Chemistry and Materials Research www.iiste.org ISSN 2224- 3224 (Print) ISSN 2225- 0956 (Online) Vol.9 No.7, 2017 24 A Formal Synthesis of (3S, 4R) (-)-fermoxetine and (3S, 4R) (-)-paroxetine from Enantioselective Desymmetrisation of N-Benzyl Imides Ibrahim U Kutama * Aminu Ahmed Saudatu C Jaafaru Department of Chemistry, Faculty of Science Kano University of Science and Technology, Wudil, PMB 3244, Kano-Nigeria Abstract Enantioselective reduction of N-benzyl 4-substituted glutarimides employing oxazaborolidine catalyst 3 derived from cis-1-amino-indan-2-ol occurred in moderate yield and excellent ee. This has led to the formal synthesis of two antidepressants (-)-fermoxetine 1 and (-)-paroxetine 2. Keywords: Enantioselective, desymmetrisation, imides, glutarimides, fermoxetine, paroxetine Introduction Recently we have reported an efficient strategy of desymmetrisation of a number of N-Bn glutarimides employing an oxazaborolidine catalyst giving access to the corresponding chiral N-Bn 2-piperidinones in good yields and excellent enantioselectivities (Kutama & Jones, 2015). Two of the chiral piperidin-2-ones are used in this work for the formal synthesis of two important antidepressants (-)-fermoxetine 1 and (-)-paroxetine 2. (-)- Paroxetine hydrochloride marketed as Paxil/Seroxat, and (-)-femoxetine are selective serotonin reuptake inhibitors used in the treatment of depression, obsessive compulsive disorder, and panic. (-)-Paroxetine hydrochloride was reported to have generated sales in excess of over $1.0 billion/year (Liu, et. al., 2001, Yu, et. al., 2000). There have been a number of reported syntheses of these two pharmaceuticals showing different ways of enantioselective constructions of the (3S)- and (4R)-stereogenic centres (Kim, M et. al., 2010). These ways include kinetic resolutions (Sugi, K. et. al. 2000, De Gonzalo, G. et. al., 2001), chiral auxiliaries (Amat, M et. al., 1996), chiral bases (Johnson, T. A. et. al., 2001, 2002), the use of chiral pool (Cossy, J. et. al., 2001), enantioselective catalysis (Senda, T. et. al., 2001, Taylor, M. S and Jacobsen, E. N., 2003) and enzymatic asymmetrisations (Yu, M. S. et. al., 2000). The desymmetrisation methodology has also been employed as an effective way of constructing these two stereogenic centres in paroxetine by some research groups. Yu et al. employed a porcine liver esterase (PLE) mediated asymmetric desymmetrisation of glutaric acid bis methyl ester (Yu, M. S. et. al., 2000). Liu et al. used desymmetrisation of 3-substituted glutaric anhydride with (S)-methylbenzylamine (Liu, L. T. et. al., 2001) while Ikariya and co-workers (Ikariya, T and co-workers, 2007) and Simpkins and co-workers (Simpkins, S. N and co- workers, 2003) in separate works employed desymmetrisation of glutarimides for the synthesis of (-)-paroxetine. In this work we have reported the enantioselective reduction of N-benzyl 4-substituted glutarimides employing oxazaborolidine catalyst 3 derived from cis-1-amino-indan-2-ol and their subsequent functionalization to the (3S, 4R) chiral lactams as yet another convenient route to the construction of the two important stereogenic centres in these important pharmaceuticals. Experimental All solvents were obtained dry from a Grubbs dry solvent system and glassware was flame dried and cooled under vacuum before use. 1 H and 13 C NMR spectra were measured using CDCl 3 or DMSO as solvent unless otherwise stated, on a Brüker 250 or 400 MHz machine with an automated sample changer (unless otherwise stated). Chemical shifts for carbon and hydrogen are given on the scale relative to TMS (tetramethylsilane, δ = 0 ppm). Coupling constants were measured in Hz. 13 C NMR spectra were recorded using the JMOD method. Infrared spectra were recorded on a Perkin-Elmer 1600 FT-IR machine using 0.5mm NaCl cells and mass spectra were recorded on a Kratos instrument using electrospray technique unless otherwise stated. General Procedure for the asymmetric reduction of glutarimides using B-Me catalyst 3 followed by conversion to the corresponding lactam A suspension of (1R, 2S)-cis-amino-2-indanol (0.15 g, 1.00 mmol) in dry toluene (3 cm 3 ) was treated with trimethylboroxine (0.05 cm 3 , 0.33 mmol) and allowed to stir under nitrogen for 30 mins. Dry toluene (5 cm 3 ) was added and the reaction distilled until approximately 2 cm 3 of solvent remained. This procedure was repeated twice after which the final volume of toluene was removed under pressure to give a yellow solid. Dry dichloromethane (5 cm 3 ) was added to give a stock solution of the B-Me catalyst 3. The catalyst (0.5 cm 3 , 10 mol %) was added to the solution of the glutarimide substrate (1.00 mmol) in dry dichloromethane (30 cm 3 ) followed by a drop-wise addition of BH 3 .THF (1 cm 3 , 1.00 mmol). The solution was then allowed to stir at room