A new synthesis of alkaloid (S)-3-hydroxypiperidin-2-one and its O-TBS protected derivative

Article abstract of DOI:10.1002/jhet.5570440239

(Chemical Equation Presented) From the known lactone (S)-4, easily derived from L-glutamic acid, a scalable approach to chiral building block O-silylated 3-hydroxypiperidin-2-one 3 and alkaloid 1 was achieved in five and six-steps respectively. The key st

Full text of DOI:10.1002/jhet.5570440239

Mar-Apr 2007
499
A New Synthesis of Alkaloid (S)-3-Hydroxypiperidin-2-one and Its
O-TBS Protected Derivative
Pei-Qiang Huang,a,b* Guo Chen,a and Xiao Zhenga
a Department of Chemistry, The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry
and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China;
b The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
Received July 24, 2006
OTBS
O
OH
O
40% HF (aq)
5 steps
N
H
O
COOH
N
H
THF, rt
78%
O
3
1
From the known lactone (S)-4, easily derived from L-glutamic acid, a scalable approach to chiral
building block O-silylated 3-hydroxypiperidin-2-one 3 and alkaloid 1 was achieved in five and six-steps
respectively. The key steps are a chemoselective amidation of lactone-ester 5 and a one-pot reductive
borane-decomplexation, N-debenzylation and cyclization.
J. Heterocyclic Chem., 44, 499 (2007).
OTBS
O
OH
O
OTBS
O
(S)-3-Hydroxypiperidin-2-one (1) is an alkaloid
recently isolated from two coccinellid beetles Harmonia
axyridis and Aiolocaria hexaspilota [1]. Before its
isolation from natural sources, several syntheses of
enantio-enriched 1 and its derivatives have been reported
[2]. Recently, we have reported an approach to N,O-
diprotected (S)-3-hydroxypiperidin-2-one 2 starting from
(S)-glutamic acid [3]. In a project aimed at the
development of a synthetic methodology for bioactive
piperidines [4], we needed a scalable approach to N-
unprotected O-protected 3-hydroxypiperidin-2-one 3. In
view of the modest yield for the oxidative cleavage of
PMB group from 2, we needed to develop an alternative
approach and now report a scalable and shorter synthesis
of 3 and (S)-3-hydroxypiperidin-2-one (1).
N
N
H
N
H
PMB
1
2
3
in methanol gave the desired lactone-ester 5 in only
moderate yields (50%-60%), which was improved to 73%
via the classical two-step procedure (SOCl2; MeOH,
CH2Cl2, NEt3, −20 °C). Selective lactone aminolysis of 5
was achieved by treating with benzylamine at rt for 48
hours, which gave 6 in 85% yield. The hydroxyl group in
6 was then protected (TBSCl, imid., DMAP, DMF, rt, 3
h) to give 7 in 93% yield. Chemoselective reduction of the
amide group with borane dimethyl sulfide complex
(BH3•SMe2) at −20 °C gave the reduced product as an N-
borane complex 8 in about 65% yield. A more economical
variation constituted in using NaBH4/I2 as a source of
diborane [6], which afforded 8 in 65% yield. Attempt to
The synthesis started from the known lactone (S)-4,
easily available from (S)-glutamic acid via a one-pot
transformation [5]. Esterification by treating 4 with DCC
Scheme 1
O
SOCl2;
TBSCl, imid.
COOMe
OH
BnNH2
BnHN
O
COOH
O
COOMe
MeOH, CH2Cl2,
TEA
73% over two steps
O
O
DAMP, DMF, r.t.
93%
CH2Cl2, rt
85%
6
5
4
OTBS
O
OTBS
O
10% Pd/C
MeOH;
NaBH4, I2, THF
Bn
COOMe
OTBS
COOMe
OTBS
+
N
BnHN
!20 oC
65%
N
H
N
O
NEt3 (cat.)
BH3
Bn
7
3 (85%)
8
9 (10%)
OH
O
40% HF (aq)
THF, rt
78%
N
H
1

500
G. Chen, X. Zheng and P. Q. Huang
Vol 44
Methyl (S)-5-(benzylamino)-2-hydroxy-5-oxopentanoate
(6). To a solution of 5 (8.58 g, 59.6 mmol) in 60 mL CH2Cl2 was
added BnNH2 (6.39 g, 59.6 mmol). The mixture was stirred at
room temperature for 48 hours, then concentrated in vacuo. The
residue was purified by flash chromatography on silica gel
(EtOAc/PE 2:1) to afford 6 (12.7 g , 85%) as white crystals. mp
cleave the benzyl group under catalytic transfer
hydrogenation conditions (HCOOH, MeOH, 10% Pd/C)
was unsuccessful. To our delight, using the method
reported recently by Couturier et al. [7] (10% Pd/C,
MeOH, rt, 4 days; then NEt3 (cat., 12 h) provided, in one-
pot, 3-silyloxypiperidin-2-one 3 in 85% yield, alongside
with about 10% of N-benzyl piperidine-2-one 9. In this
reaction, a catalytic amount of NEt3 was used to enhance
the in situ cyclization. To synthesize 1, 3 was treated with
an aqueous solution of 40% HF, which afforded the
alkaloid 1 in 78% yield. The synthetic 1 showed identical
physical and spectral data with those reported.
