Efficient preparation of (1′R)-(-)-1-(2′-hydroxy-1′- phenylethyl)piperidin-2-one: Synthesis of (2′S,3R)-(+)-stenusine

Article abstract of DOI:10.1016/j.tetasy.2005.01.023

An efficient oxidation of (2′R)-(-)-2′-phenyl-2′- (piperidin-1-yl)ethanol 2 with bromine to generate the corresponding piperidin-2-one 3 in 96% is described. In addition, starting from 3, (2′S,3R)-(+)-stenusine 8 was synthesized in 70% overall yield. The

Full text of DOI:10.1016/j.tetasy.2005.01.023

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 949–952
Efficient preparation of
(10R)-(ꢀ)-1-(20-hydroxy-10-phenylethyl)piperidin-2-one:
synthesis of (20S,3R)-(+)-stenusine
a
a,
a
Alejandro Castro-C., Jorge Juarez-P., Dino Gnecco, Joel L. Teran,
a
*
´
Alberto Galindo, Sylvain Bernes and Rau´l G. Enrıquez
´
a
a
b
`
´
a
´ ´ ´
Centro de Quımica, Instituto de Ciencias, BUAP, Lab. Sıntesis Organica, Edificio 194, Complejo de Ciencias,
Ciudad Universitaria, 72570 Puebla, Pue., Mexico
b
´
Instituto de Quımica, UNAM, Cd. Universitaria, 04510 Mexico, D.F., Mexico
Received 12 October 2004; revised 5 January 2005; accepted 18 January 2005
Abstract—An efficient oxidation of (20R)-(ꢀ)-20-phenyl-20-(piperidin-1-yl)ethanol 2 with bromine to generate the corresponding
piperidin-2-one 3 in 96% is described. In addition, starting from 3, (20S,3R)-(+)-stenusine 8 was synthesized in 70% overall yield.
The X-ray analysis of piperidine 6ÆHCl is also reported.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Ph
Ph
Ph
HO
HO
O
N
O
N
O
N
Br2
AcOH, 96%
TiCl4
Piperidine alkaloids and synthetic analogues are the
focus of great interest in the pharmaceutical industry
because they exhibit an extensive range of biological
activities.1 As a consequence, the development of new
methods for the enantioselective synthesis of piperidine
derivatives by stereoselective introduction of substitu-
ents at the carbon positions of the heterocycle consti-
tutes an area of current interest.2 In this context,
chiral piperidin-2-ones are versatile synthetic building
blocks for the asymmetric synthesis of this class of
compounds.3
Et3SiH, 84%
1
2
3
Five steps
N
(2'S,3R)-(+)-Stenusine 8
Scheme 1.
In particular, Micouin et al.4 reported a preparation of
the piperidin-2-one 3 by reduction of oxazololactam 1
following a procedure described by Romo and Meyers5
for a similar lactam. In addition, starting from 3 an
asymmetric synthesis of natural stenusine 8 was carried
out.
2. Results and discussion
Herein we found the conditions for the oxidation at C-2
of 2 with a solution of bromine in acetic acid. The best
result was obtained in the conditions described in Table
1 (entry 3).
Herein, we report an efficient oxidation of compound 26
with bromine in the presence of acetic acid7 to give
piperidin-2-one 3 in 96% yield (Scheme 1).
However, the oxidation of (10S)-(ꢀ)-1-(10-phenyl-
ethyl)piperidine under the same conditions afforded
the corresponding piperidin-2-one in 50% yield.
*
The high yield observed for the oxidation of 2 could
be explained via a mechanism, which involves the
Corresponding author. Tel.: +52 222 2453277; fax: +52 222
2295551; e-mail: rijuarez@siu.buap.mx
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.023

950
A. Castro-C. et al. / Tetrahedron: Asymmetry 16 (2005) 949–952
Table 1.
Entry Br2/AcOH
Solution Temperature Time 2 Yield
(ꢁC)
(mmol/mL) (1 M)
(h)
(%)
1
2
3
2.0/6
2.6/8
K2CO3
K2CO3
NaOH
90
90
90
1
1
1
65
80
96
3.2/10
participation of the hydroxyl function of 2 in the ring
close of I to give intermediate II.
