Bile acid derivatives and methods for synthesis and use
Provided herein, inter alia, are methods for the preparation of modulators of farnesoid X receptor (FXR), and compositions and uses of the modulators of FXR.
1. A method of synthesizing a compound having the following structure,
the method comprising,
(i) contacting a compound of formula (II)
wherein R 11 is R 11A or R 11B , with an oxidizing reagent to provide a compound of formula (III-A) or (III-B),
or
(ii) when the product of step (i) has a structure according to formula (III-A), contacting the compound of formula (III-A) with an alcohol protecting agent to provide a compound of formula (III-B);
(iii) contacting a compound of formula (III-B) with an alkylating agent in the presence of a sterically hindered base to provide a compound of formula (IV),
(iv) optionally contacting the compound of formula (IV) with an alcohol deprotecting agent to provide a compound of formula (IV-A),
(v) treatment of the compound of formula (IV) or (IV-A) with a reducing agent to provide a compound of formula (I) or (I-A),
or
and
(vi) when the product of step (v) has a structure according to formula (I-A), contacting the compound of formula with an alcohol deprotecting agent to provide a compound of formula (I-A);
wherein,
L 1 is —C(O)—, —C(O)O—, —C(O)NH—, or —CH 2 —;
R 1 is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OR 1A , —NHR 1A , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a carboxylate protecting group;
R 2 is hydrogen or unsubstituted alkyl;
R 3 is hydrogen, unsubstituted alkyl, or —OR 3A ;
R 4 is hydrogen, unsubstituted alkyl, or —OR 4A ;
R 5 is hydrogen, unsubstituted alkyl, or —OR 5A ;
R 6 is hydrogen, unsubstituted alkyl, or —OR 6A ;
R 7 is hydrogen, unsubstituted alkyl, or —OR 7A ;
R 8 is hydrogen, unsubstituted alkyl, or —OR 8A ;
R 9 is hydrogen, unsubstituted alkyl, or —OR 9A ;
R 10 is hydrogen, unsubstituted alkyl, or —OR 10A ;
R 11A is hydrogen;
R 11B is an alcohol protecting group;
R 12 is hydrogen, unsubstituted alkyl, or —OR 12A ;
R 13 is unsubstituted alkyl;
R 1A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 12A and R 13A are independently hydrogen, unsubstituted alkyl, or an alcohol protecting group.
2. The method of claim 1 , the method comprising,
(i) contacting a compound of formula (II)
wherein R 11 is R 11A , with an oxidizing reagent to provide a compound of formula (III-A),
(ii) contacting the compound of formula (III-A) with an alcohol protecting agent to provide a compound of formula (III-B),
(iii) contacting a compound of formula (III-B) with an alkylating agent in the presence of a sterically hindered base to provide a compound of formula (IV),
(iv) contacting the compound of formula (IV) with an alcohol deprotecting agent to provide a compound of formula (IV-A),
(v) treatment of the compound of formula (IV-A) with a reducing agent to provide a compound of formula (I),
3. The method of claim 1 , the method comprising,
(i) contacting a compound of formula (II)
wherein R 11 is R 11B , with an oxidizing reagent to provide a compound of formula (III-B),
(ii) contacting a compound of formula (III-B) with an alkylating agent in the presence of a sterically hindered base to provide a compound of formula (IV),
(iii) contacting the compound of formula (IV) with an alcohol deprotecting agent to provide a compound of formula (IV-A),
(iv) treatment of the compound of formula (IV-A) with a reducing agent to provide a compound of formula (I)
4. The method of claim 1 , wherein R 11B is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or —SiR 11C R 11D R 11E , wherein R 11C , R 11D , and R 11E are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
5. The method of claim 4 , wherein R 11B is tetrahydropyranyl (THP).
6. The method of claim 1 , wherein the compound of formula (I) has the following structure,
7. The method of claim 1 , wherein the compound of formula (I) has the following structure,
8. The method of claim 7 , wherein
R 1 is hydrogen;
R 2 is hydrogen or unsubstituted alkyl; and
R 4 is hydrogen or unsubstituted alkyl.
9. The method of claim 1 , wherein the compound of formula (I) has the following structure,
10. The method of claim 9 , wherein the compound of formula (I) is 6-α-ethyl-ursodeoxycholic acid (6-EUDCA) having the following structure,
11. The method of claim 1 , wherein the oxidizing reagent of step (a) is a chromium oxidant, a ruthenium oxidant, a manganese oxidant, an activated dimethylsulfoxide oxidant, or a hypervalent iodine oxidant.
12. The method of claim 11 , wherein the oxidizing reagent is pyridinium chlorochromate (PCC).
13. The method of claim 1 , wherein the alcohol oxidation proceeds with greater than about 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1 regioselectivity.
14. The method of claim 1 , wherein said sterically hindered base of step (iii) is lithium diisopropylamide (LDA), (M +1 )HMDS, (M +1 )tBuO, (M +1 )TMP, (M +1 )PhO, (M +1 )MeO, (M +1 )EtO, DBU, Dabco, N,N-dichlorohexylmethylamine, N,N-diisopropyl-2-ethylbutylamine, 2,6-di-tert-butyl-4-methylpyridine, pentamethylpiperidine, MTBD, PMDBD, TBD, or tri-tert-butylpyridine, wherein (M +1 ) is Na, K, or Li.
15. The method of claim 14 , wherein said sterically hindered base is lithium diisopropylamide (LDA).
16. The method of claim 1 , wherein step (iii) comprises a second base.
17. The method of claim 16 , wherein said base is an alkyllithium reagent.
18. The method of claim 1 , wherein said alkylation agent of step (iii) is an alkyl halide.
19. The method of claim 18 , wherein said alkylation agent is an alkyl iodide.
20. The method of claim 1 , wherein step (iii) is performed in the presence of a polar aprotic solvent.
21. The method of claim 20 , wherein said polar aprotic solvent is HMPA, HMPT, DMF, DMSO, MeCN, dioxane, methylpyrrolidone, DMPU, or a tetra-alkyl urea.
22. The method of claim 1 , wherein the reducing agent of step (v) comprises an aluminum alkoxide and an alcohol.
23. The method of claim 22 , wherein the reducing agent comprises aluminum isopropoxide and isopropyl alcohol.
24. The method of claim 1 , wherein step (v) proceeds with greater than about 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, or 20:1 stereoselectivity.