Enantioenriched Piperidinols from α-Dibenzylamino Aldehydes
FULL PAPER
suspension of NaIO4 supported on silica gel (8 g, 20% NaIO4) in
CH2Cl2 (20 mL) at 0 °C. After stirring at the same temperature for
1 h, the solid was removed by filtration and washed with CH2Cl2
(3ϫ30 mL). The filtrate was concentrated under vacuum and the
residue purified by column chromatography (silica gel, hexane/
EtOAc).
tion in the next step. The residue (0.92 mmol) was dissolved in an-
hydrous diethyl ether (4 mL) and added to a suspension of LiAlH4
(35.0 mg, 0.92 mmol) in Et2O (4 mL) at 0 °C. The mixture was
stirred for 1 h at this temperature and then quenched by addition
of a 15% NaOH aqueous solution. The mixture was filtered off
and the solids washed with Et2O. The solvent was eliminated under
vacuum and the residue purified by flash chromatography (silica
gel, CH2Cl2/MeOH).
(2S,3R)-2-(Dibenzylamino)-6-oxo-3-hexyl Acetate (anti-4a): Yield
1.02 g, 71%. Colorless oil. IR (film): ν = 1728, 1246, 749, 698 cm–1.
˜
1H NMR (CDCl3): δ = 1.06 (d, J = 9.1 Hz, 3 H), 1.72–1.89 (m, 1
H), 1.97 (s, 3 H), 1.97–2.06 (m, 1 H), 2.11–2.27 (m, 2 H), 2.78 (dq,
J1 = 6.2, J2 = 6.5 Hz, 1 H), 3.35 (d, J = 13.76 Hz, 2 H), 3.76 (d, J
= 13.76 Hz, 2 H), 5.04–5.14 (m, 1 H), 7.19–7.37 (m, 10), 9.58 (s, 1
(2S,3R)-2-Methyl-3-piperidinol (5a): Yield 90 mg, 51%. Colorless
solid with m.p. 130–131 °C (from CH2Cl2/hexane). [α]2D0 = –11.5 (c
= 0.6, CHCl3) [ref.[21]: m.p. 130 °C, [α]2D0 = +16.2 (c = 0.92, CHCl3)
for the (2R,3S) enantiomer]. IR (KBr): ν = 3402, 3275, 1050 cm–1.
˜
H) ppm. 13C NMR (CDCl3): δ = 8.3 (CH3), 20.9 (CH3), 23.7 1H NMR (CDCl3): δ = 1.18 (d, J = 6.3 Hz, 3 H), 1.21–1.38 (m, 1
(CH2), 38.8 (CH2), 54.0 (2 CH2), 54.1 (CH), 73.9 (CH), 126.9 (2
CH arom.), 128.2(4 CH arom.), 128.9 (CH arom.), 139.5 (2 C
H), 1.43–1.60 (m, 1 H), 1.68–1.77 (m, 1 H), 1.96–2-06 (m, 1 H),
2.34 (br. s, 2 H), 2.37–2.49 (m, 1 H), 2.56 (dt, J1 = 2.9, J2 = 12.2 Hz,
arom.), 170.6 (CO2), 201.6 (C=O) ppm. C22H27NO3 (353.45): 1 H), 2.91–2.98 (m, 1 H), 3.14 (ddd, J1 = 4.3, J2 = 8.2, J3 = 12.9 Hz,
calcd. C 74.76, H 7.70, N 3.96; found C 74.69, H 7.53, N 3.81.
1 H) ppm. 13C NMR (CDCl3): δ = 18.5 (CH3), 25.4 (CH2), 33.6
(CH2), 45.6 (CH2), 58.4 (CH), 73.3 (CH) ppm. C6H13NO (115.17):
calcd. C 62.57, H 11.38, N 12.16; found C 62.71, H 11.26, N 12.08.
(2S,3S)-2-(Dibenzylamino)-6-oxo-3-hexyl Acetate (syn-4a): Yield
1.04 g, 72%. Colorless oil. [α]2D0 = –18.1 (c = 0.4, CHCl3). IR (film):
ν = 1729, 1243, 749, 699 cm–1. 1H NMR (CDCl ): δ = 1.08 (d, J =
(2S,3R)-2-(Hydroxymethyl)-3-piperidinol (5b): Yield 104 mg, 53%.
