SN2 reaction of 2-substituted 3-piperidinol mesylate with retention of configuration: application to the asymmetric synthesis of (2R,3S)-CP-99,994

Article abstract of DOI:10.1016/j.tetasy.2006.12.009

Starting from protected (S)-3-hydroxyglutarimide 2a, the asymmetric synthesis of (2R,3S)-CP-99,994 8 was achieved. The crucial steps were a neighboring group participation leading to pyrrolidino-aziridinium intermediate 25 and the subsequent regioselectiv

Full text of DOI:10.1016/j.tetasy.2006.12.009

Tetrahedron: Asymmetry 17 (2006) 3265–3272
SN2 reaction of 2-substituted 3-piperidinol mesylate
with retention of configuration: application to the asymmetric
synthesis of (2R,3S)-CP-99,994
Liang-Xian Liua,b and Pei-Qiang Huanga,*
aDepartment of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, PR China
bDepartment of Chemistry and Biology, Ganan Teachers’ College, Ganzhou, Jiangxi 341000, PR China
Received 31 October 2006; accepted 4 December 2006
Abstract—Starting from protected (S)-3-hydroxyglutarimide 2a, the asymmetric synthesis of (2R,3S)-CP-99,994 8 was achieved. The cru-
cial steps were a neighboring group participation leading to pyrrolidino-aziridinium intermediate 25 and the subsequent regioselective
ring-opening reaction. In the case where neighboring group participation was not involved, only the eliminated product 15 was obtained.
ꢀ 2006 Published by Elsevier Ltd.
1. Introduction
we report the results and some interesting observations
made during the investigations.
2-Substituted 3-hydroxypiperidines and 2-substituted 3-
aminopiperidines with different stereochemical patterns
are key structural features found in a number of natural
products and pharmaceutically interesting compounds.1,2
Recently, we have shown that protected (S)-3-hydroxyglu-
tarimides 1 and 2 (Chart 1) are versatile building blocks for
the asymmetric synthesis of 3-hydroxy and 3-amino-piperi-
dines.3 Starting from 1 and 2, different methods have been
developed for establishing the (2S,3S)-, (2R,3R)-, or (2R,
3S)-stereochemistry of 2-substituted 3-hydroxypiperidines,
as demonstrated by the asymmetric synthesis of the anti-
malarial (2R,3S)-febrifugine 3,3a neurokinin substance P
receptor antagonists (2S,3S)-L-733,060 4,3b and (2R,3R)-
L-733,061 5.3c With regards to 3-aminopiperidines,4,5 the
only diastereomer that has been synthesized from the pro-
tected (S)-3-hydroxyglutarimide 2a is (2S,3S)-CP-99,994
6,4 another neurokinin substance P receptor antagonist.3a
In view of the stereochemical diversity of the bioactive nat-
ural6 and unnatural 2,3-disubstituted piperidines,1,2,4 and
in order to explore the possibility of accessing other stereo-
chemistry pattern9 from (S)-3-hydroxyglutarimides 1 and
2, we decided to investigate the asymmetric synthesis of
(2R,3R)-CP-99,994 7 and/or (2R,3S)-CP-99,994 8. Herein,
2. Results and discussion
As an initial target, (2R,3R)-CP-99,994 7 was envisioned to
be prepared from (2R,3S)-11 via an SN2 reaction.7 Thus the
known 2-piperidinone 9,3c readily prepared from (S)-2a by
a regio- and trans-diastereoselective reductive phenylation,
was converted to N-Boc protected 3-hydroxypiperidine 10
by a known transformation.3c Treatment of 10 with p-TsCl
in the presence of pyridine gave tosylate 11 in 90% yield
(Scheme 1). However, attempts to perform a nucleophilic
substitution using o-methoxybenzylamine 13 as a nucleo-
phile failed. Most of the starting material was recovered
along with a small amount of the eliminated side product
15. We then tried a more nucleophilic anionic nitrogen
nucleophile generated in situ from sulfonamide 16 and
potassium t-butoxide. Unfortunately, after being stirred
in DMF for 3 days at rt, instead of the expected product
18 only the eliminated compound 15 was isolated in 71%
yield. It was considered that the failure to perform the
nucleophilic substitution might be due to steric hindrance.8
To reduce the steric hindrance, mesylate 12 was prepared
and subjected to a reaction with sodium azide. However,
after being stirred at 70–80 ꢁC for 2 days, the eliminated
compound 15 was obtained once again as the major prod-
uct and the desired product 19 was not observed.
*
Corresponding author. E-mail: pqhuang@xmu.edu.cn
0957-4166/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2006.12.009

3266
L.-X. Liu, P.-Q. Huang / Tetrahedron: Asymmetry 17 (2006) 3265–3272
OH
N
O
OH
O
OBn
O
O
N
N
H
O
N
P
(S)-1
O
N
P
(S)-2
3. febrifugine
(a. P=PMB; b. P=Bn)
CF3
H
N
H
O
CF3
N
OCH3
N
H
Ph
N
H
Ph
OCH3
N
H
Ph
4. L-733,060
6. CP-99,994
7. ent-6
8. (2R,3S)-CP-99,994
5. ent-4, L-733,061
Chart 1. Structures of piperidine building blocks and bioactive 2-substituted 3-hydroxy- and 3-amino-piperidines.
OX
Ph
OBn
Ph
OH
Ph
ref.3c
TsCl, Py
Nu/base
71%
or
N
Boc
15
Ph
N
Boc
O
N
PMB
N
Boc
MsCl, NEt3
94%
(2R,3S)-10
(5S,6R)-9
11, X = Ts or 12, X = Ms
O H
S-N
O
H2N
O
S-Cl
O
NaN3,
DMF,
70 oC
13
16
OCH3
OCH3
t-BuOK
NO2
K2CO3,
NO2
MeCN
DMF
17
H3CO
H
N
N3
Ph
NO2
H2N
O
N
S
OCH3
N
Boc
OCH3
13
N
Boc
Ph
O
N
Boc
Ph
(2R,3R)-14
18
19
Scheme 1.
