Synthesis of (S,S)‐Reboxetine

Abstract

Advents of asymmetric reactions employing asymmetric reagents or catalysts are regarded as a paradigm shift in the field of stereoselective synthesis. In this paradigm, choices of the appropriate asymmetric reagents/catalysts control the configurations of newly created stereocenters (reagent-control). 1 This is in contrast to the traditional substrate-control, in which a pre-existing stereocenter in the starting material induces the configurations of newly created stereocenters in the product. 2 The archetype of the reagent-control strategy is probably the hexose synthesis by Sharpless-Masamune. 1b,c Here, each of the diastereomeric hexose products was synthesized from a common starting material, following a common synthetic sequence.In reality, asymmetric reagents/catalysts do not always grant an equal access to diastereomers. They are often effective in producing one diastereomer (in either enantiomeric form), but not so for other diastereomers, for which different and often lengthier synthetic sequences may have to be devised. 3 The syntheses of reboxetine offer a good example. Reboxetine is a potent selective norepinephrine reuptake inhibitor and is effective in treating depression and attention deficit/hyperactivity disorder (ADHD). 4 Initial interests were directed mainly on the syn-diastereomers [(S,S) and (R,R)], the racemic mixture of which is currently on the market. More recently, the anti-diastereomers [(R,S) and (S,R)] began to gain attentions as some anti-derivatives exhibited biological activities, which are comparable to, and at the same time, distinct from those of (S,S)-reboxetine ( Figure 1). 5 A survey of the synthetic sequences of reboxetines reveals that the pathways for reboxetine diastereomers are not parallel to each other, as in the hexose synthesis, but require different starting materials or different strategies. 6,7 For example, following the asymmetric dihydroxylation (AD) process, syn-reboxetine was synthesized via O-Aryl disconnection strategy, while anti-diastereomer required an O-Benzyl disconnection strategy. The latter is a contribution from our laboratories. 8 Having previously achieved a synthesis of (R,S)-reboxetine, we embarked on a synthetic study of (S,S)-reboxetine. Our aim was to develop a synthetic sequence for (S,S)-reboxetine, which would be parallel, as closely as possible, to our own synthetic pathway for the anti-diastereomer.Our previous work on the synthesis of (R,S)-reboxetine started with Si-protected trans-cinnamyl alcohol. The AD was the asymmetric reagent and the resulting diol was simultaneously activated in the form of the cyclic sulfate. A series of tandem reactions transposed the activation, first to C-1 (via cyclic sulfate rearrangement), 9 then to C-3 (via epoxide ring-closure), 10 allowing the sequential introductions of nucleophiles there (Nu 1 =N 3 at C-1, Nu 3 =2-ethoxyphenoxide at C-3). During this process, an inversion of configuration at C-2 and a retention (doubleinversion) of configuration at C-3 took place, so that the AD product, a syn-di...

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