Synthesis, Table of Contents Synthesis 2017; 49(06): 1410-1418DOI: 10.1055/s-0036-1588911 paper © Georg Thieme Verlag Stuttgart · New York Application of Unusual Grignard Reaction for the Stereoselective Synthesis of Antidepressant Drug (R)-(–)-Venlafaxine Subhash P. Chavan* Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune 411 008, India Email: sp.chavan@ncl.res.in , Harshali S. Khatod Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune 411 008, India Email: sp.chavan@ncl.res.in › Author Affiliations Recommend Article Abstract Buy Article All articles of this category Abstract An enantioselective synthesis of antidepressant drug (R)-(–)-venlafaxine is accomplished as an application of recently explored unusual Grignard reaction. An innovative method for the generation of chirality at extremely reactive benzylic center along with determination of absolute stereochemistry has been discussed. The key steps involved in the synthesis include Sharpless asymmetric dihydroxylation for the induction of chirality and an unusual Grignard reaction. Key words Key wordsantidepressant drug - unusual Grignard reaction - Sharpless asymmetric dihydroxylation - reductive dehydroxylation Full Text References References 1 World Health Organization WHO, Collaborative Centre for Drug Statistics Methodology: http://www.whocc.no/atcddd/ . 2a Golden RN, Nicholas L. Depress. Anxiety 2000; 12: 45 2b Preskorn S. Eur. Psychiatry 1997; 12: 2855 3 Yardley JP, Husbands GE. M, Stack G, Butch J, Bicksler J, Moyer JA, Muth EA, Andree T, Fletcher III H, James MN. G, Sielecki AR. J. Med. Chem. 1990; 33: 2899 4 Cipriani A, Signoretti A, Furukawa TA, Churchill AR, Tomelleri S, Omori IM, McGuire H, Barbui C. Cochrane Database Syst. Rev. 2007; 2: CD006530 5a Chavan SP, Kamat SK, Sivadasan L, Balakrishnan K, Khobragade DA, Ravindranathan T, Gurjar MK, Kalkote UR. US Patent US 6350912B1, 2002 ; Chem. Abstr. 2002, 136, 200009. 5b Chavan SP, Kamat SK, Sivadasan L, Balakrishnan K, Khobragade DA, Ravindranathan T, Gurjar MK, Kalkote UR. US Patent US 6504044B2, 2003 5c Chavan SP, Khobragade DA, Kamat SK, Sivadasan L, Balakrishnan K, Ravindranathan T, Gurjar MK, Kalkote UR. Tetrahedron Lett. 2004; 45: 7291 5d Chavan SP, Khobragade DA, Thakkar M, Kalkote UR. Synth. Commun. 2007; 37: 2007 Few selected examples, see: 6a Jinpei Z, Huibin Z, Xuezhen H, Wenlong HJ. J. China Pharm. Univ. 1999; 30: 249 6b Husbands GE. M, Yardley JP, Mills G, Muth EA. US Patent 4535186, 1985 6c Rathod DM, Rangaraju SG, Moreshwar M, Patel N, Deodhar M, Mandar M. Patent EP 1249447, 2001 6d Basappa Kavitha CV, Rangappa KS. Bioorg. Med. Chem. Lett. 2004; 14: 3279 6e Saigal J, Gupta R, Pandit VV, Desai AJ, Mehta NV, Rane SH. US Patent 7026513, 2006 6f Dolitzky BZ, Aronhime J, Wizel S, Nisnevich GA. US Patent 6924393, 2005 7a Davies HM. L, Ni A. Chem. Commun. 