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Synthesis 2017; 49(06): 1410-1418
DOI: 10.1055/s-0036-1588911
DOI: 10.1055/s-0036-1588911
paper
Application of Unusual Grignard Reaction for the Stereoselective Synthesis of Antidepressant Drug (R)-(–)-Venlafaxine
Further Information
Publication History
Received: 18 October 2016
Accepted after revision: 20 October 2016
Publication Date:
28 November 2016 (online)
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 dehydroxylationSupporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0036-1588911.
- Supporting Information
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References
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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.
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- 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.
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