The unexpected facile syn-elimination of 11 can be under-
stood in terms of the plausible double dipolar interactions
of both Boc carbonyl and sulfonate S@O groups with a
benzylic proton, as shown in Scheme 2.
The conformations of both 20 and 21 deserve comment.
trans-20 shows a small (2.6 Hz) vicinal coupling constant
between H-5 and H-6 (J5,6), which is an indication of a
pseudo-equatorial disposition of the two trans-protons
(Fig. 1). In other words, both the phenyl and the hydroxyl
groups in trans-20 are in an axial orientation. This is in
agreement with the conformational analysis of substituted
2-piperidinones.9 In addition, larger J5,6 (5.2 Hz) exhibited
H
Ph
O
S
N
O
N
Boc
Ph
R
O
O
O
H
11. R = Ts
12. R = Ms
OBn
10% Pd/C, HCO2H
OH
Ph
15
O
N
Ph
O
N
PMB
Scheme 2.
MeOH
90%
PMB
trans-(5S,6R)-20
At this stage, changing Boc to benzyl as the N-protective
group was envisioned, in the hope of decreasing the acidity
of the proton at the C-2 position, and thus suppressing the
elimination reaction. To this end, 2-piperidinone 9 was
converted into 2-phenyl-3-hydroxypiperidine 21 via cata-
lytic hydrogenolysis (10% Pd/C, 10% HCO2H in MeOH,
rt, 10 h, yield: 90%) and LAH reduction (LiAlH4, THF,
yield: 87%) (Scheme 3).
(5S,6R)-9
OH
OH
Ph
LAH
THF
87%
O
N
Ph
N
PMB
cis-(5S,6S)-20
PMB
(2R,3S)-21
(ref. 3a)
Scheme 3.

L.-X. Liu, P.-Q. Huang / Tetrahedron: Asymmetry 17 (2006) 3265–3272
3267
use of a weak heterogeneous base K2CO3 to deprotonate
16 and the instability of mesylate 22. The fact that only
one isomer 24 was obtained indicated that the reaction is
highly regio- and diastereoselective.
An
O
An
O
Ph
H
N
N
H
Ph
H
H
OH
OH
cis-20
trans-20
H
Nu
H
H
J5,6 = 5.2 Hz
J5,6 = 2.6 Hz
OMs
Ph
Nu
Ph
H
Ph
H
H
Ph
N
Ph
N
N
N
N
An
PMB
(2R,3S)-22
An
N
H
H
PMB
HO
PMB
26
MsO
25
H
H
trans-8
J2,3 = 7.2 Hz
trans-21
Scheme 5.
J2,3 = 8.6 Hz
Figure 1. Plausible conformations of trans/cis-20, trans-21 and trans-8.
It is worth noting that although the nucleophile-promoted
ring expansion reaction of 2-hydroxymethylpyrrolidine
mesylates and analogues 27 leading to 3-substituted
piperidines 28 as the major products (Scheme 6) is a well-
established procedure,10 formation of the pyrrolidino-
aziridinium intermediates A from 3-hydroxypiperidine
mesylates or analogues 29 is rare,11 and the subsequent
reactions show poor regioselectivity, leading to a mixture
of pyrrolidines 30 and piperidines 28 in either ca. 1:1
ratio11a,b or with the former being predominant.11c–e To
the best of our knowledge, only in a highly hindered system
has piperidine 28 been predominately formed in good
yields.12
by cis-20,3a having an pseudo-equatorial/axial disposition,
is in support of an equatorial/equatorial disposition of the
1
H-5/H-6 in trans-20. In contrast, the H NMR of trans-21
shows a large vicinal coupling constant between H-2 and
H-3 (J2,3 = 8.6 Hz), which may indicate that both the
phenyl and the hydroxyl groups are in an equatorial
disposition.
Next, treatment of 3-hydroxypiperidine 21 with MsCl at
ꢀ20 ꢁC for 2 h afforded the desired mesylate 22 as a labile
waxy solid (Scheme 4). It was observed that mesylate 22
was unstable at rt, and decomposed during the concentrat-
ing procedure. However, the decomposition of 22 can be
suppressed at lower temperature (<5 ꢁC). The key nucleo-
philic substitution was achieved by treating 22 with sulfon-
amide 16 in the presence of anhydrous K2CO3 (MeCN,
30 ꢁC), which gave 24 in 80% yield. The vicinal coupling
constant of 24 (J2,3 = 9.7 Hz) is of the same order as that
of 3-hydroxypiperidine 21 (J2,3 = 8.6 Hz), implying that
the obtained product is the trans-diastereomer 24 instead
of cis-diastereomer 23, which was confirmed by converting
24 into the known trans-(2R,3S)-CP-99,994 8 (vide infra).
Nu
H
Nu
H
Nu
X
H
N
R
27
N
R
N
R
(major)
28
X
A
(X = OMs, Cl, Br, OMe)
(Nu = Cl, Br, OMe, NR'2,CN, R)
X
H
Nu
H
H
+
28
N
R
N
R
29
N
R
A
(minor)
OH
Ph
OMs
Ph
Nu
30 (major)
Nu
MsCl, NEt3
X
N
PMB
N
PMB
CH2Cl2
90%
Scheme 6.
(2R,3S)-22
(2R,3S)-21
16
K2CO3
80%
H3CO
As such, the present study provided a singular example of
the anchimeric assistance of the nitrogen atom of piperi-
dine 22 during the substitution reaction, which leads to 3-
substituted piperidine 26 with retention of configuration.
Thus an efficient method for the transformation of 21 to
24 with retention of configuration was established.
