Reboxetine mesylate is used in the treatment of depression

Chapter 14, Problem 14.67

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Reboxetine mesylate is used in the treatment of depression and is currently marketed as the racemate. The (S,S)-enantiomer of reboxetine is being evaluated for the treatment of neuropathic pain. The following synthetic scheme was part of the synthesis of (S,S)- reboxetine completed by a research group at Pfizer (Org. Proc. Res. & Devel. 2007, 11, 354358): 2 OH OEt NaOH O HO OH OEt 3 3) H3O+ 2) MsCI, Et3N 1) TMSCI, Et3N O H OEt 5 H O Ti[OCH(CH3) 2] 4 ()-DIPT t-BuOOH NaOH 4 OH 1 (a) In the conversion of 1 to 2, (-)-DIPT serves the same function as (-)-DET. Provide the structure of 2. (b) Propose a plausible mechanism for the transformation of 2 to 3 and draw the expected configuration at each of the chirality centers in 3. (c) TMSCl is used to selectively protect the less hindered, primary OH group in 3. MsCl functions very much like TsCl by converting an OH group into a good leaving group, called a mesylate (OMs) group (see Figure 7.28). Aqueous acid then removes the protecting group to give 4. Draw the structure of 4. (d) Draw a plausible mechanism for the transformation of 4 to 5.