2006; 3110 7b Kochetkov KA, Galkina MA, Galkin OM. Mendeleev Commun. 2010; 20: 314 7c Bhuniya R, Nanda S. Tetrahedron Lett. 2012; 53: 1990 8a Chavan SP, Garai S, Pawar KP. Tetrahedron Lett. 2013; 54: 2137 8b Chavan SP, Pawar KP, Garai S. RSC Adv. 2014; 4: 14468 9 Chavan SP, Khatod HS, Das T, Vanka K. RSC Adv. 2016; 6: 50721 10 Chavan SP, Khatod HS. Tetrahedron: Asymmetry 2012; 23: 1410 11 The enantiomeric excess was confirmed with HPLC analysis and the details are provided in the Supporting Information. 12a Veeraraghavan PR, Chanda PB. Chem. Commun. 2013; 49: 3152 12b (±)-22: IR (CHCl3): 3482, 2925, 2860, 1620, 1435, 1269 cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.36–7.13 (m, 5 H), 4.11–3.98 (m, 2 H), 3.88 (dd, J = 10.74, 4.17, Hz, 1 H), 3.41 (br s, 1 H), 3.24 (br s, 1 H), 2.82 (ddd, J = 13.26, 8.46, 4.54, Hz, 1 H), 1.41–1.17 (m, 8 H), 0.83 (t, J = 6.82 Hz, 3 H). 13C NMR (50 MHz, CDCl3): δ = 140.0, 128.6, 128.1, 126.9, 76.3, 67.1, 53.5, 35.6, 31.5, 24.7, 22.5, 13.9. HRMS (ESI): m/z [M + Na]+ calcd for C15H22O3Na: 245.1659; found: 245.1655. 12c (±)-(23): IR (CHCl3): 1610, 1540, 1412, 1126 cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.36–7.16 (m, 5 H), 4.07–3.99 (m, 1 H), 3.96–3.78 (m, 2 H), 2.75 (ddd, J = 16.30, 10,87, 5.43 Hz, 1 H), 1.58 (s, 3 H), 1.47 (s, 3 H), 1.33–1.15 (m, 8 H), 0.81 (t, J = 6.82 Hz, 3 H). 13C NMR (50 MHz, CDCl3): δ = 139.1, 128.6, 128.2, 127.0, 98.3, 73.2, 65.7, 47.5, 33.3, 31.6, 29.6, 24.7, 22.5, 19.4, 14.0. MS (ESI): m/z = 285 [M + Na]+. HRMS (ESI): m/z [M + Na]+ calcd for C12H22O3Na: 285.1061; found: 285.1060. 12d (2R,3R)-13′: 1H NMR (200 MHz, CDCl3): δ = 7.08 (d, J = 8.54 Hz, 2 H), 6.85 (d, J = 8.54 Hz, 2 H), 5.72 (ddt, J = 17.09, 10.38, 6.72 Hz, 1 H), 4.95–4.88 (m, 2 H), 4.05–3.97 (m, 2 H), 3.90–3.86 (m, 1 H), 3.79 (s, 3 H), 2.78 (ddd, J = 13.12, 8.24, 4.88 Hz, 1 H), 2.02–1.90 [m, 3 H (contains two br s for 2-OH)], 1.56–1.51 (m, 1 H), 1.41–1.30 (m, 4 H). 13C NMR (50 MHz, CDCl3): δ = 158.5, 138.5, 132.0, 129.1, 114.6, 114.1, 76.2, 67.1, 55.2, 52.7, 35.1, 33.4, 24.4. 13a 19: IR (CHCl3): 1610, 1556, 1412, 1226 cm–1. 