H3CO
NO2
NO2
O
O
N
N
O
S
S
O
N
PMB
Ph
(2R,3S)-24
N
PMB
Ph
To pursue the synthesis of (2R,3S)-CP-99,994 8, compound
24 was subjected to catalytic hydrogenolytic conditions
(Scheme 7) to give product 31, which was formed with con-
comitant nitro group reduction. The selection of o-nitro-
benzenesulfonyl group as the protecting group was made
with the intention of taking advantage of Fukuyama’s
mild deprotection conditions.13 However, the cleavage of
the o-aminobenzenesulfonyl group proved to be difficult.
An attempt to use SmI2 as a cleaving agent14 was unsuc-
cessful. Finally, the procedure described by Trost15 for
(2R,3R)-23
Scheme 4.
The results meant that the configuration at C-3 was con-
served during the nucleophilic substitution, which is an
indication of neighboring group participation via an azirid-
inium intermediate 25 (Scheme 5). The neighboring group
participation can be used to account for both the successful

3268
L.-X. Liu, P.-Q. Huang / Tetrahedron: Asymmetry 17 (2006) 3265–3272
ridinol 34. Mesylation of 34 gave unstable 35, which
H3CO
N
upon treatment with 16 and anhydrous K2CO3 in MeCN
at ꢀ25 ꢁC for 2 days gave the desired trans-piperidine 36
and its cis-diastereomer in a 3:1 ratio. The similar vicinal
coupling constant of piperidine 36 (J2,3 = 9.2 Hz) com-
pared with that of 24 (J2,3 = 9.7 Hz) allowed us to assign
the trans-stereochemistry to 36. This result showed us that
the participation of the nitrogen atom of mesylated 3-pipe-
ridinol 35 during the nucleophilic substitution is still the
predominant pathway, but is in competition with a normal
SN2 reaction. The observed different outcomes of 22 and 35
can be explained by the synclinal interaction between the
N-PMB group and the phenyl group in 22, which favored
the aziridinium formation.
NH2
O
S
10% Pd/C, HCO2H
(2R,3S)-24
O
MeOH
84%
N
Ph
H
(2R,3S)-31
H
N
Na-Hg, MeOH
Na2HPO4, 45 oC
62%
OCH3
N
H
Ph
(2R,3S)-CP-99,994 8
Scheme 7.
3. Conclusion
In conclusion, the results from the present study have dem-
onstrated that the SN2 reaction of 2-substituted 3-piperid-
inol mesylate with N-nucleophiles took place with
retention of configuration due to anchimeric assistance of
the piperidine nitrogen atom. This represents a singular
example where a pyrrolidino-aziridinium ion intermediate
is formed starting from a 3-piperidinol mesylate and the
subsequent nucleophilic reaction results in a substituted
piperidine with high regioselectivity. Using this method,
(2R,3S)-CP-99,994 8 was obtained from protected (S)-3-
hydroxyglutarimide 2a in eight steps. The present method
would find application in the asymmetric synthesis of the
5,8-disubstituted indolizidine alkaloids.16
de-sulfonation was proven to be effective. The o-amin-
obenzenesulfonyl group in 31 was removed using sodium
amalgam in buffered methanolic solution (Na2HPO4,
MeOH, 45 ꢁC, 2 days), which gave 8 in 62% yield.
The final product (2R,3S)-8 shows a larger vicinal coupling
constant between H-2 and H-3 (J2,3 = 7.2 Hz) (cf. Fig. 1)
than that of the (2S,3S)-diastereomer (J2,3 = 2.3 Hz).4g In
addition, the specific rotation and mp of (2R,3S)-8
20
{½aꢁD ¼ þ73:4 (c 0.4, MeOH, HCl salt); mp = 247–249 ꢁC
(HCl salt)} are in agreement with the data reported for
20
(2S,3R)-8 {½aꢁD ¼ ꢀ78 (c 1.0, MeOH, HCl salt);
mp = 250 ꢁC (HCl salt)}.4a The stereochemistry of 24 has
been confirmed to be (2R,3S), which is in support of the
mechanism illustrated in Scheme 5.
4. Experimental
4.1. General
To gain insight into the generality of the anchimeric assis-
tance of the nitrogen atom of piperidine 22 during the sub-
stitution reaction, a similar reaction of the methyl analogue
35 was investigated (Scheme 8). Thus, the known 2-piperid-
inone 323c was debenzylated and reduced to yield 3-pipe-
Melting points were determined on a Yanaco MP-500
micromelting point apparatus and are uncorrected. Infra-
red spectra were measured with a Nicolet Avatar 330
1
FT-IR spectrometer using film KBr pellet technique. H
NMR spectra were recorded in CDCl3 on a Bruker
AV400 or a Varian unity +500 spectrometer with tetra-
methylsilane as the internal standard. Chemical shifts are
expressed in d (ppm) units downfield from TMS. Mass
spectra were recorded by Bruker Dalton Esquire 3000 plus
LC–MS apparatus. Optical rotations were measured with a
Perkin–Elmer 341 automatic polarimeter. Flash column
chromatography was carried out on silica gel (300–400
mesh). THF was distilled over sodium. Dichloromethane
was distilled over P2O5.
OBn
CH3
OH
10% Pd/C, HCO2H
O
N
PMB
32
O
N
PMB
33
CH3
MeOH, 24 h
85%
OH
BH3 SMe2
MsCl, Et3N
CH2Cl2, −10 oC
N
CH3
THF, 72 h
89%
PMB
34
4.1.1. (1S,2R)-3-(tert-Butoxycarbonyl)-2-phenyl-piperidin-1-
yl methanesulfonate trans-12. To a cooled (ꢀ23 ꢁC) solu-
tion of 103c (260 mg, 0.94 mmol) and NEt3 (0.26 mL,
1.88 mmol) in dry CH2Cl2 (10 mL) was added, under a
N2 atmosphere, MsCl (0.11 mL, 1.04 mmol). The mixture
was stirred for 2 h at that temperature. The reaction was
quenched by the addition of 0.1 M HCl (0.5 mL) and water
(10 mL) at that temperature. The aqueous phase was then
extracted with CH2Cl2 (3 · 10 mL). The combined organic
phases were washed with brine (5 mL), dried over anhy-
OMe
OMs
16, K2CO3
NO2
O
N
MeCN, −25 oC
69% (2 steps)
(ds = 3:1)
S
N
CH3
O
CH3
PMB
35
N
PMB
36
Scheme 8.

