SHORT PAPER
(S)-(+)-2-(Hydroxymethyl)-6-piperidin-2-one
2513
with data reported in the literature.1a,b Finally, the ester
group was reduced to furnish the target molecule ent-21a,b
using known conditions.
colorless sticky compound which was used in the next reaction
without further purification.
To an ice-cold solution of N-Boc-L-aspartic acid (8.2 g, 31.42
mmol) in DMF (50 mL), was added solid K2CO3 (9.54 g, 69.12
mmol). After stirring for 10 min in an ice bath, MeI (7.8 mL, 125.7
mmol) was added to the white suspension and stirring was contin-
ued at 0 °C for 30 min, whereupon the mixture solidified. The reac-
tion mixture was warmed to r.t. and stirred for an additional 1 h, at
which point TLC analysis indicated complete formation of the
methyl ester. The reaction mixture was filtered by suction and the
filtrate was partitioned between EtOAc (3 × 100 mL) and H2O (50
mL). The organic phase was washed with brine (100 mL), dried
over Na2SO4, filtered and concentrated. Silica gel column chroma-
tography of the crude product (PE–EtOAc, 8.5:1.5) gave (S)-di-
methyl 2-(tert-butoxycarbonylamino)succinate (7).
NH2
NHBoc
CO2Me
CO2H
a
b
HO2C
MeO2C
6
7
NBoc2
NBoc2
d
c
CO2Me
O
MeO2C
MeO2C
O
5
8
NBoc2
NBoc2
O
Yield: 8.5 g (87% over two steps); white solid; mp 61 °C (Lit.6b
e
MeO2C
OEt
MeO2C
OEt
60 °C); [a]D25 +30.4 (c 2.1, CHCl3) [Lit.6b +30.8 (c 2.1, CHCl3)].
9
4
IR (neat): 3445, 3032, 1731, 1720 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.45 (s, 9 H), 2.76–3.06 (m, 2 H),
3.69 (s, 3 H), 3.76 (s, 3 H), 4.53–4.62 (m, 1 H), 5.5 (m, 1 H).
f
MeO
HO
g
N
O
N
O
O
H
H
13C NMR (50 MHz, CDCl3): d = 27.5, 35.3, 51.5, 52.1, 54.5, 83.1,
151.2, 169.8, 170.6.
1
ent-2
ESI-MS: m/z = 284.32 [M + Na]+.
Scheme 2 Synthesis of ent-2. Reagents and conditions: (a) (i)
Boc2O, 1 N NaOH, dioxane/H2O, 5 °C→r.t., 3.5 h; (ii) K2CO3, MeI,
DMF, 0 °C→r.t., 1 h, 87%; (b) Boc2O, DMAP, MeCN, r.t., overnight,
93%; (c) DIBAL-H, anhyd Et2O, –78 °C, 5 min; (d) Ph3P=CHCO2Et,
anhyd THF, 60 °C, 86%; (e) H2, Pd/C, EtOAc, r.t., 2 h, 87%; (f) TFA,
CH2Cl2, 0 °C→r.t., 2 h, NaHCO3, 81%; (g) ref. 2.
(S)-Dimethyl 2-[Bis(tert-butoxycarbonyl)amino]succinate (8)
To a mixture of N-Boc amino ester 7 (1.0 g, 3.83 mmol) and DMAP
(0.094 g, 0.8 mmole) in anhyd MeCN (10 mL) was added Boc2O
(1.3 g, 5.75 mmol) at r.t. The reaction mixture became slightly red
and gas evolution was observed. After stirring for 2 h, TLC showed
some starting material remained. Excess Boc2O (0.42 g, 1.92 mmol)
was added and the mixture was stirred overnight. After completion
of reaction, solvent was evaporated in vacuo and the crude residue
was purified by silica gel column chromatography (EtOAc–PE, 1:9)
to give bis-carbamate 8.
In summary, we have accomplished a short synthesis of
(S)-2-(hydroxymethyl)-6-piperidin-2-one starting from L-
aspartic acid as a chiral pool starting material and using
Wittig olefination as a key step.