This intermediate in the presence of bromine gives III,
which generates the hexahydro-oxazolo[3,2-a]pyridin-4-
ylium IV. Finally, compound IV under basic conditions
provides V, which can be rearranged to give lactam 38,9
(Scheme 2).
Figure 1. ORTEP view of the crystal structure of compound 6ÆHCl.
Displacement ellipsoids for non-H atoms are drawn at the 20%
probability level.
Finally, alkylation of 3 with (S)-(+)-1-bromo-2-meth-
ylbutane in the presence of HMPA and sec-BuLi gave
a diastereoisomeric mixture with a ratio 9:1 (determined
by NMR). Purification of this mixture by flash chroma-
tography afforded 4 in 80% yield. The excellent diaste-
reoselectivity is in agreement with that previously
reported.4 Then, reduction of the carbonyl function with
Red-Al10 afforded 5 in quantitative yield. Hydrogenoly-
sis of 5 furnished (20S,3R)-(+)-3-(20-methylbutyl)piper-
idine hydrochloride 6ÆHCl in 95% yield. This
compound was crystallized from ethyl acetate and its
single-crystal X-ray analysis performed in order to
determine the configuration at C-3 (Fig. 1). Finally,
starting from 6ÆHCl and following the methodology de-
scribed by Micouin et al.4 the synthesis of stenusine
(20S,3R)-(+)-l-ethyl-3-(2-methylbutyl)piperidine 8 was
achieved in two steps in 96% yield. Compound 8 is iden-
tical to the product described by Enders et al.11 ([a]D,
1H, and 13C NMR) (Scheme 3). Some authors12 have re-
ported the synthesis of the four diastereoisomers of
stenusine in different ratios; however, this methodology
is only useful for preparing one of them in high yield.
Taking into account that (S)-phenylglycinol is also com-
mercially available, this procedure can provide access to
(2S,3S)-stenusine.
Ph
Ph
HO
HO
H
N
N
O
N
i
ii
iii
3
6.HCl
4
5
O
N
N
v
iv
7
8
Scheme 3. Reagents and conditions: (i) sec-BuLi, THF, HMPA,
ꢀ78 ꢁC, then (S)-(+)-1-bromo-2-methylbutane, 90%; (ii) Red-Al, THF,
0 ꢁC, 100%; (iii) H2, Pd–C 10%, MeOH, HCl, 95%; (iv) CH3COCl,
NEt3, refluxing CHCl3, 96%; (v) Red-Al, THF, 0 ꢁC, 100%.
2 with bromine in the presence of acetic acid is a conve-
nient method to prepare (10R)-(ꢀ)-1-(20-hydroxy-10-
phenylethyl)piperidin-2-one 3 in high yield.
3. Conclusion
Furthermore to the best of our knowledge, this is the
first time intermediates 4, 5, 6ÆHCl, and 7 have been
characterized fully.
In conclusion, the results reported herein show that oxi-
dation of (20R)-(ꢀ)-20-phenyl-200-(piperidin-1-yl)ethanol
Ph
Ph
Br
Ph
Ph
Br
HO
HO
H
O
O
N
N
N
N
Br2
-HBr
Br2
Br
Br
ring close
AcOH
AcOH
2
I
II
III
Ph
Ph
Ph
HO
O
O
O
O
N
N
N
-HBr
OH
H
Br
V
3
IV
Scheme 2.

A. Castro-C. et al. / Tetrahedron: Asymmetry 16 (2005) 949–952
951
4. Experimental
(CDCl3): 11.64, 18.14, 21.25, 25.63, 30.47, 31.58,
39.06, 39.53, 43.63, 58.60, 61.59, 127.41, 127.62,
128.38, 136.93, 175.12. HRMS (FAB): Calcd for
C18H27NO2: 289.2042. Found: 289.2010.
4.1. General
1H NMR spectra were recorded at 400 MHz, and 13C
NMR spectra at 100 MHz (tetramethylsilane as internal
reference). IR spectra were obtained with a Nicolet FT-
IR Magna 750 spectrometer. Optical rotations were
determined at room temperature with a Perkin–Elmer
341 polarimeter, using a 1 dm cell with a total volume
of 1 mL and are referenced to the D-line of sodium.
Mass spectra were recorded with a JEOL JEM-
AX505HA instrument at a voltage of 70 eV.
