Method for directly constructing highly optically active tetrasubstituted allenic acid compounds

Patent metadata

Field	Value
Publication number	US-11623907-B2
Application number	US-201917299082-A
Country	US
Kind code	B2
Filing date	Dec 4, 2019
Priority date	Dec 12, 2018
Publication date	Apr 11, 2023
Grant date	Apr 11, 2023

Abstract

The present invention discloses a method for directly constructing highly optically active tetrasubstituted allenic acid compounds, i.e., a one-step process for directly constructing highly optically active axially chiral tetrasubstituted allenic acid compounds by using tertiary propargyl alcohol, carbon monoxide and water as reactants in an organic solvent in the presence of palladium catalyst, chiral diphosphine ligand, monophosphine ligand and organic phosphoric acid. The method of the present invention has the following advantages: operations are simple, raw materials and reagents are readily available, the reaction conditions are mild, the substrate has high universality, the functional group has good compatibility, and the reaction has high enantioselectivity (90%˜>99% ee). The highly optically active allenic acid compounds obtained by the present invention can be used as an important intermediate to construct γ-butyrolactone compounds containing tetrasubstituted chiral quaternary carbon centers, tetrasubstituted allenic alcohol and other compounds.

First claim

What is claimed:

1. A method for preparing optically active axially chiral allenic acid compounds of formula 2 with greater than 90% enantiomeric excess, wherein, in the presence of palladium catalyst, chiral diphosphine ligand, monophosphine ligand and organic phosphoric acid, a tertiary propargyl alcohol with different substituents, carbon monoxide and water undergo asymmetric allylation reaction in an organic solvent through transition metal catalysis, preparing the optically active axially chiral allenic acid compounds in one-step synthesis, the reaction process has the following reaction equation (I):

the different substituents of the tertiary propargyl alcohol with different substituents are R 1 , R 2 , R 3 ;
wherein, R 1 is an alkyl, an alkyl with functional group, phenyl, aryl, heterocyclic group or naphthyl; R 2 is an alkyl, an alkyl with functional group, phenyl, aryl, heterocyclic group or naphthyl; R 3 is an alkyl, an alkyl with functional group, phenyl, aryl, heterocyclic group or naphthyl; the said aryl is a phenyl with electron-donating or electron-withdrawing substituents at the ortho, meta, and para positions; the said heterocyclic group is thienyl, furyl, or pyridyl with electron-donating or electron-withdrawing substituents.

2. The method of claim 1 , wherein, R 1 is a C1-C20 alkyl, a C1-C20 alkyl with functional group at the end, phenyl, aryl, heterocyclic group or naphthyl; R 2 is a C1-C10 alkyl, a C1-C10 alkyl with functional group at the end, phenyl, aryl, heterocyclic group or naphthyl; R 3 is a C1-C10 alkyl, a C1-C10 alkyl with a functional group at the end, phenyl, aryl, heterocyclic group or naphthyl; wherein, the functional group of the C1-C20 alkyl or C1-C10 alkyl with a functional group at the end, is selected from the group consisting of carbon-carbon double bond, carbon-carbon triple bond, ester group, hydroxyl group, acyl group, acyloxy group, amide group, halogen, carboxyl group, or cyano group; the aryl is a phenyl with electron-withdrawing or electron-donating substituents at the ortho, meta, and para positions; the heterocyclic group is thienyl, furyl, naphthyl or pyridyl, with electron-withdrawing or electron-donating substituents; the electron-withdrawing substituent is halogen, nitro group, ester group, carboxyl group, acyl group, amide group, cyano group; the electron-donating substituent is alkyl, alkenyl, phenyl, alkoxy group, hydroxyl, or amino group.

3. The method of claim 1 , wherein, the method comprises the following steps:
1) a palladium catalyst, a chiral diphosphine ligand, a monophosphine ligand and an organic phosphoric acid are added in sequence into a dried reaction tube, plugging the reaction tube with a rubber stopper, connecting a vacuum pump, degassing the reaction tube and refilling with argon three times, adding the tertiary propargyl alcohol, water, and a certain volume of organic solvent; freezing the reaction tube in liquid nitrogen bath, inserting carbon monoxide balloon into the dried reaction tube, degassing to remove the argon inside completely, and refilling with CO by the balloon of CO three times, returning the reaction system to room temperature, putting the reaction tube in the preset low-temperature bath or oil bath at −20-60° C. and stirring for 4-36 hours; wherein the amount of the organic solvent is 1.0-10.0 mL to 1 mmol of tertiary propargyl alcohol;
2) after the completion of the reaction in step (1), raising the reaction tube from the low-temperature bath;
after returning to the room temperature, ethyl acetate is added into the reaction tube and a mixture obtained, filtering the mixture with silica gel short column, washing with a certain amount of ethyl acetate, concentrating, and subjecting to the flash column chromatography, so as to obtain the optically active axially chiral allenic acid compounds; wherein the amount of ethyl acetate is 1.0-100 mL to 1 mmol of tertiary propargyl alcohol (+1).

