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Synlett 2009(13): 2157-2161  
DOI: 10.1055/s-0029-1217568
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Enantioselective Ring Expansion of Prolinols: An Efficient and Short Synthesis of 2-Phenylpiperidin-3-ol Derivatives and 3-Hydroxypipecolic Acids

Anne Cochia, Benjamin Burgera, Cristina Navarroa, Domingo Gomez Pardo*a, Janine Cossy*a, Yang Zhaob, Theodore Cohenb
a Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax: +33(1)40794660; e-Mail: janine.cossy@espci.fr; e-Mail: domingo.gomez-pardo@espci.fr;
b Department of Chemistry, University of Pittsburgh, Chevron Science Center, 219 Parkman Avenue, Pittsburgh, PA 15260, USA
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Publication History

Received 10 April 2009
Publication Date:
16 July 2009 (online)

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Abstract

A very short route to 2-phenylpiperidin-3-ol derivatives and 3-hydroxypipecolic acids is described. The approach uses two key steps: a one-pot reduction/Grignard addition sequence applied to alkyl proline esters and a ring expansion applied to the corresponding prolinols.

Key words

reduction - Grignard addition - aziridinium - ring expansion - 2-phenylpiperidin-3-ols - 3-hydroxypipecolic acids

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15

Ester reduction/alkylation method: DIBAL-H (1.0 M in hexane, 2.61 mL, 2.61 mmol, 1.2 equiv) was added to a solution of N-benzylproline ethyl ester (500 mg, 2.17 mmol, 1 equiv) in CH2Cl2 (10 mL) at -78 ˚C. The resulting solution was stirred at -78 ˚C for 30 min, followed by the addition of commercially available PhMgBr (1.0 M in THF, 6.52 mL, 6.52 mmol, 3 equiv) dropwise at -78 ˚C. The solution was then allowed to slowly warm to r.t. overnight. Sat. aq NH4Cl (10 mL) was added to quench the reaction. Sat. sodium tartrate solution (10 mL) was added to the resulting gel. The mixture was stirred at r.t. for 30 min, then the organic layer was extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to give a separable mixture of diastereomers 2b and 3b, which was purified by flash chromatography (SiO2; EtOAc-PE, 8:2) to give 2b as a yellow solid (155 mg, 27.5%) and 3b as a pale-yellow oil (155 mg, 27.5%).
Compound 2b: ¹7,²0b R f  = 0.1 (EtOAc-PE, 8:2); mp 93-95 ˚C; [α]D ²0 +106 (c 1.1, CHCl3). IR (neat): 3017, 1495, 1454 cm-¹. ¹H NMR (CDCl3, 400 MHz): δ = 7.43-7.20 (m, 10 H), 4.39 (d, J = 5.2 Hz, 1 H), 3.67 (d, J = 13.0 Hz, 1 H), 3.34 (d, J = 13.0 Hz, 1 H), 3.08 (m, 1 H), 2.96 (m, 1 H), 2.40 (m, 1 H), 1.94 (m, 1 H), 1.80-1.71 (m, 3 H). ¹³C NMR (CDCl3, 100 MHz): δ = 143.8 (s), 139.5 (s), 128.8 (d), 128.7 (d), 128.6 (d), 128.4 (d), 128.4 (d), 128.3 (d), 128.3 (d), 127.1 (d), 127.0 (d), 126.2 (d), 75.3 (d), 70.2 (d), 61.2 (t), 54.3 (t), 29.4 (t), 24.3 (t). MS: m/z (%) = 160 (100)[M+˙ - CHOHPh˙], 91 (71) [PhCH2 +].
Compound 3b: ¹7,²0b R f  = 0.2 (EtOAc-PE, 8:2); [α]D ²0 -54 (c 1, CHCl3). IR (neat): 3620, 2940, 2820, 1496, 1457 cm-¹. ¹H NMR (CDCl3, 400 MHz): δ = 7.41-7.19 (m, 10 H), 4.89 (d, J = 3.1 Hz, 1 H), 4.18 (d, J = 12.7 Hz, 1 H), 3.46 (d, J = 12.7 Hz, 1 H), 3.05 (m, 1 H), 2.89 (m, 1 H), 2.33 (dd, J = 17, 8.1 Hz, 1 H), 1.73 (m, 1 H), 1.65-1.56 (m, 2 H), 1.32 (m, 1 H). ¹³C NMR (CDCl3, 100 MHz): δ = 141.5 (s), 139.1 (s), 128.8 (d), 128.6 (d), 128.4 (d), 128.3 (d), 128.1 (d), 127.6 (d), 127.2 (d), 127.0 (d), 126.8 (d), 125.5 (d), 70.2 (d), 69.2 (d), 58.3 (t), 54.7 (t), 24.0 (t), 23.2 (t). MS: m/z (%) = 160 (100)[M+˙ - CHOHPh˙], 91 (71) [PhCH2 +].

