Synthesis of prostanoids
The presently disclosed subject matter provides a method of synthesizing prostaglandins and prostaglandin analogs comprising the ring closing metathesis of compounds of Formula (I). Also provided are novel compounds of Formula (I) and Formula (II). In addition to their use as synthetic intermediates in the presently disclosed methods, compounds of Formula (II) can be used as prostaglandin and/or prostaglandin analog prodrugs.
1. A method of preparing a prostaglandin or prostaglandin analog, the method comprising:
providing a compound of Formula (I):
wherein:
n and m are integers between 0 and 4, wherein n+m is 3 or 4;
R 1 is H or a hydroxyl protecting group;
R 2 is H, alkyl or aralkyl, optionally wherein the alkyl or aralkyl group further comprises one or more alkyl or aryl group substituents;
R 3 and R 4 are independently H or alkyl;
and the substituents at carbons 1 and 2 of the cyclopentane ring are oriented cis to one another and trans to the substituent at carbon 3;
reacting the compound of Formula (I) with a transition metal carbene complex catalyst to perform a ring closing metathesis reaction, thereby forming a lactone; and
reacting the lactone with a nucleophile to form a ring-opened product, wherein said ring-opened product is a prostaglandin, prostaglandin analog or synthetic intermediate thereof, wherein said prostaglandin or prostaglandin analog has the formula:
wherein m, n, R 1 , R 2 , R 3 , and R 4 are as defined above; X′ is selected from the group consisting of —OH, —SH, —NH 2 , —O-alkyl, —O-aryl, —S-alkyl, —S-aryl, —NH-alkyl, —NH-aryl, —NH-aralkyl, —NH-sulfonyl-alkyl, —NH-sulfonyl-aryl, —N(alkyl) 2 , —N(aryl) 2 , and —N(alkyl)(aryl); and the substituents at carbons 1 and 2 of the cyclopentane ring are oriented cis to one another and trans to the substituent at carbon 3.
2. The method of claim 1 , wherein the catalyst is a ruthenium benyzlidene.
3. The method of claim 2 , wherein the catalyst is benzylidene-bis(tricyclohexylphosphine)dichlororuthenium.
4. The method of claim 1 , wherein n+m=4.
5. The method of claim 1 , wherein the ring closing metathesis reaction is performed in an aprotic solvent.
6. The method of claim 5 , wherein the aprotic solvent is dichloromethane.
7. The method of claim 1 , wherein the nucleophile is selected from the group consisting of water, hydroxide, an alcohol, an alkoxide, an aryloxide, a thiol, a thiolate, an amine, an imide, and a sulfonamide, or a salt thereof.
8. The method of claim 7 , wherein the nucleophile is an alkylamine.
9. The method of claim 8 , wherein the alkylamine is ethylamine.
10. The method of claim 1 , wherein reacting the lactone with a nucleophile is performed in an aprotic solvent.
11. The method of claim 10 , wherein the aprotic solvent is tetrahydrofuran (THF).
12. The method of claim 7 , wherein the nucleophile is an alcohol, an alkoxide, an alkoxide salt, or a mixture thereof.
13. The method of claim 12 , wherein the nucleophile is 2-propanol, sodium 2-propoxide, or a mixture thereof.
14. The method of claim 1 , further comprising removing one or more hydroxyl protecting groups.
15. The method of claim 14 , wherein removing one or more hydroxyl protecting groups is performed prior to reacting the lactone with a nucleophile.
16. The method of claim 1 , wherein the prostaglandin or prostaglandin analog is selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, unoprostone, prostaglandin F 2α (PGF 2α ), carboprost, fluprostenol, 13,14-dihydro-15-(2-benzothienyl)-15-pentanor PGF 1α , and cloprostenol.
17. The method of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:
18. The method of claim 1 , wherein the compound of Formula (I) is a compound of one of Formulas (Ia) or (Ib):
19. The method of claim 1 , wherein n is 0, 2, or 3 and m is 1 or 4.
20. The method of claim 1 , wherein n is 2 or 3 and m is 1.
21. A method of preparing a prostaglandin analog, the method comprising:
providing a compound of Formula (I):
wherein:
n and m are integers between 0 and 4, wherein n+m is 3 or 4;
R 1 is a hydroxyl protecting group;
R 2 is H, alkyl or aralkyl, optionally wherein the alkyl or aralkyl group further comprises one or more alkyl or aryl group substituents;
R 3 and R 4 are independently H or alkyl; and
the substituents at carbons 1 and 2 of the cyclopentane ring are oriented cis to one another and trans to the substituent at carbon 3;
reacting the compound of Formula (I) with a transition metal carbene complex catalyst to perform a ring closing metathesis reaction, thereby forming a lactone;
reacting the lactone with a nucleophile to form a ring-opened product comprising a hydroxyl group;
oxidizing the hydroxyl group of the ring-opened product to form a ketone; and
removing the hydroxyl protecting group R 1 , thereby forming a prostaglandin analog having the formula:
wherein m, n, R 2 , R 3 , and R 4 are as defined above and wherein X′ is selected from the group consisting of —OH, —SH, —NH 2 , —O-alkyl, —O-aryl, —S-alkyl, —S-aryl, —NH-alkyl, —NH-aryl, —NH-aralkyl, —NH-sulfonyl-alkyl, —NH-sulfonyl-aryl, —N(alkyl) 2 , —N(aryl) 2 , and —N(alkyl)(aryl).
22. The method of claim 21 , wherein the prostaglandin analog is selected from sulprostone and limaprost.