In summary, a scalable approach to O-silylated 3-
hydroxypiperidin-2-one 3 and alkaloid 1 was achieved in
five and six-steps respectively from 4. The use of 3 as a
chiral building block in the asymmetric synthesis of 2-
substituted piperidin-3-ols is in progress in these
laboratories and will be reported in due course.
52-54 °C (EtOAc/PE 1:1); [α]20 = −4.6 (c 1.0, CHCl3); ir:
D
3405, 3032, 2953, 1739, 1642, 1548, 1454, 1217, 1110, 1030
1
cm-1; H nmr: δ 1.90 (m, 1H, H-3), 2.11-2.176 (m, 1H, H-3),
2.25-2.36 (m, 2H, H-4), 3.53 (br s, 1H, OH), 3.69 (s, 3H,
OCH3), 4.17 (dd, J = 3.5, 7.5 Hz, 1H, H-2), 4.33 (d, J = 13.2 Hz,
1H, Ph-CH2), 4.34 (d, J = 13.2 Hz, 1H, Ph-CH2), 5.98 (br s, 1H,
NH), 7.18-7.26 (m, 5H, Ph-H) ppm; 13C nmr: δ 29.7, 32.0, 43.7,
52.5, 69.9, 127.5, 127.8, 128.7, 138.1, 172.2, 175.0 ppm; ms:
m/z 274 (M+Na+), 252 (M+H+). Anal. Calcd. for C13H17NO4: C,
62.14; H, 6.82; N, 5.57. Found: C, 61.43; H, 6.92; N, 5.39.
Methyl (S)-5-(benzylamino)-2-(tert-butyldimethylsilyloxy)-5-
oxopentanoate (7). Under a nitrogen atmosphere, a mixture of 6
(4.23 g, 16.8 mmol), imidazole (2.87 g, 42.1 mmol), TBSCl
(4.57 g, 30.3 mmol) and DMAP (100 mg) in DMF (40 mL) was
stirred at room temperature for 3 hours. The reaction was
quenched with water (160 mL). The aqueous layer was extracted
with ether (5×30 mL). The combined organic phases were
washed with brine (10 mL), dried over anhydrous Na2SO4 and
filtered. After concentrated in vacuum, the residue was purified
by flash chromatography on silica gel (EtOAc/PE 1/5) to afford
7 (5.72 g, 93%) as a yellow oil. [α]20D = −17.8 (c 1.0, CHCl3) ; ir:
3295, 3065, 2952, 2930, 2857, 1756, 1650, 1548, 1435, 1258,
EXPERIMENTAL
Melting points were determined on a Yanaco MP-500
micromelting point apparatus and are uncorrected. Infrared
spectra were measured with a Nicolet Avatar 360 FT-IR
1
spectrometer using film KBr pellet technique. H nmr spectra
1
1132 cm-1; H nmr: δ 0.03 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3),
were recorded in CDCl3 on a Bruker Avance DPX 400 MHz or a
Varian unity +500 NMR spectrometer with tetramethylsilane as
an internal standard. Chemical shifts are expressed in δ (ppm)
units downfield from TMS. Mass spectra were recorded by a
Bruker Dalton Esquire 3000 plus liquid chromatography–mass
spectrum (direct injection). Optical rotations were measured
with a Perkin–Elmer 341 automatic polarimeter. Flash column
chromatography was carried out with silica gel (300–400 mesh).
THF was distilled over sodium. Dichloromethane was distilled
over P2O5.
0.89 (s, 9H, SiC(CH3)3), 1.98-2.05 (m, 1H, H-3), 2.09-2.16 (m,
1H, H-3), 2.27 (dd, J = 5.0, 15.0 Hz, 1H, H-4), 2.34 (dd, J = 8.5,
15.0 Hz, 1H, H-4), 3.69 (s, 3H, COOCH3), 4.30 (dd, J = 5.0, 6.5
Hz, 1H, H-2), 4.37 (d, J = 15.0 Hz, 1H, PhCH2), 4.41 (d, J =
15.0 Hz, 1H, PhCH2), 6.12 (br s, 1H, NH), 7.24-7.32 (m, 5H,
Ph-H) ppm; 13C nmr: δ −5.3, −4.9, 18.2, 25.6, 25.8, 30.6, 31.5,
43.6, 51.7, 71.2, 127.4, 127.8, 128.6, 138.3, 171.9, 173.7 ppm;
ms: m/z 366 (M+H+), 388 (M+Na+); Anal. Calcd. for
C19H31NO4Si: C, 62.43; H, 8.55; N, 3.83. Found: C, 62.36; H,
8.46; N, 3.70.
