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Synlett 2009(20): 3320-3322  
DOI: 10.1055/s-0029-1218359
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Concise Total Asymmetric Synthesis of (S)-2-Phenylpiperidin-3-one

Xavier Gaucher, Mouhamad Jida, Jean Ollivier*
Laboratoire de Synthèse Organique et Méthodologie, UMR 8182, Institut de Chimie Moléculaire et des Matériaux d"Orsay, Université de Paris-Sud XI, 91405 Orsay, France
Fax: +33(1)69157252; e-Mail: jollivie@icmo.u-psud.fr;
Further Information

Publication History

Received 27 August 2009
Publication Date:
11 November 2009 (online)

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Abstract

Starting from readily available dihydropyridinones, we have developed the first synthesis of (S)-2-phenylpiperidin-3-one. While the scaffold appears relatively common, even in its racemic form, this original product can be considered as a potential precursor of substance P antagonist.

Key words

asymmetric synthesis - conjugation - drugs - piperidines - radical reactions - ketones

    References and Notes

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12

3-Benzyloxy-2-phenylpyridine (9): Yield: 76%; deliquescent yellow solid; ¹H NMR (250 MHz, CDCl3): δ = 7.82-7.72 (m, 2 H), 7.56-7.20 (m, 8 H), 7.04 (dd, J = 1.5, 2.5 Hz, 1 H), 6.79 (dd, J = 1.5, 4.3 Hz, 1 H), 6.23 (dd, J = 2.5, 4.3 Hz, 1 H), 5.70 (s, 2 H); ¹³C NMR (62.9 MHz, CDCl3): δ = 149.8, 142.5, 139.9, 138.3, 131.5, 130.9, 129.3, 128.7, 128.6, 128.2, 127.9, 123.6, 108.7, 52.4; IR (neat): 3063, 3030, 1600 cm-¹; MS (EI): m/z (%) = 261 (78) [M+], 156 (67), 91 (100), 77 (20); HRMS: m/z calcd for C18H15NO: 261.11480; found: 261.11437.
Methyl (2 S )-Allyl(4-methylphenylsulfonyl)amino-(phenyl)acetate(11): Yield: 89%; colorless liquid; [α]D ²0
-203 (c 0.6, CH2Cl2); ¹H NMR (300 MHz, CDCl3): δ = 7.77-7.20 (m, 9 H), 5.82 (s, 1 H), 5.47-5.36 (m, 1 H), 4.80-4.74 (m, 2 H), 3.98-3.81 (m, 2 H), 3.63 (s, 3 H), 2.45 (s, 3 H); ¹³C NMR (75.5 MHz, CDCl3): δ = 170.4, 143.5, 138.3, 136.9, 134.8, 129.6, 129.2, 128.8, 128.7, 127.5, 116.5, 62.7, 52.1, 48.3, 21.6; IR (neat): 3052, 3031, 2949, 1725, 1648, 1600 cm-¹; MS (EI): m/z (%) = 359 (6) [M+], 186 (100), 144 (86), 118 (38), 91 (52); HRMS (ESI+): m/z calcd for C19H21NO4SNa: 382.10840; found: 382.10906.
(1 S ,2 S )-3-(4-Methylphenylsulfonyl)-2-phenyl-3-azabicyclo[3.1.0]hexan-1-ol (12a): Yield: 63%; deliquescent solid; [α]D ²0 -305 (c 0.7, CH2Cl2); ¹H NMR (360 MHz, CDCl3): δ = 7.40-7.12 (m, 9 H), 4.98 (s, 1 H), 3.76 (dd, J = 3.6, 10.1 Hz, 1 H), 3.53 (d, J = 10.1 Hz, 1 H), 2.37 (s, 3 H), 1.79 (br s, 1 H), 1.72 (td, J = 4.5, 9.0 Hz, 1 H), 1.30-1.15 (m, 1 H), 0.46 (t, J = 4.5 Hz, 1 H); ¹³C NMR (62.9 MHz, CDCl3): δ = 143.0, 137.9, 131.8, 129.4, 128.9, 128.3, 127.8, 126.8, 66.1, 64.9, 49.8, 23.1, 21.5, 15.8; IR (KBr): 3473, 3063, 3033, 2928, 2881, 1599 cm-¹; MS (EI): m/z (%) = 329 (8) [M+], 301 (49), 155 (78), 146 (32), 118 (32), 91 (100); HRMS (ESI+): m/z calcd for C18H20NO3S: 330.11580; found: 330.11529.
(1 R ,2 S )-3-(4-Methylphenylsulfonyl)-2-phenyl-3-azabicyclo[3.1.0]hexan-1-ol (12b): Yield: 25%; deliquescent solid; [α]D ²0 -194 (c 0.5, CH2Cl2); ¹H NMR (250 MHz, CDCl3): δ = 7.60-7.10 (m, 9 H), 4.11 (s, 1 H), 3.48 (d, J = 9.5 Hz, 1 H), 3.26 (dd, J = 4.5, 9.5 Hz, 1 H), 2.50 (br s, 1 H), 2.36 (s, 3 H), 1.56 (td, J = 4.5, 9.0 Hz, 1 H), 1.11-1.03 (m, 1 H), 0.68 (dd, J = 4.5, 9.0 Hz, 1 H); ¹³C NMR (62.9 MHz, CDCl3): δ = 144.3, 137.9, 132.0, 129.9, 129.0, 128.6, 128.2, 127.5, 68.4, 67.9, 52.2, 21.9, 21.8, 15.5; IR (KBr): 3465, 3062, 3031, 2928, 2872, 1599 cm-¹; MS (EI): m/z (%) = 329 (8) [M+], 224 (28), 207 (42), 174 (82), 146 (100), 118 (51), 91 (86). HRMS (ESI+): m/z calcd for C18H20NO3S: 330.11580; found: 330.11525.


