TETRAHEDRON LETTERS Tetrahedron Letters 42 (2001) 5705–5707 Pergamon Ring expansion: formal total synthesis of (-)-paroxetine Janine Cossy, a, * Olivier Mirguet, a Domingo Gomez Pardo a, * and Jean-Roger Desmurs b a Laboratoire de Chimie Organique associe ´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France b Rhodia, 190 avenue Thiers, 69457 Lyon Cedex 06, France Received 5 May 2001; accepted 19 June 2001 Abstract—A ring expansion and a radical dehalogenation have been used as the key steps in a formal total synthesis of (-)-paroxetine. A stereoselective ring expansion of prolinol generated the substituted piperidine ring precursor of (-)-paroxetine. © 2001 Elsevier Science Ltd. All rights reserved. 4-Arylpiperidine is an important structural element in a number of biologically active compounds, possibly due to the similarity to aryl alkylamine pharmacophore common to neurotransmitters like serotonin [5-hydroxy- tryptamine (5-HT)], dopamine (DA), noradrenaline (NA) and to antagonists of opiate receptors. Drugs that modulate the physiological and pathophysiological actions of 5-HT are useful or potentially useful in the treatment of a variety of human diseases, including depression, anxiety, alcoholism, chronic pain, emesis and eating disorders such as obesity and bulimia. 1 Such compounds can be exemplified by the antipsychotic 5-HT- and DA-antagonists, haloperidol, 2 the analgesic opioid agonist, meperidine, 3 and the selective serotonin reuptake inhibitor (SSRI), paroxetine 1 [Paxil ® , Seroxat ® ] (Fig. 1). 4 This drug is used in the treatment of depression, obses- sive compulsive disorder and panic disorder. Moreover, it had a reduced propensity to cause the side-effects usually associated with tricyclic antidepressants. 5 Paroxetine is an enantiomerically pure (-)-trans -3,4-di- substituted piperidine. Due to its biological importance, several enantiocontrolled syntheses have been disclosed. 6 In the context of our studies on ring expansion reactions 7 of enantiomerically pure substituted prolinols to enantiomerically pure substituted 3-hydroxy- piperidines 7,8 or substituted 3-chloropiperidines 7,9 (Scheme 1), we report here a formal enantioselective synthesis of the (-)-paroxetine. The retrosynthetic analysis shown in Scheme 2 envi- sions aminoalcohol (-)-9, a known precursor of the (-)-paroxetine 1, 6a arising from optically pure substi- tuted 3-chloropiperidine (-)-7, which would be derived from (L)-pyroglutamic acid via the known bicyclic lac- tam (+)-2. 10 Enantiomerically pure bicyclic lactam (+)-2 ([] D = +237, c 1.2, CHCl 3 ), obtained in three steps from (L)- pyroglutamic acid, 10 was treated with an excess of LiHMDS (2.1 equiv., THF, -78°C, 40 min) which Figure 1. Selected 4-arylpiperidines. Scheme 1. Ring expansion reactions. * Corresponding authors. Tel.: 00.33.1.40.79.46.63; fax: 00.33.1.40.79.46.60; e-mail: janine.cossy@espci.fr 0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII:S0040-4039(01)01096-6