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CN-122010655-A - Chiral spiro lactam and synthesis method thereof

CN122010655ACN 122010655 ACN122010655 ACN 122010655ACN-122010655-A

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to chiral spiro lactam and a synthesis method thereof. According to the method, by switching the metal catalyst and the chiral ligand system, the chiral spiro-lactam with a spiro quaternary carbon center, namely chiral spiro-gamma-lactam and chiral delta-lactam, is synthesized with high stereoselectivity starting from the beta-ketoamide precursor connected with the same alkynyl for the first time, and can be prepared in a large amount. Compared with the prior art, the method disclosed by the invention is mild in condition, simple, efficient, easy to operate, good in repeatability and excellent in regional and stereoselectivity.

Inventors

  • DENG QINGHAI
  • CAO ZHU
  • WU SHAOHUA
  • GONG FAN

Assignees

  • 上海师范大学

Dates

Publication Date
20260512
Application Date
20260116

Claims (10)

  1. 1. A method for synthesizing chiral spiro lactam, comprising the steps of: taking a beta-ketoamide compound as a substrate, and carrying out intramolecular cyclization reaction in the presence of a catalyst system to obtain chiral spiro lactam; wherein the structural formula of the beta-ketoamide compound is shown in the following formula 1: (1) a process for producing the same, In the formula 1, R is independently selected from hydrogen, aryl, aliphatic hydrocarbon group, halogen or ether group, and R 1 is alkyl or aryl.
  2. 2. The method for synthesizing chiral spiro-lactam according to claim 1, wherein, The catalyst system is a first catalyst system or a second catalyst system; Wherein the first catalytic system comprises copper salt and chiral pyrazine-bisoxazoline ligand, the molar ratio of the copper salt to the beta-ketoamide compound is 0.1:1 to 0.2:1, and the molar ratio of the chiral bisoxazoline ligand to the beta-ketoamide compound is 0.1:1 to 0.15:1; The second catalytic system comprises a nickel salt and a chiral bisoxazoline ligand, wherein the molar ratio of the nickel salt to the beta-ketoamide compound is 0.05:1 to 0.15:1, and the molar ratio of the chiral bisoxazoline ligand to the beta-ketoamide compound is 0.1:1 to 0.15:1.
  3. 3. A process for the synthesis of chiral spirocyclic lactams according to claim 2, characterized in that, Under the catalysis of a first catalytic system, the beta-ketoamide compound undergoes intramolecular cyclization reaction to obtain a chiral spiro gamma-lactam compound, the structural formula of which is shown as formula 2; (2), In the formula 2, R is independently selected from hydrogen, aryl, aliphatic hydrocarbon radicals, halogen or ether radicals, R 1 is alkyl or aryl; The above reaction is carried out in a halogenated alkane solvent.
  4. 4. A method of synthesizing a chiral spirolactam according to claim 3, wherein the copper salt is at least one selected from the group consisting of copper tetra-acetonitrile tetrafluoroborate, copper tetra-acetonitrile hexafluorophosphate, copper trifluoromethane sulfonate, and copper acetate.
  5. 5. A method of synthesizing a chiral spirocyclic lactam according to claim 3, characterized in that the haloalkane solvent comprises dichloromethane, 1, 2-dichloroethane or chloroform.
  6. 6. A process for the synthesis of chiral spirocyclic lactams according to claim 2, characterized in that, Under the catalysis of a second catalytic system, the beta-ketoamide compound undergoes intramolecular cyclization reaction to obtain a chiral spiro delta-lactam compound with a structural formula shown in a formula 3; (3), In the formula 3, R is independently selected from hydrogen, aryl, aliphatic hydrocarbon group, halogen or ether group, R 1 is alkyl or aryl, and the above reaction is carried out in an ester solvent.
  7. 7. The method for synthesizing chiral spiro lactam according to claim 6, wherein the nickel salt is at least one selected from the group consisting of nickel tetrafluoroborate hexahydrate, nickel perchlorate hexahydrate, nickel trifluoromethane sulfonate, and nickel acetate.
  8. 8. The method for synthesizing chiral spiro lactam according to claim 6, wherein the ester solvent comprises ethyl acetate, butyl acetate, isopropyl acetate, or t-butyl acetate.
  9. 9. A method of synthesizing a chiral spirocyclic lactam according to claim 1, characterized in that the intramolecular cyclization reaction is performed in the presence of a base; the molar ratio of the base to the β -ketoamide compound is from 1.0:1 to 1.5:1; The base is at least one selected from triethylamine, N-diisopropylethylamine, triethylenediamine, potassium carbonate, potassium hydroxide or lithium hydroxide.
  10. 10. A chiral spirocyclic lactam compound prepared by the method of any one of claims 1-9, wherein the chiral spirocyclic lactam compound is a chiral spirocyclic gamma-lactam compound or a chiral spirocyclic delta-lactam compound.