4.4. Reduction of compound 4
4.4.1. General procedure. To a solution of 4 (0.25 g,
0.85 mmol) in anhydrous THF (20 mL) under nitrogen
atmosphere was added Red-Al (4.22 mmol, solution
65% in toluene) and stirred for 24 h at room tempera-
ture. Then, the mixture was cooled at 0 ꢁC and
quenched with saturated solution of NH4Cl (2.0 mL).
Then the reaction was filtered and the solution treated
with Na2SO4. Finally, the solvent was removed in vacuo
to give 5 in quantitative yield.
4.2. Oxidation of compound 2
To a solution of 2 (1.0 g, 4.87 mmol) in acetic acid
(5.0 mL, 80%) at 0 ꢁC was added dropwise a solution
of bromine (15.60 mmol) in acetic acid (5.0 mL). The
mixture was stirred for 20 min and water (30 mL) then
added and stirred for 3 h. Afterwards, the reaction was
treated with a solution of sodium hydroxide (150 mL,
1.0 M), warmed to 90 ꢁC, and stirred during 1 h. Then,
the mixture was cooled at room temperature, saturated
with sodium chloride, extracted with dichloromethane
(6 · 80 mL) and the combined organic layer dried over
Na2SO4 and concentrated under reduced pressure to
afford 3 in 96% yield after purification by flash chroma-
tography (SiO2, AcOEt, AcOEt–MeOH = 95:5).
4.4.2. (20R,200S,3R)-(ꢀ)-20-[3-(20-Methylbutyl)piperidin-
.
(c 1.1, MeOH). IR (KBr) 1456, 704 cmꢀ1 1H NMR
1-yl]-20-phenylethanol 5. Colorless oil. [a]D = ꢀ17.8
(400 MHz, CDCl3) d (ppm, J Hz): 0.66–0.73 (m, 1H),
0.83–0.88 (m, 6H), 0.94 (m, 1H), 1.08–1.15 (m, 2H),
1.29 (m, 1H), 1.34–1.48 (m, 2H), 1.60–1.69 (m, 4H),
1.95 (dd, 10, 1H), 2.72 (dd, 9.6, 1H), 2.80 (m, 1H),
3.60 (AB, 5.2, 1H), 4.49 (AB, 5.2, 1H), 4.65 (AB, 9.6,
1H), 7.15–7.35 (m, 5H). 13C NMR (CDCl3): 11.45,
19.40, 25.76, 29.97, 30.85, 31.18, 34.28, 41.47, 46.85,
59.78, 59.83, 70.13, 127.62, 127.90, 128.81, 135.21.
HRMS (FAB): Calcd for C18H29NO: 275.2249. Found:
275.2220.
4.2.1. (10R)-(ꢀ)-1-(20-Hydroxy-10-phenylethyl)piperidin-
2-one 3. White crystals. Mp: 113–115 ꢁC. [a]D =
4.5. Catalytic hydrogenation of compound 5
1
ꢀ80.0 (c 0.5, CH2Cl2). IR (KBr) 1615 cmꢀ1. H NMR
(400 MHz, CDCl3) d (ppm, J Hz): 1.67 (m, 1H), 1.76
(m, 3H), 2.49 (m, 2H), 2.95 (AB, 4.4, 1H), 3.22 (AB,
3.6, 4.4, 1H), 3.79 (br, OH), 4.10 (AB, 5.2, 6.4, 2H),
5.85 (dd, 5.2, 5.6, 1H), 7.21–7.33 (m, 5H). 13C NMR
(CDCl3): 20.89, 23.11, 32.59, 43.43, 58.29, 61.33,
127.45, 127.58, 128.41, 136.82, 171.34.
To a solution of 5ÆHCl (0.31 g, 0.994 mmol) in methanol
(5 mL) under a hydrogen atmosphere was added Pd/C
10% (0.045 g) and the mixture stirred for 96 h at room
temperature. After, the reaction was filtered and the
methanolic solution was evaporated under reduced pres-
sure. The solid residue was crystallized in ethyl acetate
to afford 6ÆHCl in 95 % yield.
4.3. Alkylation of compound 3
4.5.1. (20S,3R)-(+)-3-(20-Methylbutyl)piperidine 6ÆHCl.
