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CN-122010966-A - Preparation method of chiral spiro framework and application of chiral spiro framework in ligand synthesis

CN122010966ACN 122010966 ACN122010966 ACN 122010966ACN-122010966-A

Abstract

The invention relates to the technical field of organic chemistry, in particular to a preparation method of a chiral spiro framework and application thereof in ligand synthesis, wherein the preparation method comprises the following steps of reacting an amino diene compound shown in a formula I with an aldehyde compound shown in a formula III under the action of a transition metal catalyst and a chiral phosphine ligand to obtain an alkenyl substituted polycyclic nitrogen heterocycle shown in a formula IV; or reacting an amino diene compound shown in a formula II with an aldehyde compound shown in a formula III under the action of a transition metal catalyst and a chiral phosphine ligand to obtain the alkenyl substituted polycyclic nitrogen heterocycle shown in a formula V. The method has the advantages of high atom economy, water as the only byproduct, simple and efficient system, simple and convenient practical operation, one-step construction of a plurality of rings, high step economy, capability of constructing chiral quaternary carbon centers and high enantioselectivity.

Inventors

  • HUANG HANMIN
  • ZHOU YANGKUN

Assignees

  • 中国科学技术大学

Dates

Publication Date
20260512
Application Date
20260130

Claims (10)

  1. 1. A preparation method of a chiral spiro framework comprises the following steps: Reacting an amino diene compound shown in a formula I with an aldehyde compound shown in a formula III under the action of a transition metal catalyst and a chiral phosphine ligand to obtain an alkenyl-substituted polycyclic nitrogen heterocycle shown in a formula IV, or reacting an amino diene compound shown in a formula II with an aldehyde compound shown in a formula III under the action of a transition metal catalyst and a chiral phosphine ligand to obtain an alkenyl-substituted polycyclic nitrogen heterocycle shown in a formula V; Wherein, the Selected from unsaturated rings; Wherein n1 and n2 are independently selected from any integer of 0 to 10; R 1 、R 2 is independently selected from hydrogen, substituted or unsubstituted alkyl of C1 to C30, cycloalkyl of C3 to C30 or aryl of C6 to C30; R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl of C1-C30, alkoxy of C1-C30, cycloalkyl of C3-C30, aryl of C6-C30, nitro, ester or amino, wherein R 3 and R 4 、R 4 and R 5 、R 5 and R 6 、R 7 and R 8 、R 8 and R 9 or R 9 and R 10 may be linked as an alicyclic or aromatic ring; The substitution is one or more than one of halogen, nitryl, ester group, amino, C1-C30 alkyl, C1-C30 halogenated alkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C6-C30 aryl or C4-C30 heteroaryl; X is independently selected from O or N-R 11 , and R 11 is selected from H, C alkyl sulfonyl of C1-C40 or aryl sulfonyl of C6-C60.
  2. 2. A method for preparing a chiral spiro backbone according to claim 1, wherein the method comprises Is benzene ring or pyridine ring; n1 and n2 are independently selected from any integer of 0 to 2.
  3. 3. The method for preparing a chiral spiro backbone according to claim 1, wherein R 1 、R 2 is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl of C1 to C6, cycloalkyl of C3 to C6, and aryl of C6 to C12; R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl of C1-C3, alkoxy of C1-C6, cycloalkyl of C3-C6, aryl of C6-C12, nitro, ester group and amino; Wherein the substitution is one or more than one substituent selected from halogen, nitro, ester, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl or C4-C12 heteroaryl; X is independently selected from O or N-R 11 , and R 11 is selected from H, C alkyl sulfonyl of 1-10 carbon atoms or aryl sulfonyl of 6-12 carbon atoms.
  4. 4. The method for preparing chiral spiro backbone according to claim 1, wherein the amino diene compound of formula I has any one of the following structures: The amino diene compound shown in the formula II has the following structure: The aldehyde compound shown in the formula III has any one of the following structures: 。
  5. 5. A chiral spiro backbone compound having a structure according to formula IV or formula V: Wherein, the 、n1、n2、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、X The range of (c) is as set forth in any one of claims 1 to 4.
  6. 6. A chiral spiro backbone compound according to claim 5, having any one of the following structures: 。
  7. 7. An aza spiro chiral ligand is characterized by having a structure shown in formula VI-formula XI: Wherein n1, n2, R 1 、R 8 、R 9 、R 10 , X are as defined in any one of claims 1 to 4; R 5' 、R 6' is independently selected from substituted or unsubstituted alkyl of C1-C30, cycloalkyl of C3-C30, aryl of C6-C30 or heteroaryl of C4-C30; r 7' 、R 8' is independently selected from hydrogen, substituted or unsubstituted alkyl of C1-C30, cycloalkyl of C3-C30, aryl of C6-C30 or heteroaryl of C4-C30, R 7' and R 8' can be connected as alicyclic or aromatic ring; R 9' 、R 10' is independently selected from substituted or unsubstituted alkyl of C1-C30, cycloalkyl of C3-C30, aryl of C6-C30 or heteroaryl of C4-C30; The substitution is one or more of halogen, nitryl, amino, C1-C30 alkyl, C1-C30 halogenated alkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C6-C30 aryl or C4-C30 heteroaryl; * The absolute configuration of chiral carbon atoms in the oxazoline structure is R configuration or S configuration.
  8. 8. The azaspiro chiral ligand according to claim 7, wherein R 5' 、R 6' is independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C6-C12 aryl and C4-C12 heteroaryl, respectively, substituted or unsubstituted; R 7' 、R 8' is independently selected from hydrogen, substituted or unsubstituted alkyl of C1-C6, cycloalkyl of C3-C6, aryl of C6-C12 or heteroaryl of C4-C12, R 7' and R 8' can be connected into a C5-C10 alicyclic ring or a C6-C12 aromatic ring; R 9' 、R 10' is independently selected from substituted or unsubstituted alkyl of C1 to C6, cycloalkyl of C3 to C6, aryl of C6 to C12 or heteroaryl of C4 to C12; The substitution is one or more of halogen, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C12 aryl or C4-C12 heteroaryl.
  9. 9. The azaspiro chiral ligand of claim 7, having any one of the following structures: 。
  10. 10. use of an azaspiro chiral ligand according to any one of claims 7-9 in transition metal catalyzed asymmetric allyl substitution, hydrogenation, hydroamination, carboamination, carbonylation reactions.

