Ortho-quinone derivatives, novel synthesis therefor, and their use in the inhibition of neoplastic cell growth
AssigneeWisconsin Alumni Research Foundation
InventorsBenjamin J. Frydman, Donald T. Witiak, deceased, Jerry Shunneng Sun, Andrew H. Geiser
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Abstract
A process for the preparation of .beta.-lapachone and dunnione derivatives of formulae I and II ##STR1## wherein, the a solution of lawsone in dimethylsufoxide at a temperature of -78.degree. 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.
Claims18
A method of synthesizing compounds of Formula I or II:
- ##STR30## wherein R.sup.1 -R.sup.6 are each, independently, selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkoxycarbonyl, --(CH.sub.2).sub.n -aryl, --(CH.sub.2).sub.n -heteroaryl, --(CH.sub.2)-heterocycle, and --(CH.sub.2).sub.n -phenyl;
- or R.sup.1 and R.sup.2 combined are a single substituent selected from the above group and R.sup.3 and R.sup.4 combined are a single substituent selected from the above group, in which case--is a double bond;
- and
- R.sup.7 is H, OH, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkoxycarbonyl, --(CH.sub.2).sub.n -amino, --(CH.sub.2).sub.n -aryl, --(CH.sub.2).sub.n -heteroaryl, --(CH.sub.2).sub.n -heterocycle, or --(CH.sub.2).sub.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.degree. 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 R.sup.8 and R.sup.9 are each, independently, selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxycarbonyl, --(CH.sub.2).sub.n -aryl, --(CH.sub.2).sub.n -heteroaryl, --(CH.sub.2)-heterocycle, and --(CH.sub.2).sub.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.
A method of synthesizing compounds of Formula I or II ##STR32## wherein R.sup.1 -R.sup.6 are each, independently, selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkoxycarbonyl, --(CH.sub.2).sub.n -aryl, --(CH.sub.2).sub.n -heteroaryl, --(CH.sub.2)-heterocycle, and --(CH.sub.2).sub.n -phenyl;
- or R.sup.1 and R.sup.2 combined are a single substituent selected from the above group and R.sup.3 and R.sup.4 combined are a single substituent selected from the above group, in which case--is a double bond;
- and
- R.sup.7 is H, OH, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkoxycarbonyl, --(CH.sub.2 ).sub.n -amino, --(CH.sub.2).sub.n -aryl, --(CH.sub.2).sub.n -heteroaryl, --(CH.sub.2).sub.n -heterocycle, or --(CH.sub.2).sub.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.degree. 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 R.sup.8 and R.sup.9 are each, independently, selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkoxycarbonyl, --(CH.sub.2).sub.n -aryl, --(CH.sub.2).sub.n -heteroaryl, --(CH.sub.2)-heterocycle, and --(CH.sub.2).sub.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.
Dependencies are inferred from the claim text.