Asymmetric syntheses of (-)-epi-pseudoconhydrine and (-)-5-hydroxysedamine based on a cis-diastereoselective 1,4-asymmetric induction

Article abstract of DOI:10.1016/j.tetasy.2008.05.002

The asymmetric syntheses of (-)-epi-pseudoconhydrine and (-)-5-hydroxysedamine are reported. The key to these syntheses is an unusual highly cis-diastereoselective 1,4-asymmetric induction in the α-amidoallylation of the new chiral building block 15.

Full text of DOI:10.1016/j.tetasy.2008.05.002

Tetrahedron: Asymmetry 19 (2008) 1297–1303
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric syntheses of (ꢀ)-epi-pseudoconhydrine and (ꢀ)-5-hydroxysed-
amine based on a cis-diastereoselective 1,4-asymmetric induction
*
Gang Liu, Jie Meng, Chen-Guo Feng, Pei-Qiang Huang
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen,
Fujian 361005, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric syntheses of (ꢀ)-epi-pseudoconhydrine and (ꢀ)-5-hydroxysedamine are reported. The
key to these syntheses is an unusual highly cis-diastereoselective 1,4-asymmetric induction in the
a-amidoallylation of the new chiral building block 15.
Received 3 January 2008
Accepted 2 May 2008
Available online 9 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
OH
R
OP2
O
ref. 4, 5
CONHP1
1 (P1 = PMB, Bn)
H
O
Due to the presence of the 6-substituted 3-piperidinol (A in
Scheme 1) as a salient structural feature in a number of bioactive
natural products and medicinal agents,1,2 the asymmetric synthe-
sis of 6-substituted 3-piperidinol containing natural and unnatural
bioactive molecules has attracted considerable attention, which
has culminated in a number of valuable synthetic strategies.3 Pre-
viously, we had demonstrated that the protected 3-hydroxyglu-
tarimides 2, easily available from enantiomeric glutamic acid via
amido-lactone 1, can serve as a valuable 3-piperidiol synthon via
the C-2 regio- and diastereoselective reductive alkylation of 2
(Scheme 1).4 Using this method, the asymmetric syntheses of sev-
eral alkaloids and interesting medicinal agents have been
accomplished.5
O
R'
N
H
A
O
N
P1
(S or R)
2
1,2-asymmetric
induction
This work
1,4-asymmetric
induction
OH
OP2
OH
O
6
O
N
P1
R
HO
N
O
R
N
R1
PMB
4
5
3
As a continuation of these studies, we sought to explore com-
pound 4 as a new 3-piperidinol building block, which would allow
the regioselective introduction of substituents at the C-6 position
to provide 6-substituted 3-hydroxypiperidin-2-ones 5 and the cor-
responding piperidines A. The latter is a framework of a number of
natural products, such as (+)-pseudoconhydrine6,7 6, (ꢀ)-5-
hydroxysedamine8,9 7, 5-hydroxypipecolic acid10 8, (ꢀ)-cassine11
9, (ꢀ)-spectaline12 10, and (ꢀ)-prosopinine13 11 (Fig. 1). In addi-
tion, cis-2-carboxymethyl-5-hydroxypiperidine14 12 has been con-
sidered as a key intermediate for the synthesis of antibiotic 593A, a
natural product possessing strong antiviral and antitumor activi-
ties.15 Although a number of 2,5-trans-diastereoselective methods
have been reported for the synthesis7 of (+)-pseudoconhydrine 6,
establishment of the 2,5-cis-stereochemistry7a,8,11–13,16 by a-ami-
doalkylation17 with high 1,4-asymmetric induction remains a chal-
lenging task. For example, in the only asymmetric synthesis of (ꢀ)-
5-hydroxysedamine 7, the desired cis-diastereomer was formed as
the minor diastereomer in 1:9 ratio.7m The a-amidoallylation-
Scheme 1.
based approaches to pseudoconhydrine always proceed with
trans-diastereoselectivity.7d,l,m trans-Diastereoselection has also
been observed in related radical reactions.7p Herein we report
the synthesis of 15, its cis-diastereoselective a-amidoalkylation
with 1,4-asymmetric induction, as well as the asymmetric synthe-
sis of epi-pseudoconhydrine16 18 and (ꢀ)-5-hydroxysedamine8,9 7.
2. Results and discussion
As outlined in Scheme 2, we sought to take advantage of the
higher reactivity of the lactone carbonyl group of amido-lactone
1 by chemoselective partial reduction with DIBAL-H. The amido-
lactol 13 was envisioned to be elaborated further into 6-substi-
tuted 3-piperidinol or 6-substituted 3-hydroxypiperidin-2-one 5.
However when lactone-amide 1 was treated with DIBAL-H at
ꢀ78 °C, 13 was obtained in only 9% yield. A stepwise approach to
4 was then explored.
* Corresponding author.
E-mail address: pqhuang@xmu.edu.cn (P.-Q. Huang).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.002

1298
G. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 1297–1303
OH
OH
OH
OH
H
CONHPMB
OH
H
NaBH4, MeOH
O
O
CONHPMB
Ph
N
HOOC
N
0 ˚C ~ rt
(89%)
.
N
HO
HCl
H
H
14
1
Me
(-)-5-hydroxy-
5-hydroxy-
pipecolic acid 8
pseudo-
conhydrine 6
OH
sedamine 7
NaNO2, Ac2O
(70%)
Ac2O, DMAP
HO
OH
HO
HO
N
O
TEA, CH2Cl2, r.t.
(73%)
O
O
PMB
4
N
H
N
H
N
n
n
OAc
H
OAc
CO2H
OH
SiMe3
(-)-cassine 9 (n = 10)
(-)-spectaline 10 (n = 12 )
(-)-prosopinine
12
N
O
AcO
N
O
11 (n = 10)
TMSOTf, CH2Cl2
-78 ˚C
PMB
PMB
15
Figure 1.
(70%)
16
OH
OH
H2, 20%Pd(OH)2
OH
O
LiAlH4, THF
H+
EtOH, r.t.;
H
DIBAL-H
N
N
reflux
(66%)
.
HO
O
HCl
1
H
AcCl, MeOH
(74%)
HO
N
CONHPMB
PMB
17
9%
PMB
18
13
4
Scheme 3.
Scheme 2.