Description

Preparation method of chiral spiro framework and application of chiral spiro framework in ligand synthesis Technical Field The invention relates to the technical field of organic chemistry, in particular to a preparation method of a chiral spiro framework and application of the chiral spiro framework in ligand synthesis. Background The spiro compound has wide application in the fields of bioactive compounds, molecular catalysts and the like. Among them, the polyspirocyclic compound is one of representative spiro compounds, which are commonly found in natural products and drugs, such as the following compounds: It has been found that spiro structures, due to their unique three-dimensional structure and skeletal rigidity, generally increase the solubility of compounds and decrease conformational entropy, which makes the introduction of chiral azaspiro compounds important for pharmaceutical chemistry studies. The skeleton feature can also fix the three-dimensional space position of the functional group, thereby expanding the application of the spiro compound in the screening of computer-aided medicaments. In addition, the multi-spiro compound can also be used as an organic catalyst to realize asymmetric reaction. It can also be used as a ligand to realize transition metal catalyzed organic reactions, and has wide application potential. The method for synthesizing chiral multi-spiro has been one of the important research contents of organic synthetic chemistry. Over the past decades, chemists have utilized traditional means of radical coupling, olefin metathesis, cycloaddition, nucleophilic substitution, and Pauson-Khand reactions to construct spiro backbones. However, these methods have the disadvantages of long synthesis steps, low atom economy and the like, and the application range is greatly limited. In recent years, some asymmetric catalytic reactions for constructing multiple spiro rings have been reported, which mainly comprise tandem reactions catalyzed by small organic molecules, azide-propargylamine cyclization reactions catalyzed by transition metals, and the like. However, the existing asymmetric synthesis method has the defects of 1) complex reaction raw materials, 2) difficult divergent synthesis and 3) limited reaction types. Therefore, the development of a novel catalytic synthesis method for realizing the modularized synthesis of chiral multi-spiro has very important significance. Disclosure of Invention In view of the above, the technical problem to be solved by the invention is to provide a preparation method of chiral spiro framework and application thereof in ligand synthesis, wherein the method has good substrate adaptability, can prepare azaspiro with various structures, and the only byproduct is water, so that the method meets the requirements of green chemistry. The invention provides a preparation method of a chiral spiro framework, which comprises the following steps: Reacting an amino diene compound shown in a formula I with an aldehyde compound shown in a formula III under the action of a transition metal catalyst and a chiral phosphine ligand to obtain an alkenyl-substituted polycyclic nitrogen heterocycle shown in a formula IV, or reacting an amino diene compound shown in a formula II with an aldehyde compound shown in a formula III under the action of a transition metal catalyst and a chiral phosphine ligand to obtain an alkenyl-substituted polycyclic nitrogen heterocycle shown in a formula V; Wherein, the Selected from unsaturated rings; n1 and n2 are independently selected from any integer of 0 to 10; R 1、R2 is independently selected from hydrogen, substituted or unsubstituted alkyl of C1 to C30, cycloalkyl of C3 to C30 or aryl of C6 to C30; R 3、R4、R5、R6、R7、R8、R9、R10 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl of C1-C30, alkoxy of C1-C30, cycloalkyl of C3-C30, aryl of C6-C30, nitro, ester or amino, wherein R 3 and R 4、R4 and R 5、R5 and R 6、R7 and R 8、R8 and R 9 or R 9 and R 10 may be linked as an alicyclic or aromatic ring; The substitution is one or more than one of halogen, nitryl, ester group, amino, C1-C30 alkyl, C1-C30 halogenated alkyl, C1-C30 alkoxy, C3-C30 cycloalkyl, C6-C30 aryl or C4-C30 heteroaryl; X is independently selected from O or N-R 11, and R 11 is selected from H, C alkyl sulfonyl of C1-C40 or aryl sulfonyl of C6-C60. The saidPreferably a six-membered unsaturated ring, more preferably a six-membered aromatic ring, most preferably a benzene ring or a pyridine ring. The n1 and n2 are independently selected from any integer of 0 to 10, preferably any integer of 0 to 5, more preferably any integer of 0 to 2, and may be, for example, 0, 1 or 2. R 1、R2 is independently preferably hydrogen, substituted or unsubstituted alkyl of C1 to C6, cycloalkyl of C3 to C6 or aryl of C6 to C12. Further preferred, the R 1、R2 is independently selected from the group consisting of amino protecting groups including, but not limited to, benz