Angelw: copper catalyzed series reaction of kinugasa / Michael for asymmetric synthesis of spiro β - lactam

β - lactam structures are widely found in natural products and bioactive compounds, such as penicillin Among them, spirocyclic β - lactam has attracted more and more attention due to its unique four membered heterocyclic structure, enhanced three-dimensional properties, and more ideal physical, chemical and biological activities Therefore, the construction method of this kind of structure has also attracted the attention of many chemists High functional spiro β - lactam (scheme1-1) can be rapidly assembled from terminal alkyne and nitrone via kinugasa reaction Since Miura first developed the catalytic asymmetric kinugasa reaction in 1995, great progress has been made in this kind of reaction However, the tandem kinugasa reaction has rarely been reported (scheme 1-2) Recently, Professor Dieter Enders, research group of Institute of organic chemistry, Aachen University of technology, Germany, has developed a copper catalyzed series reaction of kinugasa / Michael to realize the efficient synthesis of spirocyclic β - lactam In this reaction, four consecutive chiral centers were constructed by using alkynylated Cyclohexanedione and nitrone as raw materials, with high regioselectivity, chemical selectivity, enantioselectivity and enantioselectivity (scheme 1-3) The research results were published in angelw Chem Int.ed (DOI: 10.1002 / anie 201806931) (source: angelw Chem Int.ed.) firstly, the author screened the reaction conditions with Cyclohexanedione 1a and nitrone 2A as substrates (Table 1) The optimum reaction conditions were as follows: 20 mol% Cu (OTF) 2 as catalyst, 22 mol% G as ligand, 1 equivalent i-Bu 2nh as base, reacting at 0 ℃ for 48 hours The yield and EE value of the target compound 3A were 83% and 94%, respectively (source: angelw Chem Int.ed.) later, the author studied the substrate applicability of the reaction (Table 2) Cyclohexanedione shows a wide range of functional group tolerance Cyclohexadienone with R 1 as methyl, ethyl, n-propyl, n-butyl, n-amyl and n-hexyl can participate in the reaction Halogens, alkyls and heterocyclic substituted nitrones are also substrates for synthesis In addition, the absolute configuration of 3p was determined by single crystal X-ray diffraction (source: angelw Chem Int.ed.) in order to verify the practicability of the reaction, the author carried out a scale-up reaction 1a and 2A reacted at the scale of 2 mmol to obtain 3a in 77% yield 3A can further obtain compound 4 (scheme 2) through hydrogenation (source: angelw Chem Int.ed.) finally, the author puts forward the possible reaction mechanism, as shown in Figure 2: bivalent copper is reduced to univalent copper in situ and interacts with substrate 1 to obtain intermediate I, I and nitroketone are added by [3 + 2] ring to obtain intermediate II, II is further rearranged to obtain quaternary ring intermediate III, and finally spiral β is obtained by Michael addition- Lactam (source: angelw Chem Int.ed.) conclusion: Professor Dieter Enders of Aachen University of technology, Germany, has developed for the first time a highly efficient method for the synthesis of spirocyclic β - lactam based on the copper catalyzed kinugasa / Michael series reaction The reaction has high regioselectivity, chemical selectivity, non enantioselectivity and enantioselectivity, but also reflects the atomic economy Moreover, the reaction conditions are mild, the operation is simple, and the amplification reaction can be realized.