Methods and intermediates for the assymmetric synthesis of camptothecin and camptothecin analogs

A process for making a compound of the formula ##STR24## wherein R.sub.6 is lower alkyl, R.sub.7 is lower alkyl, R is lower alkyl, Y is H, F or Cl, R.sub.8 comprises a chiral moiety, and R.sub.10 is C.sub.6 -C.sub.10 alkyl, aryl or alkyl aryl, comprising the steps of:

• reacting a compound of the formula ##STR25## wherein Z is Br or I, with a base of the formula
• A.sup.+ B.sup.-
• wherein A.sup.+ is an inorganic cation, and B.sup.- is an organic anion, to form a first intermediate, then
• stereospecifically adding to the first intermediate an .alpha.-keto-ester of the formula ##STR26## to form a second intermediate of the Formula XIV, ##STR27## the R.sub.8 moiety having a configuration that forces R and the --OH group of compound XIV to take a first stereochemical orientation about the chiral carbon at position 7 by sterically hindering the formation of an opposite second stereochemical orientation about the chiral carbon at position 7, then
• acylating the second intermediate with an acyl halide of Formula XVI ##STR28## wherein X is Cl, I, or Br.

A process for making a compound of the formula ##STR31## wherein R.sub.6 is lower alkyl, R.sub.7 is lower alkyl, R is lower alkyl, and Y is H, F or Cl, comprising the steps of:

• saponifying a compound of the formula ##STR32## wherein R.sub.8 comprises a moiety of Formula XVIII ##STR33## wherein n is 1, 2, or 3, R.sub.11 is a C.sub.1 -C.sub.4 alkyl group and R.sub.12 is the same as R.sub.11, or R.sub.11 and R.sub.12 together form cyclopentane or cyclohexane, and R.sub.13 is:
• (a) phenyl substituted 1 to 5 times with C.sub.3 -C.sub.7 secondary alkyl or C.sub.4 -C.sub.7 tertiary alkyl, or
• (b) selected from the group consisting of naphthyl, anthryl, and phenanthryl optionally substituted 1 to 5 times with C.sub.3 -C.sub.7 secondary alkyl or C.sub.4 -C.sub.7 tertiary alkyl, and
• R.sub.14 is hydrogen, C.sub.6 -C.sub.10 alkyl carbonyl, aryl carbonyl or alkyl aryl carbonyl,
• with a base to form a reaction intermediate;
• then
• protonating the reaction intermediate with aqueous acid.

A compound of the formula ##STR37## wherein R.sub.6 is lower alkyl R.sub.7 is lower alkyl, is aryl or alkyl aryl, R.sub.8 is a moiety of Formula XVIII ##STR38## wherein n is 1, 2, or 3, R.sub.11 is a C.sub.1 -C.sub.4 alkyl group and R.sub.12 is the same as R.sub.11, or R.sub.11 and R.sub.12 together form cyclopentane or cyclohexane, and R.sub.13 is:

• (a) phenyl substituted 1 to 5 times with C.sub.3 -C.sub.7 secondary alkyl or C.sub.4 -C.sub.7 tertiary alkyl, or
• (b) selected from the group consisting of naphthyl, anthryl, and phenanthryl optionally substituted 1 to 5 times with C.sub.3 -C.sub.7 secondary alkyl or C.sub.4 -C.sub.7 tertiary alkyl groups,
• R is lower alkyl,
• and Y is H, F or Cl.