L.-X. Liu, P.-Q. Huang / Tetrahedron: Asymmetry 17 (2006) 3265–3272
3269
drous Na2SO4, and concentrated under reduced pressure.
Flash chromatographic purification (eluent: EtOAc/
113.97 (2C), 69.77, 66.82, 55.24, 47.09, 27.27, 23.19. MS
(ESI) (m/z): 312 (M+H+, 100%). Anal. Calcd for
C19H21NO3: C, 73.31; H, 6.75; N, 4.50. Found: C, 72.98;
H, 6.59; N, 4.39.
PE = 1:8) of the residue afforded 12 (314 mg, yield: 94%)
20
as a colorless oil. ½aꢁD ¼ ꢀ19:95 (c 0.9, CHCl3). IR (film)
1
m
max: 2975, 1691, 1417, 1364, 1175, 1145 cmꢀ1. H NMR
(400 MHz, CDCl3): d 7.45–7.35 (m, 2H, Ar–H), 7.30–
7.20 (m, 3H, Ar–H), 5.68 (br s, 1H), 5.45 (br s, 1H),
4.20–4.12 (m, 1H), 3.12 (s, 3H, O3SCH3), 2.92 (ddd,
J = 13.3, 13.3, 3.1 Hz, 1H), 2.05–1.97 (m, 1H), 1.96–1.87
(m, 1H), 1.78–1.68 (m, 1H), 1.50–1.40 (m, 1H), 1.45 (s,
9H, 3 · CH3). 13C NMR (100 MHz, CDCl3): d 155.74
(C@O), 136.51, 128.95 (2C), 127.41, 126.15 (2C), 80.33,
77.78, 57.49, 39.49, 39.05, 28.37 (3C), 25.16, 18.95. MS
(ESI) (m/z): 355 (M+H+, 100%). HRESIMS calcd for
[C17H25NO5S+H]+: 356.1532; found: 356.1525.
4.1.4. (2R,3S)-3-Hydroxyl-1-(4-methoxybenzyl)-2-phenyl-
piperidine trans-21. To a cooled (0–5 ꢁC) suspension of
lithium aluminum hydride (501 mg, 13.68 mmol) in dry
THF (20 mL) was slowly added, under an N2 atmosphere,
a solution of 20 (820 mg, 2.64 mmol) in dry THF (5 mL).
The mixture was stirred at room temperature for 3 h, then
warmed to 40 ꢁC and stirred at that temperature for 1 h.
The mixture was cooled with an ice-bath, then wet ether
(5 mL), a 10% solution of sodium hydroxide (0.4 mL)
and H2O (0.1 mL) were added successively. The mixture
was allowed to reach room temperature, stirred for
30 min, and filtered through Celite. After being concen-
trated at reduced pressure, the residue was purified by flash
chromatography on silica gel (eluent: EtOAc/PE = 1:2) to
4.1.2. 1-(tert-Butoxycarbonyl)-2,3-dehydro-2-phenylpiper-
idine 15. To a solution of 12 (40 mg, 0.11 mmol) and
DMF (1.5 mL) was added NaN3 (60 mg, 0.92 mmol) at
room temperature. The mixture was then allowed to warm
up to 80 ꢁC and stirred for 48 h at that temperature. The
mixture was cooled to room temperature after which water
(15 mL) was added to that mixture. The aqueous phase was
extracted with Et2O (5 · 10 mL) and the combined organic
layers were washed with brine (5 mL), dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced
pressure. Flash chromatography of the residue (eluent:
EtOAc/PE = 1:8) yielded 15 (20 mg, yield: 71%) as a color-
less oil. IR (film) mmax: 2928, 1692, 1414, 1365, 1170,
afford 21 (680 mg, yield: 87%) as a pale yellow solid. Mp
20
157–158 ꢁC (acetone). ½aꢁD ¼ ꢀ18:5 (c 1.0, CHCl3). IR
(film) mmax: 3399, 2926, 2789, 1513, 1268, 1239, 1101,
1035 cmꢀ1
.
1H NMR (500 MHz, CDCl3): d 7.52 (d,
J = 7.0 Hz, 2H, Ar–H), 7.40 (t, J = 7.3 Hz, 2H, Ar–H),
7.32 (t, J = 7.3 Hz, 1H, Ar–H), 7.13 (d, J = 8.4 Hz, 2H,
Ar–H), 6.81 (d, J = 8.4 Hz, 2H, Ar–H), 3.78 (s, 3H,
OCH3), 3.68–3.56 (m, 1H, H-3), 3.60 (d, J = 13.4 Hz, 1H,
NCH2), 2.92 (d, J = 8.6 Hz, 1H, H-2), 2.95–2.88 (m, 1H,
H-6), 2.81 (d, J = 13.4 Hz, 1H, NCH2), 2.15–2.08 (m,
1H, H-6), 1.94 (ddd, J = 11.8, 3.1, 2.9 Hz, 1H), 1.74–1.66
(m, 1H), 1.66–1.57 (m, 1H), 1.46–1.35 (m, 1H), 1.40 (br
s, 1H, OH, D2O exchangeable). 13C NMR (125 MHz,
CDCl3): d 158.39, 141.01, 131.36, 129.66 (2C), 128.81
(3C), 127.93 (2C), 113.41 (2C), 75.87, 73.94, 58.55, 55.21,
52.20, 32.45, 23.31. MS (ESI) (m/z): 298 (M+H+, 100%).
