Method for preparation of justicidin a derivatives of arylnaphthalene lignan structure

1. A method for preparing a precursor of an arylnaphthalene lignan compound using Scheme A:

wherein

each of A and B is independently C1-C8 alkyl or C2-C9 alkylether or A and B are linked via methylene to form a heterocycle;

X is —O, —NR1 or —CH2—;

n is 1 or 2;

R1 is C1-C8 alkyl or C7-C14 arylalkyl; and

M is lithium, potassium or sodium.

2. The method according to claim 1 , wherein the arylnaphthalene lignan compound has a structure of Chemical Formula 6 or 9:

wherein

Y is hydroxyl, sulfonate,

wherein

Ar is

R 2 is hydrogen, C 1 -C 8 alkyl, C 1 -C 4 alkyloxy, C 1 -C 4 alkylether, C 1 -C 4 alkylthiooxy, vinyl, C 3 C 8 alkylvinyl, hydroxyl, nitro (—NO 2 ), fluoro, chloro, cyano, formyl (—CHO), C 2 -C 12 acyl, C 1 -C 5 alkylester or C 7 -C 10 arylester;

R 3 is C 1 -C 10 alkyl, C 6 -C 12 aryl, C 7 -C 10 alkylaryl, C 2 -C 10 arylalkyl, C 1 -C 4 alkylether, C 1 -C 5 alkylester or C 2 -C 12 acyl;

R 4 is hydrogen, C 1 -C 6 alkyl, C 7 -C 12 cyclohexylalkyl, C 7 -C 12 arylalkyl, C 2 -C 6 alkylether, C 2 -C 6 alkylthioether, C 2 -C 6 alkylcyano, C 1 -C 4 alkylalcohol or

R 5 is independently hydrogen, C 1 -C 6 alkyl, C 7 -C 12 cyclohexylalkyl, C 7 -C 12 arylalkyl, C 2 -C 6 alkylether, C 2 -C 6 alkylthioether, C 2 -C 6 alkylcyano, C 1 -C 4 alkylalcohol or

R 6 is hydrogen, C 1 -C 6 alkyl, C 7 -C 10 ) alkylaryl, C 1 -C 4 alkylether, C 1 -C 4 alkylthioether, fluoro or chloro;

o is an integer from 1 to 5; and

p is an integer from 0 to 2, and

Z is O—R 7 ,

 or glycosyl

wherein

R 7 is hydrogen, C 1 -C 8 alkyl, C 2 -C 9 alkylether, C 1 -C 5 alkylester, C 7 -C 10 arylester or

R 8 is C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, nitro (—NO 2 ), cyano (—CN), fluoro, chloro, bromo, iodo or hydrogen;

q is an integer from 0 to 5;

r is an integer from 1 to 4;

R 9 is C 1 -C 8 alkyl or hydrogen;

s is an integer from 1 to 5; and

the glycosyl group is 4-Oβ-D-galactopyranosyl, 4-O-α-L-arabinosyl, 4O-β-D-glucopyranosyl, 4-O-β-D-xylosyl, 6′-O-methyl-4-O-β-D-glucopyranosyl, 6′-O-methyl-4-O-β-D-galactopyranosyl, 4-O-β-D-fucopyranosyl, 6′-O-benzyl-4O-β-D-glucopyranosyl or 6′-0-benzyl-4-O-β-D-galactopyranosyl.

