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 for preparing a compound of Formula (I):
comprising contacting a compound of Formula (II):
with a transition metal catalyst (preferably a chiral transition metal catalyst) under hydrogenation 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, trialkylsilyloxy, 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, trialkylsilyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, or heterocyclylalkyl;
R 6 is hydrogen, hydroxyl, halogen, nitro, cyano, carboxyl, sulfate, alkyl, alkenyl, alkynyl, amino, alkoxy, alkylamino, alkylthio, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, trialkylsilyloxy, 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 12 is H, alkyl or aralkyl.
2. The method of claim 1 , wherein the compound of Formula (I) has the formula IA:
3. The method of claim 1 , wherein the compound of Formula (I) has the formula IB:
4. The method of claim 1 , wherein the transition metal catalyst comprises an iridium complex.
5. The method of claim 4 , wherein the iridium catalyst is prepared by combining an iridium source and a chiral ligand.
6. The method of claim 5 , wherein the iridium source is selected from (acetylacetonato)(1,5-cyclooctadiene)iridium(I), (acetylacetonato)(1,5-cyclooctadiene)iridium(I), (acetylacetonato)dicarbonyliridium(I), bis[1,2-bis(diphenylphosphino)ethane]carbonyl chloroiridium(I), bis(1,5-cyclooctadiene)diiridium(I) dichloride, bis(1,5-cyclooctadiene)iridium(I) tetrafluoroborate, bis(cyclooctadiene)iridium(I) tetrakis(3,5-bis(trifluoromethyl)phenyl)borate, chlorobis(cyclooctene)iridium(I)dimer, (1,5-cyclooctadiene)bis(methyldiphenylphosphine)iridium(I) hexafluorophosphate, (1,5-cyclooctadiene)(hexafluoroacetylacetonato)iridium(I), (1,5-cyclooctadiene)-η5-indenyl)iridium(I), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer, (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate, (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate, and (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
7. The method of claim 5 , wherein the iridium source is bis(1,5-cyclooctadiene)diiridium(I) dichloride.
8. The method of claim 5 , wherein the chiral ligand is a diphosphine ligand.
9. The method of claim 8 , wherein the diphosphine ligand is selected from S—(CF 3 )-t-BuPHOX, S,S-Et-FerroTANE, S,R p -xyliphos, or S,R p -BTFM-xyliphos, R—(CF 3 )-t-BuPHOX, R,R-Et-FerroTANE, R,S p -xyliphos, and R,S p -BTFM-xyliphos.
10. The method of claim 5 , wherein the chiral ligand is S,R p -BTFM-xyliphos or R,S p -BTFM-xyliphos.
11. The method of claim 1 , wherein the transition metal catalyst is a chiral transition metal catalyst and is used in an amount from about 0.1 mol % to about 100 mol % relative to the compound of formula (II) or (VII).
12. The method of claim 1 , wherein the transition metal catalyst is a chiral transition metal catalyst and is used in an amount from about 5 mol % to about 30 mol % relative to the compound of formula (II) or (VII).
13. The method of claim 1 , wherein the iridium catalyst is used in an amount of about 20 mol % relative to the compound of formula (II) or (VII).