1H NMR (500 MHz, CDCl3): δ (dr: 9:1) = 7.40 (d, J = 8.53 Hz, 2 H), 7.08 (d, J = 7.63 Hz, 0.30 H), 6.82 (d, J = 8.53 Hz, 1.70 H), 5.71 (ddt, J = 17.06, 10.29, 6.77 Hz, 1 H), 4.95–4.86 (m, 2 H), 4.31 (dd, J = 11.55, 3.77 Hz, 1 H), 4.13 (ddd, J = 9.29, 6.53, 3.26 Hz, 1 H), 3.97–3.87 (m, 1 H), 3.80 (s, 3 H), 2.68 (ddd, J = 16.17, 10.68, 5.19 Hz, 0.10 H), 2.46–2.40 (m, 0.90 H), 1.97–1.92 (m, 2 H), 1.53 (s, 3 H), 1.52 (s, 3 H), 1.42–1.31 (m, 1 H), 1.34–1.30 (m, 1 H), 1.20–1.14 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 158.6, 158.3, 138.7, 138.6, 132.7, 131.1, 130.5, 129.0, 114.5, 114.4, 114.1, 113.4, 96.8, 96.2, 73.3, 71.2, 65.7, 55.1, 55.0, 46.5, 43.1, 33.6, 33.5, 33.0, 32.9, 29.4, 24.7, 24.4, 19.4, 19.1. HRMS (ESI): m/z [M + Na]+ calcd for C18H26O3Na: 313.2103; found: 313.2108. 13b 20: 1H NMR (500 MHz, CDCl3): δ = 7.10 (d, J = 8.55 Hz, 2 H), 6.86 (d, J = 8.55 Hz, 2 H), 5.72 (ddt, J = 16.79, 10.07, 6.41 Hz, 1 H), 4.94–4.86 (m, 2 H), 3.97 (ddd, J = 10.38, 6.43, 3.36 Hz, 1 H), 3.91 (t, J = 11.29 Hz, 1 H), 3.82–3.77 (m, 1 H), 3.79 (s, 3 H), 2.70 (ddd, J = 16.17, 10.38, 6.43 Hz, 1 H), 2.33–2.29 (m, 1 H), 2.06–1.98 (m, 1 H), 1.96–1.90 (m, 1 H), 1.57 (s, 3 H), 1.54–1.48 (m, 1 H), 1.45 (s, 3 H), 1.34–1.30 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 158.5, 138.8, 131.0, 129.0, 114.2, 114.1, 98.3, 73.2, 65.8, 55.2, 46.5, 33.5, 32.8, 29.6, 24.3, 19.3. 14a Ohtani I, Kusumi T, Kashman Y, Kakisawa H. J. Am. Chem. Soc. 1991; 113: 4092 14b Mosher’s ester of (S)-14: IR (CHCl3): 2952, 1752, 1672, 1643, 1172 cm−1. 1H NMR (200 MHz, CDCl3): δ = 7.38–7.30 (m, 5 H), 7.10 (d, J = 8.80 Hz, 2 H), 6.78 (d, J = 8.80 Hz, 2 H), 5.75–5.65 (m, 2 H), 4.98–4.92 (m, 2 H), 3.78 (s, 3 H), 3.72–3.69 (m, 2 H), 3.32 (s, 3 H), 2.96–2.91 (m, 1 H), 2.05–1.96 (m, 2 H), 1.62–1.56 (m, 2 H), 1.40–1.28 (m, 2 H), 0.87 (s, 9 H), 0.04 (s, 6 H). 13C NMR (50 MHz, CDCl3): δ = 166.0, 158.5, 138.1, 132.3, 130.8, 130.1, 129.3, 128.2, 127.4, 114.8, 113.6, 77.2, 76.5, 64.2, 55.1, 55.0, 49.9, 33.3, 31.2, 25.7, 23.9, 18.1, –5.55, –5.62. HRMS (ESI): m/z [M + 1]+ calcd for C31H43F3O5Si: 581.2374; found: 581.2378. 14c Mosher’s ester of (R)-14: 1H NMR (200 MHz, CDCl3): δ = 7.48–7.44 (m, 2 H), 7.39–7.32 (m, 3 H), 7.03 (d, J = 8.85 Hz, 2 H), 6.75 (d, J = 8.85 Hz, 2 H), 5.74 (ddt, J = 16.78, 10.07, 6.71 Hz, 1 H), 5.62–5.59 (m, 1 H), 5.00–4.92 (m, 2 H), 3.77 (s, 3 H), 3.60–3.54 (m, 2 H), 3.43 (s, 3 H), 2.91–2.87 (m, 1 H), 2.05–2.01 (m, 2 H), 1.66–1.58 (m, 2 H), 1.46–1.40 (m, 2 H), 0.86 (s, 9 H), –0.06 (s, 3 H), –0.07 (s, 3 H). 13C NMR (50 MHz, CDCl3): δ = 165.9, 158.5, 138.0, 132.5, 130.2, 129.3, 128.2, 127.5, 127.2, 114.9, 113.5, 77.2, 76.4, 63.9, 55.3, 55.1, 50.1, 33.2, 31.4, 25.7, 24.5, 18.0, –5.55, –5.60. 15 Ikawa T, Hattori K, Sajiki H, Hirota K. Tetrahedron 2004; 60: 6901 16 HPLC conditions: column, Kromasil AmyCoat (250 mm × 4.6 mm); mobile phase, EtOH– PE–Et2NH (05:94.9:0.1); wavelength, 254 nm; flow rate, 0.5 mL/min; injecting volume, 5 μL. Supplementary Material Supplementary Material Supporting Information
