1688
M. Calme`s et al. / Tetrahedron: Asymmetry 14 (2003) 1685–1689
(CH2N, two rotamers), 43.19 (C(CH3)2), 53.82 and
56.37 (CHCO, two rotamers), 77.54 and 77.61 (CH2O,
two rotamers), 84.97 and 85.38 (C(CH3)-O, two
rotamers), 116.75 (q, J=287 Hz, CF3), 157.61 (q, J=
35.8 Hz, COCF3), 168.8 (CO), 174.29 and 174.41 (CO);
MS (ESI) m/z: 352.2 [(M+H)+], 373.9 [(M+Na)+], 725.2
[(2M+Na)+].
3.6. (S)-N-(tert-Butoxycarbonyl)-2-piperidinemethanol 5
To a stirred solution of the a-methylpantolactonyl ester
(S,S)-3a (175 mg, 0.50 mmol) in ethanol was slowly
added sodium borohydride (114 mg, 6 equiv.). After
stirring for 1 h at rt and then 0.5 h at reflux TLC
indicated complete consumption of the starting mate-
rial. Glacial acetic acid was added dropwise to adjust
the pH to 2–3 and the mixture was stirred at rt for 1 h.
The reaction mixture was neutralized to pH 7 and the
solvent was eliminated at reduce pressure.
3.3. Crystal data for (S,S)-3a
The diffraction data were collected on a Enraf–Nonius
Kappa
CCD
diffractometer
using
graphite-
The residue was dissolved in 20 ml of a mixture diox-
ane/H2O followed by addition of di-tert-butyldicarbon-
ate (1.5 equiv.) and NaOH (1.5 equiv.). After stirring
for 12 h at rt, dioxane was eliminated at reduce pres-
sure, the mixture was diluted with water (10 ml) and
washed with ethyl acetate (10 ml). The aqueous phase
was acidified to pH 3–4 and extracted with
dichloromethane (3×10 ml). The organic layer was
dried and concentrated in vacuo. Column chromatogra-
phy on silica gel, eluting with hexane/ethyl acetate
(1/1); Rf=0.4), yielded the pure compound 4 as a
colorless solid (62 mg, 0.29 mmol, 57%). HPLC: Rt=
8.9 min (column I); [h]2D0 −31.2 (c 2, CHCl3); [Ref. 13b
monochrome Mo Ka radiation and the f-scan tech-
nique up to q=26.34.
Molecular formula C15H20F3NO5, molecular weight=
351, orthorhombic, space group P212121, cell constants:
,
,
a=7.0710 (10) A, b=10.4730 (10) A, c=22.0460 (10)
A, V=1632.6 (3) A , Z=4, Dcalcd=1.397 mg m−3,
T=298 K, final R=0.038, final Rw=0.046. Details of
the crystal structure determination have been deposited
at the Cambridge Crystallographic Data Centre (depo-
sition number 201754).
3
,
,
1
[h]2D0 −40.5 (c 1, CHCl3)]; H NMR (CDCl3) l=1.30–
3.4. (S)-N-(tert-Butoxycarbonyl)pipecolic acid 4
1.39 (m, 2H, CH2), 1.39 (s, 9H, C(CH3)3), 1.52–1.60 (m,
4H, CH2), 2.80 (br t, 1H, J=11.6 Hz, HCH-N), 3.54
(dd, 1H, J1=5.8 Hz and J2=11.0 Hz, HCH-OH), 3.74
(t, 1H, J1=J2=11.0 Hz HCH-OH), 3.87 (br d, 1H,
J=11.6 Hz, HCH-N), 4.22 (m, 1H, CH-CH2OH); 13C
NMR (CDCl3) l=20.04 (CH2), 25.63 (CH2), 25.67
(CH2), 28.84 (C(CH3)3), 40.37 (CH2), 52.90 (CH),
62.16 (CH2), 80.24 (C(CH3)3), 156.8 (CO); MS (ESI)
m/z: 116.0, 159.5, 215.9 [(M+H)+].
To a stirred solution of the a-methylpantolactonyl ester
(S,S)-3a (175 mg, 0.50 mmol), was added NaOH (60
mg, 1.5 mmol, 3 equiv.) in a solution of THF/H2O (7/3)
(18 ml). The mixture was stirred for 12 h at rt. The
THF was eliminated at reduced pressure and the mix-
ture was diluted with dioxane (10 ml). To the solution
of this deprotected pipecolic acid was added di-tert-
butyldicarbonate (163 mg, 0.75 mmol, 1.5 equiv.) and
NaOH (20 mg, 1 equiv.). After stirring for 12 h at rt,
the dioxane was eliminated at reduced pressure, the
mixture was diluted with water (10 ml) and washed
with ethyl acetate (10 ml). The aqueous phase was
acidified to pH 3–4 and extracted with dichloromethane
(3×10 ml). The organic layer was dried and concen-
trated in vacuo. Column chromatography on silica gel,
eluting with hexane/ethyl acetate (7/3); Rf=0.5) yielded
the pure compound 4 as a colorless solid (97 mg, 0.42
3.7. (1S)-Camphanic acid ester of N-(tert-butoxy-
carbonyl)-2-piperidinemethanol
To a mixture of (S)-N-(tert-butoxycarbonyl)-2-pipe-
ridinemethanol ( 21 mg, 0.1 mmol) and (1S)-camphanic
acid chloride (24 mg, 0.11 mmol, 1.1 equiv.) in 0.5 ml
of dry CH2Cl2 were added at 0°C triethylamine (17 ml,
0.12 mmol, 1.2 equiv.) and a catalytic amount of 4-
dimethylaminopyridine. The mixture was then stirred at
rt for 12 h. The resulting mixture was diluted with
CH2Cl2 (5 ml), washed successively with a 1N HCl
solution (5 ml) and a saturated NaHCO3 solution (5
ml), dried with Na2SO4 and concentrated in vacuo to
afford the expected ester in quantitative yield.
1
mmol, 85%). H NMR (CDCl3) l=1.28–1.43 (br m,
2H), 1.41 (s, 9H), 1.63 (br m, 3H), 2.15 (br d, 1H), 2.91
(br m, 1H), 3.92 (br m, 1H), 4.72 and 4.88 (br s, 1H).
HPLC (column IV): (S)-4: 92–90%, Rt=23.7 min, (R)-
4: 8–10%, Rt=26.7 min (broad signals); column I:
Rt=9.7 min; MS (ESI) m/z: 129.9, 173.9, 229.9 [(M+
H)+], 459.1 [(2M+H)+].
HPLC: column II condition B: (1S,2%S)-enantiomer:
92%, Rt=9.6 min, (1S,2%R)-enantiomer: 8%, Rt=11.4
min. Racemic sample was prepared after N-Boc protec-
tion of the commercially available racemic 2-
piperidinemethanol.
3.5. N-(tert-Butoxycarbonyl)-2-piperidinecarboxylic
acid benzylamide
The benzylamide derivative of (S)-4 was obtained as
previously described,15 using 2-chloro-1-methylpyri-
dinium iodide, benzylamide and triethylamine. HPLC:
column III: (S)-enantiomer: 92–90%, Rt=17.3 min,
(R)-enantiomer: 8–10%, Rt=14.3 min. Racemic sample
was prepared after N-Boc protection of the commer-
cially available racemic pipecolic acid.
References
1. (a) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hanakata,
H.; Kino, T.; Goto, T.; Hashimoto, M.; Taga, T. J. Am.
Chem. Soc. 1987, 109, 5031–5033; (b) Ireland, R. E.;