The synthesis of (R,S)-reboxetine employing a tandem cyclic sulfate rearrangement—opening process

(R,S)-Reboxetine was synthesized in nine steps and with 43% overall yield starting from trans-cinnamyl alcohol. Following silylation and AD steps, the two hydroxyl groups at C-1 and C-2 were simultaneously activated to the cyclic sulfate. A series of tandem reactions initiated by desilylation transposed the activation to C-3, then to C-1, where nucleophilic displacements took place in succession. During this process, the configuration at C-2 was inverted while that at C-1 was retained through a double inversion.

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(1S,2R)-3-Azido-1-(2-ethoxyphenoxy)-1-phenylpropan-2-olC17H19N3O3[α]D29=+33.8(c1.04,EtOH)Absolute configuration: (1S,2R)Source of chirality: asymmetric synthesis

(R)-2-[(S)-(2-Ethoxyphenoxy)(phenyl)methyl]morpholine [(R,S)-reboxetine]C19H23NO3[α]D28=+16.0(c0.68,CH2Cl2)Absolute configuration: (2R,1’S)Source of chirality: asymmetric synthesis