Engineering an Enantioselective Amine Oxidase for the Synthesis of Pharmaceutical Building Blocks and Alkaloid Natural Products
Engineering an Enantioselective Amine Oxidase for the Synthesis of Pharmaceutical Building Blocks and Alkaloid Natural Products
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DOI：
10.1021/ja4051235
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发表时间：
2013-07-24
影响因子：
15
通讯作者：
Turner, Nicholas J.
中科院分区：
文献类型：
--
作者：
Ghislieri, Diego;Green, Anthony P.;Turner, Nicholas J.
开发具有成本效益和可持续的催化方法来生产对映体纯的手性胺是制药和精细化工行业面临的关键挑战。估计40-45%的候选药物含有手性胺，这突出了这一挑战，推动了对广泛适用的合成方法的需求，这些方法以高产率和对映体过量提供目标结构。在这里，我们描述了一个“工具箱”的单胺氧化酶的变种尼日尔（MAO-N），显示显着的底物范围和空间要求的图案，包括一个新的变种，它表现出高活性和对映体选择性对基板含有氨基二苯基甲烷（二苯甲基胺）模板的耐受性的发展和应用。通过将合理的结构导向工程与高通量筛选相结合，已经可以扩展MAO-N的底物范围以容纳含有大体积芳基取代基的胺底物。这些工程化的MAO-N生物催化剂已应用于去外消旋反应中，用于有效不对称合成通用活性药物成分索利那新和左西替利嗪以及天然产物（R）-毒芹碱、（R）-榄香碱和（R）-leptaflorine。我们还报道了一种新的MAO-N介导的不对称氧化Pictet-Spengler方法来合成（R）-harmicine。
The development of cost-effective and sustainable catalytic methods for the production of enantiomerically pure chiral amines is a key challenge facing the pharmaceutical and fine chemical industries. This challenge is highlighted by the estimate that 40-45% of drug candidates contain a chiral amine, fueling a demand for broadly applicable synthetic methods that deliver target structures in high yield and enantiomeric excess. Herein we describe the development and application of a "toolbox" of monoamine oxidase variants from Aspergillus niger (MAO-N) which display remarkable substrate scope and tolerance for sterically demanding motifs, including a new variant, which exhibits high activity and enantioselectivity toward substrates containing the aminodiphenylmethane (benzhydrylamine) template. By combining rational structure-guided engineering with high-throughput screening, it has been possible to expand the substrate scope of MAO-N to accommodate amine substrates containing bulky aryl substituents. These engineered MAO-N biocatalysts have been applied in deracemization reactions for the efficient asymmetric synthesis of the generic active pharmaceutical ingredients Solifenacin and Levocetirizine as well as the natural products (R)-coniine, (R)-eleagnine, and (R)-leptaflorine. We also report a novel MAO-N mediated asymmetric oxidative Pictet-Spengler approach to the synthesis of (R)-harmicine.