White crystals. Mp: 171–173 ꢁC. [a]D = +12.7 (c 0.92,
To a solution of 3 (0.29 g, 1.32 mmol) in THF (15 mL)
under a nitrogen atmosphere at ꢀ78 ꢁC was added
HMPA (0.6 mL) and sec-BuLi (5.3 mmol). The mixture
was stirred for 1 h and (S)-(+)-1-bromo-2-methylbutane
(3.3 mmol) was added and the reaction mixture stirred
for 2.5 h. Finally, the mixture was treated with a satu-
rated solution of NH4Cl (4.0 mL), extracted with ethyl
acetate (3 · 20 mL), dried over Na2SO4, and finally,
concentrated under reduced pressure. The crude mixture
was purified by flash chromatography (SiO2, AcOEt–
petroleum ether 1:1, AcOEt–petroleum ether = 6:4) to
give 4 in 90% yield.
MeOH). IR (KBr) 1585, 1449 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) d (ppm, J Hz): 0.84–0.86 (m, 6H),
1.03–1.05 (m, 2H), 1.12–1.22 (m, 2H), 1.33 (m, 1H),
1.42 (m, 1H), 1.88–1.95 (m, 3H), 2.04 (m, 1H), 2.49
(m, 1H), 2.79 (m, 1H), 3.36 (m, 1H), 3.47 (m, 1H). 13C
NMR (CDCl3): 11.22, 19.01, 22.12, 28.84, 29.65,
30.70, 30.79, 40.65, 44.36, 49.56.
4.5.2. Crystal structure of 6ÆHCl. Colorless plate,
0.65 · 0.60 · 0.10 mm3, C10H22ClN. Monoclinic, C2,
a = 10.295(2), b = 7.334(2), c = 17.395(4) A, Z = 4,
˚
q
collected at T = 296(1) K using Mo-Ka radiation
calcd = 0.987 g cmꢀ3. A set of 3339 reflections was
4.3.1. (10R,200S,3R)-(ꢀ)-1-(2-Hydroxy-10-phenylethyl)-3-
(200-methylbutyl)piperidin-2-one
4. Colorless
oil.
(k = 0.71073 A, Bruker P4 diffractometer), correspond-
˚
[a]D = ꢀ17.3 (c 2.25, CH2Cl2). IR (KBr) 1612 cmꢀ1
.
ing to 2hmax = 55ꢁ. Raw data were corrected for absorp-
tion (W-scans, transmission factors in the range 0.777–
0.974) and 2971 independent reflections (Rint = 0.0269)
were used for the refinement of 109 parameters, without
restraints or constraints (SHELXTL 5.10 package). H
atoms bonded to N1 were found on difference maps,
1H NMR (400 MHz, CDCl3) d (ppm, J Hz): 0.86–0.91
(m, 6H), 1.18–1.48 (m, 5H), 1.64–1.81 (m, 3H), 1.83–
1.95 (m, 1H), 2.47 (m, 1H), 2.87 (AB, 5.1, 1H), 3.19
(AB, 5.4, 1H), 3.67 (br, OH), 4.05–4.17 (m, 2H), 5.80
(dd, 5.4, 5.7, 1H), 7.22–7.35 (m, 5H). 13C NMR

952
A. Castro-C. et al. / Tetrahedron: Asymmetry 16 (2005) 949–952
while the remaining H atoms were placed on idealized
positions. All H atoms were refined using a riding mod-
el. Final R indices: R1 = 0.0677 for 1924 reflections with
I > 2r (I) and wR2 = 0.1883 for all data. The correctness
of the absolute configuration was checked on the basis
of a refined Flack parameter: x = 0.18(12) for 1369 mea-
sured Friedel pairs. CCDC deposition number: 257396.
Structure factors and raw files are available on request
to authors.
Acknowledgements
We are grateful to CONACyT for financial support
(project J35088-E) and BUAP (project VIEP II-
110G02). A.C.C. thanks CONACyT for the doctoral
scholarship (166996).
References
4.6. Synthesis of (20S,3R)-(+)-stenusine 8
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To a solution of 6ÆHCl (0.127 g, 0.663 mmol) in CHCl3
(10 mL) at 0 ꢁC was added triethylamine (0.5 mL) and
the reaction mixture stirred for 30 min. Afterwards, ace-
tyl chloride (0.2 mL) was added and the reaction mix-
ture refluxed and stirred for 90 min. Then, this mixture
was treated with a solution of NH4Cl and extracted with
ethyl ether (3 · 15 mL). The organic layer was dried
with sodium sulfate, filtered and the solvent removed
under reduced pressure. The residue was purified by
flash chromatography (SiO2, petroleum ether–
AcOEt = 40:60) to give 7 in 96 % yield. Reduction of
7 was carried out under the same conditions described
in Section 4.4.1 to furnish stenusine 8 in quantitative
yield.
