Total synthesis of 20(S) and 20(R)-camptothecin and compthothecin derivatives

Claim 1

A method for producing substantially pure 20(S)-camptothecin, 20(R)-camptothecin or analogs thereof, comprising the steps of: (a) reacting a mixture of enantiomeric lactones having formula (I), wherein X is an achiral ketal group which upon treatment with-an acid is converted into a keto group, ##STR6## with a substantially enantiomerically pure primary or secondary amine having the formula RR 1 NH, wherein R is an alkyl or aralkyl group containing a single chiral carbon and R 1 is hydrogen or an achiral alkyl, aralkyl or aryl group, to produce a mixture of diastereomeric amides with formula (II) ##STR7## (b) triturating said diastereomeric amide mixture with a non-polar organic solvent whereby a precipitate enriched in the more polar amide of said diastereomeric mixture and a mother liquor enriched in the less polar amide of said diastereomeric amide mixture are formed; (c) separating said precipitate from said mother liquor; (d) treating said precipitated amide with acid, whereby said precipitated amide is lactonized and deprotected to give an enantiomerically enriched ketolactone having formula (III) ##STR8## (e) reacting said ketolactone with an ortho-amino carbonyl compound having the formula ##STR9## wherein n=1 or 2 and R 2 is a member selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, cyano, methylenedioxy, formyl, hydroxy, nitro, amino, amido, chloro, bromo, iodo, fluoro, aminomethyl, trifluoromethyl, azido, and hydrazinyl groups, R 3 is H or C 1-8 alkyl; and R 4 is a side-chain of one of the twenty naturally occurring amino acids, to produce said camptothecin or camptothecin analog; and (f) isolating said camptothecin or camptothecin analog.

Claim 2

A method for producing substantially pure 20(S)-camptothecin, 20(R)-camptothecin or analogs thereof, comprising the steps of: (a) reacting a mixture of enantiomeric lactones having formula (I), wherein X is an achiral ketal group which upon treatment with-an acid is converted into a keto group, ##STR6## with a substantially enantiomerically pure primary or secondary amine having the formula RR 1 NH, wherein R is an alkyl or aralkyl group containing a single chiral carbon and R 1 is hydrogen or an achiral alkyl, aralkyl or aryl group, to produce a mixture of diastereomeric amides with formula (II) ##STR7## (b) triturating said diastereomeric amide mixture with a non-polar organic solvent whereby a precipitate enriched in the more polar amide of said diastereomeric mixture and a mother liquor enriched in the less polar amide of said diastereomeric amide mixture are formed; (c) separating said precipitate from said mother liquor; (d) treating said precipitated amide with acid, whereby said precipitated amide is lactonized and deprotected to give an enantiomerically enriched ketolactone having formula (III) ##STR8## (e) reacting said ketolactone with an ortho-amino carbonyl compound having the formula ##STR9## wherein n=1 or 2 and R 2 is a member selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, cyano, methylenedioxy, formyl, hydroxy, nitro, amino, amido, chloro, bromo, iodo, fluoro, aminomethyl, trifluoromethyl, azido, and hydrazinyl groups, R 3 is H or C 1-8 alkyl; and R 4 is a side-chain of one of the twenty naturally occurring amino acids, to produce said camptothecin or camptothecin analog; and (f) isolating said camptothecin or camptothecin analog.