Efficient and practical asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate, a useful intermediate for the synthesis of nociceptin antagonists

Article abstract of DOI:10.1016/j.tetasy.2009.07.046

An efficient and practical asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate 1, a useful intermediate for the synthesis of nociceptin antagonists, has been developed. This method i

Full text of DOI:10.1016/j.tetasy.2009.07.046

Tetrahedron: Asymmetry 20 (2009) 2439–2446
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient and practical asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-
4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate,
a useful intermediate for the synthesis of nociceptin antagonists
*
Hideki Jona , Jun Shibata, Masanori Asai, Yasuhiro Goto, Sachie Arai, Shigeru Nakajima, Osamu Okamoto,
Hiroshi Kawamoto, Yoshikazu Iwasawa
Banyu Tsukuba Research Institute, Okubo-3, Tsukuba, Ibaraki 300-2611, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and practical asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-
1H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate 1, a useful intermediate for the synthesis of nocicep-
tin antagonists, has been developed. This method includes the following key steps: (1) diastereoselective
reduction of a chiral enaminoester 3 having (R)-1-phenylethylamine as a chiral pool constituent with the
use of a combined TFA–NaBH4 reduction system and (2) efficient isomerization from 3,4-cis-substituted
piperidine 8 to 3,4-trans-substituted piperidine 1 under basic conditions. The above methods proved to
be applicable for large-scale operation and hundred grams of enantiomerically pure compound 1
(>98% ee) was obtained.
Received 2 June 2009
Accepted 1 July 2009
Available online 14 November 2009
Ó 2009 Published by Elsevier Ltd.
1. Introduction
thesis of the compounds and their chiral intermediate without
using a resolution, chiral HPLC system, or separation of diastereo-
The opioid receptor-like 1 (ORL-1), recently named NOP, was
identified in 1994 as a G-protein-coupled receptor that has a high
degree of amino acid sequence homology to classic opioid recep-
mers is yet to be reported. Therefore, development of a practical
asymmetric synthesis of 1-tert-butyl-3-methyl-(3R,4R)-4-(2-oxo-
2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate 1,26
the key intermediate for the synthesis of nociceptin antagonists
with distinct protection of three functional groups, was desired
in order to explore further structure–activity relationship (SAR)
studies on its analogues. Herein, we report an efficient and practi-
cal asymmetric synthetic method for the preparation of 1 starting
from commercially available 2.
tors (l, j
, and d).1–9 Since the discovery of nociceptin (orphanin
FQ) as an endogenous ligand of ORL-1, many research groups have
reported on the possible involvement of the nociceptin/ORL-1
system in pain regulation,10 cognition,11–13 anxiety,14 and in the
cardiovascular system.15,16 Interest in ORL-1 has resulted in an
increase of publications in scientific and patent literature on re-
lated antagonists.17,18 A decade ago, we identified a series of potent
and selective non-peptide ORL-1 antagonists exemplified by
J-113397 possessing two stereogenic centers on the piperidine ring
(Fig. 1).19,20 There are many publications on biological experiments
using J-113397, and some critical pharmacological results of noci-
ceptin antagonists were subsequently reported.21,22 The stereogen-
ic centers on the piperidine ring are very important for potency
and selectivity against other classical opioid receptors;19 however,
our initial synthesis of J-113397 was not effective for further
exploration because the separation of both diastereomers and
enantiomers was required.20 There are some reports on the im-
proved synthesis of J-113397 and its analogues involving base-pro-
moted cis–trans isomerization,21,23 enantiomeric resolution using
diastereomeric salt,22,24 and separation of diastereomers in the late
stages.25 Nevertheless, an efficient and practical asymmetric syn-
HO
O
N
N
N
J-113397
Figure 1.
2. Results and discussion
2.1. Retrosynthesis
We designed 1 as a key intermediate to synthesize J-113397
analogues, distinctly functionalized with a Boc group, methyles-
ter, and proton in order to modify R1, R2, and R3, respectively
* Corresponding author. Tel.: +81 297 46 2770.
E-mail address: hjjona0328@yahoo.co.jp (H. Jona).
0957-4166/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2009.07.046

2440
H. Jona et al. / Tetrahedron: Asymmetry 20 (2009) 2439–2446
COOMe
COOMe
i), ii), iii)
MeOOC
R1
O
H
N
O
BocN
BnN
·HCl
OH
92% 3 steps
Boc
N
N
N H
R3
N
N
N
R2
3
2
Scheme 2. Reagents and conditions: (i) H2 (1 atm), 10% Pd–C/MeOH, rt; (ii) Boc2O,
NaHCO3/dioxane–H2O, rt; iii) (R)-1-phenylethylamine, AcOH/THF–MeOH, 80 °C.
Key intermediate 1
(Chiral form)
J-113397 analogues
(3S,4S)-trans-5b (undesired form) were produced as given in Table
1, with the desired products 4a and 5a having the same (R) orien-
tation at the 4-position. We first tried diastereoselective reduction
using 4 equivalents of NaBH4 and 20 equiv of AcOH in MeCN at
0 °C, which gave a mixture of 4 and 5 in high yield (entry 1). As ex-
pected, we obtained 4a and 5a as major products with moderate
diastereoselectivity (desired 4a+5a:undesired 4b+5b = 3.4:1).
Next, we reduced the amounts of AcOH to verify its reactivity
and selectivity (entry 2). In this case, the diastereoselectivity was
improved to 4.7:1 while the starting material 3 remained. Thus,
the combination of 12 equiv of AcOH and 4 equiv of NaBH4 affor-
ded better stereoselectivity than the use of 20 equiv of AcOH. We
next examined various carboxylic acids such as formic acid, propi-
onic acid, butanoic acid, pivalic acid, and TFA (entries 3–7). Among
them, TFA gave the best result in high diastereoselectivity with a
9.8:1 ratio of desired products 4a and 5a to the undesired products
4b and 5b in high yield (entry 7). Even at ꢀ45 °C using 2 equiv of
NaBH4 and 6 equiv of TFA, the stereoselective reduction proceeded
smoothly to give 4a as a major product in high yield (entries 8 and
9). Unfortunately, when we examined the experiment on a 10 g
scale with reaction conditions similar to those of entry 9, a large
amount of the starting material remained. We considered that
MeCN would be partially reduced during the preparation of the
reducing agent, and the reducing agent would be consumed before
use in substrate reduction in this large scale due to the time re-
quired when compared to smaller scale experiments. Therefore,
we screened the above reaction with solvents other than MeCN. Fi-
nally, we found that the use of THF for reducing agent preparation
was efficient, while the addition of MeCN solution of the substrate
was also beneficial in this reduction to afford the desired products
with high diastereoselectivity and in high yield (entry 10 vs 9). It
should be noted that when we used only THF as a solvent in this
reaction, no reaction was observed. This result indicates that MeCN
plays an important role in this reduction system to enhance
MeOOC
MeOOC
P-N
MeOOC
P-N
NR4R5
NR4R5
NR4R5
P-N
asymmetric
reduction
A
C
B
isomerization
Scheme 1. Retrosynthesis of 1.
(Scheme 1). We thought that the construction of benzimidazolid-
inone unit from A could be easily accomplished by the previously
reported method.20 The 3,4-trans intermediate A could be pre-
pared by isomerization of 3,4-cis intermediate B under basic con-
ditions, as reported by Pollini et al.23 The stereogenic centers of
intermediate B would be constructed by stereoselective reduction
of enaminoester C.