148.5 °C (MeOH/Et2O); lit.7m mp 148 °C], specific rotation value
20
20
{½aꢁD ¼ ꢀ10:2 (c 1.0, EtOH); lit.7m ½aꢁD ¼ ꢀ9:1 (c 1.0, EtOH)}, and
the spectral data of our synthetic material are identical with those
reported.7m
The synthesis started from the reduction18 of the amido-ester 1
by sodium borohydride (Scheme 3). Chemoselective oxidation of
the primary hydroxyl group of diol 14 under Bandgar’s condi-
tions19 directly provided the tautomer 4 as a 1:1 diastereomeric
mixture in 70% yield. As the acetyl group has been shown to be
an excellent neighboring participating group in inducing trans-dia-
stereoselective a-amidoallylation,7d,20 N,O-acetal 15 was selected
as the substrate for investigating a-amidoalkylation.17 Thus, com-
pound 4 was bis-acetylated (Ac2O, NEt3, DMAP, CH2Cl2, rt, 24 h)
to provide a diastereomeric mixture of 2-piperidinone N,O-acetal
15. Due to the lability of 15 and more importantly, on the basis
of the consideration that the a-amidoalkylation17 generally occurs
via an N-acyliminium intermediate that can be generated from
either diastereomer, the diastereomeric mixture of N,O-acetal 15
was subjected to a-amidoallylation conditions (allyltrimethylsi-
lane, THF, TMSOTf, ꢀ78 °C). Indeed, the desired product 16 was ob-
tained as the only isolable diastereomer in 70% yield. The
stereochemistry of 16 was determined by ultimate conversion of
16 into the known epi-pseudoconhydrine16 18 (Scheme 3). Lithium
aluminum hydride reduction of 16 (LiAlH4, THF, reflux, 5 h) fur-
nished the corresponding piperidine 17 in 66% yield. Concurrent
hydrogenation and N-deprotection [Pd(OH)2, 1 atm H2, EtOH, rt]
gave (ꢀ)-epi-pseudoconhydrine 18, which was isolated as its
hydrochloride salt16 in 74% yield. The melting point [mp 148.0–
The stereochemical outcome of the a-amidoallylation may be
due to, on one hand, the difficulty in forming a bicyclic oxonium
intermediate of the more rigid piperidin-2-one ring system,21
and, on the other hand, the preferential formation of half-chair
conformer C over conformer B (Scheme 4). The allylation of con-
former C proceeds with stereoelectronic control22 to give the more
favorable chair conformation E over twist-boat one D.
Next, we turned our attention to the synthesis of (ꢀ)-5-
hydroxysedamine 7. Thus, in the presence of TMSOTf, treatment
of 1-phenyl-1-(trimethylsilyloxy)ethene 19 with 15 at ꢀ78 °C fur-
nished the desired product 20a,b with a 2.4:1 (cis/trans) diastereo-
selectivity (Scheme 5). The two inseparable diastereomers 20a
and 20b were converted, via 21a,b, into the corresponding THP
derivatives 22 and 23, which were easily separated by flash chro-
matography. Treatment of the major diastereomer 22 with p-TsOH
in methanol at 45 °C regenerated the alcohol 21a in 93% yield.
One-pot reduction of the ketone and amide carbonyl groups in
21a was achieved by successive treatment of 21a with LiAl(O-t-
Bu)3H7m and lithium aluminum hydride, which gave 5-hydroxy-
sedamine derivative 25 as the only isolable diastereomer in 86%
overall yield (Scheme 6). The stereochemistry of compound 25
H
Me3Si
OAc
O
OAc
O
H
N
Ar
+
TMSOTf
OAc
D
N+
N
O
O
AcO
N
H
H
Ar
Ar
H
PMB
OAc
O
C
OAc
B
N
H
15
Me3Si
Ar
E
Scheme 4.

G. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 1297–1303
1299
OAc
OTMS
(19)
OAc
O
O
Ph
Ph
N
O
AcO
N
TMSOTf, CH2Cl2
-78 oC
PMB
20a,b
PMB
15
(76%)
(cis/trans = 2.4: 1)
OH
AcCl
O
DHP
MeOH
TsOH
Ph
N
PMB
O
(96%)
(85%)
21a,b
OTHP
OTHP
O
O
O
+
Ph
N
Ph
N
O
23
22
PMB
OH
PMB
O
(93%)
MeOH, TsOH
45 oC, 2 h
Figure 2. X-ray crystallographic structure of compound 25 (CCDC 673124).
Ph
N
O
21a
PMB
OAc
O
OAc
O
Scheme 5.
RuCl3, NaIO4
PhMgBr
N
N
MeCN-H2O
(6: 1, v/v)
THF
(74%)
CHO PMB
OH
PMB
OH
O
O
LiAl(O-t-Bu)3H;
OH
(69%)
H
27
16
Ph
N
O
Ph
N
OX
O
OAc
LiAlH4
(86%)
O
OH
a) IBX, DMSO
PMB
21a
PMB
24
(73%)
Ph
N
Ph
N
O
OH
PMB
PMB
28a, b
b) MeOH, AcCl
(90%)
H
OH
H2, Pd(OH)2/C
20a. X= Ac
21a. X= H
Ph
N
Boc2O, EtOH
(64%)
Scheme 7.
PMB
25
starting from the allylation products 16 (Scheme 7). Thus Yang’s
procedure23 was adopted for the oxidative cleavage of the C–C
double bond in compound 16, which gave the aldehyde 27 in
69% yield. Treatment of the aldehyde 27 with phenyl magnesium
bromide produced the alcohol 28 as a diastereomeric mixture in
2.5:1 ratio (combined yield: 74%), which, without separation, was
oxidized with o-iodoxybenzoic acid (IBX) in DMSO.24 In this way,
compound 20a was obtained in 73% yield. Treatment of 20a with
a solution of acetyl chloride-containing methanol at room temper-
ature overnight furnished alcohol 21a in 90% yield, which thus
established a highly diastereoselective synthesis of (ꢀ)-5-hydroxy-
sedamine 7 via 16.
OH
OH
H
OH
H
OH
LiAlH4
(80%)
Ph
N
Ph
N
CH3
Boc
26
7
Scheme 6.
was determined by single crystal crystallographic analysis (Fig. 2).
The results imply that the major product in the a-amidoalkylation
of N,O-acetal 15 is the cis-diastereomer, and the reduction of the
ketone 21a with LiAl(O-t-Bu)3H7m is highly diastereoselective with
the approach of hydride from the less hindered Re-face of the car-
bonyl group.7m
To introduce the N-methyl group, piperidine 25 was first con-
verted to its N-tert-Boc derivative 26 by one-pot debenzylation–
carbamation [H2, l atm, 20% Pd(OH)2/C, (Boc)2O, EtOH], which led
directly to 26 in 64% yield. Then the N-Boc group was converted
into a N-Me group by reducing with lithium aluminum hydride
3. Conclusions
In summary, we have shown that, in contrast with the generally
observed trans-diastereoselection in the a-amidoalkylation of N,O-
acetal of piperidine carbamate derivatives, the a-amidoallylation of
2-piperidinone N,O-acetal 15 is highly cis-diastereoselective,
affording cis-16 as the only isolable diastereomer; and the similar
reaction of 15 with 19 proceeded with a 2.4:1 cis/trans diastereo-
selectivity, which is also different from the literature precedents.