HRESIMS calcd for [C19H23NO2+H]+: 298.1802; found:
298.1797.
1
1107 cmꢀ1. H NMR (400 MHz, CDCl3): d 7.42–7.23 (m,
5H, Ar–H), 6.06–5.97 (m, 1H, H-3), 5.90–5.78 (m, 1H),
5.65–5.40 (m, 1H), 4.20–4.00 (m, 1H), 2.92 (ddd,
J = 13.0, 13.0, 4.0 Hz, 1H), 2.38–2.25 (m, 1H), 2.10–1.98
(m, 1H), 1.45 (s, 9H, 3 · CH3). 13C NMR (100 MHz,
CDCl3): d 154.66 (C@O), 141.32, 128.27 (2C), 127.51,
127.30, 127.21 (2C), 126.22, 79.76, 54.98, 36.65, 28.47
(3C), 24.96. MS (ESI) (m/z): 260 (M+H+, 100%). HRE-
SIMS calcd for [C16H21NO2+H]+: 260.1651; found:
260.1647.
4.1.5. (2R,3S)-3-[N-(2-Methoxybenzyl)-N-(2-nitrobenzene-
sulfonyl)]amino-1-(4-methoxybenzyl)-2-phenylpiperidine trans-
24. To a cooled (ꢀ20 ꢁC) solution of 21 (787 mg,
2.65 mmol) and NEt3 (0.55 mL, 3.97 mmol) in dry CH2Cl2
(20 mL) was added, under an N2 atmosphere, MsCl
(0.25 mL, 3.18 mmol). After being stirred for 2 h at
ꢀ20 ꢁC, the reaction was quenched by the addition of
0.1 M HCl (0.5 mL) and water (20 mL) at that tempera-
ture. The aqueous phase was extracted with CH2Cl2
(3 · 15 mL). The combined organic phases were washed
with brine (5 mL), dried over anhydrous Na2SO4, and con-
centrated under reduced pressure. Flash chromatographic
purification (eluent: EtOAc/PE = 1:4) of the residue affor-
ded unstable 22 as a white solid (890 mg, yield: 90%), which
was used in the next step immediately.
4.1.3. (5S,6R)-5-Hydroxyl-1-(4-methoxybenzyl)-6-phenyl-2-
piperidinone trans-20. To a solution of 93c (1.51 g,
3.77 mmol) and formic acid (1 mL) in methanol (10 mL)
was added Pd/C (450 mg, 10% Pd). After being stirred
overnight at room temperature, the mixture was filtered
through silica gel and the solvent was removed under
reduced pressure. Flash chromatographic purification of
the residue on silica gel (eluent: EtOAc/PE = 1:1) afforded
20 (1.05 g, yield: 90%) as white crystals. Mp 130–131 ꢁC
20
(EtOAc). ½aꢁD ¼ þ53:0 (c 1.0, CHCl3). IR (film) mmax
:
3381, 2935, 1616, 1511, 1474, 1452, 1245, 1174,
1032 cmꢀ1. H NMR (500 MHz, CDCl3): d 7.38–7.20 (m,
1
3H, Ar–H), 7.10 (d, J = 8.0 Hz, 2H, Ar–H), 7.02 (d,
J = 8.5 Hz, 2H, Ar–H), 6.75 (d, J = 8.5 Hz, 2H, Ar–H),
5.45 (d, J = 14.8 Hz, 1H, NCH2), 4.35–4.28 (m, 1H, H-
6), 3.98–3.90 (m, 1H, H-5), 3.71 (s, 3H, OCH3), 3.25 (d,
J = 14.8 Hz, 1H, NCH2), 2.72 (ddd, J = 18.0, 10.7,
7.1 Hz, 1H, H-3), 2.48 (ddd, J = 18.0, 6.5, 3.4 Hz, 1H, H-
3), 2.20–1.90 (br s, 1H, OH, D2O exchangeable), 1.90–
1.80 (m, 1H, H-4), 1.76–1.62 (m, 1H, H-4). 13C NMR
(125 MHz, CDCl3): d 170.39 (C@O), 158.87, 138.75,
129.42 (2C), 129.00 (2C), 128.87, 128.01, 126.91 (2C),
A suspension of 16 (640 mg, 1.99 mmol), anhydrous
K2CO3 (552 mg, 4.00 mmol) in CH3CN (10 mL) was stir-
red under an N2 atmosphere at room temperature for
1 h. To the resulting mixture was added a solution of 22
(500 mg, 1.33 mmol) in dry CH3CN (5 mL). After being
stirred at 30 ꢁC for 24 h, water (10 mL) and CH2Cl2
(10 mL) were added successively and the layers were sepa-
rated. The aqueous phase was extracted with CH2Cl2

3270
L.-X. Liu, P.-Q. Huang / Tetrahedron: Asymmetry 17 (2006) 3265–3272
(3 · 10 mL) and the combined organic layers were washed
with brine (5 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. Flash chroma-
tography of the residue (eluent: EtOAc/PE = 1:2) yielded
dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. Flash chromatography of the resi-
due (eluent: CH2Cl2/NH3ÆH2O/MeOH = 100:1:3) yielded
(2R,3S)-CP-99,994 8 (41 mg, yield: 62%) as a colorless
20
24 (640 mg, yield: 80%) as a yellow solid. Mp 133–
oil. ½aꢁD ¼ þ73:4 (c 0.4, MeOH, dihydrochloride). IR
20
135 ꢁC (EtOAc/PE = 3:1). ½aꢁD ¼ ꢀ7:1 (c 1.0, CHCl3). IR
(neat, free base) mmax: 3350, 2930, 1480, 1230 cmꢀ1 1H
.
