C2-Symmetric hemiaminal ethers and diamines: new ligands for copper-catalyzed desymmetrization of meso-1,2-diols and asymmetric Henry reactions

The synthesis of novel, enantiomerically pure C2-symmetrical hemiaminal ethers and diamines containing piperazine core is presented. The key steps of the synthesis involve the dimerization of an in situ generated α-amino aldehyde into the corresponding cyclic bis-hemiaminal, followed by dehydration in the presence of a base to give a 7-oxa-2,5-diaza-bicyclo[2.2.1]heptane derivative, which can be regarded as a bicyclic bis-hemiaminal inner ether. These compounds represent a new class of molecule, with a structure unambiguously established for the first time. Finally, sodium triacetoxy-borohydride reduction gave the corresponding diamines. Both classes of compounds, new diamines and hemiaminal ethers, were shown to be good ligands for the copper(II)-catalyzed desymmetrization of meso-diols (up to 87% ee) and Henry reactions (up to 84% ee).

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(8R,8aS,16R,16aS)-2,3,10,11-Tetramethoxy-8a,16a-diphenyl-5,6,8,8a,13,14,16,16a-octahydro-8,16-epoxypyrazino[2,1-a:5,4-a′]diisoquinolineC36H36N2O5[α]D23=+199.1 (c 1, CH2Cl2)Source of chirality: asymmetric synthesis from l-tartaric acidAbsolute configuration: (8R,8aS,16R,16aS)

(8R,8aS,16R,16aS)-8a,16a-Bis(3,5-dimethylphenyl)-2,3,10,11-tetramethoxy-5,6,8,8a,13,14,16,16a-octahydro-8,16-epoxypyrazino[2,1-a:5,4-a′]diisoquinolineC40H44N2O5[α]D23=+113.1 (c 1, CH2Cl2)Source of chirality: asymmetric synthesis from l-tartaric acidAbsolute configuration: (8R,8aS,16R,16aS)

(8R,8aS,16R,16aS)-2,3,10,11-Tetramethoxy-8a,16a-di(naphthalen-2-yl)-5,6,8,8a,13,14,16,16a-octahydro-8,16-epoxypyrazino[2,1-a:5,4-a′]diisoquinolineC44H40N2O5[α]D23=+46.2 (c 1, CH2Cl2)Source of chirality: asymmetric synthesis from l-tartaric acidAbsolute configuration: (8R,8aS,16R,16aS)

(8aS,16aS)-2,3,10,11-Tetramethoxy-8a,16a-dimethyl-5,6,8,8a,13,14,16,16a-octahydropyrazino[2,1-a:5,4-a′]diisoquinolineC26H34N2O4[α]D23=+206.2 (c 1, CH2Cl2)Source of chirality: asymmetric synthesis from l-tartaric acidAbsolute configuration: (8aS,16aS)

(8aS,16aS)-2,3,10,11-Tetramethoxy-8a,16a-diphenyl-5,6,8,8a,13,14,16,16a-octahydropyrazino[2,1-a:5,4-a′]diisoquinolineC36H38N2O4[α]D23=+107.3 (c 1, CH2Cl2)Source of chirality: asymmetric synthesis from l-tartaric acidAbsolute configuration: (8aS,16aS)

(8aS,16aS)-8a,16a-Dibenzyl-2,3,10,11-tetramethoxy-5,6,8,8a,13,14,16,16a-octahydropyrazino[2,1-a:5,4-a′]diisoquinolineC38H42N2O4[α]D23=+134.4 (c 0.74, CH2Cl2)Source of chirality: asymmetric synthesis from l-tartaric acidAbsolute configuration: (8aS,16aS)

((8aS,16aS)-8a,16a-Bis(3,5-dimethylphenyl)-2,3,10,11-tetramethoxy-5,6,8,8a,13,14,16,16a-octahydropyrazino[2,1-a:5,4-a′]diisoquinolineC40H46N2O4[α]D23=+83.8 (c 1, CH2Cl2)Source of chirality: asymmetric synthesis from l-tartaric acidAbsolute configuration: 8aS,16aS

(8aS,16aS)-2,3,10,11-Tetramethoxy-8a,16a-di(naphthalen-2-yl)-5,6,8,8a,13,14,16,16a-octahydropyrazino[2,1-a:5,4-a′]diisoquinolineC44H42N2O4[α]D23=+76.9 (c 1, CH2Cl2)Source of chirality: asymmetric synthesis from l-tartaric acidAbsolute configuration: (8aS,16aS)