Optically pure 1,2-diols and 1,3-diols are crucial structural motifs, serving both as key building blocks for numerous small-molecule pharmaceuticals and as core frameworks in various asymmetric catalysts. While numerous methods for their synthesis have been developed, these approaches invariably rely on toxic metal catalysts or stereochemically pure olefins as starting materials. Consequently, the development of a cost-effective, highly selective, and environmentally benign method for the synthesis of optically pure 1,2-diols and 1,3-diols remains an urgent challenge.
The Kong group at Wuhan University previously achieved stereoselective functionalization of the C(sp³)-H bonds adjacent to oxygen in tetrahydrofuran and glycoside epoxy rings through a photopromoted HAT/nickel-catalyzed strategy (J. Am. Chem. Soc. 2023, 145, 5231–5241; Nat. Chem. 2024, 16, 2054–2065). Building on this strategy, the authors proposed a modular synthesis of optically pure 1,2-diols and 1,3-diols directly from bulk chemicals such as ethylene glycol or 1,3-propanediol. This approach involves repeated stereoselective functionalization of C(sp³)-H bonds adjacent to oxygen, significantly reducing reaction costs while enhancing efficiency and environmental sustainability by obviating the need for multistep preparation of complex precursors.
However, this strategy faces several significant challenges: 1. Controlling Selectivity: Stereoselective functionalization of chain-like C(sp³)-H bonds adjacent to oxygen remains largely unexplored, making selectivity control particularly difficult; 2. Side Reactions: The dihydroxy structure may undergo side reactions with functionalization reagents or even deactivate the catalyst;3. Sequential Functionalization: Achieving high selectivity during the second functionalization of C(sp³)-H bonds is critical for the modular synthesis of optically pure 1,2-diols and 1,3-diols. These challenges underscore the complexity of developing a practical and efficient methodology for such transformations.
The authors proposed an in situ protection strategy to address the challenges mentioned above by converting diols into oxacyclic structures using protecting groups. This approach not only mitigates side reactions caused by the dihydroxy moiety but also transforms the flexible linear structure into a rigid cyclic framework, facilitating stereoselective control during the reaction. Following extensive screening, the authors identified that the simplest acetonide structure provided excellent performance. Under optimized conditions, they successfully synthesized a series of chiral precursors to 1,2-diols and 1,3-diols.
Subsequently, the authors aimed to synthesize more challenging 1,2- and 1,3-chiral diols containing two chiral centers. After a series of condition optimizations, they were able to achieve excellent diastereoselectivity, obtaining 1,n-diols with two chiral centers and various functional groups. Notably, the rigid oxacyclic ring structure played a crucial role in ensuring the high diastereoselectivity of the reaction.
Mechanistically, deuterium labeling experiments revealed that the hydrogen atom transfer (HAT) step involving the oxacyclic ring is not the rate-determining step of the reaction. Additionally, when TBDAT undergoes HAT with the oxacyclic ring, it preferentially occurs on the less sterically hindered face. Following experiments with alkyl and aryl nickel complexes developed by the authors' group, two possible reaction pathways were proposed, as illustrated in the figure.