1
(film) mmax: 2924, 1544, 1511, 1245, 1161, 1033 cmꢀ1. H
NMR (500 MHz, CDCl3, free base): d 7.54–7.40 (m, 6H,
Ar–H), 7.10 (d, J = 7.5 Hz, 1H, Ar–H), 6.90–6.80 (m,
2H, Ar–H), 3.82 (s, 3H, OCH3), 3.73 (d, J = 13.4 Hz,
1H, NCH2), 3.49 (d, J = 7.3 Hz, 1H, H-2), 3.43 (d,
J = 13.4 Hz, 1H, NCH2), 3.18 (ddd, J = 7.3, 7.3, 1.5 Hz,
1H, H-3), 2.93–2.85 (m, 1H, H-6), 2.77–2.69 (m, 1H, H-
6), 2.10–1.86 (br s, 2H, NH), 1.83 (ddd, J = 17.5, 8.1,
5.0 Hz, 1H, CH2CH2), 1.75–1.62 (m, 2H, CH2CH), 1.47
(ddd, J = 17.5, 8.1, 8.1 Hz, 1H, CH2CH2). 13C NMR
(125 MHz, CDCl3, free base): d 157.74, 142.42, 130.07,
128.49, 128.29 (2C), 128.08 (3C), 127.10, 120.33, 110.18,
66.54, 64.42, 55.15, 47.22, 46.17, 27.97, 24.79. MS (ESI)
(m/z): 297 (M+H+, 100%). HRESIMS calcd for
[C19H24N2O+H]+: 297.1967; found: 297.1961.
NMR (500 MHz, CDCl3): d 7.60–7.50 (m, 3H, Ar–H),
7.40–7.15 (m, 9H, Ar–H), 6.95–6.85 (m, 2H, Ar–H),
6.60–6.50 (m, 3H, Ar–H), 4.86 (d, J = 16.0 Hz, 1H,
NCH2), 4.72 (d, J = 16.0 Hz, 1H, NCH2), 4.59 (d,
J = 9.7 Hz, 1H, H-2), 3.90 (s, 3H, OCH3), 3.70 (s, 3H,
OCH3), 3.54–3.42 (m, 1H, H-3), 3.36 (d, J = 12.3 Hz, 1H,
NCH2), 3.02 (d, J = 12.3 Hz, 1H, NCH2), 2.67–2.56 (m,
1H, H-6), 2.22–2.10 (m, 1H, H-6), 1.95–1.84 (m, 1H,
CH2CH), 1.75–1.57 (m, 1H, CH2CH), 1.57–1.36 (m, 2H,
CH2CH2). 13C NMR (125 MHz, CDCl3): d 158.29,
156.68, 148.38, 137.32, 134.66, 132.71, 132.30, 131.58,
131.16, 130.13 (2C), 129.76, 129.61, 128.97, 127.94 (2C),
127.78, 125.19, 124.02 (2C), 120.94, 113.24 (2C), 110.30,
67.14, 64.84, 60.70, 55.32, 55.17, 54.43, 44.04, 28.46,
23.79. MS (ESI) (m/z): 602 (M+H+, 100%). HRESIMS
calcd for [C33H35N3O6S+H]+: 602.2319; found: 602.2326.
4.1.8. (5S,6R)-5-Hydroxyl-1-(4-methoxybenzyl)-6-methyl-2-
solution of 323c (850 mg,
piperidinone 33. To
a
2.51 mmol) and formic acid (2.5 mL) in methanol
(25 mL) was added Pd/C (300 mg, 10% Pd), and the mix-
ture was stirred overnight at rt. The mixture was filtered
through silica gel and the solvent was removed under
reduced pressure. Flash chromatographic purification on
4.1.6. (2R,3S)-3-[N-(2-Aminobenzenesulfonyl)-N-(2-meth-
oxybenzyl)]amino-2-phenyl piperidine trans-31. To a solu-
tion of 24 (620 mg, 1.03 mmol) and formic acid (0.8 mL)
in methanol (8 mL) was added Pd/C (150 mg, 10% Pd).
After being stirred overnight at room temperature, the mix-
ture was filtered through silica gel and the solvent removed
under reduced pressure. Flash chromatographic purifica-
tion of the residue on silica gel (eluent: EtOAc/PE/
silica gel (eluent: EtOAc/PE = 1:1) provided 33 (530 mg,
25
85%) as a colorless oil. ½aꢁD ¼ þ64:1 (c 1.6, CHCl3).
IR (film) mmax: 3379, 2925, 1613, 1513, 1246, 1177 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 7.18 (d, J = 8.5 Hz, 2H,
Ar–H), 6.82 (d, J = 8.5 Hz, 2H, Ar–H), 5.16 (d,
J = 15.0 Hz, 1H, NCH2), 3.92 (d, J = 15.0 Hz, 1H,
NCH2), 3.77 (br s, 1H, H-5), 3.75 (s, 3H, OCH3), 3.33
(dq, J = 2.8, 6.7 Hz, 1H, H-6), 2.85 (d, J = 3.2 Hz, 1H,
OH, D2O exchangeable), 2.66 (ddd, J = 18.2, 7.4, 2.4 Hz,
1H, H-3), 2.36 (ddd, J = 18.2, 7.1, 3.0 Hz, 1H, H-3), 2.00
(ddd, J = 17.5, 7.1, 2.4 Hz, 1H, H-4), 1.84 (ddd, J = 17.5,
7.4, 3.0 Hz, 1H, H-4), 1.13 (d, J = 6.7 Hz, 3H, CH3). 13C
NMR (100 MHz, CDCl3): d 169.61 (C@O), 158.73,
129.32, 129.05 (2C), 113.88 (2C), 68.17, 57.81, 55.17
(OCH3), 46.93, 26.89, 23.87, 18.32 (CH3). MS (ESI): 250
(M+H+, 30), 272 [(M+23)+, 40], 521 [(2M+23)+, 100].
