Synthesis of tetrahydroisoquinoline (TIQ)–oxazoline ligands and their application in enantioselective Henry reactions

A novel family of eleven new tetrahydroisoquinoline (TIQ)–oxazoline intermediates and five corresponding copper(II) catalysts has been developed and applied to the catalytic asymmetric Henry reaction of various aldehydes with nitromethane to provide β-hydroxy nitroalkanes in high conversion (>99%). This paper describes the synthesis of the TIQ compounds from l-dihydroxyphenylalanine (l-DOPA) as the starting material. The chiral ligands were complexed in situ with various transition metals such as Cu, Sc, Co, Zn, Ni and Mn and tested as a chiral catalyst for the Henry reaction. The reaction was optimized in terms of the metal, counter ion, solvent, temperature and over a range of substrates. The corresponding catalyst with copper(II) acetate and 2-propanol as the solvent provides the best enantioselectivities (up to 77% ee) of the corresponding nitroalcohol for 4-chlorobenzaldehyde.

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2-((1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-4,5-dihydrooxazoleC20H22N2O3[α]D20=-39.5 (c 0.19, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S)

(R)-2-((1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-4-isopropyl-4,5-dihydrooxazoleC23H28N2O3[α]D20=-63.6 (c 0.22, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S,2′R)

(S)-2-((1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-4-isopropyl-4,5-dihydrooxazoleC23H28N2O3[α]D20=-42.1 (c 0.38, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S,2′S)

(R)-2-((1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-4-phenyl-4,5-dihydrooxazoleC26H26N2O3[α]D20=-46.4 (c 0.14, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S,2′R)

(S)-2-((1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-4-phenyl-4,5-dihydrooxazoleC26H26N2O3[α]D20=-57.1 (c 0.28, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S,2′S)

(1R,3S)-2-(Benzyloxycarbonyl)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acidC26H25NO6[α]D20=+23.0 (c 0.13, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S)

(1R,3S)-Benzyl 3-(2-hydroxyethylcarbamoyl)-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquino-line-2(1H)-carboxylateC28H30NO6[α]D20=+44.0 (c 0.5, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S)

(1R,3S)-Benzyl 3-((R)-1-hydroxy-3-methylbutan-2-ylcarbamoyl)-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylateC31H36N2O6[α]D20=+36.4 (c 0.11, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S,2′R)

(1R,3S)-Benzyl 3-((R)-2-hydroxy-1-phenylethylcarbamoyl)-6,7-dimethoxy-1-phenyl-3,4-dih-ydroisoquinoline-2(1H)-carboxylateC34H34N2O6[α]D20=+23.1 (c 0.13, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S,2′R)

(1R,3S)-Benzyl 3-((S)-2-hydroxy-1-phenylethylcarbamoyl)-6,7-dimethoxy-1-phenyl-3,4-dih-ydroisoquinoline-2(1H)-carboxylateC34H34N2O6[α]D20=+39.1 (c 0.23, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S,2′R)

(1R,3S)-Benzyl 3-(4,5-dihydrooxazol-2-yl)-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylateC28H28N2O5[α]D20=-3.2 (c 0.62, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S)

(1R,3S)-Benzyl 3-((R)-4-isopropyl-4,5-dihydrooxazol-2-yl)-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylateC31H34N2O5[α]D20=+3.2 (c 0.31, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S,2′R)

(1R,3S)-Benzyl 3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylateC31H34N2O5[α]D20=+17.65 (c 0.17, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S,2′S)

(1R,3S)-Benzyl 6,7-dimethoxy-1-phenyl-3-((R)-4-phenyl-4,5-dihydrooxazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC34H32N2O5[α]D20=-14.3 (c 0.28, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S,2′R)

(1R,3S)-Benzyl 6,7-dimethoxy-1-phenyl-3-((S)-4-phenyl-4,5-dihydrooxazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC34H32N2O5[α]D20=-39.3 (c 0.28, CH2Cl2)Source of chirality: l-3,4-dihydroxyphenylalanine (l-DOPA)Absolute configuration: (1R,3S,2′S)