Myoglobin-Catalyzed C-H Functionalization of Unprotected Indoles.
Myoglobin-Catalyzed C-H Functionalization of Unprotected Indoles.
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DOI：
10.1002/anie.201804779
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发表时间：
2018-07-26
期刊：
影响因子：
--
通讯作者：
Fasan R
中科院分区：
文献类型：
--
作者：
Vargas DA;Tinoco A;Tyagi V;Fasan R
功能化吲哚是生物活性天然产物和药物中反复出现的基序。虽然过渡金属催化的卡宾转移提供了一条有吸引力的途径来获得 C3 功能化吲哚，但由于来自更容易的 NH 插入反应的竞争，这些方案仅在 N 保护吲哚存在的情况下才可行。本文报道了一种能够使未受保护的吲哚直接进行 CH 官能化的生物催化策略。肌红蛋白的工程变体为这一反应提供了高效的生物催化剂，这在生物界中是没有先例的，能够在 α-重氮乙酸乙酯存在下转化多种吲哚，以高转化率和优异的化学选择性生成相应的 C3 功能化衍生物。该策略可用于开发一种简洁的化学酶途径来生产非甾体类抗炎药吲哚美辛。无保护催化：报道了一种通过肌红蛋白催化卡宾转移合成 C3 功能化吲哚的新型生物催化策略。这种方法能够以高效率和优异的化学选择性转化多种带有未受保护的NH基团的吲哚衍生物，并且这种转化可以整合到制备规模合成药物分子（吲哚美辛）的化学酶方案中。
Functionalized indoles are recurrent motifs in bioactive natural products and pharmaceuticals. While transition metal-catalyzed carbene transfer has provided an attractive route to afford C3-functionalized indoles, these protocols are viable only in the presence of N-protected indoles, due to competition from the more facile N—H insertion reaction. Herein, a biocatalytic strategy for enabling the direct C—H functionalization of unprotected indoles is reported. Engineered variants of myoglobin provide efficient biocatalysts for this reaction, which has no precedents in the biological world, enabling the transformation of a broad range of indoles in the presence of ethyl α-diazoacetate to give the corresponding C3-functionalized derivatives in high conversion yields and excellent chemoselectivity. This strategy could be exploited to develop a concise chemoenzymatic route to afford the nonsteroidal anti-inflammatory drug indomethacin. Catalysis without protection: A novel biocatalytic strategy for the synthesis of C3-functionalized indoles via myoglobin-catalyzed carbene transfer is reported. This approach enabled the transformation of a broad range of indole derivatives bearing unprotected N—H groups with high efficiency and excellent chemoselectivity and this transformation could be integrated into a chemoenzymatic scheme for the synthesis of a drug molecule (indomethacin) at the preparative scale.
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影响因子：
62.1
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