Methyl (S)-5-oxo-tetrahydrofuran-2-carboxylate (5).
Thionyl chloride (21.9 mL, 35.7 g, 300 mmol) was added to 4
(13.9 g, 107 mmol) at room temperature. The mixture was
refluxed for 4 hours followed by stirred at room temperature for
12 hours. The excess SOCl2 was removed under reduced
pressure. The residue was resolved in CH2Cl2 (140 mL). To the
resulting mixture was added dropwise, at −20 °C, a mixture of
MeOH (4.0 mL, 100 mmol) and Et3N (16.6 mL, 120 mmol). The
reaction mixture was warmed to room temperature and stirred
for 12 hours. The reaction was quenched with water (80 mL).
The resulting mixture was extracted with CH2Cl2 (6×30mL). The
organic phases were washed with brine (30 mL×2), dried over
anhydrous Na2SO4 and filtered. After concentrated in vacuum,
the residue was purified by flash chromatography (EtOAc/PE
1/2) to afford 5 (11.3 g, 73% overall yield from 4) as a colorless
oil. [α]20 = 14.5 (c 1.1, MeOH) [lit.: for (S)-5: [α]20 = 14.9 (c
Methyl (S)-5-(benzylamino)-2-(tert-butyldi-methylsilyloxy)
pentanoate borane complex (8). To a mixture of 7 (5.64 g,
15.4 mmol), NaBH4 (1.05 g, 27.8 mmol) in anhydrous THF (75
mL) was added, under a nitrogen atmosphere and at −20 °C, a
solution of I2 (3.53 g, 13.9 mmol) in anhydrous THF (30 mL).
The resulting mixture was stirred at room temperature for 8
hours. After dilution with ethyl acetate (75 mL) at −20 °C, the
reaction was quenched with water (30 mL). The aqueous layer
was extracted with ethyl acetate (3×30 mL); the combined
organic phases were washed with brine (10 mL), dried over
anhydrous Na2SO4 and filtered. After concentrated in vacuum,
the residue was purified by flash chromatography on silica gel
(EtOAc/PE 1/15) to afford 8 (3.63 g, 65%) as a colorless oil,
which is a mixture of two diastereoisomers in a ratio of 6: 4 as
determined by H nmr integration. Major diastereomer: [α]20
1
=
D
D
D
−16.9 (c 1.0, CHCl3); ir: 3202, 3031, 2953, 2930, 2856, 2374,
2320, 2274, 1755, 1738, 1456, 1252, 1168, 1139 cm-1; 1H nmr: δ
0.01 (s, 3H, SiCH3), 0.05 (s, 3H, SiCH3), 0.87 (s, 9H,
SiC(CH3)3), 1.52-1.94 (m, 7H, BH3, H-3, H-4), 2.60-2.67 (m,
2H, H-5), 3.52 (br s, 1H, NH), 3.65 (d, J = 13.5 Hz, 1H, PhCH2),
3.69 (s, 3H, COOCH3), 4.10-4.13 (m, 1H, H-2), 4.20 (d, J =
13.5, 1H, PhCH2), 7.26-7.39 (m, 5H, Ph-H) ppm; 1H nmr (minor
1.1, MeOH) [8a], [α]25 = 15.8 (c 0.65, MeOH) [8b]; ir: 2959,
D
1786, 1744, 1632, 1440, 1375, 1329, 1225, 1175, 1107, 1069
1
cm-1; H nmr: δ 2.19-2.27 (m, 1H, H-3), 2.41-2.56 (m, 3H, H-3,
H-4), 3.72 (s, 3H, OCH3), 4.68 (dd, J = 4.5, 8.0 Hz, 1H, H-2)
ppm; 13C nmr: δ 25.3, 26.3, 52.2, 75.3, 170.0, 175.8 ppm; ms:
m/z 167.2 (M+Na+), 162 (M++H2O).