HRESIMS calcd for [C14H19NO3+H]+: 250.1443; found:
250.1440.
NH3ÆH2O/MeOH = 100:100:1:5) provided 31 (392 mg,
20
yield: 84%) as a yellow waxy solid. ½aꢁD ¼ þ91:7 (c 0.2,
CHCl3). IR (film) mmax: 3461, 3374, 2942, 1615, 1601,
1484, 1453, 1320, 1242, 1140, 1031 cmꢀ1
.
1H NMR
(500 MHz, CDCl3): d 7.52 (d, J = 7.9 Hz, 1H, Ar–H),
7.37 (d, J = 7.5 Hz, 1H, Ar–H), 7.24–7.15 (m, 7H, Ar–
H), 6.85 (t, J = 7.4 Hz, 1H, Ar–H), 6.80 (d, J = 8.1 Hz,
1H, Ar–H), 6.64 (m, 2H, Ar–H), 5.04 (br s, 2H, NH2),
4.65 (d, J = 10.3 Hz, 1H, H-2), 4.49 (d, J = 16.0 Hz, 1H,
NCH2), 4.45 (d, J = 16.0 Hz, 1H, NCH2), 3.79 (s, 3H,
OCH3), 3.60 (ddd, J = 10.3, 6.4, 6.4 Hz, 1H, H-3), 2.80
(ddd, J = 9.3, 5.5, 5.5 Hz, 1H, H-6), 2.73–2.66 (m, 1H,
H-6), 1.92–1.84 (m, 1H, CH2CH), 1.88 (br s, 1H, NH),
1.75–1.66 (m, 2H, CH2CH2), 1.64–1.54 (m, 1H, CH2CH).
13C NMR (125 MHz, CDCl3): d 156.43, 145.92, 137.19,
133.84, 130.47, 130.18, 129.71 (2C), 128.39, 128.17 (2C),
127.93, 125.85, 122.51, 120.47, 117.64, 117.40, 110.04,
65.44, 58.28, 55.16, 46.21, 42.64, 28.92, 24.80. MS (ESI)
(m/z): 452 (M+H+, 100%). HRESIMS calcd for
[C25H29N3O3S+H]+: 452.2002; found: 452.2010.
4.1.9. (2R,3S)-3-Hydroxyl-1-(4-methoxybenzyl)-2-methyl-
piperidine 34. To a cooled (0 ꢁC) solution of 33 (300 mg,
1.20 mmol) in dry THF (12 mL) was added slowly
BH3ÆSMe2 (0.34 mL, 3.59 mmol) under an N2 atmosphere.
After the mixture had reacted at 0 ꢁC for 72 h, MeOH
(2 mL) was added and the mixture was stirred at room tem-
perature for another 3 h. After being concentrated at
reduced pressure, the residue was purified by flash
4.1.7. (2R,3S)-3-(2-Methoxybenzyl)amino-2-phenylpiperi-
dine trans-8 (2R,3S)-CP-99,994. To a mixture of 31
(103 mg, 0.23 mmol), Na–Hg (3.3 g, 5% Na) and Na2HPO4
(284 mg, 2.00 mmol) was added methanol (4 mL). The
resulting suspension was stirred at 40 ꢁC for 48 h. Water
(5 mL) and CH2Cl2 (5 mL) were added successively to the
resulting mixture, and the layers were separated. The aque-
ous phase was extracted with CH2Cl2 (3 · 5 mL) and the
combined organic layers were washed with brine (3 mL),
chromatography on silica gel (eluent: EtOAc/PE = 1:2) to
20
afford 34 (252 mg, 89%) as a waxy solid. ½aꢁD ¼ ꢀ32:7 (c
2.1, CHCl3). IR (film) mmax: 3406, 2934, 1512, 1246,
1036 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 7.22 (d,
J = 8.5 Hz, 2H, Ar–H), 6.85 (d, J = 8.5 Hz, 2H, Ar–H),
3.78 (s, 3H, OCH3), 3.64 (d, J = 13.2 Hz, 1H, NCH2),
3.52–3.47 (m, 1H, H-3), 3.40 (d, J = 13.2 Hz, 1H,

L.-X. Liu, P.-Q. Huang / Tetrahedron: Asymmetry 17 (2006) 3265–3272
3271
NCH2), 2.92 (s, 1H, OH), 2.70–2.62 (m, 1H, H-6), 2.57–
2.48 (m, 1H, H-6), 2.25 (dq, J = 2.8, 6.6 Hz, 1H, H-2),
1.78–1.66 (m, 2H), 1.53–1.38 (m, 2H), 1.11 (d,
J = 6.6 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): d
158.56, 130.74, 129.87 (2C), 113.56 (2C), 70.49, 59.74,
57.75, 55.13 (OCH3), 46.68 (NCH2), 27.94, 20.98, 10.28
(CH3). MS (ESI): 236 (M+H+, 100), 258 [(M+23)+, 5].
HRESIMS calcd for [C14H21NO2+H]+: 236.1650; found:
236.1644.
