Enzyme catalysed Pictet-Spengler formation of chiral 1,1'-disubstituted- and spiro-tetrahydroisoquinolines.
Enzyme catalysed Pictet-Spengler formation of chiral 1,1'-disubstituted- and spiro-tetrahydroisoquinolines.
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DOI：
10.1038/ncomms14883
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发表时间：
2017-04-03
影响因子：
16.6
通讯作者：
Ward JM
中科院分区：
文献类型：
--
作者：
Lichman BR;Zhao J;Hailes HC;Ward JM
Pictet-Spengler反应涉及β-芳乙胺和羰基化合物之间的缩合和闭环反应。在PSR中，多巴胺和酮的结合会导致1，1‘-二取代四氢异喹啉(THIQ)的形成，这种结构很难合成，但存在于许多生物活性天然产物和合成药物中。在这里，我们发现TfNCS可以催化多巴胺和未活化酮之间的PSR，从而促进1，1‘-二取代THIQ的生物催化生成。TfNCS的变种具有更好的转化率，已被发现并用于合成新型手性1，1‘-二取代和螺环-THIQ。酶催化的PSR与未活化酮的反应是史无前例的，而且，还没有同等的立体选择性化学方法来进行这些转化。这一发现促进了酶在体外和体内产生不同的THIQ的效用。β-芳乙胺与羰基化合物的Pictet-Spengler缩合反应是生物活性生物碱合成的重要步骤。在这里，作者报告了去甲黄嘌呤合成酶及其工程变体催化的多巴胺和未活化酮之间的Pictet-Spengler反应。
The Pictet–Spengler reaction (PSR) involves the condensation and ring closure between a β-arylethylamine and a carbonyl compound. The combination of dopamine and ketones in a PSR leads to the formation of 1,1′-disubstituted tetrahydroisoquinolines (THIQs), structures that are challenging to synthesize and yet are present in a number of bioactive natural products and synthetic pharmaceuticals. Here we have discovered that norcoclaurine synthase from Thalictrum flavum (TfNCS) can catalyse the PSR between dopamine and unactivated ketones, thus facilitating the facile biocatalytic generation of 1,1′-disubstituted THIQs. Variants of TfNCS showing improved conversions have been identified and used to synthesize novel chiral 1,1′-disubstituted and spiro-THIQs. Enzyme catalysed PSRs with unactivated ketones are unprecedented, and, furthermore, there are no equivalent stereoselective chemical methods for these transformations. This discovery advances the utility of enzymes for the generation of diverse THIQs in vitro and in vivo. The Pictet-Spengler condensation of β-arylethylamine and carbonyl compounds is an important step in the synthesis of bioactive alkaloids. Here, the authors report a Pictet-Spengler reaction between dopamine and unactivated ketones catalysed by norcoclaurine synthase and its engineered variants.