The observed cis-diastereoselective 1,4-asymmetric induction pro-
vides an entry into cis-6-substituted 3-piperidinol A, a skeleton
found in several natural products and medicinal agents. The utility
of the cis-diastereoselective allylation method was demonstrated
by the synthesis of (ꢀ)-epi-pseudoconhydrine 18 and (ꢀ)-5-
hydroxysedamine 7. Compound 16 may also be useful for the
20
to afford (ꢀ)-5-hydroxysedamine 7 {½aꢁD ¼ ꢀ53:4 (c 0.5, MeOH);
22
20
lit.8 ½aꢁD ¼ ꢀ40 (c 0.3, MeOH), lit.7f ½aꢁD ¼ ꢀ53 (c 0.3, MeOH); lit.7m
20
½aꢁD ¼ ꢀ51:0 (c 2.5, MeOH)} in 80% yield. The 1H and 13C NMR
spectral data of our synthetic material are identical with those
reported.8
To overcome the problem of low stereoselectivity in the forma-
tion of compound 20a, a three-step procedure was developed

1300
G. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 1297–1303
synthesis of b-amino acid 12, a key intermediate for the synthesis
of antiviral and antineoplastic antibiotic 593A.
159.8, 173.6, 173.9 ppm; MS (ESI) m/z: 274 (M+Na+, 100); HRMS
(ESI) calcd for [C13H17NO4+H]+ 252.1230, found 252.1232.
4.1.3. (3S,6R/S)-3,6-Diacetoxy-1-(4-methoxybenzyl)-2-
piperidinone 15
4. Experimental
4.1. General
To an ice-bath cooled solution of the diastereomeric mixture of
4 (2.075 g, 8.27 mmol) in CH2Cl2 were added successively DMAP
(1.052 g, 8.62 mmol), Ac2O (4.0 mL, 42.25 mmol), and Et3N
(5.9 mL, 42.25 mmol). The mixture was stirred at room tempera-
ture overnight. The reaction was quenched with 10 mL of saturated
aqueous NaHCO3 solution and 10 mL of water at 0 °C. The organic
layer was seperated and the aqueous layer was extracted with
EtOAc (4 ꢂ 20 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica
gel eluting with EtOAc/petroleum ether (1:1) to afford 15 (colorless
oil, 2.022 g, yield: 73%) as an inseparable mixture of two diastereo-
mers in a 2.5:1 ratio, which was used in the next step without fur-
Melting points were determined (uncorrected) on a Yanaco
MP-500 micro-melting point apparatus. Infrared spectra were
measured with a Nicolet Avatar 360 FT-IR spectrometer. NMR
spectra were recorded in CDCl3 or in CD3CN, or in CD3OD (1H at
400 or 500 MHz and 13C at 100 or 125 MHz) at room tempera-
ture. Mass spectra were recorded on Bruker Dalton Esquire
3000 plus LC–MS (ESI direct injection). Optical rotations were
measured with Perkin–Elmer 341 automatic polarimeter. THF
used in the reactions was dried by distilling over metallic sodium;
dichloromethane was distilled over P2O5. Silica gel (Zhifu, 300–
400 mesh) was used for column chromatography, eluting (unless
otherwise stated) with ethyl acetate/petroleum ether (60–90 °C)
mixtures.
ther separation. IR (film) 1743, 1677, 1515, 1370, 1229, 1174 cmꢀ1
;
1H NMR (400 MHz, CD3CN, two diastereomers, 15a/15b = 2.5:1,
data read from the spectrum of the diastereomeric mixture). Com-
pound 15a: d 1.76–2.22 (m, 4H, CH2CH2), 1.84 (s, 3H, COCH3), 2.02
(s, 3H, COCH3), 3.69 (s, 3H, OCH3), 4.09 (d, J = 14.9 Hz, 1H, ArCH),
4.70 (d, J = 14.9 Hz, 1H, ArCH), 5.26 (dd, J = 12.3, 6.2 Hz, 1H,
NCOCH), 5.88 (m, 1H, NCH), 6.77–6.85 (m, 2H, ArH), 7.07–7.15
(m, 2H, ArH) ppm; 13C NMR (100 MHz, CDCl3) d 21.0, 21.1, 23.4,
26.7, 48.4, 55.8, 69.7, 81.3, 114.7, 118.3, 130.4, 160.0, 169.2,
170.7, 170.9 ppm. Compound 15b: d 1.76–2.22 (m, 4H, CH2CH2),
1.86 (s, 3H, COCH3), 2.01 (s, 3H, COCH3), 3.69 (s, 3H, ArOCH3),
4.16 (d, J = 14.9 Hz, 1H, ArCH2), 4.68 (d, J = 14.9 Hz, 1H, ArCH2),
5.28 (dd, J = 12.3, 6.2 Hz, 1H, NCOCH), 5.94 (m, 1H, NCH), 6.77–
6.85 (m, 2H, ArH), 7.07–7.15 (m, 2H, ArH) ppm; 13C NMR
(100 MHz, CDCl3) d 21.1, 21.2, 23.6, 25.3, 48.3, 55.8, 69.1, 81.2,
114.8, 118.3, 129.9, 130.3, 168.5, 170.6, 170.9 ppm; MS (ESI) m/z
358 (M+Na+, 100); HRMS (ESI) calcd for [C17H21NO6+H]+
336.1442, found 336.1441.
4.1.1. (S)-N-(4-Methoxybenzyl)-2,5-dihydroxypentanamide 14
To a solution of amido-lactone 1 (2.978 g, 11.96 mmol) in MeOH
(20 mL) was added NaBH4 (1.363 g, 35.88 mmol) at 0 °C. The mix-
ture was allowed to warm to rt and stirred for 1 h. The reaction was
quenched with 10 mL of saturated aqueous NaHCO3 solution and
10 mL of brine at 0 °C. MeOH was removed under reduced pres-
sure. The residue was diluted with water (10 mL) and extracted
with EtOAc (3 ꢂ 20 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography on sil-
ica gel eluting with EtOAc/MeOH (10:1) to give 14 as a white solid
20
(2.693 g, yield: 89%). Mp 103 °C (EtOAc/PE); ½aꢁD ¼ ꢀ23:8 (c 1.0,
CH3OH); IR (film) 3377, 3302, 1610, 1515, 1315, 1108 cmꢀ1 1H
;
NMR (400 MHz, CD3OD) d 1.60–1.72 (m, 3H, CH2CH2), 1.78–1.93
(m, 1H, CH2CH2), 3.61 (t, J = 6.3 Hz, 2H, CH2OH), 3.80 (s, 3H,
OCH3), 4.08 (dd, J = 7.0, 3.7 Hz, 1H, COCH), 4.38 (s, 2H, ArCH2),
6.84–6.89 (m, 2H, ArH), 7.19–7.25 (m, 2H, ArH) ppm; 13C NMR
(100 MHz, CD3OD) d 29.3, 32.5, 43.1, 55.6, 55.7, 62.7, 72.7, 114.9,
129.9, 131.9, 160.4, 177.0 ppm; MS (ESI) m/z 276 (M+Na+, 100).
Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found: C,
61.48; H, 7.50; N, 5.47.
4.1.4. (3S,6S)-6-Allyl-1-(4-methoxybenzyl)-2-oxo-piperidin-3-yl
acetate 16
To a cooled (ꢀ78 °C) diastereomeric mixture of 15 (1.030 g,
3.07 mmol) and allyltrimethylsilane (1.0 mL, 6.15 mmol) in anhy-
drous CH2Cl2 (15 mL) was added dropwise TMSOTf (0.7 mL, 4.61
mmol) over a period of 15 min. The mixture was stirred for 4 h
at the same temperature and then quenched with 5 mL of satu-
rated aqueous NaHCO3 solution. The mixture was warmed up
and an additional 5 mL of water was added. The organic layer
was separated and the aqueous layer was extracted with CH2Cl2
(3 ꢂ 10 mL). The combined organic layers were washed with
brine (5 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash
chromatography on silica gel eluting with EtOAc/petroleum ether
(1:1) to afford 16 (682 mg, yield: 70%) as a pale yellow oil.
4.1.2. (3S,6R/S)-1-(4-Methoxybenzyl)-3,6-dihydroxypiperidin-2-
one 4
To a suspension of diol 14 (500 mg, 1.98 mmol) and NaNO2
(410 mg, 5.94 mmol) in CH2Cl2 (5 mL) was added Ac2O (0.3 mL,
2.97 mmol). After stirring at room temperature for 20 min, the
mixture was extracted with ether (2 ꢂ 10 mL). The combined
organic layers were washed with 5 mL of saturated aqueous NaHCO3
solution, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash chroma-
tography on silica gel eluting with EtOAc/petroleum ether (2:1) to
afford 4 (colorless oil, 347 mg, yield: 70%) as a inseparable mixture
of two diastereomers in a 1:1 ratio, which was used in the next
step without further separation. IR (film) 3373, 1644, 1511, 1246,
20
½aꢁD ¼ þ44:0 (c 1.0, CHCl3); IR (film) 3075, 2953, 2837, 1744,
1656, 1613, 1513, 1457, 1373, 1303, 1241, 1211, 1176, 1085,
1034 cmꢀ1
; d 1.65–1.70 (m, 2H,
1H NMR (500 MHz, CDCl3)
CH2CH2), 1.83–2.05 (m, 2H, CH2CH2), 2.08 (s, 3H, COCH3), 2.20–
2.30 (m, 1H, @CHCH2), 2.44–2.50 (m, 1H, @CHCH2), 3.22–3.28
(m, 1H, NCH), 3.72 (s, 3H, OCH3), 3.80 (d, J = 15.0 Hz, 1H, ArCH2),
5.00–5.08 (m, 2H, @CH2), 5.16 (dd, J = 7.0, 10.5 Hz, 1H, COCH),
5.24 (d, J = 15.0 Hz, 1H, ArCH2), 5.50–5.60 (m, 1H, @CH), 6.76–
7.11 (m, 4H, ArH) ppm; 13C NMR (125 MHz, CDCl3) d 21.0, 22.8,
23.3, 36.2, 47.3, 54.4, 55.2, 69.4, 114.0, 118.4, 129.0, 129.4,
134.0, 159.0, 167.2, 170.3 ppm; MS (ESI) m/z 340 (M+Na+, 100).
Anal. Calcd for C18H23NO4 C, 68.12; H, 7.30; N, 4.41. Found: C,
68.53; H, 7.24; N, 4.27.
1038 cmꢀ1
;
1H NMR (400 MHz, CD3CN) d 1.48–2.21 (m, 8H,
CH2CH2), 2.36 (s, 1H, OH), 3.78 (s, 6H, OCH3), 3.92 (s, 1H, OH),
3.94 (dd, J = 10.2, 7.2 Hz, 1H, NCOCH), 4.03 (d, J = 14.9 Hz, 1H,
ArCH2), 4.05 (dd, J = 14.3, 7.1 Hz, 1H, NCOCH), 4.27 (d, J = 14.4 Hz,
1H, ArCH2), 4.24–4.31 (m, 1H, NCH), 4.81 (d, J = 14.4 Hz, 1H,
ArCH2), 4.75–4.87 (m, 1H, NCH), 5.03 (d, J = 14.9 Hz, 1H, ArCH2),
6.83–6.90 (m, 4H, ArH), 7.18–7.24 (m, 4H, ArH) ppm; 13C NMR
(100 MHz, CD3CN) d 24.3, 26.5, 29.1, 29.4, 46.1, 47.0, 55.8 (2C),
68.3, 69.3, 79.3, 80.3, 114.6 (2C), 130.0 (2C), 130.6, 130.7, 159.7,

G. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 1297–1303
1301
4.1.5. (2R,5S)-2-Allyl-5-hydroxyl-1-(4-methoxybenzyl)-
piperidine 17
J = 7.3, 10.6 Hz, 1H, NCOCH), 6.79–6.84 (m, 2H, ArH), 7.18–7.21
(m, 2H, ArH), 7.42–7.50 (m, 2H, ArH), 7.52–7.61 (m, 1H, ArH),
7.85–7.92 (m, 2H, ArH) ppm; 13C NMR (100 MHz, CDCl3) d 20.8,
23.0, 25.0, 40.5, 47.9, 51.6, 55.0, 69.6, 113.9, 127.8, 128.8, 129.32,
133.43, 136.2, 158.9, 167.5, 170.1, 197.3 ppm. Compound 20b: d
1.64–2.34 (m, 4H, CH2CH2), 3.12 (dd, J = 8.8, 17.2 Hz, 1H, COCH2),
3.29 (dd, J = 3.7, 17.2 Hz, 1H, COCH2), 3.76 (s, 3H, OCH3), 4.08–
4.20 (m, 1H, NCH), 4.18 (d, J = 14.9 Hz, 1H, ArCH2), 5.00 (d,
J = 14.9 Hz, 1H, ArCH2), 5.37 (dd, J = 5.8, 7.6 Hz, 1H, NCOCH),
6.79–6.84 (m, 2H, ArH), 7.18–7.21 (m, 2H, ArH), 7.42 (m, 2H,
ArH), 7.52–7.61(m, 1H, ArH), 7.79–7.83 (m, 2H, ArH) ppm; 13C
NMR (100 MHz, CDCl3) d 20.8, 24.9, 41.9, 47.5, 51.9, 68.2, 127.7,
128.7, 129.1, 136.1, 158.8, 167.5, 169.9, 196.9 ppm; MS (ESI) m/z
396 (M+H+). Anal. Calcd for C23H25NO5: C, 69.86; H, 6.37; N, 3.54.