Description

Chiral spiro lactam and synthesis method thereof Technical Field The invention belongs to the technical field of organic synthesis, and particularly relates to chiral spiro lactam and a synthesis method thereof. Background Spiro gamma-lactams and delta-lactams are an important structural unit, widely exist in drug molecules and natural products, and have good biological activity and stereoselectivity; the rigid helical chiral structure thereof enables precise three-dimensional arrangement of pharmacophores, typically translating into enhanced target selectivity and metabolic stability. Despite the continuing interest in these structural motifs in the chemical community, asymmetric synthesis of spiro rings remains highly challenging, mainly due to the difficulty in constructing chiral tetra-substituted spirocarbon centers. Conventional synthetic methods typically require multiple steps of reactions, are harsh in conditions, have difficult stereoselective control, and have difficulty achieving regioselective switching. In the last decade, a series of innovative asymmetric catalytic methods provide a practical platform for constructing chiral spiro backbones. In particular, catalyzing asymmetric intramolecular alkyne nucleophilic addition reactions has become a very important and atom-economical method for constructing chiral pure backbones in modern synthesis. However, the ability to selectively switch between 5-exo-dig and 6-endo-dig cyclization modes while achieving highly enantioselective synthesis remains an unresolved challenge. For the presently reported examples of chiral spiro ring synthesis via 5-exo-dig cyclization mode, although there is better stereoselectivity, none is able to control the regioselectivity of alkynes. In 2021, the university of Xiamen She Longwu and the university of Zhejiang Hong Xin develop a strategy for directly activating alkynylamides by chiral Bronsted acid, realize high-enantioselectivity dearomatization spiro cyclization reaction of naphthol, phenol and pyrrole alkynylamides, efficiently construct chiral spirocyclic ketone and 2H-pyrrole frameworks, break through the limitation of traditional chiral acid catalysis for (Zhang, Y.-Q.; Chen, Y.-B.; Liu, J.-R.; Wu, S.-Q.; Fan, X.-Y.; Zhang, Z.-X.; Hong, X.; Ye, L.-W. Nat. Chem. 2021, 13, 1093-1100).2021 years, develop a double silver/diamine compound catalytic system by the university of Huadong university of Italian, liu Zhenhe Cheng Rui Chinese group, realize asymmetric vinyl Conia-ene reaction of alkynyl cyclohexenone, efficiently construct chiral all-carbon spiro compound for (Zou, C.; Yang, L.; Zhang, L.; Liu, C.; Ma, Y.; Song, G.; Liu, Z.; Cheng, R.; Ye, J. ACS Catal. 2021, 11, 6865-6871).2022 years, and develop an asymmetric gold catalytic dearomatization cyclization method based on a metal-chiral ligand synergetic strategy by the university of California, saint Bara advance sheet and Shanghai organic chemistry institute of book force team. By designing and synthesizing the novel bifunctional axial chiral phosphine ligand, the high-enantioselectivity spirocyclization reaction of naphthol and phenol derivatives is realized, a chiral spiro [5,5] trienone skeleton is efficiently constructed for (Zhao, K.; Kohnke, P.; Yang, Z.-G.; Cheng, X.-P.; You, S.-L.; Zhang, L.-M. Angew. Chem., Int. Ed. 2022, 61, No. e202207518).2025 years, a chiral proton donor and gold (I) co-catalytic system is developed by the university of Harvard Eric N.Jacobsen team, the high-enantioselectivity dearomatization spirocyclization reaction of naphthol is realized, and a spirocyclic compound containing a quaternary carbon chiral center is efficiently constructed (Adrianov, T.; jacobsen, E.N.J. Am. chem. Soc.2025, 147, 41229-41236). In sharp contrast, to date, only a few examples of the construction of spiro delta-lactams by 6-endo-dig cyclization mode have been reported and all are racemized. In 2023, the university of science and technology of Jiangxi Luo Mugu and the Shougang team develop an electrochemical method without catalyst and chemical oxidant, aromatic radical cations are generated through anodic oxidation, the biaryl alkyne ketone and alcohol are promoted to carry out spiro cyclization reaction, the alkoxylated spiro [5,5] triene ketone is efficiently synthesized in (Zhou, W.; Li, Z.-Q.; Cheng, C.; Lu, L.; Yang, R.; Song, X.-R.; Luo, M.-J.; Xiao, Q. Org. Lett. 2023, 25, 9158-9163).2025, the university of Zhejiang industry Liang Renjiao and the university of Tianjin industry Gu Yixia develop a 1, 6-eneyne cycloisomerization reaction of palladium-catalyzed alkynyl-connection benzofuran and indole, and the spiro dihydrobenzofuran and indoline compound (Lu, J.-B. Wang, Y.-F.; Xu, X.-T. Wang, B.-X.; Liang, R.-X.; Jia, Y.-X. Chem. Commun. 2025, 61, 7616-7619). are still efficiently constructed through 6-endo-dig cyclization, and the traditional method such as intramolecular cyclization, rearrangement reaction or multicomponent reaction is stil