JACS: asymmetric synthesis of cyclobutanone by series cyclopropane / half pinacol rearrangement catalyzed by Lewis acid

Cyclobutene derivatives exist in many natural products, and are also important structural units or target molecules in pharmaceutical chemistry, so they have attracted more and more attention Among the various synthesis methods, enantioselective synthesis is a simple and effective method, such as the use of cobalt catalyzed enantioselective intramolecular hydrogenation and palladium catalyzed asymmetric allylic alkylation to construct a chiral cyclobutanone with a-quaternary carbon center; or the use of 1,2-alkyl migration of Cyclopropanol (half frequency alcohol rearrangement) to synthesize cyclobutanone (scheme 1a) Recently, alexakis group synthesized β - halospirocyclic butanone by catalyzing and halogenating 1-vinylcyclopropanol rearrangement with chiral phosphoric acid (CPA); toste and Trost group developed the enantioselective ring extension reaction of allylic Cyclopropanol catalyzed by transition metal gold and palladium respectively The half frequency rearrangement of cyclopropane involves the transfer of 1,2-alkyl group to carbonyl group α - hydroxy or α - siloxycyclobutanone can be obtained Although this reaction has been reported for decades, its asymmetric catalytic version has not been reported so far (scheme 1b) Recently, the do Hyun Ryu research group of chengjunguan University / Jinan University in South Korea realized the asymmetric synthesis of cyclobutanone (scheme 1c) through the series cyclopropanation / half pinacol rearrangement catalyzed by chiral Lewis acid The relevant papers were published on J am Chem SOC (DOI: 10.1021 / JACS 8b06835) (photo source: J am Chem SOC.) firstly, in the presence of 20 mol% Cobi catalyst 4, the enantioselective synthesis conditions of cyclobutanone (Table 1) were studied by using the reaction substrates of siloxyacrolein and phenyldiazole When the reaction is carried out in dichloromethane or toluene, the enantioselectivity is poor; when propiononitrile is used as solvent, the enantioselectivity is significantly improved, but the non enantioselectivity is still low In addition to path a, which is obtained by the series cyclopropanization / half pinacol rearrangement of the substrate, there is also the possibility of 1,2-hydrogen migration to generate the diazo carbon insertion by-product 3 (path B) So the author screened all kinds of catalysts and found that the catalyst with larger steric hindrance had the best effect in 4 days In addition, the addition of 3 Å zeolite in the reaction can improve the reactivity, and then reduce the reaction temperature to - 78 ° C, the enantioselectivity and non enantioselectivity are further improved (photo source: J am Chem SOC.) after optimizing the selective synthesis conditions of cyclobutanone, the author evaluated the applicability of the method with a series of diazo esters (Table 2) All kinds of toluene and 2-naphthyldiazo esters have good reactivity and excellent non enantioselectivity; all kinds of halogen substituted aryldiazo esters are also suitable substrates with good yields and excellent DR and EE values; 4-cyanoarydiazo ester substrates have high yields and EE values, but poor non enantioselectivity Different ester substituted p-methylphenyl diazo ester substrates can produce corresponding cyclobutanone products with good yield, good to excellent enantioselectivity and non enantioselectivity The method has also been successfully applied to the substrate of alkyl diazo ester In addition, the absolute configuration of 2R was confirmed by X-ray analysis, and the same relative configuration of β - phenylcyclobutanone 2C and β - ethylcyclobutanone 2R was confirmed by noe analysis (photo source: J am Chem SOC.) in order to prove the practicability of this method, the product 2 - (triethylsiloxy) cyclobutanone (2n), which has optical activity, was further chemically transformed (scheme 2) The single enantiomeric cyclobutanol 5 can be obtained by the reduction of 2n with NaBH 4; the β - quaternary carbon - γ - lactone 6 can be obtained by the oxidation of Baeyer Villiger; the carbonyl addition of 2n with trimethylsilyldiazomethane under the catalysis of Lewis acid at low temperature, and the single enantiomeric α - silylcyclopentenone 7 can be obtained by the ring expansion of Tiffeneau demjanov type (photo source: J am Chem SOC.) in order to verify the mechanism and enantioselectivity of half pinacol rearrangement, the author conducted a control experiment (scheme 3) After 24 hours reaction, trans cyclopropane 1I and cyclobutanone 2I were obtained, and the only product 2I and trace 1I were obtained after prolonging the reaction time, which indicated that cyclopropane 1I could be converted to cyclobutanone 2I (scheme 3a) under Lewis acid condition In addition, 2I and some uncertain impurities were obtained under Cobi catalysis, and the enantioselectivity was unchanged before and after the reaction (scheme 3b) The results of the control experiment show that the substrate first reacts to form cyclopropane intermediate 1, and then 1 is converted to cyclobutanone 2 by stereoselective semipinacol rearrangement under Lewis acid condition (photo source: J am Chem SOC.) based on the results of preliminary mechanism study, the transition state model of cyclobutanone enantioselective synthesis process (Figure 1) is presented After asymmetric cyclopropanization of α - siloxyacrolein and diazoate, Cobi catalyst can activate the donor acceptor cyclopropane (8) This activation takes place in C1 with electron withdrawing group instead of C2 with two hydrogen groups This stereoselective half pinacol rearrangement results in the formation of the intermediate 9, which then migrates through the silica group to produce chiral (1s, 2R) - 1-siloxycyclobutanone 2 (photo source: J am Chem SOC.) conclusion: do Hyun Ryu research group has developed a series cyclopropanation / semipinacol rearrangement reaction of α - siloxyacrolein and α - alkyl or aryldiazo ester catalyzed by chiral Lewis acid, which realizes the enantioselective synthesis of cyclobutanone A variety of α - siloxycyclobutanone with chiral β - quaternary carbon centers can be obtained by this method, which has excellent enantioselectivity and non enantioselectivity α - siloxycyclobutanone can be used as a valuable intermediate in the synthesis of complex molecules.