Methoxamine Synthesis in a Biocatalytic 1-Pot 2-Step Cascade Approach
Methoxamine Synthesis in a Biocatalytic 1-Pot 2-Step Cascade Approach
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DOI：
10.1021/acscatal.9b01081
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发表时间：
2019-08-01
期刊：
影响因子：
12.9
通讯作者：
Rother, Doerte
中科院分区：
文献类型：
--
作者：
Erdmann, Vanessa;Sehl, Torsten;Rother, Doerte
由于其作为血管加压剂的功能，邻位氨基醇甲氧胺是治疗低血压和尿失禁的潜在候选药物，或在眼科中有应用。在这项研究中，开发了一种生物催化方法，以生产甲氧胺的四个立体异构体中的每一个在一个连续的1锅2步级联反应，从容易获得的丙酮酸和2，5-二甲氧基-苯甲醛没有中间体分离。所有四种异构体都可以通过具有高立体选择性的碳连接酶和转氨酶的模块化组合以高转化率和非常好的立体选择性获得。这些级联的开发是通过整合来自巴氏醋杆菌的丙酮酸脱羧酶的最近工程化的三重变体（ApPDC-E469 G-468 A-W543 F）等因素而成为可能的，其提供了获得具有98%的高对映体过量的中间体（S）-1-羟基-1-（2，5-二甲氧基苯基）丙-2-酮的途径。对于这些空间要求高的2-羟基酮的胺化，巨大芽孢杆菌转氨酶特别被证明是高活性和选择性的催化剂。获得了所有四种甲氧胺立体异构体，异构体含量在94%和99%之间，两个步骤的总转化率在59%和80%之间。采用两柱串联的超临界流体色谱法，可以在不衍生的情况下分离每种异构体。包括非优化产物分离的制备规模（75 mL）的1-锅2-步级联至（1 S，2 R）-甲氧胺显示85 mg HCl盐（46%分离产率），纯度（NMR）为94%，异构体含量为98%。
Due to its function as a vasopressor, the vicinal amino alcohol methoxamine is a potential candidate for the treatment of hypotension and incontinence or has applications in ophthalmology. In this study, a biocatalytic method was developed to produce each of the four stereoisomers of methoxamine in a sequential 1-pot 2-step cascade reaction, starting from readily available pyruvate and 2,5-dimethoxy-enzaldehyde without intermediate isolation. All four isomers are accessible with high conversions and very good stereoselectivities through the modular combination of carboligases and transaminases with high stereoselectivities. The development of these cascades was made possible, among other factors, by the integration of a recently engineered triple variant of the pyruvate decarboxylase from Acetobacter pasteurianus (ApPDC-E469G-468A-W543F), which provided access to the intermediate (S)-1-hydroxy-1-(2,5-dimethoxyphenyl)propan-2-one with a high enantiomeric excess of 98%. For the amination of these sterically demanding 2-hydroxy ketones, Bacillus megaterium transaminase in particular has proven to be a highly active and selective catalyst. All four methoxamine stereoisomers were achieved with isomeric contents between 94% and 99% and total conversions of both steps between 59% and 80%. Separation of each isomer without derivatizing was possible using supercritical fluid chomratographie with two columns connected in a row. A preparative scale (75 mL) of the 1-pot 2-step cascade to (1S,2R)-methoxamine including nonoptimized product isolation showed 85 mg HCl salt (46% isolated yield) with 94% purity (NMR) and an isomeric content of 98%.