(400 MHz, CDCl3): d 7.96 (d, J = 7.6 Hz, 1H, Ar–H),
7.66–7.54 (m, 3H, Ar–H), 7.52 (d, J = 7.6 Hz, 1H, Ar–
H), 7.21 (t, J = 7.5 Hz, 1H, Ar–H), 7.15 (d, J = 8.1 Hz,
2H, Ar–H), 6.90 (t, J = 7.5 Hz, 1H, Ar–H), 6.78 (d,
J = 8.4 Hz, 3H, Ar–H), 4.64 (d, J = 16.1 Hz, 1H, NCH2),
4.58 (d, J = 16.1 Hz, 1H, NCH2), 3.80–3.68 (m, 1H, H-
3), 3.80 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.73 (d,
J = 13.0 Hz, 1H, NCH2), 3.30 (d, J = 13.0 Hz, 1H,
NCH2), 2.76 (dq, J = 4.9, 6.6 Hz, 1H, H-2), 2.57 (ddd,
J = 16.3, 9.0, 1.6 Hz, 1H, H-6), 2.20 (ddd, J = 16.3, 9.1,
1.3 Hz, 1H, H-6), 1.83 (m, 1H), 1.60–1.48 (m, 1H), 1.38–
1.22 (m, 2H), 1.17 (d, J = 6.6 Hz, 3H, CH3). 13C NMR
(100 MHz, CDCl3): d 158.46, 156.66, 147.87, 134.15,
133.10, 132.02, 131.32 (2C), 130.87 (2C), 129.52, 128.69,
125.72, 123.83, 120.56, 113.50 (2C), 110.12, 66.69, 61.21,
59.01, 55.20 (OCH3), 55.12 (NCH2), 54.61 (OCH3), 41.65
(NCH2), 28.08, 24.01, 15.25 (CH3). MS (ESI): 540
(M+H+, 100). HRESIMS calcd for [C28H33N3O6S+H]+:
540.2168; found: 540.2167.
4.1.10. (2R,3S)-3-[N-(2-Methoxybenzyl)-N-(2-nitrobenzene-
sulfonyl)amino-1-(4-methoxybenzyl)-2-methylpiperidine 36
and the cis-diastereomer. To a cooled (ꢀ20 ꢁC) solution
of 34 (85 mg, 0.36 mmol) and NEt3 (0.10 mL, 0.72 mmol)
in dry CH2Cl2 (4 mL) was added MsCl (0.034 mL,
0.44 mmol) under an N2 atmosphere. After being stirred
for 2 h at the same temperature, the reaction was quenched
by the addition of H2O (6 mL). The aqueous phase was
extracted with CH2Cl2 (3 · 5 mL). The combined organic
phases were washed with brine (3 mL), dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced
pressure. After flash chromatographic purification (eluent:
EtOAc/PE = 1:4), unstable 35 (92 mg, 82%) was obtained
as a colorless oil, which was used in the subsequent step
as it was. A mixture of 16 (95 mg, 0.29 mmol) and anhy-
drous K2CO3 (50 mg, 0.36 mmol) in dry CH3CN (10 mL)
was stirred under an N2 atmosphere, at ꢀ25 ꢁC for 1 h,
after which a solution of 35 (92 mg, 0.29 mmol) in dry
CH3CN (2 mL) was added and the resulting mixture was
stirred at that temperature for 48 h. Water (8 mL) and
CH2Cl2 (10 mL) were added successively and the layers
separated. The aqueous phase was extracted with CH2Cl2
(2 · 8 mL) and the combined organic layers were washed
with brine (3 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. Flash chroma-
tography (eluent: EtOAc/PE = 1:3) of the residue yielded
36 (100 mg, yield: 63%) and the cis-diastereoisomer
Acknowledgments
The authors are grateful to the NSF of China (20572088;
203900505) and the Ministry of Education (Key Project
104201) for financial support. Partial support from the pro-
gram for Innovative Research Team in Science and Tech-
nology in Fujian Province University is acknowledged.
References
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Asymmetry 2002, 13, 587–593.
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P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911–4913; (b)
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(32 mg, yield: 20%) both as yellow waxy solids. Major
25
trans-diastereomer 36: ½aꢁD ¼ ꢀ50:4 (c 1.4, CHCl3). IR
1
(film) mmax: 2938, 1544, 1511, 1245, 1162, 1031 cmꢀ1. H
NMR (500 MHz, CDCl3): d 7.94 (d, J = 7.6 Hz, 1H, Ar–
H), 7.66–7.54 (m, 3H, Ar–H), 7.50 (d, J = 7.6 Hz, 1H,
Ar–H), 7.21 (t, J = 7.4 Hz, 1H, Ar–H), 7.10 (d,
J = 8.6 Hz, 2H, Ar–H), 6.88 (t, J = 7.4 Hz, 1H, Ar–H),
6.82 (d, J = 8.6 Hz, 2H, Ar–H), 6.75 (d, J = 8.3 Hz, 1H,
Ar–H), 4.69 (d, J = 16.0 Hz, 1H, NCH2), 4.55 (d,
J = 16.0 Hz, 1H, NCH2), 3.83 (d, J = 13.5 Hz, 1H,
NCH2), 3.79 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.66
(ddd, J = 9.2, 9.2, 4.2 Hz, 1H, H-3), 3.20 (d, J = 13.5 Hz,
1H, NCH2), 2.69–2.62 (m, 1H, H-6), 2.32 (dt, J = 9.2,
6.1 Hz, 1H, H-2), 1.79 (ddd, J = 11.3, 3.6, 3.6 Hz, 1H,
H-6), 1.75–1.65 (m, 1H), 1.55–1.38 (m, 3H), 1.02 (d,
J = 6.1 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): d
158.44, 156.75, 147.58, 134.24, 133.04, 131.45, 131.34,
130.88 (2C), 130.16, 128.73, 125.53, 123.85, 120.47,
113.43 (2C), 110.13, 110.08, 61.40, 58.51, 56.48, 55.39
(OCH3), 54.89 (OCH3), 51.46 (NCH2), 42.18 (NCH2),
29.61, 24.25, 16.13 (CH3). MS (ESI): 540 (M+H+, 100).
Anal. Calcd for C28H33N3O6S: C, 62.32; H, 6.16; N, 7.79;
S, 5.94. Found: C, 62.23; H, 6.14; N, 7.59; S, 6.06. Minor
25
cis-diastereomer: ½aꢁD ¼ þ10:2 (c 2.3, CHCl3). IR (film)
1
m
max: 2960, 1545, 1512, 1245, 1163, 1033 cmꢀ1. H NMR

3272
L.-X. Liu, P.-Q. Huang / Tetrahedron: Asymmetry 17 (2006) 3265–3272
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