Found: C, 69.39; H, 6.78; N, 3.36.
A suspension of 16 (678 mg, 2.14 mmol) and LiAlH4 (406 mg,
10.69 mmol) in THF (12 mL) was refluxed for 5 h. After cooling to
0 °C, the mixture was diluted with Et2O (40 mL) and quenched
by careful addition of solid Na2SO4ꢃ10H2O. The mixture was fil-
tered and the filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
eluting with EtOAc/petroleum ether/aqueous NH3 (1:2:0.01) to af-
20
ford 17 (368 mg, yield: 66%) as a colorless oil. ½aꢁD ¼ ꢀ73:9 (c 1.1,
CHCl3); IR (film) 3391, 3072, 2931, 2855, 2796, 1639, 1611, 1584,
1511, 1457, 1245, 1176, 1036 cmꢀ1 1H NMR (500 MHz, CDCl3) d
;
1.46–1.58 (m, 2H, CH2CH2), 1.68–1.77 (m, 2H, CH2CH2), 2.16 (dd,
J = 1.7, 11.6 Hz, 1H, NCH2), 2.35–2.44 (m, 3H, @CHCH2, NCH2),
2.40 (s br, 1H, OH, D2O exchangeable), 2.69–2.75 (m, 1H, NCH),
3.17 (d, J = 13.1 Hz, 1H, ArCH2), 3.73–3.75 (m, 1H, CHOH), 3.80 (s,
3H, OCH3), 4.02 (d, J = 13.1 Hz, 1H, ArCH2), 5.08–5.11 (m, 2H,
@CH2), 5.82–5.92 (m, 1H, @CH), 6.82–7.22 (m, 4H, ArH) ppm; 13C
NMR (125 MHz, CDCl3) d: 25.8, 30.4, 36.0, 55.2, 56.8, 57.0, 60.0,
65.4, 113.7 (2C), 116.9, 129.9 (2C), 130.8, 135.1, 158.6 ppm; MS
(ESI) m/z 262 (M+H+, 100); HRMS (ESI) calcd for [C16H23NO2+H]+
262.1802, found 262.1807.
4.1.8. (3S,6S)-1-(4-Methoxybenzyl)-6-(2-oxo-2-phenylethyl)-3-
(tetrahydro-2H-pyran-2-yloxy)piperidin-2-one 22
To a solution of 20 (500 mg, 1.27 mmol) in MeOH (20 mL) was
added AcCl (0.7 mL) at 0 °C. The mixture was stirred at room tem-
perature overnight. The solvent was evaporated under reduced
pressure, and the residue was purified by column chromatography
on silica gel eluting with EtOAc/petroleum ether (1:2) to afford a
colorless oil (431 mg, yield: 96%). To this material (402 mg,
1.1 mmol) and TsOH (cat.) in anhydrous CH2Cl2 (5 mL) was added
3,4-dihydro-2H-pyran (DHP, 0.25 mL, 2.75 mmol) at 0 °C. The mix-
ture was stirred at room temperature for 1 h before quenching
with 1 mL of saturated NaHCO3 solution, the organic layer was sep-
arated, and the aqueous layer was extracted with CH2Cl2
(3 ꢂ 5 mL). The combined organic layers were washed with brine
and dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by chromatography on
silica gel eluting with EtOAc/petroleum ether (1:2) to afford two
4.1.6. (ꢀ)-(2R,5S)-epi-Pseudoconhydrine hydrochloride salt 18
A suspension of 17 (151 mg, 0.58 mmol) and 20% Pd(OH)2/C
(38 mg) in EtOH (6 mL) was stirred under an atmosphere of H2
for 24 h. The catalyst was filtered, and the filtrate was concentrated
under reduced pressure. The resulting residue was dissolved in
water (5 mL) and the pH was adjusted to 1 with 1 M HCl. The mix-
ture was washed with Et2O (3 mL). The pH was re-adjusted to 14
with a 2 M NaOH solution, and the mixture was extracted with
CHCl3 (5 ꢂ 4 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was dissolved in 3 mL of MeOH/AcCl (10:1) and
concentrated under reduced pressure. The residue was crystallized
from MeOH/Et2O to afford hydrochloride salt of 18 (77 mg, yield:
74%) as white crystals. Mp 148–148.5 °C (MeOH/Et2O) [lit.7m Mp
main diastereomers 22 (323 mg, yield: 58%) and 23 (145 mg, yield:
20
26%) as colorless oils. 22: ½aꢁD ¼ ꢀ65:4 (c 1.0, CHCl3); IR (KBr) mmax
:
2946, 1681, 1648, 1510, 1444, 1249, 1025 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d 1.47–2.20 (m, 10H, CH2CH2), 3.25 (dd, J = 3.4,
15.4 Hz, 1H, COCH2), 3.35 (dd, J = 9.0, 15.4 Hz, 1H, COCH2), 3.50–
3.59 (m, 1H, OCH2), 3.87 (s, 3H, OCH3), 3.89 (m, 1H, OCH2), 3.94
(d, J = 14.7 Hz, 1H, ArCH2), 4.10–4.18 (m, 1H, NCH), 4.27 (dd,
J = 6.7, 9.8 Hz, 1H, COCH), 5.12 (d, J = 14.7 Hz, 1H, ArCH2), 5.26
(dd, J = 2.0, 4.7 Hz, 1H, OCHO), 6.80 (m, 2H, ArH ), 7.18 (m, 2H,
ArH), 7.45 (m, 2H, ArH), 7.6 (m, 1H, ArH), 7.87 (m, 2H, ArH)
ppm; 13C NMR (100 MHz, CDCl3) d 19.6, 25.3, 25.4, 30.5, 41.1,
47.6, 51.7, 55.1, 62.9, 71.7, 100.0, 114.0, 127.9, 128.6, 129.1,
129.3, 133.5, 136.4, 158.9, 170.7, 197.5 ppm; MS (ESI) m/z 438
(M+H+). Anal. Calcd for C26H31NO5: C, 71.37; H, 7.14; N, 3.20.
Found: C, 71.66; H, 7.47; N, 3.01.
20
20
148 °C]; ½aꢁD ¼ ꢀ10:2 (c 1.0, EtOH) {lit.7m ½aꢁD ¼ ꢀ9:1 (c 1.0,
EtOH)}; IR (KBr) 3411, 2958, 2933, 2871, 2821, 2717, 2542, 2393,
1566, 1442, 1086, 1037 cmꢀ1 1H NMR (500 MHz, CD3OD) d 0.96
;
(t, J = 7.2 Hz, 3H, CH3), 1.30–1.90 (m, 8H, CH2CH2), 3.00–3.30 (m,
3H, NCH, NCH2), 4.07 (s, 1H, CHOH) ppm; 13C NMR (125 MHz,
CD3OD) d 14.1, 19.4, 24.3, 29.7, 36.8, 51.0, 57.9, 62.3 ppm; MS
(ESI) m/z 144 (M+H+, 100); HRMS (ESI) calcd for [C8H17NO+H]+
144.1383, found 144.1385.
