Ene Reductase Enabled Intramolecular β-C-H Functionalization of Substituted Cyclohexanones for Efficient Synthesis of Bridged Bicyclic Nitrogen Scaffolds.
Ene Reductase Enabled Intramolecular β-C-H Functionalization of Substituted Cyclohexanones for Efficient Synthesis of Bridged Bicyclic Nitrogen Scaffolds.
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Ene 还原酶使取代环己酮的分子内 β-C-H 功能化，以有效合成桥联双环氮支架。
DOI：
10.1002/anie.202302125
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Zhao,Huimin
中科院分区：
文献类型：
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作者：
Jiang,Guangde;Huang,Chunshuai;Harrison,Wesley;Li,Hongxiang;Zhou,Megan;Zhao,Huimin
在这里，我们报道了烯烃还原酶(EREDs)可以促进一种前所未有的分子内β-C−H官能化反应，用于合成含有6-氮杂双环[3.2.1]辛烷支架的桥联双环氮杂环化合物。为了简化这些特权基序的合成，我们利用现成的N-苯甘氨酸和可以从生物质中获得的环己酮，将Ir光催化与EREDs相结合，开发了克级规模的一锅化学酶串联反应。进一步的酶促或化学衍生化反应可将6-氮杂双环[3.2.1]辛烷-3-酮转化为6-氮杂双环[3.2.1]辛烷-3-α-ol，可用于氮丙酚及其类似物的合成和药物开发。机理研究表明，该反应需要氧气，可能需要氧气来生成氧化黄素，黄素可以选择性地使3-取代环己酮衍生物脱氢，形成α，β-不饱和酮，然后在碱性条件下进行自发的分子内aza-Michael加成反应。
Herein we report that ene reductases (EREDs) can facilitate an unprecedented intramolecular β‐C−H functionalization reaction for the synthesis of bridged bicyclic nitrogen heterocycles containing the 6‐azabicyclo[3.2.1]octane scaffold. To streamline the synthesis of these privileged motifs, we developed a gram‐scale one‐pot chemoenzymatic cascade by combining iridium photocatalysis with EREDs, using readily availableN‐phenylglycines and cyclohexenones that can be obtained from biomass. Further derivatization using enzymatic or chemical methods can convert 6‐azabicyclo[3.2.1]octan‐3‐one into 6‐azabicyclo[3.2.1]octan‐3α‐ols, which can be potentially utilized for the synthesis of azaprophen and its analogues for drug discovery. Mechanistic studies revealed the reaction requires oxygen, presumably to produce oxidized flavin, which can selectively dehydrogenate the 3‐substituted cyclohexanone derivatives to form the α,β‐unsaturated ketone, which subsequently undergoes spontaneous intramolecular aza‐Michael addition under basic conditions.