Enantioselective synthesis of pyrrolidines substituted with flavones, and intermediates thereof

1. A process for the preparation of the compound (−)-trans-(1-methyl-3-(2,4,6-trimethoxyphenyl)pyrrolidin-2-yl)-methanol represented by Formula A;

comprising treating the compound (−)-trans-1-methyl-5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2-carboxylic acid of the following Formula E;

(hereinafter referred to as compound E), with a reducing agent in a solvent.

2. The process according to claim 1 , wherein the reducing agent is a hydride.

3. The process according to claim 2 , wherein the hydride is selected from lithium aluminium hydride, diisobutyl aluminium hydride and sodium borohydride.

4. The process according to claim 1 , wherein the solvent used is an ether.

5. The process according to claim 4 , wherein the ether is selected from tetrahydrofuran, dioxane and diethyl ether.

6. The process according to claim 1 , wherein the compound E is prepared by

(a) carrying out a stereospecific Michael addition of dimethyl malonate to (E)-methyl-2-nitro-3-(2,4,6-trimethoxyphenyl)acrylate in a solvent in the presence of a catalyst complex, a base and molecular sieves, wherein the catalyst complex comprises a chiral bis(oxazoline) ligand and a metal complex, to obtain (+)-trimethyl-3-nitro-2-(2,4,6-trimethoxyphenyl) propane-1,1,3-tricarboxylate represented by the following Formula B;

(hereinafter referred to as compound B);

(b) treating compound B as obtained in step (a) with a reducing agent in a solvent to obtain (+)-dimethyl-5-oxo-3-(2,4,6-trimethoxyphenyl)-pyrrolidine-2,4-dicarboxylate represented by the following Formula C;

(hereinafter referred to as compound C);

(c) treating compound C with sodium chloride in a solvent and heating the resulting reaction mixture to a temperature in the range of 120° C. to 170° C. to obtain (+)-methyl-5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2-carboxylate as a mixture of cis and trans isomers, represented by the following Formula D;

(hereinafter referred to as compound D);

(d) reacting compound D with a methylating agent in a solvent and a base selected from an alkaline metal hydride and an alkaline metal carbonate; followed by subjecting the resulting mixture of cis and trans compounds to alkaline hydrolysis with an alkaline metal hydroxide in an alcohol, and heating the resulting reaction mixture to a temperature in the range of 50° C. to 100° C. to obtain compound E as a single trans isomer.

7. The process according to claim 6 , wherein the chiral bis(oxazoline) ligand used in step (a) is (3aS,3a′S,8aR,8a′R)-2,2′(cyclopropane-1,1-diyl)bis(8,8a-dihydro-3aH-indeno[1,2d]oxazole).

8. The process according to claim 6 , wherein the metal complex used in step (a) is selected from magnesium trifluoromethanesulphonate, magnesium perchlorate, copper trifluoromethanesulphonate, zinc trifluoromethanesulphonate, lanthanum trifluoromethanesulphonate, nickel trifluoromethanesulphonate, magnesium bromide, copper bromide, zinc bromide, nickel bromide, magnesium iodide, copper iodide, zinc iodide, nickel iodide, magnesium acetylacetonate, copper acetylacetonate, zinc acetylacetonate, and nickel acetylacetonate.

9. The process according to claim 8 , wherein the metal complex is magnesium trifluoromethanesulphonate.

10. The process according to claim 6 , wherein the base used in step (a) is selected from triethylamine, diisopropylamine, 2,6-lutidine, N-methylmorpholine, N-ethylpiperidine, imidazole and 5,6-dimethylbenzimidazole.

11. The process according to claim 10 , wherein the base is N-methylmorpholine.

12. The process according to claim 6 , wherein in step (b), the treatment of compound B with a reducing agent in a solvent is carried out using stannous chloride as the reducing agent.

13. The process according to claim 12 , wherein the solvent is ethyl acetate.

14. The process according to claim 6 , wherein in step (b), the treatment of compound B with a reducing agent in a solvent is carried out using Raney nickel as the reducing agent.

15. The process according to claim 14 , wherein the solvent is selected from tetrahydrofuran, dioxane and N,N-dimethylformamide.