Electrophilic reagent zinc homoenol: conversion of Cyclopropanol to Cyclopropylamine

The introduction of metal groups into organic molecules often reverses the polarity of the molecules The central carbon atom changes from lack of electricity to rich electricity, and the molecules change from electrophilic to nucleophilic Typical examples are Grignard reaction and reformasky reaction Among them, Grignard reagent is widely used in organic synthesis, and Grignard won the Nobel Prize In fact, the reformasky reaction induced by metallic zinc was found earlier In the reaction, α - iodoacetate and zinc formed enol zinc salt, and the polarity reversed, which turned into nucleophilic reagent The C-C bond of Cyclopropanol is broken by metal induction, and the metal organic reagent with polarity reversal, metal homopolymers, can be obtained The reagent is nucleophilic and can react with a series of electrophilic reagents to form β - functionalized aldehydes or ketones, or to form C-C or C-X bonds under the catalysis of transition metals As one of the metal reagents of high enol, zinc high enol can carry out many kinds of reactions, including carbonyl addition, copper catalyzed conjugation addition and allylation Fig 1 Electrophilic and nucleophilic reactions in which high enol zinc is involved J am Chem SOC Source: the nucleophilicity of J am Chem SOC High enol zinc is undoubted, and there are many related studies However, Sophie A L rousseaux, an assistant professor from the Department of chemistry, University of Toronto, and his team have a strange idea They use zinc homoenol as a carbonyl electrophilic reagent to react with amine nucleophiles, and obtain trans Cyclopropylamine with high yield and high enantioselectivity, which has application value in the field of Medicine (J am Chem SOC., 2017, 139 (33), pp11357 – 11360 doi: 10.1021/jacs.7b07104) Fig 2 A corner of Laboratory of Sophie A.L rousseaux and rousseaux group: J am Chem SOC The author imagined that after the formation of zwitterionic zinc intermediate a from Cyclopropanol under the action of metal zinc, the nucleophile amine attacked the carbonyl group to form imine intermediate B, and then carried out intramolecular nucleophilic ring closing to obtain trans Cyclopropylamine Although there are many reports on the synthesis of trans Cyclopropylamine, how to achieve high enantioselectivity and non enantioselectivity is still a challenge Fig 3 The source of trans Cyclopropylamine synthesis process proposed by the author: J am Chem SOC In order to study the electrophilic activity of zinc homoenol, the author screened the reaction conditions with Cyclopropanol 1a and morpholine as substrates The first selected zinc salt is Et2Zn The experimental data show that the increase of 1A equivalent and the addition of inorganic base Na2CO3 can significantly improve the yield Due to the functional group limitation of Et2Zn, the author also investigated other zinc salts The results showed that the effect of Zn (CN) 2 was the best, and the product 2A could be obtained with high yield and excellent enantioselectivity At the same time, two groups of control experiments were designed to prove that zinc is indispensable in the reaction Two parallel reactions were designed to verify the hypothesis of zwitterionic zinc high enol intermediate Figure 4 Screening source of reaction conditions: after J am Chem SOC Had the best conditions, the author studied the universality of the reaction substrate The results show that heterocyclic amines of different sizes can react well with 1A under the action of Zn (CN) 2, and can be compatible with acetals, nitrates, carbamates, unsaturated heterocycles and other groups The reaction activity of indoline and acyclic secondary amine was better under the action of ET 2Zn Primary amines need to reduce the temperature at the end of the reaction to avoid the ring opening imine by-product becoming the main product On the other hand, the zinc (CN) 2 equivalent needed by different cyclopropanols in the reaction process is quite different Figure 5 Research source of substrate universality: J am Chem SOC In order to verify whether this method can become a means of building complex target products in the pharmaceutical industry, the author synthesized gsk2879552, an inhibitor of lysine demethylase 1 (LSD1) This inhibitor is currently being used as a therapeutic drug for small cell lung cancer Figure 6 Synthesis source of (±) - gsk2879552: J am Chem SOC Finally, the researchers also found that if α - chloroaldehyde was used as the substrate, Cyclopropylamine could be prepared in one pot without quenching reaction and separation of Cyclopropanol Conclusion: it can be used as electrophilic reagent to react with amines to form trans Cyclopropylamine This transformation process shows that the zinc homoenol derivatives are amphoteric, which makes them have the potential to develop new synthesis methods The author is further studying the synthesis of enantioselective Cyclopropylamine and exploring other nucleophiles that can perform similar ring closing process.