(2 S )-1-(4-Methylphenylsulfonyl)-2-phenyl-1,6-dihydro-3 (2 H )-pyridinone (13): Yield: 25%; yellow oil; [α]D ²0 -145 (c 0.3, CH2Cl2); ¹H NMR (360 MHz, CDCl3): δ = 7.64-7.25 (m, 9 H), 6.71 (td, J = 4.7, 10.4 Hz, 1 H), 5.95 (td, J = 2.5, 10.4 Hz, 1 H), 5.63 (s, 1 H), 4.49 (ddd, J = 2.5, 4.7, 20.1 Hz, 1 H), 3.85 (ddd, J = 2.5, 4.7, 20.1 Hz, 1 H), 2.41 (s, 3 H); ¹³C NMR (62.9 MHz, CDCl3): δ = 192.1, 144.6, 144.5, 136.4, 133.1, 129.9, 128.9, 128.5, 127.6, 127.1, 126.8, 64.0, 41.7, 21.6; IR (neat): 3064, 3032, 2964, 1687, 1633, 1598 cm-¹; MS (EI): m/z (%) = 327 (9) [M+], 207 (18), 196 (75), 194 (35), 172 (86), 146 (100), 118 (43), 91 (78); HRMS (ESI+): m/z calcd for C18H18NO3S: 328.10270; found: 328.10218.
(2 S )-1-(4-Methylphenylsulfonyl)-2-phenylpiperidin-3-one (14): Yield: 68%; deliquescent solid; [α]D ²0 +5 (c 0.2, CH2Cl2); ¹H NMR (300 MHz, CDCl3): δ = 7.74-7.28 (m, 9 H), 5.58 (s, 1 H), 3.87 (td, J = 5.1, 13.8 Hz, 1 H), 3.45 (td, J = 4.2, 14.1 Hz, 1 H), 2.44 (s, 3 H), 2.38 (td, J = 4.2, 14.1 Hz, 1 H), 2.20 (td, J = 5.1, 13.8 Hz, 1 H), 1.76-1.68 (m, 2 H); ¹³C NMR (62.9 MHz, CDCl3): δ = 204.4, 143.8, 142.6, 133.9, 130.0, 129.1, 128.1, 127.1, 125.7, 66.8, 41.8, 36.7, 23.5, 21.6; IR (neat): 3063, 2957, 1722, 1598 cm-¹; MS (EI): m/z (%) = 329 (9) [M+], 224 (29), 174 (93), 146 (100), 118 (46), 91 (77); HRMS (ESI+): m/z calcd for C18H19NO3SNa: 352.09780; found: 352.09813.
(2 S )-2-Phenylpiperidin-3-one (1): Yield: 68%; deliquescent solid; [α]D ²0 +12 (c 0.1, CH2Cl2); ¹H NMR (300 MHz, CDCl3): δ = 7.36-7.22 (m, 5 H), 4.88 (s, 1 H), 2.66-2.45 (m, 4 H), 2.44 (br s, 1 H), 1.68-1.52 (m, 2 H); ¹³C NMR (62.9 MHz, CDCl3): δ = 205.2, 134.9, 124.9, 128.7, 127.1, 72.2, 43.2, 33.6, 26.1; IR (neat): 3059, 2955, 1720, 1598
cm-¹; MS (EI): m/z (%) = 175 (24) [M+], 147 (34), 146 (100), 131 (60), 121 (70), 120 (53); HRMS (ESI+): m/z calcd for C11H13NONa: 198.18840; found: 198.18834.