Department of Biochemical Engineering, University College London, Gower Street, London WC1E 6BT, UK.
Department of Chemistry, University College London, Christopher Ingold Building, 20 Gordon Street, London, WC1H 0AJ, UK.
Nat Commun. 2017 Apr 3;8:14883. doi: 10.1038/ncomms14883.
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.
Pictet-Spengler 反应（PSR）涉及β-芳基乙胺和羰基化合物之间的缩合和环化。多巴胺和 PSR 中的酮结合会导致 1,1'-取代的四氢异喹啉（THIQ）的形成，这些结构难以合成，但存在于许多生物活性天然产物和合成药物中。在这里，我们发现唐松草中的 norcoclaurine 合酶（TfNCS）可以催化多巴胺和未活化酮之间的 PSR，从而促进 1,1'-取代的 THIQ 的简便生物催化生成。已经鉴定出显示改进转化率的 TfNCS 变体，并用于合成新型手性 1,1'-取代和螺-THIQ。用未活化酮进行的酶催化 PSR 是前所未有的，而且，对于这些转化，没有等效的立体选择性化学方法。这一发现提高了酶在体外和体内生成各种 THIQ 的实用性。