3. (a) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953–2989; (b)
´
Micouin, L.; Diez, A.; Castells, J.; Lopez, D.; Rubiralta,
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´ ´
Bonin, M.; Celerier, J.-P.; Husson, H.-P.; Lhommet, G.;
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´
Tetrahedron 1996, 52, 7719–7726; (e) Rodrıguez, R.;
Estiarte, M. A.; Diez, A.; Rubiralta, M.; Colell, A.;
4.6.1. (20S,3R)-(+)-1-[3-(20-Methylbutyl)piperidin-1-yl]-
ethanone 7. Colorless oil. [a]D = +42.2 (c 1.16, MeOH).
´
´
´
Garcıa-Ruız, C.; Fernandez-Checa, J. C. Tetrahedron
1996, 52, 7727–7736; (f) Micouin, L.; Quirion, J.-C.;
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J.-C.; Husson, H.-P. Tetrahedron Lett. 1994, 35, 2529–
2532.
IR (KBr) 1646, 1440 cmꢀ1
.
1H NMR (400 MHz,
CDCl3) d (ppm, J Hz): 0.81–0.89 (m, 6H), 0.96–1.08
(m, 2H), 1.09–1.23 (m, 2H), 1.33 (m, 1H), 1.40–1.47
(m, 2H), 1.52 (m, 1H), 1.69 (m, 1H), 1.86 (m, 1H),
2.08 (s, 3H), 2.23 (m, 1H), 2.63 (m, 1H), 2.71 (m, 1H),
2.98 (m, 1H). 13C NMR (CDCl3): 11.24, 19.08, 21.44,
24.59, 29.74, 30.67, 30.89, 33.20, 40.37, 42.28, 48.00,
5. Romo, D.; Meyers, A. I. Tertrahedron 1991, 47, 9503–
9569.
´
6. Juarez, J.; Gnecco, D.; Galindo, A.; Marazano, C.;
Enrıquez, R. G.; Reynolds, W. F. Tetrahedron: Asymme-
´
168.26. HRMS (FAB): Calcd for C12H23NO
197.1780. Found: 197.1750.
:
try 1997, 8, 203–206.
7. Duffield, A. M.; Budzikiewicz, H.; Djerassi, C. J. Am.
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4.6.2. (20S,3R)-(+)-1-Ethyl-3-(20-methylbutyl)piperidine
8. Colorless oil. [a]D = +67.4 (c 0.76, EtOH). IR
8. Acheson, R. M.; Ferris, M. J.; Sinclair, N. M. J. Chem.
Soc., Perkin Trans. 1 1980, 579–585.
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Synlett 1994, 35, 143–144.
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11. Enders, D.; Tiebes, J.; De Kimpe, N.; Keppens, M.;
Stevens, C.; Smagghe, G.; Betz, O. J. Org. Chem. 1993, 58,
4881–4884.
1
(KBr) 1585, 1449 cmꢀ1. H NMR (400 MHz, CDCl3)
d (ppm, J Hz): 0.75 (m, 1 H), 0.83 (d, 6.2, 3H), 0.85 (t,
7.2, 7.6, 3H), 0.96 (m, 1H), 1.08 (t, 6.8, 7.6, 3H), 1.11–
1.16 (m, 2H), 1.28–1.35 (m, 2H), 1.50 (m, 1H), 1.58
(m, 1H), 1.65 (m, 1H), 1.74–1.80 (m, 2H), 2.32–2.43
(m, 2H), 2.83 (m, 1H), 2.91 (m, 1H). 13C NMR (CDCl3):
11.42, 12.10, 19.34, 25.63, 30.02, 31.11, 31.20, 33.63,
41.92, 52.81, 53.86, 61.00.
12. Poupon, E.; Kunesch, N.; Husson, H.-P. Angew. Chem.,
Int. Ed. 2000, 39, 1493–1495, and references cited therein.