2.2. Stereoselective reduction of 3
To begin, we planned to use chiral enaminoester 3 for the con-
struction of the stereogenic centers according to Palmieri’s meth-
od27,28 because of its simplicity and cost effectiveness using (R)-
1-phenylethylamine. Chiral enaminoester 3 was prepared from
commercially available hydroxyl ester 2 in high yield in three
steps: deprotection of the benzyl group, followed by Boc protection
of the nitrogen atom on the piperidine ring, and formation of an
enaminoester with (R)-1-phenyethylamine and AcOH (Scheme 2).
Next we tried diastereoselective reduction using the NaBH4 and
AcOH-combined system as reported by Palmieri et al.27,28 In this
reaction, 4 diastereomers (3S,4R)-cis-4a (desired form), (3R,4S)-
cis-4b (undesired form), (3R,4R)-trans-5a (desired form), and
Table 1
Stereoselective reduction of 3
COOMe
COOMe
COOMe
COOMe
COOMe
Conditions
H
N
H
N
H
N
H
N
H
N
BocN
Ph
BocN
Ph
BocN
Ph
BocN
Ph BocN
Ph
4a (cis, desired)
4b (cis, undesired)
3 (Yield%)
5a (trans, desired)
5b (trans, undesired)
3
Entrya
Reducing agent (molar equiv)b
Solvent
Temperature
4 and 5 (Yield%)
Desired:undesiredc (cis-4a:trans-5a)
1
2
3
4
5
6
7
8
9
NaBH4 (4) + AcOH (20)
NaBH4 (4) + AcOH (12)
NaBH4 (4) + HCOOH (12)
NaBH4 (4) + EtCOOH (12)
NaBH4 (4) + iPrCOOH (12)
NaBH4 (4) + tBuCOOH (12)
NaBH4 (4) + TFA (12)
NaBH4 (4) + TFA (12)
NaBH4 (2) + TFA (6)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
0 °C, ON
0 °C, ON
0 °C, ON
0 °C 1 h, rt ON
0 °C 1 h, rt ON
0 °C 1 h, rt ON
0 °C, 1 h
ꢀ45 °C, 1 h
ꢀ45 °C, 1 h
ꢀ45 °C, 1 h
92
64
70
50
20
57
94
96
92
95
0
3.4:1 (3.4:1)
4.7:1 (4.4:1)
4.9:1 (4.4:1)
2.6:1 (2.5:1)
2.0:1 (1.7:1)
2.7:1 (2.5:1)
9.8:1 (9.6:1)
19:1 (18:1)
19:1 (19:1)
28:1 (26:1)
25
16
30
41
35
0
0
0
0
MeCN
10
NaBH4 (2) + TFA (6)
THF–MeCNd
a
b
c
1 mmol of 3 was used.
The standard compound was the starting material 3.
The ratios were determined by chiral HPLC analysis after purification.
d
Reducing agent was prepared in THF (3 ml) for 1 h and MeCN (1 ml) solution of 3 was added thereto.

H. Jona et al. / Tetrahedron: Asymmetry 20 (2009) 2439–2446
2441
reactivity. Furthermore, it was revealed that the optimized reac-
2.3. Toward key intermediate 1
tion conditions (entry 10) could be applicable for the large-scale
preparation of 1 in Scheme 5. All peaks of the isomers were sepa-
rable by chiral HPLC (CHIRALPAK AD-H) and the ratio was deter-
mined after isolation. The cis- and trans-stereoconfigurations of
the products were determined by 1H NMR spectroscopy. Moreover,
the absolute stereochemistry of 4a and 5a was determined by con-
version into 1 independently, as described later in Scheme 3.
After major products 4a and 5a were separated by chiral col-
umn, the transformation of 4a and 5a to the key intermediate 1
was performed independently in order to confirm the absolute ste-
reochemistry and establish the synthetic route (Scheme 3). Depro-
tection of the (R)-1-phenyethyl group of 4a was examined in the
presence of 10% Pd–C in an H2 atmosphere, and was followed by
MeOOC
COOMe
MeOOC
BocN
MeOOC
BocN
O
O
H
BocN
NH NO2
N
NH
i), ii)
69%
iii), iv)
76%
v)
N
NH
BocN
N
Ph
4a
70%
6
8
1
MeOOC
COOMe
MeOOC
O
iii), iv)
70%
i), ii)
66%
H
N
BocN
NH NO2
BocN
Ph
BocN
N
NH
1
7
5a
Scheme 3. Reagents and conditions: (i) H2 (1 atm), 10% Pd–C/MeOH, rt; (ii) 2-fluoronitrobenzene, Na2CO3 /DMF, 100 °C; (iii) H2 (1 atm), 10% Pd–C/MeOH;
(iv) carbonyldiimidazole/CHCl3, rt; (v) Na2CO3 /MeOH reflux.
In this reaction, the major product 4a proved to have the same
cis-(R) orientation as the products reported by Palmieri et al.27,28
The reaction mechanism is not yet clear but the possible mechanis-
tic pathway for the high stereoselectivity could be explained in
accordance with Palmieri’s proposed mechanism in Figure 2
(replacement of AcOH with TFA). TFA is a bulky carboxylic acid
and stronger than the other acids given in Table 1; therefore, the
boron atom could tightly combine to the enol oxygen so that the
bulky boron complex could effectively release a hydride from the
less-hindered side of the phenylethylimine moiety. Protonation
of the enolate from the less-hindered face could afford the desired
cis = isomer predominantly. In addition, we speculated that the
essential reducing agent would be NaBH2(TFA)2 because gas evolu-
tion and exothermic reaction were observed when up to 2 equiv of
TFA was added to the NaBH4 suspension in THF but not with the last
1 equiv of TFA, which might be required for reduction, that is,
2 equiv of TFA might be consumed for the production of NaBH2(T-
FA)2 and the remaining 1 equiv of TFA could serve for the activation
of enaminoester 3 and as a proton source for the reaction.
a substitution reaction with 2-fluoronitrobenzene in the presence
of Na2CO3 to affordcis-6 in good yield. Then, reduction of the nitro
group and subsequent cyclization using carbonyldiimidazole (CDI)
were carried out to give cis-8. Finally, the isomerization reaction of
8 was attempted according to the modified conditions of Giardina’s
method21,23 by using Na2CO3 instead of NaOMe as a base to exclu-
sively furnish the key intermediate trans-1 in 70% yield. When we
used NaOMe as a base in this reaction, a significant hydrolysis reac-
tion was observed. Thus the obtained compound 1 was proved to
be enantiomerically pure and to have the desired (4R)-stereocon-
figuration. In the same manner, transformation of 5a to 1 was per-
formed. Deprotection of the (R)-phenylethyl group of 5a by
hydrogenolysis followed by substitution with 2-fluoronitroben-
zene afforded trans-7 in high yield. The transformation of 7 to 1
was carried out via reduction of the nitro group and cyclization
with CDI. Thus the obtained compound 1 from 5a was also proved
to be enantiomerically pure and to have the desired (4R)-stereo-
configuration as described later in Scheme 4.
It should be noted that cis-8 was the appropriate substrate for the
isomerization reaction rather than cis 6 (Fig. 3). When we used 8 as
the starting material for the reaction, perfect isomerization to 1 was
observed under basic conditions using Na2CO3 in MeOH. On the
other hand, isomerization using cis-6 did not work well and only
afforded 6–7 in a 2:3 ratio. The above phenomenon is well
explained considering the heat of formations of each compound
COOEt
COOEt
NaBH4 - TFA
H
N
H
N
BocN
BocN
(MOPAC, AM1). As shown in Figure 3, the
DE of 8 versus 1 was large
major
H+
compared to the E of 6 versus 7 so that the isomerization of cis-8
D
proceeded smoothly to afford the corresponding trans-1 exclusively.