Colorless solid with m.p. 120–121 °C (MeOH/Et2O). [α]2D0 = –44.5
˜
3
6.9 Hz, 3 H), 1.78–2.21 (m, 4 H), 2.1 (s, 3 H), 2.81–2.92 (m, 1 H),
3.32 (d, J = 13.6 Hz, 2 H), 3.92 (d, J = 13.6 Hz, 2 H), 4.90–5.0 (m, (c = 0.4, MeOH) [ref.[13]: [α]2D1 = +58.3 (c = 1.06, MeOH) for the
1 H), 7.20–7.40 (m, 10 H), 9.52 (s, 1 H) ppm. 13C NMR (CDCl3): (2R,3S) enantiomer]. IR (KBr): ν = 3420, 1050 cm–1. 1H NMR
˜
δ = 9.1 (CH3), 21.1 (CH3), 24.1 (CH2), 39.8 (CH2), 54.3 (2 CH2),
54.4 (CH), 75.5 (CH), 126.9 (2 CH arom.), 128.1 (4 CH arom.),
(CD3OD): δ = 1.25–1.41 (m, 1 H), 1.43–1.58 (m, 1 H), 1.68–1.77
(m, 1 H), 1.98–2.06 (m, 1 H), 2.38 (td, J1 = 3.1, J2 = 9.8 Hz, 1 H),
128.9 (CH arom.), 140.0 (2 C arom.), 170.7 (CO2), 201.4 2.52 (td, J = 2.5, 12.1 Hz, 1 H), 2.93–3.02 (m, 1 H), 3.23–3.34 (m,
(C=O) ppm. C22H27NO3 (353.45): calcd. C 74.76, H 7.70, N 3.96;
found C 74.88, H 7.58, N 4.09.
1 H), 3.55 (dd, J1 = 7.2, J2 = 10.7 Hz, 1 H), 3.88 (dd, J1 = 3.1, J2
= 10.7 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 26.1 (CH2), 34.9
(CH2), 46.5 (CH2), 63.7 (CH2), 65.0 (CH), 69.6 (CH) ppm.
C6H13NO2 (131.17): calcd. C 54.94, H 9.99, N 10.86; found C
55.06, H 10.10, N 10.74.
(2S,3R)-1-(tert-Butyldimethylsilyloxy)-2-(dibenzylamino)-6-oxo-3-
hexyl Acetate (anti-4b): Yield 1.26 g, 70%. Colorless oil. [α]2D0
=
+12.6 (c = 0.6, CHCl ). IR (film): ν = 1729, 1243, 749, 699 cm–1.
˜
3
1H NMR (CDCl3): δ = 0.09 (s, 3 H), 0.13 (s, 3 H), 0.95 (s, 9 H),
(2R,3S)-2-Phenyl-3-piperidinol (5c): Yield 146 mg, 55%. Colorless
1.82–1.98 (m, 2 H), 1.97 (s, 3 H), 2.01–2.28 (m, 2 H), 2.85 (ddd, J1 solid with m.p. 144–146 °C (MeOH/Et2O). [α]2D0 = –32.4 (c = 1.0,
= 3.0, J2 = 6.1, J3 = 9.4 Hz, 1 H), 3.65 (d, J = 13.6 Hz, 2 H), 3.83
(dd, J1 = 6.1, J2 = 10.7 Hz, 1 H), 3.91 (d, J = 13.6 Hz, 2 H), 3.97
CHCl3) [ref.[14]: m.p. 143–144 °C, [α]2D2 = –23.0 (c = 1.5, MeOH)].
1
IR (KBr): ν = 3250, 750, 700 cm–1. H NMR (CDCl ): δ = 1.32–
˜
3
(dd, J1 = 3.0, J2 = 10.7 Hz, 1 H), 5.22 (dt, J1 = 5.7, J2 = 9.4 Hz, 1 1.48 (m, 1 H), 1.55–1.79 (m, 2 H), 1.90 (br. s, 2 H), 2.08–2.15 (m,
H), 7.22–7.41 (m, 10 H), 9.5 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 1 H), 2.62 (td, J1 = 3.0, J2 = 11.6 Hz, 1 H), 2.91–2.99 (m, 1 H),
–5.6 (2 CH3), 18.1 (C), 21.1 (CH3), 23.4 (CH2), 25.8 (3 CH3), 38.5
(CH2), 55.1 (2 CH2), 58.6 (CH), 59.0 (CH2), 70.7 (CH), 126.9 (2
CH arom.), 128.3 (4 CH arom.), 129.1 (4 CH arom.), 139.8 (C
3.24 (d, J = 8.8 Hz, 1 H), 3.48 (ddd, J1 = 4.4, J2 = 8.8, J3 = 10.7 Hz,
1 H), 7.15–7.37 (m, 5 H) ppm. 13C NMR (CDCl3): δ = 25.2 (CH2),
33.2 (CH2), 46.7 (CH2), 69.3 (CH), 72.5 (CH), 127.8 (CH arom.),
arom.), 170.2 (CO2), 201.8 (C=O) ppm. C28H41NO4Si (483.71): 128.1 (2 CH arom.), 128.5 (2 CH arom.), 141.4 (C arom.) ppm.
calcd. C 69.52, H 8.54, N 2.90; found C 69.66, H 8.67, N 2.81.