3. The method according to claim 1 , wherein the arylnaphthalene lignan compound is 9-(benzo[d][1,3]dioxol-5-yl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one (justicidin A), t-butyl 9-hydroxy-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 9-(t-butoxycarbonyloxy)-6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate, 9-(benzo[d][1,3]dioxol-5-yl)-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl t-butylcarbonate, 9-(benzo[d][1,3]dioxol-5-yl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one (diphyllin), 9-(3,4-dimethoxyphenyl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one (cilinaphthalide B), t-butyl 9-(3,4-dimethoxyphenyl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 9-(3,4-dimethoxyphenyl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 9-(3,5-dimethoxyphenyl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one, t-butyl 9-(3,5-dimethoxyphenyl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 9-(3,5-dimethoxyphenyl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 4,6,7-trimethoxy-9-(4-methoxyphenyl)naphtho[2,3-c]furan-1(3H)-one, t-butyl 6,7-dimethoxy-9-(4-methoxyphenyl)-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 4-hydroxy-6,7-dimethoxy-9-(4-methoxyphenyl)naphtho[2,3-c]furan-1(3H)-one, 4,6,7-trimethoxy-9-phenylnaphtho[2,3-c]furan-1(3H)-one, t-butyl 6,7-dimethoxy-1oxo-9-phenyl-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 4-hydroxy-6,7-dimethoxy-9-phenylnaphtho[2,3-c]furan-1(3H)-one, 4,6,7-trimethoxy-9-(4-vinylphenyl)naphtho[2,3-c]furan-1(3H)-one, t-butyl 6,7-dimethoxy-1oxo-9-(4-vinylphenyl)-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 4-hydroxy-6,7-dimethoxy-9-(4-vinylphenyl)naphtho[2,3-c]furan-1(3H)-one, 9-(4-fluorophenyl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one, t-butyl 9-(4-fluorophenyl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 9-(4-fluorophenyl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 4-(9-hydroxy-6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl)benzonitrile, t-butyl 9-(4-cyanophenyl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 4-(9-hydroxy-6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl)benzonitrile, 9-(4-acetylphenyl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one, 9-(4-acetylphenyl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl t-butylcarbonate, 9-(4-acetylphenyl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 4,6,7-trimethoxy-9-(thiophen-3-yl)naphtho[2,3-c]furan-1(3H)-one, 4-hydroxy-6,7-dimethoxy-9-(thiophen-3-yl)naphtho[2,3-c]furan-1(3H)-one, 9-(furan-3-yl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one, t-butyl 9-(furan-3-yl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 9-(furan-3-yl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, (E)-4,6,7-trimethoxy-9-styrylnaphtho[2,3-c]furan-1(3H)-one, (E)-4-hydroxy-6,7-dimethoxy-9-styrylnaphtho[2,3-c]furan-1(3H)-one, 5-(1,3-benzodioxol-5-yl)-9-methoxy-furo[3′,4′:6,7]naphtho[2,3-d]-1,3-dioxol-6(8H)-one (justicidin F, taiwanin E methyl ether), t-butyl 9-hydroxy-1oxo-1,3-dihydronaphtho[2,3-d]-1,3-dioxol[2,3-c]furan-4-yl carbonate, 9-(t-butoxycarbonyloxy)-3-oxo-1,3-dihydronaphtho[2,3-d]-1,3-dioxol[2,3-c]furan-4-yl trifluoromethanesulfonate, 9-(benzo[d][1,3]dioxol-5-yl)-1-oxo-1,3-dihydronaphtho[2,3-d]-1,3-dioxol[2,3-c]furan-4-yl t-butylcarbonate, 5-(1,3-benzodioxol-5-yl)-9-hydro-furo[3′,4′:6,7]naphtho[2,3-d]-1,3-dioxol-6(8H)-one (taiwanin E), 4-(benzo[d][1,3]dioxol-5-yl)-6,'7,9-trimethoxynaphtho[2,3-c]furan-1(3H)-one (justicidin C), 9-hydroxy-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl methanesulfonate, 6,7,9-trimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl methanesulfonate or 9-benzo[1,3]dioxol-5-yl-4,6,7-trimethoxy-2-methyl-2,3-dihydro-benzo[f]isoindol-1-one.

4. The method according to claim 1 , wherein Scheme A comprises:

Michael reaction;

aldol reaction; and

benzannulation.

5. The method according to claim 1 , wherein the base in Scheme A is one or more selected from a group consisting of lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium t-butoxide, potassium t-butoxide, sodium t-butoxide, lithium diisopropylamide, s-butyllithium and t-butyllithium.

6. The method according to claim 1 , wherein, in Scheme A, the α,β-unsaturated carbonyl compound

is used in an amount of 1.0-3.0 equivalents based on the compound of Chemical Formula 1.

7. A method of preparing an arylnaphthalene lignan compound, the method comprising:

forming a precursor of an arylnaphthalene lignan compound by the method according to claim 2 , and

forming the arylnaphthalene lignan compound using the precursor of the arylnaphthalene lignan compound,

wherein the arylnaphthalene lignan compound is the compound of Chemical Formula 6, and the forming the arylnaphthalene lignan compound comprises Schemes B, C and D sequentially following Scheme A:

wherein

P is a protecting group of a hydroxyl group;

Q is sulfonyl; and

Scheme D is a Suzuki-Miyaura reaction.

8. The method according to claim 7 , wherein the preparation method further comprises Scheme E of deprotecting the protecting group of the hydroxyl group at 4-position of the compound of Chemical Formula 4 following Scheme D:

9. The method according to claim 8 , wherein the preparation method further comprises Scheme F of converting the hydroxyl group of the compound of Chemical Formula 5 to Z following Scheme E:

10. A method for preparing an arylnaphthalene lignan compound, the method comprising:

forming a precursor of an arylnaphthalene lignan compound by the method according to claim 2 , and

forming the arylnaphthalene lignan compound using the precursor of the arylnaphthalene lignan compound,

wherein the arylnaphthalene lignan compound is the compound of Chemical Formula 9, and the forming of the arylnaphthalene lignan compound comprises Schemes G, H and I sequentially following Scheme A:

wherein

Q is sulfonyl; and

Scheme I is a Suzuki-Miyaura reaction.

11. The method according to claim 7 ,

wherein the sulfonyl group Q is SO 2 R 10 ;and

wherein R 10 is methyl, trifluoromethyl, methylphenyl or nitrophenyl.

12. The method according to claim 8 ,

wherein the sulfonyl group Q is SO 2 R 10 ;and

wherein R 10 is methyl, trifluoromethyl, methylphenyl or nitrophenyl.

13. The method according to claim 9 ,

wherein the sulfonyl group Q is SO 2 R 10 ;and

wherein R 10 is methyl, trifluoromethyl, methylphenyl or nitrophenyl.

14. The method according to claim 10 ,

wherein the sulfonyl group Q is SO 2 R 10 ;and

wherein R 10 is methyl, trifluoromethyl, methylphenyl or nitrophenyl.