Asymmetric synthesis of both the enantiomers of antidepressant venlafaxine and its analogues Rajib Bhuniya, Samik Nanda ⇑ Department of Chemistry, IIT-Kharagpur, Kharagpur 721302, India article info Article history: Received 9 December 2011 Revised 2 February 2012 Accepted 6 February 2012 Available online 13 February 2012 Keywords: Antidepressants Hydroxynitrile lyase Lipase catalyzed kinetic resolution Asymmetric synthesis abstract Chemoenzymatic asymmetric synthesis of antidepressant agent venlafaxine and its analogue have been reported in this communication. The main highlight of the reported synthesis is the stereoselective syn- thesis of cyanohydrins by (S)-hydroxynitrile lyase (Hevea brasiliensis) followed by lipase catalyzed kinetic resolution. Ó 2012 Elsevier Ltd. All rights reserved. Venlafaxine hydrochloride belongs to a class of well known antidepressant agents generally known as SNRIs (serotonin-nor- epinephrine reuptake inhibitor). It is widely known by its brand name EffexorXR Ò , which was first introduced by Wyeth and now marketed globally by Pfizer, is approved for the effective treatment of major depressive disorder (MDD) and generalized anxiety disor- der (GAD). Effexor XR Ò made history when it became Wyeth’s larg- est selling drug accounting for 16–18% of net revenue from 2006 to 2008. The reported synthetic routes for racemic venlafaxine mainly involve the condensation of cyclohexanones with 4-methoxy- phenyl acetic acids or 4-methoxyphenyl acetonitriles followed by functional group manipulation. 1 There is also another report which involves an efficient HDA (Hetero Diels–Alder) reaction of an azadiene followed by transketalization and hydroxymethylation reaction. 2 Recently an efficient enzymatic resolution of (±)-venla- faxine has been reported by Kochetkov et al. 3 We are interested to develop an asymmetric synthetic route for both the enantiomers of venlafaxine, as both the enantiomers have a role in its antide- pressant activity [(+)-enantiomer inhibiting serotonin reuptake and the ()-enantiomer inhibiting norepinephrine reuptake]. We thought that cyanohydrins generated from cyclohexanones and its analogues can be synthetically manipulated to both the enanti- omers of venlafaxine (1). Our retrosynthetic scheme is outlined be- low (Scheme 1). The cyanohydrins are easily synthesized from the corresponding ketone by an enzymatic route applying (S)- hydroxynitrile lyase (HNL) from Hevea brasiliensis (HbHNL). 4 We have also decided to synthesize two venlafaxine analogues (2 and 3) by the same strategy. For the synthesis of (R)-venlafaxine (1) we have started from cyclohexanone. Cyclohexanone is converted to its corresponding cyanohydrin (4) by an enzymatic transcyanation reaction with ace- tone cyanohydrin and HbHNL as the enzyme. Chemistry of the cya- nohydrin formation by similar HNL is well established in our laboratory and elsewhere. 5,6 By applying a transcyanation protocol with acetone cyanohydrins as a cyanide source cyclohexanone cya- nohydrin is synthesized on a 10 g scale by using crude the enzy- matic extract of HNL from rubber tree (Hevea brasiliensis). The role of enzyme in this particular reaction is unique as the biocata- lytic reaction is very fast and high yielding (almost quantitative conversion is achieved) than the corresponding chemical reaction. The biocatalytic reaction is also highly stereoselective in the case of cyanohydrins’ formation from 4-methyl cyclohexanone (for syn- thesis of 3), as it yields only one diastereomer (syn addition of CN ion; Me is equatorial). Syn addition of CN ion to cyclohexanone analogue by similar (S)-HNL is reported by Effenberger co-work- ers. 7 This fixes the alcohol functionality in axial and CN group in the equatorial position of the cyclohexane ring in the case of 4- methylcyclohexanone. The free hydroxyl group in compound 4 was protected as its EOM ether by treatment with EOM-Cl (ethoxy- methyl chloride) with DIPEA (diisopropyl ethyl amine) to afford EOM-protected cyanohydrin 7 in a 90% yield. Addition of Grignard reagent (generated from 4-bromo anisole) on compound 7 fol- lowed by acidic work-up afforded ketone 10 in an 85% yield. Wittig reaction with ketone 10 and triphenylphosphonium methyl iodide in the presence of KOtBu afforded the olefin 13 in an 82% yield. Asymmetric hydroboration reaction with ()-Ipc 2 BH was 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2012.02.025 ⇑ Corresponding author. E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda). Tetrahedron Letters 53 (2012) 1990–1992 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet