Methods for preparing bis-tetrahydroisoquinoline-containing compounds
(−)-Jorumycin, ecteinascidin 743, saframycin A and related compounds, methods of preparing the same, formulations comprising the compounds, and methods of treating proliferative diseases with the same are provided.
1. A method of preparing a compound of Formula (II):
comprising combining a compound of Formula (III):
with a compound of Formula (IV):
and
a transition metal catalyst under cross-coupling conditions, wherein, as valence and stability permit:
R 1 and R 7 are each independently hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, alkylsilyloxy, or acylamino;
each instance of R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , and R 11 is independently hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, alkylsilyloxy, acylamino, aryl, heteroaryl, carbocyclyl, or heterocyclyl;
R 6 is hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, alkylsilyloxy, or acylamino; or
any two of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , together with the carbon atoms to which they are attached, form an aryl, heteroaryl, carbocyclyl, or heterocyclyl; or
any two of R 7 , R 8 , R 9 , R 10 , and R 11 , together with the carbon atoms to which they are attached, form an aryl, heteroaryl, carbocyclyl, or heterocyclyl; and
R 13 and R 14 are each independently hydroxyl, nitro, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, alkylsilyloxy, or acylamino.
2. The method of claim 1 , wherein R 13 and R 14 are each independently unsubstituted alkyl or alkyl substituted with one or more substituents selected from hydroxy, alkoxy, acyloxy, amino and thio.
3. The method of claim 1 , wherein the transition metal catalyst comprises a nickel, palladium, or platinum catalyst.
4. The method of claim 3 , wherein the transition metal catalyst comprises a palladium catalyst is-selected from Pd/C, Pd 2 (DBA) 3 , Pd(PPh 3 ) 4 , Pd(OC(O)R c ) 2 , Pd(OAc) 2 , PdCl 2 , Pd(PhCN) 2 Cl 2 , Pd(CH 3 CN) 2 Cl 2 , PdBr 2 , Pd(acac) 2 , [Pd(allyl)Cl]2, Pd(TFA) 2 , Pd 2 (pmdba) 3 , Pd(P(t-Bu) 2 Me) 2 , and pre-formed Pd(II)-ligand complexes; wherein R C is optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl.
5. The method of claim 4 , wherein the palladium catalyst is Pd(P(t-Bu) 2 Me) 2 .
6. The method of claim 3 , wherein the transition metal catalyst is used in an amount from about 0.5 mol % to about 50 mol % relative to the compound of formula (III) or (IV).
7. The method of claim 1 , wherein R 1 is hydrogen.
8. The method of claim 1 , wherein R 1 is unsubstituted alkyl or alkyl substituted with one or more substituents selected from hydroxy, alkoxy, acyloxy, amino, and thio.
9. The method of claim 1 , wherein R 2 is selected from H, halo and hydroxy.
10. The method of claim 1 , wherein R 3 is alkyl.
11. The method of claim 1 , wherein R 4 is alkoxy.
12. The method of claim 1 , wherein R 5 is hydroxy or alkoxy.
13. The method of claim 1 , wherein R 6 is unsubstituted alkyl or alkyl substituted with one or more substituents selected from hydroxy, alkoxy, acyloxy, amino and thio.
14. The method of claim 1 , wherein R 7 is unsubstituted alkyl or alkyl substituted with one or more substituents selected from hydroxy, alkoxy, acyloxy, amino, and thio.
15. The method of claim 1 , wherein R 7 is H, halo or hydroxy.
16. The method of claim 1 , wherein R 8 is alkoxy.
17. The method of claim 1 , wherein R 9 is alkyl.
18. The method of claim 1 , wherein R 10 is hydroxy or alkoxy.
19. The method of claim 1 , wherein R 11 is H.
20. The method of claim 1 , wherein each instance of R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , and R 11 is independently unsubstituted alkyl or alkyl substituted with one or more substituents selected from hydroxy, alkoxy, acyloxy, amino, and thio.