Recently, the research group led by Yongtao Xie made new progress in the enzymatic construction of chiral organophosphorus compounds. The work was published in the Journal of the American Chemical Society under the title "Taming Highly Enolizable Aldehydes via Enzyme Catalysis for Enantiocomplementary Construction of β‑Hydroxyphosphonates."
β-Chiral hydroxyphosphonates/phosphonic acids are privileged bioactive scaffolds ubiquitous in pharmaceuticals, agrochemicals and natural products. Conventional syntheses rely on kinetic resolution (KR) of racemic alcohols or esters mediated by esterases or organocatalysts, limiting the theoretical yield to <50 %. Although several asymmetric reduction strategies have been developed to access these motifs, they suffer from lengthy substrate preparation and low efficiency. Recently, the Yong-Tao Xie group disclosed a C–C coupling tactic that assembles β-chiral hydroxyphosphonates directly—namely, asymmetric addition of nucleophiles to highly enolizable 2-phosphonoacetaldehydes. Conceptually this approach represents an ideal route to β-chiral hydroxyphosphonic acids (cheap, readily available starting materials; facile product diversification), yet it faces formidable challenges: (1) the strongly acidic α-hydrogen of the enolizable aldehyde can quench the nucleophile; (2) competing aldol-type side reactions are rampant; (3) effective asymmetric strategies to “tame” such highly enolizable aldehydes are lacking; (4) the aldehydes themselves are intrinsically unstable.
To overcome these hurdles, the Xie group reprogrammed ThDP-dependent enzymes, achieving the first asymmetric addition to highly enolizable aldehydes en route to β-chiral hydroxyphosphonates. The key innovation is the in-situ generation of a dynamically reversible acyl-anion nucleophile, whose transient nature shields it from quenching by the acidic α-proton. Confined within the enzyme’s active-site pocket, precise non-covalent contacts steer the incoming aldehyde and deliver the adduct in high yield and exceptional stereoselectivity. Two complementary enzymes were identified that furnish opposite product configurations, enabling stereodivergent synthesis; detailed mechanistic studies unveiled how subtle reshaping of the active-site landscape inverts facial selectivity.
This work was carried out primarily by postdoctoral fellow Huan-Gong Li. The research was supervised by Prof. Yong-Gui Chi (Nanyang Technological University / Guizhou University) and was financially supported by the National Natural Science Foundation of China, the National Key R&D Program of the Ministry of Science and Technology, and the Fundamental Research Funds for the Central Universities.
