Highly diastereoselective construction of the 4,5-spirocycle via palladium-catalyzed intramolecular alkenylation
A diastereoselective method of preparing benzofuran-based 4,5-spirocycles via metal catalyzed alkenylation is described. The method can be used to provide compounds containing the benzofuranone-4,5-spirocyclic motif of the phainanoids, a class a natural products having immunosuppressive activity. Synthetic analogs of phainanoids, e.g., compounds that mimic the structure of the “western” part of the structure of the phainanoids and that contain the benzofuranone-4,5-spirocycle are described, as well as their synthetic intermediates, and their methods of synthesis.
1. A method of preparing a phainanoid analog, the method comprising:
(a) providing a compound of Formula (I) or Formula (II):
wherein:
X is selected from the group consisting of a halide and —O—S(═O) 2 —R, wherein R is selected from alkyl, substituted alkyl, aryl, and substituted aryl;
R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, aryloxy, amino, and acetamido;
R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, aryloxy, amino, acetamido, and nitro; and
R 9 is selected from the group consisting of H, hydroxyl, and alkoxy; and
(b) contacting the compound of Formula (I) or Formula (II) with a metal compound, a ligand precursor, and a non-nucleophilic base to perform an intramolecular ketone alkenylation reaction; thereby providing the phainanoid analog, wherein the phainanoid analog has a structure of Formula (III) or Formula (IV):
wherein R 3 —R 9 are as defined for the compounds of Formulas (I) and (II).
2. The method of claim 1 , wherein X is —O—S(═O) 2 —CF 3 (—OTf).
3. The method of claim 1 , wherein the metal compound is a Pd compound.
4. The method of claim 1 , wherein the ligand precursor is a phosphine.
5. The method of claim 1 , wherein the base is selected from the group consisting of lithium hexamethyldisilamide (LiHMDS), potassium hexamethyldisilamide (KHMDS), sodium hexamethyldisilamide (NaHMDS), cesium carbonate (Cs 2 CO 3 ), lithium tert-butoxide (LiO t Bu), potassium tert-butoxide (KO t Bu), and sodium tert-butoxide (NaO t Bu).
6. The method of claim 1 , wherein the method comprises providing a compound of Formula (I), and wherein the compound of Formula (I) is contacted with a Pd compound, a phosphine, and the non-nucleophilic base in the presence of an ether solvent.
7. The method of claim 1 , wherein the method comprises providing a compound of Formula (II), and wherein the compound of Formula (II) is contacted with a Pd compound, a phosphine, and the non-nucleophilic base in the presence of an aromatic solvent.
8. The method of claim 1 , wherein the compound of Formula (III) or Formula (IV) is provided in a yield of about 65% or more and/or in a diastereomeric ratio of about 20:1 or greater.
9. A method of preparing a phainanoid analog, the method comprising:
(a) providing a compound of Formula (I) or Formula (II):
wherein:
X is selected from a halide and —O—S(═O) 2 —R, wherein R is selected from alkyl, substituted alkyl, aryl, and substituted aryl; and
R 3 , R 4 , R 5 R 6 , R 7 , R 8 , and R 9 are each H; and
(b) contacting the compound of Formula (I) or Formula (II) with a metal compound, a ligand precursor, and a non-nucleophilic base to perform an intramolecular ketone alkenylation reaction; thereby providing the phainanoid analog selected from the group consisting of:
10. A compound of one of Formulas (V) or (VI):
wherein:
each R 2 is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, aryloxy, amino, and acetamido;
R 9 is selected from the group consisting of H, ═O, hydroxyl, protected hydroxyl, and alkoxy; and
R 10 forms a substituted or unsubstituted monocyclic or bicyclic aromatic ring structure selected from the group consisting of benzene, indole, furan, pyrrole and benzofuran.
11. The compound of claim 10 , wherein R 10 forms a substituted or unsubstituted benzene ring structure, and wherein the compound of Formula (VI) is a compound of Formula (Via):
wherein;
each R 1 is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, aryloxy, amino, acetamido, and nitro;
each R 2 is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, aryloxy, amino, and acetamido; and
R 9 is selected from the group consisting of H, ═O, hydroxyl, protected hydroxyl, and alkoxy.
12. The compound of claim 10 , wherein the compound of Formula (V) or Formula (VI) is a compound of Formula (III) or Formula (IV):
wherein:
R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, aryloxy, amino, and acetamido;
R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, aryloxy, amino, acetamido, and nitro; and
R 9 is selected from the group consisting of H, ═O, hydroxyl, protected hydroxyl, and alkoxy.
13. The compound of claim 12 , wherein R 9 is ═O and the compound of Formula (IV) is a compound of Formula (IVb):
14. The compound of claim 12 , wherein R 9 is selected from H, hydroxyl, protected hydroxyl, and alkoxy, and the compound of Formula (IV) is a compound of Formula (IVa):
15. A compound selected from the group consisting of:
16. A pharmaceutical composition comprising a compound of claim 10 .
17. A compound of one of Formulas (I′), (II′) or (II″):
wherein:
is a double or single bond;
X is selected from the group consisting of a halide and —O—S(═O) 2 —R, wherein R is selected from the group consisting of alkyl, substituted alkyl, aryl, and substituted aryl;
R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, aryloxy, amino, and acetamido;
R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, aryloxy, amino, acetamido, and nitro;
R 9 is selected from the group consisting of H, hydroxyl, and alkoxy; and
R 11 is selected from the group consisting of ═O, hydroxyl, and protected hydroxyl.
18. The compound of claim 17 , wherein X is —O—S(═O) 2 —CF 3 (—OTf).
19. A compound selected from the group consisting of:
wherein —OTf is —O—S(═O) 2 —CF 3 .
20. The method of claim 1 , wherein R is —CF 3 , —CH 3 , —C 6 H 4 CH 3 , or —C n F 2n+1 , where n is an integer between 2 and 12.
21. The method of claim 20 , where n is an integer between 2 and 6.
22. The method of claim 1 , wherein the metal compound is a palladium (Pd), nickel (Ni) or platinum (Pt) compound and wherein the ligand precursor is a N-heterocyclic carbene (NHC) precursor or a phosphine.
23. The method of claim 3 , wherein the Pd compound is a Pd(II) compound.
24. The method of claim 23 , wherein the Pd(II) compound is palladium acetate (Pd(OAc) 2 ).
25. The method of claim 4 , wherein the phosphine is a dialkylarylphosphine.
26. The method of claim 25 , wherein the dialkylarylphosphine comprises one or both of a ferrocenyl group and a tert-butyl group.
27. The method of claim 6 , wherein the ether solvent is tetrahydrofuran (THF).
28. The method of claim 7 , wherein the aromatic solvent is toluene.
29. The compound of claim 17 , wherein R is —CF 3 , —CH 3 , —C 6 H 4 CH 3 , or —C n F 2n+1 , wherein n is an integer between 2 and 12.
30. The compound of claim 29 , wherein n is an integer between 2 and 6.