The absolute stereoconfiguration of 1 was determined by
sequential conversion to J-113397 as follows (Scheme 4): alkyl-
ation of nitrogen with EtI and K2CO3 followed by deprotection of
the Boc group, reductive alkylation with cyclooctylcarboxalde-
hyde,24 and reduction of the methylester using LAH afforded
J-113397 in 69% overall yield which was specifically identified by
its retention time in chiral HPLC analysis and its specific rota-
tion.20,24 The absolute stereoconfiguration of 1 was proved to be
(3R,4R)-orientation on the piperidine ring which was the desired
stereochemistry.
EtO
EtO
OCOCF3
O
O
N
OCOCF3
B
H
H
B
H
OCOCF3
Me
OCOCF3
Me
BocN
N
BocN
H
H
H
Ph
Palmieri, et al.
Figure 2. Putative reaction mechanism.
Ph

2442
H. Jona et al. / Tetrahedron: Asymmetry 20 (2009) 2439–2446
HO
MeOOC
BocN
MeOOC
BocN
O
O
MeOOC
O
O
ii), iii)
80%
iv)
i)
N
NEt
N
NH
N
N
N
N
N
N
96%
90%
9
10
J-113397
1
Scheme 4. Reagents and conditions: (i) EtI, K2CO3 /DMF, rt; (ii) 4 N HCl in dioxane/MeOH, rt; (iii) cyclooctylcarboxaldehyde, NaHB(OAc)3 /DMF, rt; (iv) LAH/THF, ꢀ78 to 0 °C.
ee. This result indicated that the asymmetric reduction of 3 pro-
O
O
H
MeOOC
BocN
ΔE =
ceeded with high diastereoselectivity. Purification of the crude
product by crystallization afforded 614 g of pure 1 in 26% overall
yield with >98% ee. It is noteworthy that the above sequential pro-
cedures do not need any chromatography or resolution methods.
BocN
-4.116 kcal / mol
R
H
N
NH
N
NH
i)
exclusively trans
R = COOMe
trans-1
E = -153.876 kcal / mol
cis-8
3. Conclusion
E = -149.760 kcal / mol
In conclusion, we have developed an efficient and practical
asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-(2-oxo-
2,3-dihydro-1H-benzimidazol-1-yl)-1,3-piperidinedicarboxylate 1
with a distinct protecting group, a useful intermediate for the syn-
thesis of nociceptin antagonists. The essential stereocenters were
constructed by diastereoselective reduction of the chiral enamino-
ester 3 having (R)-1-phenylethylamine as a chiral constituent
with the use of a TFA–NaBH4 combined reduction system and
afforded cis-4a predominantly. The efficient isomerization of 3,4-
cis-substituted piperidine 8 to 3,4-trans-substituted piperidine 1
was also accomplished using Na2CO3 as a base. In addition, it
should be noted that the above methods were proved to be appli-
cable for large-scale operation and a hundred grams of enantio-
merically pure compound 1 (>98% ee) was obtained in 26%
overall yield without silicagel column chromatography and reso-
lution methods.
H
MeOOC
BocN
COOMe
BocN
H
ΔE =
NH NO2
NH NO2
-1.381 kcal / mol
i)
cis : trans = 2 : 3
cis-6
E = -146.549 kcal / mol
trans-7
E = -147.930 kcal / mol
Figure 3. Heat of formation (MOPAC: AM1). Reagents and conditions: (i) Na2CO3
(1.5 equiv)/MeOH, 70 °C, 20 h.
2.4. Large-scale preparation of 1
Now that we had established an efficient asymmetric synthetic
method for 1, the large-scale preparation of 1 was finally per-
formed subsequent to the optimization of each reaction step
(Scheme 5). Starting from 1.5 kg of commercially available 2, 3
was prepared by transformation of the protecting group from Bn
to Boc followed by enaminoester formation with (R)-1-phenyeth-
ylamine. Next, the stereoselective reduction of 3 was performed.
Combined reducing agent TFA (ꢁ6)–NaBH4 (ꢁ2) was prepared in
THF below 10 °C, MeCN solution of 3 was then added dropwise
at a range of ꢀ70 °C to ꢀ20 °C, and further stirred for 1 h to afford
the desired cis 4a as a major product, as determined by NMR spec-
troscopy. Deprotection of the phenylethyl group and the subse-
quent substitution reaction with 2-fluoronitrobenzene in basic
conditions were carried out to predominantly give cis-6. Reduction
of the nitro group of 6 followed by cyclization with CDI afforded 8
as a major product. In the last stage, the isomerization of 8 using
Na2CO3 was successfully carried out and gave crude 1 with 95%
4. Experimental
4.1. General experimental
In general, reagents and solvents were used as purchased with-
out further purification. The NMR spectra were obtained at
400 MHz on a MERCURY-400 (Varian) or on a JMN-AL400 (JEOL)
spectrometer, with chemical shift (d, ppm) expressed relative to
TMS as an internal standard. High resolution mass spectra were
recorded with electrospray ionization (ESI) on a micromass Q-
Tof-2 instrument. Flash chromatography was carried out with
prepacked silica gel columns (KP-Sil silica) from Biotage or
(Purif-Pack) from Moritex. Preparative thin layer chromatography
COOMe
OH
COOMe
COOMe
MeOOC
BocN
MeOOC
BocN
O
i), ii), iii)
iv)
v), vi)
vii), viii)
H
N
H
N
BnN
·HCl
BocN
Ph
BocN
Ph
NH NO2
N
NH
2
3
4a (major)
6 (major)
8 (major)
1.5 kg
ix), x)
MeOOC
O
N
BocN
NH
1
614g, 26% (over all)
> 98% ee
Scheme 5. Large scale preparation of 1. Reagents and conditions: (i) H2, 10% Pd–C/MeOH, rt; (ii) Boc2O, NaHCO3 /dioxane–H2O; (iii) (R)-1phenylethylamine, AcOH/THF–
MeOH, 80 °C; (iv) NaBH4, TFA/MeCN–THF, ꢀ70 °C to ꢀ20 °C; (v) H2, Pd– C, AcOH/MeOH, rt; (vi) 2-nitrofluorobenzene, Na2CO3/DMF, 100 °C; (vii) H2 (3 atm), 10% Pd–C/MeOH;
(viii) carbonyldiimidazole/THF, 0 °C; (ix) Na2CO3/MeOH–THF, 60 °C; (x) crystallization.

H. Jona et al. / Tetrahedron: Asymmetry 20 (2009) 2439–2446
2443
(TLC) was performed on TLC Silica Gel 60 F (Merck KGaA). Purifi-
cation by preparative HPLC was carried out on CHIRALPAK AD,
AD-H or CHIRALPAK IC, eluting with a gradient of hexane/EtOH
with 0.1% Et2NH or hexane/isopropanol with 0.1% Et2NH. HPLC
analysis was performed on CHIRALPAK AD, AD-H or CHIRALPAK
IC, eluting with a gradient of hexane/EtOH with 0.1% Et2NH or
hexane/isopropanol with 0.1% Et2NH. IR spectra were recorded
on SHIMADZU FTIR 8900. Optical rotations were measured with
a JASCO P-1020 polarimeter. Melting points were determined
with a Tanaco MP-J3 instrument. All calculations were carried
out on Silicon Graphics Octane R10000 workstations. Heat of for-
mation was calculated with the semi-empirical method using the
AM1 Hamiltonian in MOPAC 6 in Cerius2 (v. 3.8, Molecular Sim-
ulations Inc.).
(0.270 ml, 4.44 mmol) was added at 0 °C to quench the reaction.
