Application of Unusual Grignard Reaction for the Stereoselective Synthesis of Antidepressant Drug (R)-(–)-Venlafaxine

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

antidepressant drug - unusual Grignard reaction - Sharpless asymmetric dihydroxylation - reductive dehydroxylation

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• 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.