4.1.7. (3S,6R/S)-1-(4-Methoxybenzyl)-6-(2-oxo-2-phenylethyl)-
2-oxopiperidin-3-yl acetate 20
To a cooled (ꢀ78 °C) solution of 1-phenyl-1-(trimethylsilyl-
oxy)ethene 19 (1.3 mL, 6.10 mmol) and 15 (687 mg, 2.05 mmol)
in anhydrous CH2Cl2 (8 mL) was added dropwise TMSOTf
(0.4 mL, 2.20 mmol). After being stirred for 4 h, the reaction was
quenched with 4 mL of saturated aqueous NaHCO3 solution. The
organic layer was separated and the aqueous phase was extracted
with CH2Cl2 (3 ꢂ 5 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by chro-
matography on silica gel eluting with EtOAc/petroleum ether
(1:2) to give 20 (colorless oil, 615 mg, yield: 76%) as an inseparable
diastereomeric mixture in 2.4:1 ratio. IR (KBr) mmax: 2941, 1744,
4.1.9. (3S,6S)-1-(4-Methoxybenzyl)-3-hydroxy-6-(2-oxo-2-
phenylethyl)piperidin-2-one 21a
From 22: To a solution of 22 (200 mg, 0.46 mmol) in MeOH
(5 mL) was added p-TsOH (cat.). After stirring at 45 °C for 2 h, the
solvent was evaporated under reduced pressure. The residue was
purified by chromatography on silica gel eluting with EtOAc/petro-
leum ether (1:2) to give 21a (150 mg, yield: 93%) as a colorless oil.
From 20a: To a solution of 20a (77 mg, 0.19 mmol) in MeOH
(3 mL) were added three drops of AcCl at 0 °C. The mixture was
stirred at room temperature overnight. The solvent was evaporated
under reduced pressure, and the residue was purified by chroma-
tography on silica gel eluting with EtOAc/petroleum ether (1:2)
1652, 1516, 1453, 1366, 1246, 1034 cmꢀ1 1H NMR (400 MHz,
;
20
CDCl3, two diastereomers, 20a/20b = 2.4:1, data read from the
spectrum of the diastereomeric mixture). Compound 20a: d 1.80–
2.04 (m, 4H, CH2CH2), 2.18 (s, 3H, COCH3) 3.30–3.36 (m, 2H,
COCH2), 3.76 (s, 3H, OCH3), 4.00 (d, J = 14.7 Hz, 1H, ArCH2), 4.08–
4.20 (m, 1H, NCH), 5.09 (d, J = 14.7 Hz, 1H, ArCH2), 5.13 (dd,
to give 21a (62 mg, yield: 90%) as a colorless oil. ½aꢁD ¼ ꢀ10:6 (c
1.1, CHCl3); IR (KBr) mmax: 3423, 2951, 1677, 1628, 1520, 1449,
1242, 1109 cmꢀ1 1H NMR (400 MHz, CDCl3) d 2.22–1.79 (m, 4H,
;
CH2CH2), 3.23 (dd, J = 3.0, 17.6 Hz, 1H, PhCOCH2), 3.33 (dd, J = 9.0,
17.6 Hz, 1H, PhCOCH2), 3.77 (s, 3H, OCH3), 3.84 (s, 1H, OH, D2O

1302
G. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 1297–1303
20
22
exchangeable), 3.99 (d, J = 14.7 Hz, 1H, ArCH2), 4.09 (dd, J = 10.7,
6.5 Hz, 1H, NCOCH), 4.16–4.23 (m, 1H, NCH), 5.04 (d, J = 14.7 Hz,
1H, ArCH2), 6.81 (d, J = 8.6 Hz, 2H, ArH), 7.19 (d, J = 8.6 Hz, 2H,
ArH), 7.47 (t, J = 7.8 Hz, 2H, ArH), 7.59 (t, J = 7.4 Hz, 1H, ArH),
7.89 (d, J = 7.4 Hz, 2H, ArH) ppm; 13C NMR (100 MHz, CDCl3) d
24.3. 24.9, 41.0, 48.1, 52.2, 55.2, 68.4, 114.1, 128.0, 128.8, 129.3,
133.7, 136.3, 159.1, 172.6, 197.3 ppm; MS (ESI) m/z 354 (M+H+).
Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C,
71.67; H, 7.01; N, 3.57.
80%). ½aꢁD ¼ ꢀ53:4 (c 0.5, MeOH) {lit.8 ½aꢁD ¼ ꢀ40 (c 0.3, MeOH);
20
20
lit.7f ½aꢁD ¼ ꢀ53 (c 0.3, MeOH); lit.7m ½aꢁD ¼ ꢀ51:0 (c 2.5, MeOH)};
IR (KBr) mmax: 3365, 2934, 2859, 2793, 1661, 1453, 1055 cmꢀ1 1H
;
NMR (400 MHz, CDCl3) d 1.40–1.75 (m, 4H, CH2CH2), 1.89 (ddd,
J = 14.3, 5.7, 2.8 Hz, 1H, PhCHCH2), 2.16 (ddd, J = 14.3, 10.4,
7.8 Hz, 1H, PhCHCH2), 2.46 (s, 3H, NCH3), 2.56 (dd, J = 12.8,
3.6 Hz, 1H, NCH2), 2.68–2.76 (m, 1H, NCH), 2.85 (dd, J = 12.8,
7.2 Hz, 1H, NCH2), 3.90 (tt, J = 7.3, 3.6 Hz, 1H, NCH2CH), 4.85 (dd,
J = 10.4, 2.8 Hz, 1H, PhCH), 7.20–7.45 (m, 5H, PhH) ppm; 13C
NMR (100 MHz, CDCl3) d 145.3, 128.3, 127.2, 125.5, 73.7, 63.7,
59.6, 57.4, 42.7, 39.7, 30.2, 24.3 ppm; MS (ESI) m/z 236 (M+H+);
HRMS (ESI) calcd for [C14H21NO2+H]+ 236.1645, found 236.1648.
