Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, California 93106, United States.
School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
J Am Chem Soc. 2024 Jul 24;146(29):20263-20269. doi: 10.1021/jacs.4c05581. Epub 2024 Jul 13.
α,β-Diamino acids are important structural motifs and building blocks for numerous bioactive natural products, peptidomimetics, and pharmaceuticals, yet efficient asymmetric synthesis to access these stereoarrays remains a challenge. Herein, we report the development of a pyridoxal 5'-phosphate (PLP)-dependent enzyme that is engineered to catalyze stereoselective Mannich-type reactions between free α-amino acids and enolizable cyclic imines. This biocatalyst enabled one-step asymmetric enzymatic synthesis of the unusual pyrrolidine-containing amino acid L-tambroline at gram-scale with high enantio- and diastereocontrol. Furthermore, this enzymatic platform is capable of utilizing a diverse range of α-amino acids as the Mannich donor and various cyclic imines as the acceptor. By coupling with different imine-generating enzymes, we established versatile biocatalytic cascades and demonstrated a general, concise, versatile, and atom-economic approach to access unprotected α,β-diamino acids, including structurally complex α,α-disubstituted α,β-diamino acids with contiguous stereocenters.
α,β-二氨基酸是许多生物活性天然产物、肽模拟物和药物的重要结构基元和构建块，但高效地不对称合成这些立体结构仍然是一个挑战。在此，我们报告了一种吡哆醛 5'-磷酸（PLP）依赖性酶的开发，该酶经过工程改造可催化游离α-氨基酸和烯醇化环状亚胺之间的立体选择性曼尼希型反应。这种生物催化剂能够以克级规模、高对映选择性和非对映选择性一步不对称酶法合成不寻常的含吡咯烷的氨基酸 L-坦布罗林。此外，该酶平台能够利用各种α-氨基酸作为曼尼希供体和各种环状亚胺作为受体。通过与不同的亚胺生成酶偶联，我们建立了多功能的生物催化级联反应，并展示了一种通用、简洁、多功能和原子经济的方法来获得未保护的α,β-二氨基酸，包括具有连续立体中心的结构复杂的α,α-二取代的α,β-二氨基酸。
