Method for the asymmetric synthesis of beta-lactone compounds
View Patent ↗The present invention features methods of treating a cancer in a subject by administering an effective amount of a beta-lactone to the subject. The invention also features methods of inhibiting angiogenesis in a subject by administering an effective amount of an inhibitor of fatty acid synthase to the subject. These methods can be used to treat a variety of cancers and other diseases and conditions. The invention also features methods of identifying beta-lactones and other compounds that can be used in the methods of the invention for the treatment of tumors, inhibition of angiogenesis, and the treatment of diseases and conditions that involve pathological angiogenesis. The invention also features methods of synthesizing beta-lactones and features novel beta-lactone compounds.
1. A method for the asymmetric synthesis of beta-lactone compounds comprising the steps of:
(a) forming a ketene dimer from an acid chloride, in the presence of a catalyst, wherein the catalyst is selected from the group consisting of QND, O-TBS QND, O-TMS QND, and O-TMS QUIN; and
(b) hydrogenating the ketene dimer to generate a cis-beta-lactone in the presence of a catalyst.
2. The method of claim 1 wherein the beta-lactone synthesis method is a one-pot synthesis method.
3. The method of claim 1 wherein the ketene dimer formed in step (a) is isolated before the hydrogenation step.
4. The method of claim 3 wherein the isolation of the ketene dimer is performed by silica gel purification.
5. The method of claim 1 wherein the acid chloride has the formula VII below
wherein R comprises a hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkoxy group, a halogenated alkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, an amide, an ester, a carbonate group, a carboxylic acid, an aldehyde, a keto group, an ether group, a halide, a urethane group, a silyl group or a sulfo-oxo group.
6. The method of claim 5 wherein R comprises n-butyl, cyclopentyl, cyclohexyl, benzyl, CH.sub.2CO.sub.2Me or 11-methoxynonyl.
7. The method of claim 6 wherein R is n-butyl.
8. The method of claim 1 wherein the step of hydrogenating the ketene dimer comprise using a palladium on carbon catalyst.
9. The method of claim 8 wherein the catalyst is at a concentration of about between 1 mol % and 5 mol %.
10. The method of claim 9 wherein the catalyst is at a concentration of about 1 mol %.
11. The method of claim 8 what the catalyst is accompanied by an amine.
12. The method of claim 11 wherein the mine is triethylamine.
13. The method of claim 8 wherein the step of hydrogenating a ketene dimer is performed for 30 minutes at 30 psi H.sub.2.
14. The method of claim 1 further comprising an epimerization step.
15. The method of claim 14 wherein the epimerization step comprises the further steps of:
(a) deprotonating the cis-beta lactone; and
(b) quenching the deprotonated species under low temperature.
16. The method of claim 15 wherein the step of deprotonating is performed using lithium hexamethyldisilazide (LiHMDS) or related bases such as lithium diisopropylamide (LDA), sodium hexamethyldisilazide (NaHMDS), or lithium tetramethylpiperidide (LiTMP).
17. The method of claim 15 wherein the step of quenching the deprotonated species is performed using acetic acid.
18. The method of claim 1 further comprising converting the cis-beta-lactone to a trisubstituted species by the further steps of:
(a) enolization of the cis-beta-lactone; and
(b) addition of electrophiles.
19. The method of claim 18 wherein the converting step comprises alkylation or acylation.
20. The method of claim 18 wherein the enolization step is performed using LDA, LiHMDS or NaHMDS.
21. The method of claim 18 wherein the electrophile comprises methyl iodide, benzyl or CO.sub.2benzyl.