Enantiocomplementary synthesis of β-adrenergic blocker precursors via biocatalytic nitration of phenyl glycidyl ethers

• Published in: Bioorganic chemistry 2023-09, Vol.138, p.106640-106640, Article 106640
• Main Authors: Wang, Hui-Hui, Wan, Nan-Wei, Da, Xin-Yu, Mou, Xue-Qing, Wang, Zhu-Xiang, Chen, Yong-Zheng, Liu, Zhi-Qiang, Zheng, Yu-Guo
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - chemistry; Biocatalysis; Catalysis; Nitration; Nitrite; Phenyl Ethers; Stereoisomerism; β-Adrenergic blockers; β-Nitroalcohols
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106640

[Display omitted] •HHDHamb was engineered for enantiocomplementary bio-nitration of epoxides.•Chiral (R)- and (S)-β-nitroalcohols were synthesized with good yields and ee values.•Various chiral β-nitroalcohols were synthesized as β-adrenergic blockers precursors.•The bio-nitration method could tolerate a high substrate concentration of 150 g/L. Enantiopure β-nitroalcohols, as an important class of nitro-containing compounds, are essential building blocks in pharmaceutical and organic chemistry, particularly for the synthesis of β-adrenergic blockers. In this study, we present the successful protein engineering of halohydrin dehalogenase HHDHamb for the enantioselective bio-nitration of various phenyl glycidyl ethers to the corresponding chiral β-nitroalcohols, using the inexpensive, commercially available, and safer nitrite as a nitrating agent. The chiral (R)- and (S)-1-nitro-3-phenoxypropan-2-ols were synthesized by the several enantiocomplementary HHDHamb variants through the whole-cell biotransformation, which showed good catalytic efficiency (up to 43% isolated yields) and high optical purity (up to >99% ee). In addition, we also demonstrated that the bio-nitration method was able to tolerate the substrate at a high concentration of 1000 mM (150 g/L). Furthermore, representative synthesis of two optically active enantiomers of the β-adrenergic blocker metoprolol was successfully achieved by utilizing the corresponding chiral β-nitroalcohols as precursors.