16

General procedure for the ring expansion of pyrrolidines to piperidines: Trifluoroacetic anhydride (3-4 equiv) was added to a stirred solution of N-alkyl pyrrolidine (1 equiv) in THF under argon at r.t. and Et3N (4-7 equiv) was added. The solution was stirred and heated at 100 ˚C for 3 h under microwave irradiation. The resulting solution was cooled to r.t. and a solution of aqueous 3.75 M NaOH was added. After stirring for 30 min, EtOAc was added and the two layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over anhydrous MgSO4 and evaporated under reduced pressure to give the crude product. Compound 4: Chromatography (SiO2; EtOAc-PE, 7:3), R f  = 0.33 (EtOAc-PE, 7:3); ee >99% determined by supercritical fluid chromatography on Daicel Chiralpak OD-H column (MeOH 5%, flow rate 5 mL/min, t = 3.94 min); [α]D ²0 -25 (c 1.15, CHCl3). IR (neat): 3588, 3016, 2946, 1493, 1454 cm-¹. ¹H NMR (CDCl3, 400 MHz): δ = 7.51-7.19 (m, 10 H), 3.87 (d, J = 13.6 Hz, 1 H), 3.74 (m, 1 H), 3.34 (d, J = 1.7 Hz, 1 H), 3.0 (m, 1 H), 2.88 (d, J = 13.6 Hz, 1 H), 2.05-1.89 (m, 3 H), 1.61 (m, 1 H), 1.47 (m, 1 H). ¹³C NMR (CDCl3, 100 MHz): δ = 141.1 (s), 139.1 (s), 128.7 (d), 128.6 (d), 128.5 (d), 128.4 (d), 128.3 (d), 128.2 (d), 128.1 (d), 128.0 (d), 127.4 (d), 126.6 (d), 73.9 (d), 72.4 (d), 59.4 (t), 53.4 (t), 31.3 (t), 19.9 (t). MS: m/z (%) = 267 (3)[M+˙], 266 (3), 222 (15), 210 (6), 194 (15), 177 (13), 176 (100) [M+˙ - PhCH2 ˙ ], 106 (10), 91 (52) [PhCH2 +].
Compound 5: ¹7,²0b Chromatography (SiO2; EtOAc-PE, 8:2), R f  = 0.2 (EtOAc-PE, 8:2); ee >99% determined by supercritical fluid chromatography on Daicel Chiralpak OD-H column (MeOH 5%, flow rate 5 mL/min, t = 4.14 min); mp 139-141 ˚C; [α]D ²0 +27 (c 1, CHCl3). IR (neat): 3588, 3016, 2946, 1493, 1454 cm-¹. ¹H NMR (CDCl3, 400 MHz): δ = 7.55-7.14 (m, 10 H), 3.66 (d, J = 13.6 Hz, 1 H), 3.59 (m, 1 H), 2.91 (d, J = 8.6 Hz, 1 H), 2.89 (m, 1 H), 2.83 (d, J = 13.6 Hz, 1 H), 2.09 (m, 1 H), 1.93 (m, 1 H), 1.70-1.60 (m, 2 H), 1.38 (m, 1 H). ¹³C NMR (CDCl3, 100 MHz): δ = 141.1 (s), 139.6 (s), 128.8 (d), 128.7 (d), 128.6 (d), 128.2 (d), 128.1 (d), 127.9 (d), 127.8 (d), 127.6 (d), 126.9 (d), 126.7 (d), 76.0 (d), 73.9 (d), 59.3 (t), 52.4 (t), 32.5 (t), 23.3 (t). MS: m/z (%) = 267 (3)[M+˙], 266 (3), 222 (15), 210 (6), 194 (15), 177 (13), 176 (100) [M+˙ - PhCH2 ˙ ], 106 (10), 91 (52) [PhCH2 +].