4.1.10. (3S,6S)-1-(4-Methoxybenzyl)-6-((S)-2-hydroxy-2-
phenylethyl)piperidin-3-ol 25
To a solution of 21a (120 mg, 0.34 mmol) in anhydrous THF
(10 mL) was added LiAlH(O-t-Bu)3 (260 mg, 1.02 mmol) at room
temperature, and the mixture was refluxed for 4 h. After cooling
to room temperature, LiAlH4 (129 mg, 3.4 mmol) was added and
the mixture was refluxed for another 4 h. After cooling to room
temperature, the reaction was quenched by careful addition of
powdered Na2SO4ꢃ10H2O, and the mixture was stirred until a
white precipitate formed. The mixture was filtered through a Celite
pad and the filtrate was concentrated under reduced pressure. The
residue was purified by chromatography on silica gel eluting with
EtOAc/petroleum ether (2:1) to give 25 as colorless crystals
(100 mg, yield: 86%). Mp 144–145 °C (EtOAc/petroleum ether).
4.1.13. (3S,6S)-1-(4-Methoxybenzyl)-2-oxo-6-(2-
oxoethyl)piperidin-3-yl acetate 27
To a stirring mixture of compound 16 (114 mg, 0.36 mmol) and
an aqueous solution of RuCl3 (0.25 mL, 0.0125 mmol, 3.5 mol %) in
MeCN (6 mL) and distilled water (1 mL) was added portionwise
NaIO4 (154 mg, 0.72 mmol) over a period of 5 min at room temper-
ature. After stirring for 2 h, the reaction was quenched with satu-
rated aqueous solution of Na2S2O3, and the two layers were
separated. The aqueous layer was extracted with EtOAc
(3 ꢂ 10 mL), and the combined organic layer was washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated un-
der reduced pressure. The residue was purified by flash column
chromatography on silica gel eluting with EtOAc/petroleum ether
20
½aꢁD ¼ ꢀ59:3 (c 1.0, CHCl3); IR (KBr) mmax: 3394, 2942, 1611,
1515, 1445, 1242, 1065, 1034 cmꢀ1 1H NMR (400 MHz, CDCl3) d
;
1.33–1.55 (m, 3H, CH2CH2), 1.80–1.90 (m, 1H, CH2CH2), 1.95–
2.10 (m, 1H, PhCHCH2), 2.19–2.30 (m, 1H, PhCHCH2), 2.69–2.78
(m, 1H, NCH2), 2.82 (m, 1H, NCH), 3.04–3.12 (m, 1H, NCH2), 3.79
(s, 3H, OCH3), 3.80 (d, J = 12.7 Hz, 1H, ArCH2), 3.86 (d, J = 12.7 Hz,
1H, ArCH2), 3.87 (tt, J = 10.0, 5.0 Hz, 1H, CHOH), 4.75 (dd, J = 10.6,
2.0 Hz, 1H, PhCH), 6.85–6.91 (m, 2H, ArH), 7.18–7.38 (m, 7H,
ArH) ppm; 13C NMR (100 MHz, CDCl3) d 24.1. 29.9, 38.4, 51.4,
55.2, 56.5, 57.7, 62.7, 75.03, 125.5, 127.0, 128.2, 130.0, 130.1,
144.96, 158.9 ppm; MS (ESI) m/z 342 (M+H+). Anal. Calcd for
(2:1) to afford 27 (79 mg, yield: 69%) as
a
colorless oil.
½aꢁD ¼ þ51:0 (c 1.0, CHCl3); IR (film) 2951, 1744, 1663, 1512,
1366, 1244, 1029 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.89–1.76
20
;
(m, 1H, CH2CH2), 2.01–1.90 (m, 1H, CH2CH2), 2.14–2.01 (m, 2H,
CH2CH2), 2.16 (s, 3H, COCH3), 2.89–2.84 (m, 2H, CH2CHO), 3.79
(s, 3H, OCH3), 3.94 (d, J = 14.8 Hz, 1H, ArCH2), 4.03–3.97 (m, 1H,
NCH), 5.08 (d, J = 14.8 Hz, 1H, ArCH2), 5.13 (dd, J = 10.2, 7.3 Hz,
1H, NCOCH), 6.90–6.81 (m, 2H, ArH), 7.21–7.13 (m, 2H, ArH),
9.69 (s, 1H, CHO) ppm; 13C NMR (100 MHz, CDCl3) d 20.9, 22.9,
25.2, 46.3, 47.9, 49.6, 55.2, 69.5, 114.1, 128.6, 129.4, 159.1, 167.2,
170.2, 199.2 ppm; MS (ESI) m/z 374 [(M+MeOH+Na)+, 100]. Anal.
Calcd for C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found: C, 63.50;
H, 6.22; N, 4.10.
C21H27NO3: C, 73.87; H, 7.97; N, 4.10. Found: C, 73.74; H, 8.02;
N, 3.95.
4.1.11. (2S,5S)-tert-Butyl 5-hydroxy-2-((S)-2-hydroxy-2-
phenylethyl)piperidine-1-carboxylate 26
A suspension of 25 (80 mg, 0.18 mmol), 20% Pd(OH)2/C (30 mg),
and Boc2O (0.16 mL, 0.70 mmol) in EtOH (5 mL) was stirred under
an atmosphere of H2 overnight. After filtration of the catalyst, the
filtrate was concentrated under reduced pressure. The residue
was purified by chromatography on silica gel eluting with EtOAc/
petroleum ether (1:1) to afford 26 (48 mg, yield: 64%) as a colorless
4.1.14. (3S,6S,20R/S)-1-(4-Methoxybenzyl)-6-(2-hydroxy-2-
phenylethyl)-2-oxopiperidin-3-yl acetate 28a,b
To a cooled (ꢀ20 °C) solution of 27 (40 mg, 0.125 mmol) in THF
(3 mL) was added dropwise 0.3 mL of a 0.5 M solution of PhMgBr in
THF (0.15 mmol). After stirring at ꢀ20 °C for 1 h, the reaction was
quenched with saturated aqueous NH4Cl (3 mL) and the mixture
was extracted with Et2O (3 ꢂ 5 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was puri-
fied by flash chromatography on silica gel eluting with EtOAc/
petroleum ether (2:1) to afford 28 (colorless oil, 37 mg, yield:
74%) as a mixture of two diastereomers in 2.5:1 ratio, which was
used in the next step without further separation. IR (film) 3382,
2952, 2855, 1731, 1636, 1461, 1378, 1237; 1H NMR (400 MHz,
CDCl3, two diastereomers, 28a/28b = 2.5:1, data read from the
20
oil. ½aꢁD ¼ ꢀ62:4 (c 0.8, CHCl3). IR (KBr) mmax: 3390, 2929, 2863,
1656, 1415, 1361, 1253, 1150, 1058; 1H NMR (400 MHz, CDCl3) d
1.44 (s, 9H, (CH3)3), 1.60–1.94 (m, 4H, CH2CH2), 1.98–2.32 (m,
2H, PhCHCH2), 2.57 (m, 1H, NCH2), 3.48–3.66 (m, 1H, NCH),
3.90–4.20 (m, 1H, NCH2), 4.20–4.44 (m, 1H, NCH2CH), 4.65–4.80
(m, 1H, PhCH), 7.20–7.40 (m, 5H, PhH) ppm; 13C NMR (100 MHz,
CDCl3) d 27.3. 28.4, 29.7, 39.6, 45.9, 47.3, 67.1, 72.5, 80.3, 125.7,
127.4, 128.4, 144.4, 155.2 ppm; MS (ESI) m/z 344 (M+Na+); HRMS
(ESI) calcd for [C18H27NO4+H]+ 322.2013, found 322.2016.
