The research team led by Prof. Zhaobin Wang at Westlake University has recently published a scientific paper titled “Cr-Catalyzed Asymmetric Cross Aza-Pinacol Couplings for β-Amino Alcohol Synthesis” in the Journal of the American Chemical Society. Their work revolves around the development of a chromium-catalyzed asymmetric cross-coupling reaction between aldehydes and imines, utilizing a radical polar crossover strategy to facilitate the modular synthesis of high-value chiral β-amino alcohols.

This accomplishment introduces a fresh synthetic pathway for compounds containing amino alcohol frameworks and chiral ligands. Prof. Zhaobin Wang, from the School of Science at Westlake University, is the corresponding author for this research, while Dr. Hui Hu is the first author of the article.

The chiral β-amino alcohol scaffold is not only prevalent in pharmaceuticals, agrochemicals, and natural products but also serves as a crucial chiral ligand in asymmetric catalysis. While organic chemists have dedicated their efforts to developing synthetic methods for chiral β-amino alcohols, such as the aldol addition of α-amino enolates and aldehydes, the Mannich reaction of α-alkoxy enolates and imines, the hydrogenation of α-amino ketones or α-hydroxy amines, the ring-opening reactions of epoxides or aziridines, and the hydroamination of alkenes, these techniques often face limitations related to specific substrates or multi-step synthetic intermediates, leading to elevated synthesis costs and hindrance in their widespread adoption in organic synthesis. Hence, there exists an urgent necessity to formulate novel catalytic synthesis strategies for the efficient construction of chiral β-amino alcohol compounds from readily available starting materials.

Aldehydes and imines, as readily accessible and economical starting materials, hold promise for the modular synthesis of chiral β-amino alcohols. However, achieving both chemical and stereochemical selectivity remains a formidable challenge within this context. In the reaction system, aldehydes and imines are prone to undergo reduction and nucleophilic addition reactions as electrophilic reactants, resulting in competition for the generation of byproducts such as 1,2-diols or 1,2-diamines. Furthermore, the establishment of adjacent chiral centers in β-amino alcohols poses a daunting task within this reaction. In recent years, some advancements have been made in this field. Nevertheless, the attainment of stereochemically selective catalytic intermolecular cross-coupling reactions between aldehydes and imines remains a formidable challenge.

Figure 1 The cross-coupling strategy for chiral β-amino alcohols synthesis.

Zhaobin Wang’s research team has devoted their research efforts to the exploration of radical polar crossover strategies, resulting in a series of significant achievements (Angew. Chem. Int. Ed. 2022, 61, e202117114; Nat. Commun. 2022, 13, 5036; ACS Catal. 2022, 12, 11152; ACS Catal. 2023, 13, 3170; Angew. Chem. Int. Ed. 2023, 62, e202305987). Building upon this foundation, the team has employed an α-amino radical polar crossover strategy to realize the chromium-catalyzed asymmetric cross-coupling of aldehydes and imines. This approach has efficiently yielded β-amino alcohol compounds with adjacent chiral centers. In this process, the authors strategically utilized strongly electron-withdrawing protective groups to modulate the reduction potential of imines, thereby enabling preferential reduction of imines over aldehydes, resulting in the formation of α-amino radicals. Subsequently, the α-amino radicals generated within the system were rapidly sequestered by chromium(II) to form alkyl chromium intermediates, effectively suppressing the addition of α-amino radicals to imines. The chromium metal ions' oxygenophilic nature allowed the alkyl chromium intermediates to selectively undergo nucleophilic addition with aldehydes rather than imines.

Figure 2 Substrate scope

To underscore the synthetic applicability of this strategy, the authors conducted scale-up experiments on the reaction. Through straightforward recrystallization and the removal of protective groups, they successfully obtained chiral β-amino alcohol products that were previously challenging to synthesize, achieving an impressive 99% enantiomeric excess (ee). Subsequent transformations allowed for the synthesis of modified cyano-oxazoline ligands, thereby highlighting the potential practical utility of this strategy in the synthesis of chiral amino alcohols and novel nitrogen ligands.

The research team has pioneered the development of a class of chromium-catalyzed asymmetric cross-coupling reactions between aldehydes and imines. Diverging from previous methodologies involving ketyl radical addition to imines, this innovative approach employs an α-amino radical polar crossover strategy to precisely govern the chemical and stereochemical selectivity of the reaction. This methodology, commencing from readily accessible raw materials, offers a platform for the modular synthesis of high-value chiral β-amino alcohols, thereby introducing a fresh avenue for the synthesis of compounds housing amino alcohol frameworks and chiral ligands.