The mixture was poured into EtOAc and H2O, and then extracted
with EtOAc. The combined organic layer was washed with brine
and dried over Na2SO4. The drying agent was filtered off, and the
solvent was removed under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/EtOAc = 3/
1) to give a mixture of 4a (predominantly), 4b, 5a, and 5b
(191 mg, 95.0%) as a colorless oil. The ratios of all isomers given
in Table 1 were determined by analytical chiral HPLC (CHIRALPAK
AD, 0.46 ꢁ 25 cm hexane/iPrOH = 40/1 + 0.1% Et2NH, flow rate =
1 ml/min): 4a = 12.1 min, 4b = 11.3 min, 5a = 13.6 min, 5b = 15.9
min. Separation of all isomers was performed by Preparative HPLC
(CHIRALPAK AD, 2 ꢁ 25 cm, hexane/iPrOH = 50/1 + 0.1% Et2NH,
flow rate = 15 ml/min).
4.2. Asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-
(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1,3-
dicarboxylate 1
4.2.2.1. 1-tert-Butyl 3-methyl (3S,4R)-4-{[(1R)-1-phenylethyl]-
amino}piperidine-1,3-dicarboxylate 4a (cis, desired).
½
a 2D4
ꢂ
¼ þ30
(c 1.0, CHCl3); IR (neat): 2972, 1732, 1693, 1427, 1148 cmꢀ1
;
1H
NMR (CDCl3) d: 7.30–7.26 (4H, m), 7.24–7.17 (1H, m), 3.96 (1H,
br s), 3.82 (1H, q, J = 6.5 Hz), 3.70–3.67 (1H, br m), 3.68 (3H, s),
3.11 (1H, dd, J = 3.9, 13.7 Hz), 2.94 (1H, ddd, J = 3.9, 9.4, 13.7 Hz),
2.82–2.70 (1H, br m), 2.80 (1H, ddd, J = 3.9, 4.3, 8.6 Hz), 1.77–
1.63 (2H, m), 1.46 (9H, s), 1.24 (3H, d, J = 6.5 Hz); 13C NMR (CDCl3)
d: 172.7, 154.5, 145.8, 128.5, 128.5, 127.0, 126.5, 126.5, 79.6, 54.9,
52.5, 51.6, 43.4, 42.2, 41.2, 29.2, 28.4, 28.4, 28.4, 24.9; HRMS: (ESI)
calcd for C20H31N2O4 [M+H]+: 363.2284, found, 363.2274.
4.2.1. 1-tert-Butyl 3-methyl 4-{[(1R)-1-phenylethyl]amino}-
5,6-dihydropyridine-1,3(2H)-dicarboxylate 3
To a suspension of methyl 1-benzyl-4-hydroxy-1,2,5,6-tetrahy-
dropyridine-3-carboxylate hydrochloride 2 (50.0 g, 176 mmol) in
methanol (200 mL) was added 10% Pd–C (5.00 g, 50% wet) and
the mixture was stirred under a hydrogen atmosphere (1 atm) at
room temperature for 16 h. After replacement of hydrogen with
nitrogen, the catalyst was filtered off with a Celite pad, and the sol-
vent was removed under reduced pressure to give methyl 4-hydro-
4.2.2.2. 1-tert-Butyl 3-methyl (3R,4S)-4-{[(1R)-1-phenylethyl]-
xy-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride as
a
amino}piperidine-1,3-dicarboxylate 4b (cis, undesired).
½
a 2D5
ꢂ
¼
crude oil. To a stirred solution of the crude product and NaHCO3
(32.5 g, 387 mmol) in dioxane (150 ml)—H2O (150 ml) was added
dropwise di-tert-butyl dicarbonate (BOC2O, 39.3 g, 180 mmol)
and the reaction mixture was stirred at room temperature for
5 h. The reaction mixture was poured into EtOAc and H2O, and ex-
tracted with EtOAc. The combined organic layer was washed with
brine and dried over MgSO4. The drying agent was filtered off, and
the solvent was removed under reduced pressure to give 1-tert-bu-
tyl 3-methyl 4-hydroxy-5,6-dihydropyridine-1,3(2H)-dicarboxyl-
ate as a crude oil. To a stirred solution of the crude product in
THF (100 mL)–MeOH (100 mL) were added AcOH (13.1 ml,
229 mmol) and (R)-methylbenzylamine (25.6 g, 211 mmol), and
the reaction mixture was stirred at reflux for 3 h. After removal
of the solvent, the mixture was diluted with EtOAc and aqueous
NaOH. The organic layer was washed with H2O and brine, and
dried over MgSO4. The drying agent was filtered off, and the sol-
vent was removed under reduced pressure. The residue was puri-
fied by silica gel column chromatography (hexane/EtOAc = 80/20)
to give 1-tert-butyl 3-methyl 4-{[(1R)-1-phenylethyl]amino}-5,6-
dihydropyridine-1,3(2H)-dicarboxylate 3 (58.0 g, 91.5%) as a pale
þ47 (c 1.0, CHCl3); IR (neat): 2972, 1730, 1693, 1421, 1146 cmꢀ1
;
1H NMR (CDCl3) d: 7.29–7.17 (5H, m), 3.84 (1H, q, J = 6.6 Hz),
3.78 (1H, dd, J = 7.4, 13.7 Hz), 3.63–3.53 (1H, m), 3.61 (3H, s),
3.35 (1H, dd, J = 3.5, 13.7 Hz), 3.16 (1H, ddd, J = 3.5, 7.4, 13.3 Hz),
2.74 (1H, ddd, J = 3.5, 3.5, 8.2 Hz), 2.60–2.51 (1H, br m), 1.90–
1.79 (1H, m), 1.75–1.52 (1H, br m), 1.39 (9H, s), 1.26 (3H, t,
J = 6.6 Hz); 13C NMR (CDCl3) d: 172.8, 154.6, 145.5, 128.4, 128.4,
126.9, 126.6, 126.6, 79.6, 54.4, 51.5, 50.9, 45.5, 43.0, 40.2, 28.3,
28.3, 28.3, 27.2, 25.2; HRMS: (ESI) calcd for C20H31N2O4 [M+H]+:
363.2284, found, 363.2274.
4.2.2.3. 1-tert-Butyl 3-methyl (3R,4R)-4-{[(1R)-1-phenylethyl]-
amino}piperidine-1,3-dicarboxylate 5a (trans, desired).
½
a 2D5
ꢂ
¼
þ14 (c 1.0, CHCl3); IR (neat): 2930, 1732, 1693, 1427, 1150 cmꢀ1
;
1H NMR (CDCl3) d: 7.30–7.23 (4H, m), 7.21–7.16 (1H, m), 4.07–
3.89 (2H, br m), 3.75 (1H, q, J = 6.6 Hz), 3.71 (3H, s), 2.96–2.75
(1H, br m), 2.84 (1H, ddd, J = 4.3, 10.6, 10.6 Hz), 2.63 (1H, ddd,
J = 2.3, 12.5, 12.5 Hz), 2.27 (1H, ddd, J = 3.5, 9.8, 9.8 Hz), 1.76–
1.65 (1H, br m), 1.39 (9H, s), 1.23 (3H, d, J = 6.6 Hz), 1.13–1.00
(1H, br m); 13C NMR (CDCl3) d: 173.6, 154.4, 146.5, 128.4, 128.4,
126.9, 126.4, 126.4, 79.9, 55.9, 55.4, 51.8, 49.8, 45.1, 42.8, 32.1,
28.3, 28.3, 28.3, 24.1; HRMS: (ESI) calcd for C20H31N2O4 [M+H]+:
363.2284, found, 363.2278.