spectrum of the diastereomeric mixture). Compound 28a:
d
4.1.12. (ꢀ)-Hydroxysedamine 7
1.79–2.20 (m, 6H, CH2CH2 and NCHCH2), 2.12 (s, 3H, COCH3),
3.66–3.74 (m, 1H, NCH), 3.77 (d, J = 14.5 Hz, 1H, ArCH2), 3.79 (s,
3H, ArOCH3), 4.86 (d, J = 8.7 Hz, 1H, PhCH), 5.20 (dd, J = 10.1,
7.8 Hz, 1H, NCOCH), 5.26 (d, J = 14.5 Hz, 1H, ArCH2), 6.78–6.87
(m, 2H, ArH), 7.15–7.21 (m, 2H, ArH), 7.28–7.43 (m, 5H, ArH)
ppm. Compound 28b: d 1.79–2.20 (m, 6H, CH2CH2 and NCHCH2),
2.14 (s, 3H, COCH3), 3.25–3.34 (m, 1H, NCH), 3.61 (d, J = 14.5 Hz,
1H, ArCH2), 3.77 (s, 3H, ArOCH3), 4.64 (d, J = 6.8 Hz, 1H, PhCH),
5.20 (dd, J = 10.1, 7.8 Hz, 1H, NCOCH), 5.24 (d, J = 14.5 Hz, 1H,
ArCH2), 6.71–6.78 (m, 2H, ArH), 6.88–6.93 (m, 2H, ArH),
To a solution of 26 (40 mg, 0.12 mmol) in anhydrous THF (3 mL)
was added LiAlH4 (45 mg, 1.20 mmol) at room temperature, and
the mixture was refluxed for 4 h. After cooling to room tempera-
ture, the reaction was quenched by careful addition of powdered
Na2SO4ꢃ10H2O, and the mixture was stirred until a white precipi-
tate formed. The mixture was filtered through a Celite pad and
the filtrate concentrated under reduced pressure. The residue
was purified by chromatography on silica gel eluting with
CH2Cl2/MeOH (10:1) to give 7 as a colorless oil (23 mg, yield:

G. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 1297–1303
1303
7.28–7.41 (m, 5H, ArH) ppm; 13C NMR (100 MHz, CDCl3, diastereo-
meric mixture) 28: d 21.0, 23.0, 23.1, 23.9, 25.0, 40.0, 40.7, 41.1,
47.0, 47.3, 52.0, 52.3, 69.3, 71.5, 72.6, 113.9, 125.5, 125.9, 128.0,
128.2, 128.7, 128.9, 129.0, 129.3, 129.6, 129.7, 143.6, 144.0, 158.9
(2C), 161.5, 167.0, 167.1, 170.4 ppm; MS (ESI) m/z 420 (M+Na+,
100%). Anal. Calcd for C23H27NO5: C, 69.50; H, 6.85; N, 3.52. Found:
C, 69.38; H, 7.09; N, 3.49.
6. For confirmation of the structure of pseudoconhydrine by synthesis, see: (a)
Marion, L.; Cockburn, W. F. J. Am. Chem. Soc. 1949, 71, 3402–3404; (b) Hill, R. K.
J. Am. Chem. Soc. 1958, 80, 1611–1613; For isolation of N-methyl
pseudoconhydrine, see: (c) Roberts, M. F.; Brown, R. T. Phytochemistry 1981,
20, 447–449.
7. For recent syntheses of pseudoconhydrine, see: (a) Plehiers, M.; Hootelé, C.
Tetrahedron Lett. 1993, 34, 7569–7570; (b) Takahata, H.; Inose, K.; Momose, T.
Heterocycles 1994, 38, 269–272; (c) Oppolzer, W.; Bochet, C. G. Tetrahedron Lett.
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4.1.15. (3S,6S)-1-(4-Methoxybenzyl)-6-(2-oxo-2-phenylethyl)-
2-oxopiperidin-3-yl acetate 20a
To a solution of 28a,b (37 mg, 0.1 mmol) in DMSO (3 mL) was
added o-iodoxybenzoic acid (IBX, 52 mg, 0.19 mmol). After stirring
at room temperature for 2 h, the reaction mixture was diluted with
Et2O (5 mL) and quenched with H2O (3 mL). The mixture was fil-
tered, through a pad of Celite and washed with Et2O. The organic
layer was separated, washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The res-
idue was purified by flash chromatography on silica gel eluting
with EtOAc/petroleum ether (1:1) to afford 20a (27 mg, yield:
20
73%) as a colorless oil. ½aꢁD ¼ þ6:9 (c 1.4, CHCl3); IR (film) 3386,
2929, 1735, 1652, 1507, 1454, 1364, 1233, 1029 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 1.80–1.88 (m, 1H, CH2CH2), 1.89–2.00 (m, 1H,
CH2CH2), 2.03–2.11 (m, 2H, CH2CH2), 2.14 (s, 3H, COCH3), 3.23–
3.38 (m, 2H, PhCOCH2), 3.73 (s, 3H, ArOCH3), 3.95 (d, 1H,
J = 14.7 Hz, ArCH2), 4.10–4.18 (m, 1H, NCH), 5.07 (d, 1H,
J = 14.7 Hz, ArCH2), 5.09 (dd, 1H, J = 10.6, 7.5 Hz, NCOCH), 6.76–
6.82 (m, 2H, ArH), 7.13–7.18 (m, 2H, ArH), 7.40–7.47 (m, 2H,
ArH), 7.52–7.59 (m, 1H, ArH), 7.81–7.87 (m, 2H, ArH) ppm; 13C
NMR (100 MHz, CDCl3) d 21.0, 23.1, 25.2, 40.6, 48.1, 51.7, 55.2,
69.8, 114.1, 128.0, 128.8, 128.9, 129.5, 133.6, 136.4, 159.1, 167.4,
170.4, 197.5 ppm. MS (ESI) m/z 418 (M+Na+, 100%).
Acknowledgments
The authors are grateful to the NSFC (20572088), Qiu Shi Sci-
ence and Technologies Foundation, and the program for Innovative
Research Team in Science and Technology (University) in Fujian
Province for financial support. The project is partially supported
by Fujian Provincial Training Foundation for ‘Bai-Qian-Wan Talents
Engineering’. We thank Professor Y. F. Zhao for the use of her Bru-
ker Dalton Esquire 3000 plus LC–MS apparatus.
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