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Yield: 1.3 g (93%); oily compound; [a]D –60.5 (c 2.0, CHCl3)
[Lit.6b –61.0 (c 2.0, CHCl3)].
All reactions were carried out under argon or nitrogen in oven-dried
glassware using standard gas-tight syringes, cannula and septa. Sol-
vents and reagents were purified and dried by standard methods pri-
or to use. Progress of all the reactions were monitored by TLC using
glass plates precoated with silica gel 60 F254 to a thickness of 0.25
mm (Merck). Column chromatography was performed on silica gel
(60–120 mesh) using petroleum ether (PE)–EtOAc mixture as the
eluent. PE refers to the fraction boiling in the 60–80 °C range. Op-
tical rotations were measured with a JASCO DIP-360 digital pola-
rimeter at 25 °C. IR spectra were recorded with a Perkin–Elmer FT-
IR spectrophotometer. 1H and 13C NMR spectra were recorded with
a Bruker AC-200 spectrometer at 200 MHz and are reported in parts
per million (d) downfield relative to CDCl3 as internal standard.
ESI-MS were obtained with an API-Q-Star Applied Biosystems
spectrometer. Elemental analyses were carried out with a Carlo
Erba CHNSO analyzer.
IR (neat): 3032, 1731, 1720 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.43 (s, 18 H), 2.66–2.77 (m, 1 H),
3.18–3.30 (m, 1 H), 3.69 (s, 3 H), 3.72 (s, 3 H), 5.41–5.47 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 27.5, 35.2, 51.4, 52.0, 54.4, 83.0,
151.1, 169.7, 170.5.
ESI-MS: m/z = 384.55 [M + Na]+, 400.54 [M + K]+.
(S,E)-1-Ethyl 6-Methyl 5-[Bis(tert-butoxycarbonyl)amino]hex-
2-enedioate (9)
To a solution of the dimethyl ester 8 (1.0 g, 2.77 mmol) in anhyd
Et2O (27.7 mL), was added dropwise DIBAL-H (1.32 mL, 2.3 M in
toluene, 2.77 mmol) at –78 °C. The reaction mixture was stirred for
5 min and quenched with H2O (0.35 mL, 19.4 mmol). After stirring
for 30 min, the reaction mixture was dried over Na2SO4 and filtered
through a pad of Celite. The solvent was evaporated to give alde-
hyde 5 as a colorless oil.
(S)-Dimethyl 2-(tert-Butoxycarbonylamino)succinate (7)
A solution of Boc2O (9.03 g, 41.2 mmol) in dioxane (45 mL) was
added to an ice-cold magnetically stirred solution of L-aspartic acid
(6; 5.0 g, 37.6 mmol) in 1 N NaOH (3.0 g in 75.2 mL H2O) by means
of an addition funnel. The two-phase mixture was stirred at 5 °C for
30 min then allowed to warm to 25 °C over 3.5 h, at which time
TLC analysis showed the reaction to be complete. The reaction mix-
ture was concentrated to half of the original volume at 45 °C, cooled
in ice bath, acidified to pH 2–3 by the slow addition of 1 N KHSO4
(13.6 g in 100 mL) and then extracted with EtOAc (3 × 150 mL).
The combined extract was washed with brine (100 mL), dried over
Na2SO4, filtered and concentrated to give N-Boc-L-aspartic acid as
To a solution of aldehyde 5 (0.92 g, 2.78 mmol) in anhyd THF (15
mL), was added ethyl (triphenylphosphoranylidene)acetate (1.5 g,
4.2 mmol) at r.t., and the reaction mixture was stirred overnight. Af-
ter completion of the reaction, solvent was evaporated and the crude
residue was purified by silica gel column chromatography (EtOAc–
PE, 5:95) to furnish 9.
Yield: 0.96 g (86% over two steps); colorless oil; [a]D25 –50.3 (c 1.0,
CHCl3).
IR (neat): 1743, 1654 cm–1.
Synthesis 2010, No. 15, 2512–2514 © Thieme Stuttgart · New York