yellow solid. Mp 88–90 °C; ½a D24
ꢂ
¼ ꢀ277 (c 1.0, CHCl3); IR (KBr):
2976, 1734, 1693, 1601, 1145 cmꢀ1
,
1H NMR (CDCl3) d: 9.25 (1H,
d, J = 6.8 Hz), 7.36–7.30 (2H, m), 7.28–7.21 (3H, m), 4.61 (1H, dq,
J = 6.8, 6.8 Hz), 4.16–3.98 (2H, br m), 3.72 (3H, s), 3.47–3.37 (1H,
m), 3.32–3.30 (1H, m), 2.47–2.32 (1H, br m), 2.12–1.98 (1H, br
m), 1.50 (3H, d, J = 6.8 Hz), 1.43 (9H, s); 13C NMR (CDCl3) d:
169.4, 157.5, 154.7, 145.1, 128.9, 128.9, 127.1, 125.4, 125.4, 88.1,
79.7, 52.3, 50.5, 41.4, 38.9, 28.4, 28.4, 28.4, 26.2, 25.2; HRMS:
(ESI) calcd for C20H29N2O4 [M+H]+: 361.2127, found, 361.2122.
4.2.2.4. 1-tert-Butyl 3-methyl (3S,4S)-4-{[(1R)-1-phenylethyl]-
amino}piperidine-1,3-dicarboxylate 5b (trans, undesired).
½
a 2D5
ꢂ
¼
þ32 (c 1.0, CHCl3); IR (neat): 2930, 1732, 1693, 1427, 1148 cmꢀ1
;
1H NMR (CDCl3) d: 7.31–7.25 (2H, m), 7.23–7.17 (3H, m), 4.32–
3.93 (2H, br m), 3.90 (1H, q, J = 6.6 Hz), 3.65 (3H, s), 2.80–2.63
(1H, br m), 2.59 (1H, ddd, J = 3.9, 10.6, 10.6 Hz), 2.57–2.45 (1H, br
m), 2.33–2.22 (1H, br m), 2.07–1.97 (1H, br m), 1.39 (9H, s), 1.25
(3H, d, J = 6.6 Hz), 1.15–1.03 (1H, m); 13C NMR (CDCl3) d: 173.0,
154.3, 145.0, 128.3, 128.3, 126.9, 126.5, 126.5, 79.9, 53.9, 53.6,
51.7, 49.5, 45.0, 42.4, 30.6, 28.3, 28.3, 28.3, 25.6; HRMS: (ESI) calcd
for C20H31N2O4 [M+H]+: 363.2284, found, 363.2275.
4.2.2. Stereoselective reduction of 3 (representative method:
Table 1, entry 10)
To a stirred suspension of NaBH4 (42.0 mg, 1.11 mmol) in THF
(3 ml) were added dropwise TFA (0.256 ml, 3.33 mol) at 0 °C and
3 (200 mg, 0.550 mmol) in MeCN (1 ml) at ꢀ45 °C and the mixture
was stirred for 1 h at the same temperature. After the reaction mix-
ture was stirred at 0 °C for a further 1 h, 25% aqueous NH3

2444
H. Jona et al. / Tetrahedron: Asymmetry 20 (2009) 2439–2446
4.2.3. 1-tert-Butyl 3-methyl (3S,4R)-4-[(2-nitrophenyl)amino]-
piperidine-1,3-dicarboxylate 6
atmosphere (1 atm) at room temperature for 2 h. After removal of
hydrogen, the catalyst was filtered off and the solvent was removed
under reduced pressure to give crude product containing 1-tert-
butyl 3-methyl (3S,4R)-4-[(2-aminophenyl)amino]piperidine-1,3-
dicarboxylate. To a stirred solution of the crude product in CHCl3
(3 ml) was added CDI (53.8 mg, 0.332 mmol) and the reaction mix-
ture was stirred at room temperature for 2 h. After removal of the
solvent, the residue was diluted with EtOAc and H2O, and extracted
with EtOAc. The combined organic layer was washed with brine and
dried over MgSO4. The drying agent was filtered off and the solvent
was removed under reduced pressure. The residue was purified by
thin layer chromatography (hexane/EtOAc = 3/7) to give 1-tert-bu-
tyl 3-methyl (3S,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-
yl)piperidine-1,3-dicarboxylate 8 (49.0 mg, 76.0%) as a colorless
To a solution of 4a (130 mg, 0.359 mmol) in MeOH (2 ml) was
added 10% Pd–C (11.5 mg, 50% wet) and stirred under a hydrogen
atmosphere (1 atm) at room temperature for 19 h. After replace-
ment of the hydrogen with nitrogen, the catalyst was filtered off
and the solvent was removed under reduced pressure to give a
crude oil containing 1-tert-butyl 3-methyl (3S,4R)-4-aminopiperi-
dine-1,3-dicarboxylate. To a solution of the crude product in
DMF (1 L) were added Na2CO3 (45.8 mg, 0.432 mol) and 2-nitroflu-
orophenol (55.9 mg, 0.396 mmol) at room temperature, and the
mixture was stirred at 100 °C for 20 h. The mixture was poured
into EtOAc and H2O, and the aqueous layer was extracted with
EtOAc. The combined organic layer was washed with H2O and
brine, and dried over Na2SO4. The drying agent was filtered off
and the solvent was removed under reduced pressure. The residue
was purified by thin layer chromatography (hexane/EtOAc = 7/3)
to give 1-tert-butyl 3-methyl (3S,4R)-4-[(2-nitrophenyl)amino]-
piperidine-1,3-dicarboxylate 6 (94.0 mg, 68.8%) as a yellow oil.
solid. ½a 2D5
ꢂ
¼ 31 (c 1.0, CHCl3); IR (KBr): 3200, 2978, 1738, 1697,
1481, 1433, 1366, 1165 cmꢀ1
;
1H NMR (CDCl3) d: 9.79 (1H, br s),
7.30–7.21 (1H, m), 7.07–6.96 (3H, m), 4.69–4.26 (2H, m), 3.39
(3H, s), 3.29–2.77 (4H, m), 1.84–1.72 (2H, br m), 1.44 (9H, s); 13C
NMR (CDCl3) d: 171.8, 155.5, 154.4, 129.5, 127.9, 121.4, 121.2,
110.9, 109.7, 79.9, 54.1, 51.7, 45.6, 43.4, 42.6, 28.4, 28.4, 28.4, 25.3;
HRMS: (ESI) calcd for C19H26N3O5 [M+H]+: 376.1872, found,
376.1881. Heat of formation: ꢀ149.760 kcal/mol.
½
a 2D5
ꢂ
¼ ꢀ60 (c 1.0, CHCl3); IR (neat): 2900, 1732, 1693, 1614,
1504, 1421, 1130 cmꢀ1 1H NMR (CDCl3) d: 8.62 (1H, br s), 8.19
;
(1H, dd, J = 1.5, 8.5 Hz), 7.44 (1H, ddd, J = 1.5, 7.1, 8.5 Hz), 6.90
(1H, d, J = 8.5 Hz), 6.67 (1H, ddd, J = 1.2, 7.1, 8.5 Hz), 4.16 (1H,
ddd, J = 4.1, 7.8, 12.0 Hz), 4.00 (1H, dd, J = 7.3, 14.4 Hz), 3.73–3.59
(1H, m), 3.68 (3H, s), 3.42 (1H, ddd, J = 4.4, 7.8, 12.0 Hz), 2.99–
2.87 (1H, br m), 2.12–1.98 (1H, br m), 1.92–1.58 (2H, br m), 1.47
(9H, s); 13C NMR (CDCl3) d: 171.2, 154.4, 144.0, 136.2, 132.6,
127.2, 115.8, 113.6, 80.2, 52.0, 49.3, 44.1, 42.9, 40.3, 28.4, 28.3,
28.3, 28.3; HRMS: (ESI) calcd for C18H26N3O6 [M+H]+: 380.1822,
found, 380.1833; Heat of formation: ꢀ146.549 kcal/mol.
