Ortho-quinone derivatives, novel synthesis therefor, and their use in the inhibition of neoplastic cell growth
First Claim
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1. A method of synthesizing compounds of Formula I or II:
- ##STR30## wherein R1 -R6 are each, independently, selected from the group consisting of H, C1 -C6 alkyl, C2 -C6 alkenyl, C1 -C6 alkoxy, C1 -C6 alkoxycarbonyl, --(CH2)n -aryl, --(CH2)n -heteroaryl, --(CH2)-heterocycle, and --(CH2)n -phenyl;
or R1 and R2 combined are a single substituent selected from the above group and R3 and R4 combined are a single substituent selected from the above group, in which case--is a double bond; and
R7 is H, OH, C1 -C6 alkyl, C2 -C6 alkenyl, C1 -C6 alkoxy, C1 -C6 alkoxycarbonyl, --(CH2)n -amino, --(CH2)n -aryl, --(CH2)n -heteroaryl, --(CH2)n -heterocycle, or --(CH2)n -phenyl;
and wherein n is an integer of from 0 to 10;
comprising;
(a) generating a lithium salt of lawsone by contacting a solution of lawsone in dimethylsulfoxide at a temperature of -78°
C. or less with lithium hydride and warming the solution to allow the lithium hydroxide to dissolve into the solution;
then(b) alkylating the lithium salt of lawsone with an allyl halide of the formula;
##STR31## in the presence of lithium iodide, wherein R8 and R9 are each, independently, selected from the group consisting of H, C1 -C6 alkyl, C2 -C6 alkenyl, C1 -C6 alkoxycarbonyl, --(CH2)n -aryl, --(CH2)n -heteroaryl, --(CH2)-heterocycle, and --(CH2)n -phenyl,X is a halide, to yield a mixture of C-alkylated and O-alkylated lawsone derivatives; and
then(c) cyclizing the C-alkylated lawsone derivatives to yield a compound of Formula I or II.
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Abstract
A process for the preparation of β-lapachone and dunnione derivatives of formulae I and II ##STR1## wherein, the a solution of lawsone in dimethylsufoxide at a temperature of -78° C. or less is reacted with lithium hydride forming the lithium salt of lawsone; alkylating the lithium salt with an allyl halide; and cyclizing the C-alkylated lawsone derivative.
55 Citations
18 Claims
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1. A method of synthesizing compounds of Formula I or II:
- ##STR30## wherein R1 -R6 are each, independently, selected from the group consisting of H, C1 -C6 alkyl, C2 -C6 alkenyl, C1 -C6 alkoxy, C1 -C6 alkoxycarbonyl, --(CH2)n -aryl, --(CH2)n -heteroaryl, --(CH2)-heterocycle, and --(CH2)n -phenyl;
or R1 and R2 combined are a single substituent selected from the above group and R3 and R4 combined are a single substituent selected from the above group, in which case--is a double bond; andR7 is H, OH, C1 -C6 alkyl, C2 -C6 alkenyl, C1 -C6 alkoxy, C1 -C6 alkoxycarbonyl, --(CH2)n -amino, --(CH2)n -aryl, --(CH2)n -heteroaryl, --(CH2)n -heterocycle, or --(CH2)n -phenyl; and wherein n is an integer of from 0 to 10;
comprising;(a) generating a lithium salt of lawsone by contacting a solution of lawsone in dimethylsulfoxide at a temperature of -78°
C. or less with lithium hydride and warming the solution to allow the lithium hydroxide to dissolve into the solution;
then(b) alkylating the lithium salt of lawsone with an allyl halide of the formula;
##STR31## in the presence of lithium iodide, wherein R8 and R9 are each, independently, selected from the group consisting of H, C1 -C6 alkyl, C2 -C6 alkenyl, C1 -C6 alkoxycarbonyl, --(CH2)n -aryl, --(CH2)n -heteroaryl, --(CH2)-heterocycle, and --(CH2)n -phenyl,X is a halide, to yield a mixture of C-alkylated and O-alkylated lawsone derivatives; and
then(c) cyclizing the C-alkylated lawsone derivatives to yield a compound of Formula I or II. - View Dependent Claims (2, 3, 4, 5, 6, 7)