Mar-Apr 2007 A New Synthesis of (S)-3-Hydroxypiperidin-2-one and Its O-TBS Protected Derivative
501
diastereoisomer): δ 0.01 (s, 3H, SiCH3), 0.05 (s, 3H, SiCH3),
0.87 (s, 9H, SiC(CH3)3), 1.52-1.94 (m, 7H, BH3, H-3, H-4),
2.67-2.76 (m, 2H, H-5), 3.45 (br s, 1H, NH), 3.62 (d, J = 13.5
Hz, 1H, PhCH2), 3.68 (s, 3H, COOCH3), 4.13-4.15 (m, 1H, H-
2), 4.20 (d, J = 13.5, 1H, PhCH2), 7.26-7.39 (m, 5H, Ph-H)
ppm; 13C nmr (mixture of two diastereoisomers): δ −5.6, −5.3,
−4.9, 18.2, 21.9, 25.6, 25.8, 32.2, 51.7, 51.9, 52.0, 52.7, 52.9,
59.7, 71.5, 128.7, 129.0, 129.4, 134.1, 173.6 ppm; ms: m/z 383
(M++H2O); Anal. Calcd. for C19H36BNO3Si: C, 62.45; H, 9.93;
N, 3.83. Found: C, 62.22; H, 9.88; N, 3.79.
H-4), 1.82-1.92 (m, 1H, H-4), 1.93-2.02 (m, 1H, H-5), 2.27-2.33
(m, 1H, H-5), 3.29-3.39 (m, 2H, H-6), 3.66 (br s, 1H, OH), 4.05
(dd, J = 7.7, 13.8 Hz, 1H, H-3), 5.99 (br s, 1H, NH) ppm; 13C
nmr: δ 20.6, 28.4, 42.4, 67.7, 174.4 ppm; ms: m/z 116 (M+H+),
138 (M+Na+).
Acknowledgment. The authors are grateful to the NSF of
China (20390050, 20572088) and the Ministry of Education
(Key Project 104201) for financial support. Partial support from
the program for Innovative Research Team in Science and
Technology in Fujian Province University is acknowledged.
(S)-3-(tert-Butyldimethylsilyloxy) piperidin-2-one (3). To a
mixture of 8 (2.95 g, 8.07 mmol) and 10% Pd/C (1.12 g) was
added methanol (30 mL). The reaction vessel was quickly sealed
and stirred at r.t. for 4 days. To the resulting mixture was added
Et3N (0.1 mL, 0.72 mmol) and stirred for 12 hours. The resulting
mixture was filtered through Celite and washed with methanol.
After concentrated in vacuum, the residue was purified by flash
chromatography on silica gel (EtOAc/PE 1/5) to afford 3 (1.57
g, 85%), along sides with about 10% of N-benzyl piperidin-2-
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one 9 (317 mg, 10%). 3: colorless oil. [α]20 = −36.6 (c 1.0,
D
CHCl3); ir: 3223, 3097, 2951, 2929, 2855, 1679, 1471, 1333,
1
1251, 1146, 1107, 1032 cm-1; H nmr: δ 0.14 (s, 3H, SiCH3),
0.16 (s, 3H, SiCH3), 0.90 (s, 9H, SiC(CH3)3), 1.70-1.76 (m, 1H,
H-4), 1.80-1.88 (m, 1H, H-4), 1.94-2.02 (m, 2H, H-5), 3.21-3.25
(m, 1H, H-6), 3.27-3.32 (m, 1H, H-6), 4.07 (dd, J = 4.0, 7.5 Hz,
1H, H-3), 5.78 (br s, 1H, CONH) ppm; 13C nmr: δ −5.5, −4.6,
18.2, 19.3, 25.8, 30.7, 42.0, 69.0, 172.5 ppm; ms: m/z 230
(M+H+); Anal. Calcd. for C11H23NO2Si: C, 57.59; H, 10.11; N,
6.11. Found: C, 57.87; H, 10.03; N, 5.88.
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Lett., 3, 465-467 (2001).
(S)-3-Hydroxypiperidin-2-one (1). To a solution of 3 (92
mg, 0.40 mmol) in acetonitrile (2 mL) was added a solution of
40% aqueous HF (0.13 mL). The mixture was stirred at r.t. for 6
hours. After cooled to 0 °C, the reaction was quenched with
saturated aqueous NaHCO3 (3 mL), diluted with water (3 mL)
and extracted with ethyl acetate (6 × 5 mL). The combined
organic phases were washed with brine, dried over anhydrous
Na2SO4 and filtered. After concentrated in vacuum, the residue
was purified by flash chromatography on silica gel
(EtOAc/MeOH 10/1) to afford 1 (36 mg, 78%) as white crystals.
mp 144-146 °C (EtOAc); [α]20D = −11.2 (c 1.0, CH3OH) lit. [2f]:
[8a] S. Drioli, P. Nitti, G. Pittaco, L. Tossut and E. Valentin,
Tetrahedron: Asymmetry, 10, 2713–2728 (1999); [b] E. M. Rustoy, E.
N. Pereyra, S. Moreno and A. Baldessari, Tetrahedron: Asymmetry, 15,
3763–3768 (2004).
for (R)-1: [α]20 = +6.0 (c 1.0, CHCl3)]; ir: 3307, 3205, 2957,
D
2939, 2868, 1656, 1319, 1095 cm-1; 1H nmr: δ 1.69-1.78 (m, 1H,