4.2.6. 1-tert-Butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-
benzimidazol-1-yl) piperidine-1,3-dicarboxylate 1 from 7
To a solution of 7 (71.0 mg, 0.187 mmol) in MeOH (2 L) was
added 10% Pd–C (39.8 mg, 50% wet) and stirred under a hydrogen
atmosphere (1 atm) at room temperature for 2 h. After removal of
hydrogen, the catalyst was filtered off and the solvent was
removed under reduced pressure to give the crude product
containing 1-tert-butyl 3-methyl (3R,4R)-4-[(2-aminophenyl)amino]
piperidine-1,3-dicarboxylate. To a stirred solution of the crude
product in CHCl3 (3 ml) was added CDI (36.4 mg, 0.225 mmol)
and the reaction mixture was stirred at room temperature for
18 h. After removal of the solvent, the residue was diluted with
EtOAc, washed with aqueous 0.5 M HCl and brine, and dried over
Na2SO4. The drying agent was filtered off and the solvent was re-
moved under reduced pressure. The residue was purified by thin
layer chromatography (hexane/EtOAc = 2/1) to give 1-tert-butyl
4.2.4. 1-tert-Butyl 3-methyl (3R,4R)-4-[(2-nitrophenyl)amino]-
piperidine-1,3-dicarboxylate 7
To a solution of 5a (100 mg, 0.276 mmol) in MeOH (2 ml) was
added 10% Pd–C (11.5 mg, 50% wet) and stirred under a hydrogen
atmosphere (1 atm) at room temperature for 19 h. After replace-
ment of hydrogen with nitrogen, the catalyst was filtered off and
the solvent was removed under reduced pressure to give a crude
oil containing 1-tert-butyl 3-methyl (3R,4R)-4-aminopiperidine-
1,3-dicarboxylate. To a solution of the crude product in DMF (1 L)
were added Na2CO3 (35.9 mg, 0.339 mmol) and 2-nitrofluorophe-
nol (43.9 mg, 0.311 mmol) at room temperature, and the mixture
was stirred at 100 °C for 18 h. The mixture was poured into EtOAc
and H2O, and the aqueous layer was extracted with EtOAc. The
combined organic layer was washed with H2O and brine, and dried
over Na2SO4. The drying agent was filtered off and the solvent was
removed under reduced pressure. The residue was purified by thin
layer chromatography (hexane/EtOAc = 3/1) to give 1-tert-butyl 3-
methyl (3R,4R)-4-[(2-nitrophenyl)amino]piperidine-1,3-dicarbox-
3-methyl
(3R,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-
yl)piperidine-1,3-dicarboxylate 1 (49.0 mg, 69.7%) as a colorless so-
lid. Mp 210–211 °C; ½a D25
ꢂ
¼ þ50 (c 1.0, CHCl3); IR (KBr): 3246,
2928, 1734, 1713, 1665, 1491, 1433, 1367, 1186, 1163 cmꢀ1
;
1H
NMR (CDCl3) d: 9.79 (1H, br s), 7.30–7.21 (1H, m), 7.07–6.96 (3H,
m), 4.69–4.26 (2H, m), 3.39 (3H, s), 3.29–2.77 (4H, m), 1.84–1.72
(2H, br m), 1.44 (9H, s). 13C NMR (CDCl3) d: 171.7, 155.0, 154.4,
129.3, 127.9, 121.5, 121.3, 109.8, 108.5, 80.5, 52.8, 52.1, 45.7,
44.1, 43.2, 28.4, 28.4, 28.4, 27.9; HRMS (ESI): calcd for
C19H26N3O5 [M+H]+: 376.1872, found, 376.1884. Anal. Calcd for
C19H26N3O5: C, 60.79; H, 6.71; N, 11.19. Found: C, 60.55; H, 6.69;
N, 11.07. Heat of formation: ꢀ153.876 kcal/mol. The enantiomeric
excess was determined by chiral HPLC (CHIRALPAK IC, 0.46 ꢁ 25 cm
hexane/iPrOH = 95/5–50/50 gradient, containing 0.1% Et2NH, flow
rate = 1 ml/min): 1 = 11.0 min, enantiomer of 1 = 13.5 min.
ylate 7 (71.0 mg, 66.2%) as a yellow oil. ½a D25
¼ ꢀ140 (c 1.0, CHCl3);
ꢂ
IR (neat): 2900, 1732, 1695, 1614, 1504, 1416, 1136 cmꢀ1; 1H NMR
(CDCl3) d: 8.17 (1H, dd, J = 1.7, 8.5 Hz), 8.10 (1H, d, J = 8.5 Hz), 7.44
(1H, ddd, J = 1.7, 7.5, 8.5 Hz), 6.95 (1H, d, J = 8.5 Hz), 6.68 (1H, ddd,
J = 1.0, 7.5, 8.5 Hz), 4.42–3.94 (2H, br m), 4.01 (1H, dddd, J = 3.9,
8.5, 10.0, 10.0 Hz), 3.63 (3H, s), 3.35–2.97 (1H, m), 3.03 (1H, ddd,
J = 2.9, 11.2, 13.9 Hz), 2.64 (1H, ddd, J = 4.1, 10.0, 10.0 Hz), 2.22–
2.11 (1H, m), 1.48–1.48 (1H, m), 1.48 (9H, s); 13C NMR (CDCl3) d:
172.3, 154.2, 144.0, 136.3, 132.3, 127.1, 116.0, 114.0, 80.4, 52.2,
51.6, 47.8, 44.7, 41.8, 30.9, 28.3, 28.3, 28.3; HRMS: (ESI) calcd for
C18H26N3O6 [M+H]+: 380.1822, found, 380.1828. Heat of formation:
ꢀ147.930 kcal/mol.
4.2.7. 1-tert-Butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-
benzimidazol-1-yl) piperidine-1,3-dicarboxylate 1 from 8
To a solution of a crude 8 (27.8 mg, 0.0710 mmol) in MeOH
(1 ml) was added Na2CO3 (15.1 mg, 0.143 mmol) and the mixture
was stirred at 100 °C for 18 h. The reaction mixture was diluted
with EtOAc and H2O, and extracted with EtOAc. The combined or-
ganic layer was washed with aqueous 1 M HCl and brine, and dried
over MgSO4. The drying agent was filtered off and the solvent was
removed under reduced pressure. The residue was purified by thin
layer chromatography (hexane/EtOAc = 3/7) to give 1-tert-butyl 3-
methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) piper-
4.2.5. 1-tert-Butyl 3-methyl (3S,4R)-4-(2-oxo-2,3-dihydro-1H-
benzimidazol-1-yl) piperidine-1,3-dicarboxylate 8
To a solution of 6 (62.9 mg, 0.166 mmol) in MeOH (2 ml) was
added 10% Pd–C (31 mg, 50% wet) and stirred under a hydrogen

H. Jona et al. / Tetrahedron: Asymmetry 20 (2009) 2439–2446
2445
idine-1,3-dicarboxylate 1 (19.5 mg, 70.1%) as a colorless solid. All
data of 1 were in agreement as before.