C11H15NO (177.24): calcd. C 75.54, H 8.53, N 7.90; found C 75.62,
H 8.66, N 7.79.
(1R,2S)-1-(Dibenzylamino)-5-oxo-1-phenyl-2-pentyl Acetate (anti-
4c): Yield 1.27 g, 75 %. Colorless oil. IR (film): ν = 1726, 750,
Synthesis of 2,6-Substituted 3-Piperidinol Derivative 7
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697 cm–1. 1H NMR (CDCl3): δ = 1.63 (s, 3 H), 1.90–2.07 (m, 1 H),
2.16–2.31 (m, 1 H), 2.34–2.49 (m, 1 H), 2.58–2.69 (m, 1 H), 3.08
(d, J = 13.3 Hz, 2 H), 3.80 (d, J = 10.3 Hz, 1 H), 3.91 (d, J =
13.3 Hz, 2 H), 5.75–5.87 (m, 1 H), 7.15–7.52 (m, 15 H), 9.70 (s, 1
H) ppm. 13C NMR (CDCl3): δ = 21.5 (CH3), 28.3 (CH2), 35.6
(CH2), 54.8 (2 CH2), 65.8 (CH), 72.9 (CH), 126.9 (2 CH arom.),
127.1 (CH arom.), 127.8 (2 CH arom.), 128.1 (4 CH arom.), 128.6
(4 CH arom.), 129.4 (2 CH arom.), 134.5 (C arom.), 139.4 (2 CH
arom.), 170.8 (CO2), 201.5 (C=O) ppm. C27H29NO3 (415.52):
calcd. C 78.04, H 7.03, N 3.37; found C 78.17, H 7.11, N 3.26.
(1R,2S)-1-(Dibenzylamino)-5-oxo-1-phenyl-2-hexyl Acetate (6):
Oxygen was bubbled through a solution of ent,anti-3c (372 mg,
0.92 mmol), palladium chloride bis(acetonitrile) complex (34 mg,
0.13 mmol, 0.14 equiv.), and cupric chloride (176 mg, 1.3 mmol,
1.4 equiv.) in methanol (7 mL) at room temperature. After stirring
for 25 h, the reaction mixture was filtered and the solvent evapo-
rated under reduced pressure. The residue was treated with ethyl
acetate (15 mL), water (15 mL), and an aqueous ammonia solution
(3 mL). The organic layer was separated, dried with anhydrous
Na2SO4, evaporated under reduced pressure, and purified by col-
umn chromatography on silica gel (hexane/ethyl acetate, 8:1) to give
Synthesis of 2-Substituted 3-Piperidinols 5a–c: 20 % Pd(OH)2/C
(100 mg) was added in one portion to a solution of the appropriate
dibenzylamino aldehyde 4 (1.5 mmol) in methanol (20 mL). The
mixture was stirred under 1 atm of hydrogen and the reaction mon-
itored by TLC. After completion of the reaction, the catalyst was
removed by filtration through Celite. The Celite was washed with
methanol (20 mL) and the solvent evaporated under reduced pres-
sure to afford a yellowish residue which was used without purifica-
6 (308 mg, 78%) as a colorless oil. [α]2D0 = +97.7 (c = 1.0, CHCl3).
1
IR (film): ν = 1736, 1718, 1241, 735, 701 cm–1. H NMR (CDCl ):
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3
δ = 1.61 (s, 3 H), 1.82–1.95 (m, 1 H), 2.11 (s, 3 H), 2.20–2.32 (m,
1 H), 2.38–2.50 (m, 1 H), 2.59–2.68 (m, 1 H), 3.06 (d, J = 13.5 Hz,
2 H), 3.79 (d, J = 10.5 Hz, 1 H), 3.95 (d, J = 13.5 Hz, 2 H), 5.75
(ddd, J1 = 3.0, J2 = 7.9, J3 = 10.5 Hz, 1 H), 7.22–7.44 (m, 15
H) ppm. 13C NMR (CDCl3): δ = 20.5 (CH3), 25.6 (CH2), 29.9
Eur. J. Org. Chem. 2007, 1803–1810
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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