- ##STR30## wherein R1 -R6 are each, independently, selected from the group consisting of H, C1 -C6 alkyl, C2 -C6 alkenyl, C1 -C6 alkoxy, C1 -C6 alkoxycarbonyl, --(CH2)n -aryl, --(CH2)n -heteroaryl, --(CH2)-heterocycle, and --(CH2)n -phenyl;
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8. A method of synthesizing compounds of Formula I or II ##STR32## wherein R1 -R6 are each, independently, selected from the group consisting of H, C1 -C6 alkyl, C2 -C6 alkenyl, C1 -C6 alkoxy, C1 -C6 alkoxycarbonyl, --(CH2)n -aryl, --(CH2)n -heteroaryl, --(CH2)-heterocycle, and --(CH2)n -phenyl;
- or R1 and R2 combined are a single substituent selected from the above group and R3 and R4 combined are a single substituent selected from the above group, in which case--is a double bond; and
R7 is H, OH, C1 -C6 alkyl, C2 -C6 alkenyl, C1 -C6 alkoxy, C1 -C6 alkoxycarbonyl, --(CH2 )n -amino, --(CH2)n -aryl, --(CH2)n -heteroaryl, --(CH2)n -heterocycle, or --(CH2)n -phenyl, and wherein n is an integer of from 0 to 10;
comprising;(a) generating a lithium salt of lawsone by contacting a solution of lawsone in dimethylsulfoxide at a temperature of -78°
C. or less with lithium hydride and warming the solution to allow the lithium hydroxide to dissolve into the solution;
then(b) alkylating the lithium salt of lawsone with an allyl halide of the formula;
##STR33## in the presence of lithium iodide, wherein R8 and R9 are each, independently, selected from the group consisting of H, C1 -C6 alkyl, C2 -C6 alkenyl, C1 -C6 alkoxy, C1 -C6 alkoxycarbonyl, --(CH2)n -aryl, --(CH2)n -heteroaryl, --(CH2)-heterocycle, and --(CH2)n -phenyl;X is a halide to yield a mixture of C-alkylated and O-alkylated lawsone derivatives; and
then(c) cyclizing the C-alkylated lawsone derivatives to yield a tricyclic ortho-naphthoquinone by; (i) separating the mixture of C-alkylated and O-alkylated lawsone derivatives from one another to yield a first portion of C-alkylated derivatives and a portion of O-alkylated derivatives; and
then(ii) rearranging the portion of O-allylated lawsone derivatives to yield a second portion of C-alkylated lawsone derivatives; and
then(iii) cyclizing the first and second portions of C-alkylated lawsone derivatives to yield a tricyclic ortho-naphthoquinone. - View Dependent Claims (9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
- or R1 and R2 combined are a single substituent selected from the above group and R3 and R4 combined are a single substituent selected from the above group, in which case--is a double bond; and
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Current AssigneeWisconsin Alumni Research Foundation (University of Wisconsin System)
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Original AssigneeWisconsin Alumni Research Foundation (University of Wisconsin System)
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InventorsGeiser, Andrew H., Witiak, deceased, Donald T., Sun, Jerry Shunneng, Frydman, Benjamin J.
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Primary Examiner(s)Dees, Jose'G.
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Assistant Examiner(s)BADIO, BARBARA P
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Application NumberUS08/948,374Time in Patent Office740 DaysField of Search549/391, 549/389, 549/461US Class Current549/389CPC Class CodesA61K 31/122 having the oxygen directly ...A61K 31/135 having aromatic rings , e.g...A61K 31/336 having three-membered rings...A61K 31/343 condensed with a carbocycli...A61K 31/352 condensed with carbocyclic ...C07C 323/22 containing thio groups and ...C07C 46/00 Preparation of quinonesC07C 50/32 the quinoid structure being...C07D 307/92 Naphthofurans; Hydrogenated...C07D 311/92 Naphthopyrans; Hydrogenated...