Na2SO4 was added and further stirred for 16 h. The drying agent
was filtered off, and the solvent was removed under reduced pres-
sure. The residue was purified by thin layer chromatography
(CHCl3/MeOH = 9/1) to give 1-[(3R,4R)-1-(cyclooctylmethyl)-3-
(hydroxymethyl)piperidin-4-yl]-3-ethyl-1,3-dihydro-2H-benzimi-
dazol-2-one J-113397 (160 mg, 90.0%) as colorless crystals.
4.3. From 1 to J-113397
4.3.1. 1-tert-Butyl 3-methyl (3R,4R)-4-(3-ethyl-2-oxo-2,3-
dihydro-1H-benzimidazol-1-yl) piperidine-1,3-dicarboxylate 9
To a suspension of 1 (300 mg, 0.799 mmol) and K2CO3 (221 mg,
1.60 mmol) in DMF (3 ml) was added iodoethane (0.129 ml,
1.60 mmol) at room temperature, and the reaction mixture was stir-
red for 16 h at 65 °C. The reaction mixture was poured into EtOAc
and H2O. The aqueous layer was extracted with EtOAc, and the com-
bined organic layer was washed with H2O and brine, and dried over
MgSO4. The drying agent was filtered off and the solvent was
removed under reduced pressure. The residue was purified by
silicagel column chromatography (hexane/EtOAc = 1/1) to give 1-
tert-butyl 3-methyl (3R,4R)-4-(3-ethyl-2-oxo-2,3-dihydro-1H-ben-
zimidazol-1-yl)piperidine-1,3-dicarboxylate 9 (310 mg, 96.0%) as a
½
a 2D4
ꢂ
¼ þ7:8 (c 1.0, 2-propanol); IR (KBr): 3398, 2920, 1705, 1684,
1493, 1406, 1377, 1192 cmꢀ1 1H NMR (CDCl3) d: 7.33 (1H, d,
;
J = 7.2 Hz), 7.14–7.03 (3H, m), 4.46–4.33 (1H, br m), 3.98 (1H, dq,
J = 7.2, 14.6 Hz), 3.96 (1H, dq, J = 7.2, 14.6 Hz), 3.39–3.30 (2H, br
m), 3.08–2.74 (2H, br m), 2.69–2.53 (1H, m), 2.38–2.00 (6H, m),
1.92–1.84 (1H, m), 1.81–1.39 (13H, m), 1.34 (3H, t, J = 7.2 Hz),
1.30–1.18 (2H, m); 13C NMR (CDCl3) d: 154.6, 129.2, 128.0, 121.1,
121.1, 110.2, 107.9, 66.1, 61.9, 56.4, 53.6, 51.7, 41.0, 36.1, 34.9,
30.9, 30.9, 28.7, 27.2, 27.1, 26.5, 25.6, 25.6, 13.6; HRMS (ESI): calcd
for C24H38N3O2 [M+H]+: 400.2964, found, 400.2967. Confirmation
of each isomer was performed by HPLC: CHIRALPAK AD-H,
0.46 ꢁ 25 cm, hexane/iPrOH = 4/1 + 0.1% Et2NH, flow rate = 1 ml/
min J-113397, rt = 10.31 min; its enantiomer, rt = 7.47 min).
colorless solid. ½a D24
ꢂ
¼ 50 (c 1.0, CHCl3); IR (KBr): 2978, 1728,
1705, 1682, 1493, 1196, 1161, 1136 cmꢀ1
;
1H NMR (CDCl3) d:
7.10–7.05 (3H, m), 7.02–6.97 (1H, m), 4.67–4.17 (3H, br m), 3.92
(2H, q, J = 7.2 Hz), 3.56 (1H, ddd, J = 4.1, 11.2, 11.2 Hz), 3.42 (3H,
s), 3.09–2.74 (2H, br m), 2.57–2.44 (1H, m), 1.86–1.78 (1H, br m),
1.50 (9H, s), 1.32 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3) d: 171.8,
154.2, 153.2, 129.1, 128.6, 121.1, 121.0, 108.2, 107.6, 80.3, 53.1,
51.9, 45.6, 44.1, 42.8, 35.7, 28.4, 28.4, 28.4, 27.9, 13.5; HRMS (ESI):
calcd for C21H30N3O5 [M+H]+: 404.2185, found, 404.2188.
4.4. Large-scale preparation of 1
4.4.1. Preparation of 1-tert-butyl 3-methyl 4-{[(1R)-1-phenyl-
ethyl]amino}-5,6-dihydropyridine-1,3(2H)-dicarboxylate 3
To a suspension of methyl 1-benzyl-4-hydroxy-1,2,5,6-tetrahy-
dropyridine-3-carboxylate hydrochloride 2 (763 g, 2.69 mol) in
MeOH (2.5 L) was added 10% Pd–C on carbon (157 g, 50% wet) and
stirred under a hydrogen atmosphere (3 atm) at room temperature
for 4 h. After removal of hydrogen, the catalyst was filtered off with
Celite pad and solvent was removed under reduced pressure to give
520 g of crude oil including methyl 4-hydroxy-1,2,5,6-tetrahydro-
pyridine-3-carboxylate hydrochloride. In the same manner, 620 g
of crude product was obtained from 747 g of 2. To a stirred solution
of the crude product of methyl 4-hydroxy-1,2,5,6-tetrahydropyri-
dine-3-carboxylate hydrochloride (1.10 kg) in dioxane (3.3 L) H2O
(3.3 L) were added BOC2O (1.25 L, 5.43 mol) and NaHCO3 (983 g,
11.7 mol), and the reaction mixture was stirred at room temperature
for 4 h. The reaction mixture was poured into EtOAc (4 L) and H2O
(3 L), and extracted with EtOAc (4.5 L). The combined organic layer
was washed with brine and dried over Na2SO4. The drying agent
was filtered off, and the solvent was removed under reduced pres-
sure to give 1.48 kg of crude oil containing 1-tert-butyl 3-methyl
4-hydroxy-5,6-dihydropyridine-1,3(2H)-dicarboxylate. To the stir-
red solution of the crude product of 1-tert-butyl 3-methyl 4-hydro-
xy-5,6-dihydropyridine-1,3(2H)-dicarboxylate (1.48 kg) in THF
(3 L) and MeOH (5 L) were added (R)-1-phenylethylamine (823 ml,
6.38 mol) and AcOH (396 ml, 6.92 mmol), and the reaction mixture
was stirred at reflux for 4 h. After removal of the solvent, the mixture
was diluted with EtOAc, washed with H2O, 0.5 N aqueous NaOH, and
brine, and dried over Na2SO4. The drying agent was filtered off, and
the solvent was removed under reduced pressure to give 1.94 kg of
1-tert-butyl 3-methyl 4-{[(1R)-1-phenylethyl]amino}-5,6-dihydro-
pyridine-1,3(2H)-dicarboxylate 3 as a pale yellow oil.
4.3.2. Methyl (3R,4R)-1-(cyclooctylmethyl)-4-(3-ethyl-2-oxo-2,3-
dihydro-1H-benzimidazol-1-yl)piperidine-3-carboxylate 1024
To a solution of 9 (270 mg, 0.669 mmol) in MeOH (3 ml) was
added 4 M HCl in dioxane (3 ml) at room temperature, and the
reaction mixture was stirred for 16 h at the same temperature.
