Novel tetrahydroisoquinoline based organocatalysts for asymmetric Diels–Alder reactions: insight into the catalytic mode using ROESY NMR and DFT studies

For the first time an organocatalyst bearing a secondary nitrogen within a cyclohexane ring has been evaluated in the asymmetric Diels–Alder reaction. This organocatalyst is also the first of its kind based on a (1R,3S)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline backbone. These catalysts were tested over a range of dienes and dienophiles and displayed promising chemical conversions of up to 100% with up to 64% ee with triflic acid as the cocatalyst. Density functional theory computational studies and 2D NMR spectroscopy were used to determine the structure of the intermediate iminium ion formed between the most efficient catalyst and cinnamaldehyde. The reaction profile for each of the four possibilities in this reaction were calculated and it was found that the iminium intermediate leading to the major product is higher in energy but kinetically preferred. The activation energies of all possible reaction paths were calculated and the results correlated with the observed products. These experiments revealed that the presence of both (E)- and (Z)-isomers of the cinnamaldehyde were contributing factors for the low enantioselectivity of the reaction products.

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(1R,3S)-Isopropyl 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylateC21H25NO4[α]D20=-70.0 (c 0.12, CHCl3)Source of chirality: (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid or l-DOPAAbsolute configuration: (1R,3S)

(1R,3S)-2-Benzyl-6,7-dimethoxy-3-(methoxydiphenylmethyl)-1-phenyl-1,2,3,4-tetrahydroisoquinolineC38H37NO3[α]D20=-80.0 (c 0.10 CHCl3)Source of chirality: (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid or l-DOPAAbsolute configuration: (1R,3S)

(1R,3S)-6,7-Dimethoxy-3-(methoxydiphenylmethyl)-1-phenyl-1,2,3,4-tetrahydroisoquinolineC31H31NO3[α]D20=-80.0 (c 0.10, CHCl3).Source of chirality: (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid or l-DOPAAbsolute configuration: (1R,3S)

(1R,3S)-3-(Diphenyl(trimethylsilyloxy)methyl)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolineC33H37NO3Si[α]D20=-10.0 (c 0.11, CHCl3)Source of chirality: (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid or l-DOPAAbsolute configuration: (1R,3S)