of the methodology. The key intermediate for Echinocandin synthesis (3u) and other valuable derivatives were obtained in high yield and selectivity. Finally, a detailed mechanistic investigation was conducted to understand the stereoselectivity of the reaction, including control experiments and density functional theory (DFT) calculations.

The study's key findings include the development of a highly efficient and stereodivergent method for synthesizing chiral succinimides. The use of a tethered rhodium catalyst in asymmetric transfer hydrogenation enabled the selective synthesis of both *syn*- and *anti*-3-hydroxy-4-substituted succinimides. High enantioselectivities (>99% ee) and diastereoselectivities (>99:1 dr) were achieved across a wide range of substrates with diverse N-protecting groups and C4 substituents. The method's versatility was demonstrated by the synthesis of N-unprotected substrates, with the possibility of selectively reducing either the enol group or both the enol and imide groups. Gram-scale synthesis demonstrated the scalability and practicality of the approach. Mechanistic studies, including control experiments and DFT calculations, revealed that the reaction likely proceeds via reduction of the keto form, with the stereoselectivity determined by the transition states in the hydride transfer step. The anti-product formation is favored over the syn-product due to a lower energy barrier.

The reported method significantly advances the synthesis of chiral succinimides, offering a straightforward and highly selective approach to access all four stereoisomers from readily available starting materials. This stereodivergent synthesis provides access to valuable building blocks for the synthesis of complex molecules and natural products. The high efficiency, broad substrate scope, and scalability of the method make it a promising tool for pharmaceutical and medicinal chemistry applications. The detailed mechanistic understanding gained from this work provides valuable insights for the future design of more efficient and selective catalysts for asymmetric transfer hydrogenation. The ability to control the stereochemical outcome by simply adjusting the reaction conditions is a significant advantage, and provides opportunities to synthesize various stereoisomers of succinimides.

This research successfully developed a highly efficient and stereodivergent method for the synthesis of chiral succinimides using a Rh-catalyzed asymmetric transfer hydrogenation. The method demonstrated high yields, excellent enantio- and diastereoselectivities across a broad substrate scope. Gram-scale synthesis confirmed the scalability of the approach. Mechanistic insights provide a strong foundation for further catalyst development and reaction optimization. Future work could explore the application of this methodology to the synthesis of other complex molecules and the development of more sustainable and environmentally friendly reaction conditions.

While the methodology exhibits broad substrate scope and high stereoselectivity, some limitations exist. The diastereoselectivity was slightly lower for ortho-substituted substrates. The mechanism study mainly focused on DFT calculations, experimental validation could be further strengthened. Further optimization might be necessary for certain substrate classes to achieve even higher yields and stereoselectivities.