After completion of the reaction, the mixture was evaporated in va-
cuo to give a crude oil, which was used in the next step without
further purification. To a stirred solution of crude product and cyc-
looctylcarboxyaldehyde (188 mg, 1.34 mmol) in DMF (3 ml) was
added NaBH(OAc)3 (425 mg, 2.01 mmol) portionwise at room tem-
perature, and the reaction mixture was stirred for 3 h at the same
temperature. After completion of the reaction, MeOH was added
and the mixture was diluted with EtOAc, washed with saturated
NaHCO3, H2O, and brine, and dried over MgSO4. The drying agent
was filtered off and the solvent was removed under reduced pres-
sure. The residue was purified by silicagel column chromatography
(CHCl3/MeOH = 95/5), and then by thin layer chromatography
(hexane/EtOAc = 1/1) to give methyl (3R,4R)-1-(cyclooctylmethyl)-
4-(3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) piperidine-
3-carboxylate 10 (230 mg, 80.0%) as a colorless solid. ½a D24
¼ 24
ꢂ
(c 1.0, MeOH); IR (KBr): 2922, 1730, 1690, 1491, 1194, 1161 cmꢀ1
;
1H NMR (CDCl3) d: 7.20–7.15 (1H, m), 7.10–7.05 (2H, m), 7.01–6.95
(1H, m), 4.54–4.28 (1H, br m), 3.92 (2H, q, J = 7.2 Hz), 3.79–3.61
(1H, br m), 3.44 (3H, s), 3.21–3.15 (1H, m), 3.03–2.96 (1H, m),
2.64–2.49 (1H, m), 2.29–2.11 (4H, m), 1.81–1.39 (14H, m), 1.32
(3H, t, J = 7.2 Hz), 1.28–1.15 (2H, m); 13C NMR (CDCl3) d: 172.6,
153.3, 129.1, 120.83, 120.80, 108.7, 107.4, 107.4, 65.0, 55.9, 53.0,
53.0, 51.7, 44.2, 35.7, 35.1, 30.7, 30.6, 27.9, 27.2, 27.1, 26.4, 25.6,
25.6, 13.5; HRMS (ESI): calcd for C25H38N3O3 [M+H]+: 428.2913,
found, 428.2920.
4.4.2. Stereoselective reduction of 3-methyl 4-{[(1R)-1-phenyl-
ethyl]amino}-5,6-dihydropyridine-1,3(2H)-dicarboxylate 3
To a stirred suspension of NaBH4 (295 g, 7.79 mol) in THF (5.7 L)
was added dropwise TFA (1.77 L, 23.0 mol) while keeping below
10 °C for 1.5 h, and then crude 3 (1.42 kg) in MeCN (1.8 L) below
ꢀ20 °C for 1.5 h. After the reaction mixture was stirred further for
1 h, 25% aqueous NH3 (1.59 L, 23.4 mol) was added dropwise at
ꢀ20 °C to quench the reaction. The mixture was poured into EtOAc
(11 L) and H2O (11 L), and extracted with EtOAc (4.3 L). The com-
bined organic layer was washed with brine (11 L) and dried over
Na2SO4. The drying agent was filtered off, and the solvent was
removed under reduced pressure to give 1.66 kg of a green oil
4.3.3. 1-[(3R,4R)-1-(Cyclooctylmethyl)-3-(hydroxymethyl)piper-
idin-4-yl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one J-
11339720,24
To a stirred suspension of LAH (33.7 mg, 0.889 mmol) in THF
(6 ml) was added 10 (190 mg, 0.444 mmol) in THF (3 ml) at
ꢀ78 °C and the reaction mixture was gradually warmed to 0 °C.
After Na2SO4ꢃ10H2O was added to the mixture at 0 °C, anhydrous

2446
H. Jona et al. / Tetrahedron: Asymmetry 20 (2009) 2439–2446
containing 1-tert-butyl 3-methyl (3S,4R)-4-{[(1R)-1-phenylethyl]amino}
piperidine-1,3-dicarboxylate 4a as a major product. In the same
manner, 660 g of crude product 4a was obtained from 550 g of 3.
3-dicarboxylate 1 as a major product (94.8% ee). Next, MeOH (4 L)
was added to the crude product and stirred at 60 °C for 1 h. After
cooling, the precipitate was collected by filtration, washed with
MTBE (700 ml ꢁ three times), and dried in vacuo to give 509.3 g
of 1 in pure form (>99% ee, pale brown solid). In the same manner,
the second crop (46.0 g, >99% ee) and the third crop (60.1 g, 98.6%
ee) were obtained in high purity (total: 614 g, 25.9% yield over all
from 2, >98% ee). The analytical data of 1 are the same as those
before.
4.4.3. Deprotection of methylbenzyl group and the
introduction of the nitrophenol unit
To a solution of crude 4a (1.16 kg, 2.69 mol) in MeOH (3.6 L)
were added AcOH (238 ml, 4.16 mol) and 10% Pd–C on carbon
(293 g, 50% wet) and stirred under
a hydrogen atmosphere
(3 atm) at room temperature for 16 h. After removal of hydrogen,
the catalyst was filtered off with Celite pad and the solvent was re-
moved under reduced pressure. The mixture was diluted with H2O
(4.6 L), washed with methyl-tert-butylether (MTBE, 3.5 L), and the
organic layer was extracted with H2O. The combined aqueous layer
was neutralized with aqueous 1 M NaOH (4.3 L), extracted with
MTBE–THF (2:1), and further with EtOAc (several times). The com-
bined organic layer was washed with brine and dried over Na2SO4.
The drying agent was filtered off and the solvent was removed un-
der reduced pressure to give 580 g of crude oil containing 1-tert-
butyl 3-methyl (3S,4R)-4-aminopiperidine-1,3-dicarboxylate. In
the same manner, 520 g of crude oil was obtained from 1.12 kg
of crude 4a. To a solution containing crude product 1-tert-butyl
3-methyl (3S,4R)-4-aminopiperidine- 1,3-dicarboxylate (580 g) in
DMF (2.9 L) was added Na2CO3 (286 g, 2.69 mol) at room temper-
ature, and the mixture was stirred at 80 °C for 16 h. The reaction
mixture was poured into EtOAc (4.5 L) and H2O (5 L), and the aque-
ous layer was extracted with EtOAc (3 L). The combined organic
layer was washed with H2O and brine, and dried over Na2SO4.
The drying agent was filtered off and the solvent was removed
under reduced pressure to give 860 g of crude oil containing 1-
tert-butyl 3-methyl (3S,4R)-4-[(2-nitrophenyl)amino]piperidine-
1,3- dicarboxylate 6 as a major product. In the same manner,
780 g of crude oil was obtained from 500 g of crude 4a.
Acknowledgments
We thank Mr. Masayuki Ogawa, Mr. Hirokazu Ohsawa, and Dr.
Akio Morohashi for their analytical support. We also thank the
members of the process chemistry group and the members of the
medicinal chemistry group of the nociceptin antagonist program
for their technical support in the large-scale operation. We also
thank Mr. Yoshimi Tsuchiya for his useful discussion.
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benzimidazolidinone unit
To a solution of 6 (860 g) in MeOH (2 L) was added 10% Pd–C on
carbon (139 g, 50% wet) and stirred under a hydrogen atmosphere
(3 atm) at room temperature for 4 h. After removal of hydrogen,
the catalyst was filtered off and the solvent was removed under
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3-methyl (3S,4R)-4-[(2-aminophenyl)amino]piperidine-1,3-dicar-
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4.4.5. Synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-
dihydro-1H-benzimidazol-1-yl) piperidine-1,3-dicarboxylate 1
To a solution of crude 8 (1.68 kg) in THF (3.4 L)–MeOH (3.4 L)
was added Na2CO3 (265 g, 2.50 mol) and the mixture was stirred
at 70 °C for 16 h. After removal of the solvents, the residue was di-
luted with THF (3.5 L) and 2-butanone (7.5 L), washed with aque-
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was filtered off, and the solvent was removed under reduced pres-
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