4. The method of claim 1 , wherein the palladium catalysts are any one or more of dis-(allyl-palladium chloride), tetra-(triphenylphosphine) palladium, tri-(dibenzylidene-acetone) dipalladium, dis-(cinnamyl-palladium chloride), dis-(dibenzylidene-acetone) monopalladium, palladium chloride, palladium acetate, dis-(triphenylphosphine) palladium chloride and bis-(acetonitrile) palladium chloride.

5. The method of claim 1 , wherein the chiral diphosphine ligand is selected from the group consisting of (R)-L2-(R)-L4 and its enantiomer (S)-L2-(S)-L4 in the following structures; wherein, “Ar” is a phenyl, an aryl, heterocyclic group or naphthyl; the aryl is a phenyl substituted by alkyl and/or alkoxy group at the ortho, meta, and para positions; the heterocyclic group is thienyl, furyl, naphthyl or pyridyl substituted by alkyl or alkoxy group, furan substituted by alkyl or alkoxy group, pyridine substituted by alkyl or alkoxy group;

6. The method of claim 5 , wherein the chiral diphosphine ligand is selected from (R)-L4 and its enantiomer (S)-L4, the said structure of (R)-L4 is as follows:
wherein, “Ar” is 3,5-dialkyl-4-alkoxyphenyl, 3,5-dialkylphenyl or phenyl;

7. The method of claim 1 , wherein the monophosphine ligands are selected from the group consisting of tributylphosphine, tricyclohexylphosphine, triphenylphosphine, tris(ortho-methyl-phenyl)phosphine, tris(meta-methyl-phenyl) phosphine, tris(para-methyl-phenyl)phosphine, tris(para-methoxyphenyl)phosphine, tris(3,5-di-tri-fluoromethyl-phenyl) phosphine, and trifuryl-phosphine; and/or, the organic solvents are selected from the group consisting of N-methyl pyrrolidone, 1,4-dioxane, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, chlorobenzene, toluene, trifluorotoluene, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, and acetic acid.

8. The method of claim 1 , wherein the organic phosphoric acid is selected from any one or more of organic phosphoric acid 1, organic phosphoric acid 2, organic phosphoric acid 3, the structure of which is as follows; wherein, R 1 is hydrogen, C1-C6 alkyl, phenyl or aryl; the said aryl is a phenyl substituted by C1-C6 alkyl at the ortho, meta, and para positions; R 2 is C1-C6 alkyl, phenyl or aryl; the said aryl is a phenyl substituted by C1-C6 alkyl at the ortho, meta, and para positions,

organic phosphoric acid 1, organic phosphoric acid 2, organic phosphoric acid 3.

9. The method of claim 1 , wherein the molar ratio of tertiary propargyl alcohol (±1) with different substituents, water, palladium catalyst, chiral diphosphine ligand, monophosphine ligand and organic phosphoric acid in equation (I) of the present invention is 1.0: (1.0-30.0): (0.005-0.1): (0.005-0.1): (0.01-0.3): (0.01-0.3); and/or, the reaction temperature of the invention is 20-60° C.; and/or, the dosage of the organic solvent is 1.0-10.0 mL to 1 mmol of tertiary propargyl alcohol.

10. The method of claim 2 , wherein the palladium catalysts are any one or more of dis-(allyl-palladium chloride), tetra-(triphenylphosphine) palladium, tri-(dibenzylidene-acetone) dipalladium, dis-(cinnamyl-palladium chloride), dis-(dibenzylidene-acetone) monopalladium, palladium chloride, palladium acetate, dis-(triphenylphosphine) palladium chloride and bis-(acetonitrile) palladium chloride.

11. The method of claim 3 , whe

Assignees

• Univ Fudan
• Fudan Univeristy

Inventors

• Ma Shengming
• Zheng Weifeng
• Qian Hui

Classifications

• C07D307/58

  One oxygen atom, e.g. butenolide · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07C253/30

  by reactions not involving the formation of cyano groups · CPC title

• C07D333/24

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07C51/12 Primary

  on an oxygen-containing group in organic compounds, e.g. alcohols · CPC title