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 compound of the Formula VI:
wherein R 1 is cyclopentyl, cyclohexyl, benzyl, CO 2 Me or MeO—(CH 2 ) 9 —;
R 2 , R 3 and R 4 comprises a hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkoxy group, a hydroxyalkyl group, a halogenated alkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a hydroxy group, an amine 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, a sulfo-oxo group, or a combination thereof;
wherein R 2 is not phenyl or methyl when R 1 is benzyl or —CO 2 Me; and
wherein the stereochemistry at carbons a and b is R or S.
2. A compound of the Formula VI:
wherein R 1 and R 4 are n-butyl and R 2 and R 3 are hydrogen; and
wherein the stereochemistry at carbons a and b is R or S.
3. A compound wherein the compound is a compound selected from the group consisting of (3R,4S)-3-butyl-4-pentyloxetan-2-one, (3R,4R)-3-butyl-4-pentyloxetan-2-one; (3R,4S)-3-butyl-3-methyl-4-pentyloxetan-2-one, (3S,4S)-3-benzyl-3-butyl-4-pentyloxetan-2-one; and (3S,4S)-benzyl 3-butyl-2-oxo-4-pentyloxetane-3-carboxylate.
4. A compound of the Formula VI:
wherein R 1 is cyclopentyl, cyclohexyl, benzyl, CO 2 Me or MeO—(CH 2 ) 9 —;
R 2 , R 3 and R 4 comprises a hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkoxy group, a hydroxyalkyl group, a halogenated alkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a hydroxy group, an amine 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, a sulfo-oxo group, or a combination thereof;
wherein R 2 is not phenyl or methyl when R 1 is benzyl or —CO 2 Me;
wherein the stereochemistry at carbons a and b is R or S; and
wherein said compound is synthesized using a method comprising the steps of:
(a) forming a ketene dimer from an acid chloride; and
(b) hydrogenating the ketene dimer to generate a cis-beta-lactone.
5. A compound of the Formula VI:
wherein R 1 is cyclopentyl, cyclohexyl, benzyl, CO 2 Me or MeO—(CH 2 ) 9 —;
R 2 , R 3 and R 4 comprises a hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkoxy group, a hydroxyalkyl group, a halogenated alkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a hydroxy group, an amine 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, a sulfo-oxo group, or a combination thereof;
wherein R 2 is not phenyl or methyl when R 1 is benzyl or —CO 2 Me;
wherein the stereochemistry at carbons a and b is R or S; and
wherein said compound is synthesized using a method of comprising the steps of:
(a) forming a ketene dimer from an acid chloride;
(b) hydrogenating the ketene dimer to generate a cis-beta-lactone; and
(c) performing an epimerization step further comprising the steps of:
(i) deprotonating the cis-beta lactone; and
(ii) quenching the deprotonated species under low temperature.
6. A compound of the Formula VI:
wherein R 1 is cyclopentyl, cyclohexyl, benzyl, CO 2 Me or MeO—(CH 2 ) 9 —;
R 2 , R 3 and R 4 comprises a hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkoxy group, a hydroxyalkyl group, a halogenated alkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a hydroxy group, an amine 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, a sulfo-oxo group, or a combination thereof;
wherein R 2 is not phenyl or methyl when R 1 is benzyl or —CO 2 Me;
wherein the stereochemistry at carbons a and b is R or S; and
wherein said compound is synthesized using a method comprising the steps of:
(a) forming a ketene dimer from an acid chloride;
(b) hydrogenating the ketene dimer to generate a cis-beta-lactone; and
(c) converting the cis-beta-lactone to a trisubstituted species.
7. The compound of claim 4 , wherein the method is a one-pot synthesis method.
8. The compound of claim 4 , wherein the ketene dimer formed in step (a) is isolated before the hydrogenation step.
9. The compound of claim 8 , wherein the isolation of the ketene dimer is performed by silica gel purification.
10. The compound of claim 4 , wherein the acid chloride has the formula VII below
wherein R is cyclopentyl, cyclohexyl, benzyl, CO 2 Me or MeO—(CH 2 ) 9 —.
11. The compound of claim 4 wherein the step of forming a ketene dimer from an acid chloride comprises using a catalyst wherein said catalyst is selected from the group consisting of QND, O-TBS QND, O-TMS QND, and O-TMS QUIN.
12. The compound of claim 11 wherein the catalyst is QND.
13. The compound of claim 11 wherein the catalyst is O-TMS QUIN.
14. The compound of claim 4 wherein the step of hydrogenating the ketene dimer comprises using a palladium on carbon catalyst.
15. The compound of claim 14 wherein the catalyst is at a concentration of about 1 mol % and 5 mol %.
16. The compound of claim 15 wherein the catalyst is at a concentration of about 1 mol %.
17. The compound of claim 14 wherein the catalyst is accompanied by an amine.
18. The compound of claim 17 wherein the amine is triethylamine.
19. The compound of claim 14 wherein the step of hydrogenating a ketene dimer is performed for 30 minutes at 30 psi H 2 .
20. The compound of claim 4 , wherein the method further comprises an epimerization step.
21. The compound of claim 20 wherein the epimerization step comprises the further steps of:
(a) deprotonating the cis-beta lactone; and
(b) quenching the deprotonated species under low temperature.
22. The compound of claim 21 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).
23. The compound of claim 21 wherein the step of quenching the deprotonated species is performed using acetic acid.
24. The compound of claim 4 further comprising converting the cis-beta-lactone to a trisubstituted species.
25. The compound of claim 24 wherein the converting step comprises alkylation or acylation.
26. The compound of claim 24 wherein the converting step comprises the further steps of:
(a) enolization of the cis-beta-lactone; and
(b) addition of electrophiles.
27. The compound of claim 26 wherein the enolization step is performed using LDA, LiHMDS or NaHMDS.
28. The compound of claim 26 wherein the electrophiles added to the enolated species from the group consisting of electrophiles.
29. The compound of claim 28 wherein the electrophile is a bulky electrophile or a smaller electrophile.
30. The compound of claim 26 wherein the electrophile comprises CH 3 , benzyl or CO 2 Me.