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

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

References and Notes

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  The excellent diastereoselectivity in the DIBAL-H/Grignard sequence was probably due to catalysis of the conversion of R2 to R1 (Scheme  [³] ) due to the presence of MgBr₂ in the Grignard reagent, whereas ZnCl₂ or heat was used for this purpose in Ref. 14c

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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 ⁺].