A facile synthesis of enantiopure 7-benzyloxycarbonyl-7-azabicyclo [2.2.1]heptane-2-carboxylic acid

Article abstract of DOI:10.1016/j.tetasy.2013.11.010

An efficient procedure for the preparation of enantiopure 7-benzyloxycarbonyl-7-azabicyclo[2.2.1]heptane-2-carboxylic acids is described.

Full text of DOI:10.1016/j.tetasy.2013.11.010

Tetrahedron: Asymmetry xxx (2013) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A facile synthesis of enantiopure 7-benzyloxycarbonyl-7-azabicyclo
[2.2.1]heptane-2-carboxylic acid
⇑
Wen-Hua Chiou , Yu-Min Chiang, Guei-Tang Chen
Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient procedure for the preparation of enantiopure 7-benzyloxycarbonyl-7-azabicyclo[2.2.1]hep-
tane-2-carboxylic acids is described.
Received 6 October 2013
Accepted 14 November 2013
Available online xxxx
Ó 2013 Published by Elsevier Ltd.
1. Introduction
N-tosyl-7-azabicyclo [2.2.1]heptane carbaldehydes using an aza-
Prins–pinacol rearrangement strategy.7 However, these methodol-
As part of a program on the synthesis of natural products and
research into peptidomimetics, we required an N-protected enan-
tiopure 7-azabicyclo[2.2.1]heptanecarboxylic acid 1. The structure
of 7-azabicyclo[2.2.1]heptane has been found in epibatidine
(Fig. 1), a dendrobatid alkaloid isolated from the skin of the
ogies all suffered from a moderate yield or selectivity issues for the
title compound. Herein we report an efficient and scalable ap-
proach to obtain enantiomerically pure N-protected 7-azabicy-
clo[2.2.1]heptane-2-carboxylic acid 1.
2. Results and discussion
Our approach commenced with the preparation of racemic
7-azabicyclo[2.2.1]heptanecarboxylic acid, using conditions re-
ported by Fevig,8 with a modification based on Bai’s procedure.
Tropinone 2 was treated with ClCO2Ph to afford phenyl carbamate
Cl
R
H
N
N
CO2H
N
H
H
3
in 79% yield, followed by reaction with CuBr2 to the
7-azabicyclo[2.2.1]
heptanecarboxylic acid
R = Cbz, 1
epibatidine
corresponding -bromide 4. Treatment of 4 with benzyl alkoxide
a
in benzyl alcohol initiated a Favorskii rearrangement to give a
7-azabicyclo[2.2.1]heptane skeleton as well as transesterification
to a Cbz group, to afford benzyl ester 5. The resulting benzyl ester
5 was hydrolyzed with 30% NaOH in the presence of 2-propanol,
yielding acid 1 in 62% yield over three steps (Scheme 1).
Figure 1. 7-Azabicyclo[2.2.1]heptane-2-carboxylic acid and epibatidine.
Ecuadoran poison frog Epipedobates tricolor.1 Enantiopure 7-azabi-
cyclo[2.2.1]heptane carboxylic acid has been viewed as a rigidified
b-amino acid, used in the synthesis of b-peptides.2 In addition, the
application of 7-azabicyclo[2.2.1]heptane carboxylic acid in organ-
ocatalytic aldol reactions has been investigated3.
Various strategies have been developed for the preparation of
this unique molecule; Bai et al. reported on the synthesis of N-pro-
tected 7-azabicyclo[2.2.1]heptanecarboxylic acid using a Favorskii
ring contraction strategy.4 Trudell et al. utilized Diels–Alder reac-
tions of substituted pyrroles using a 3-bromopropynoate strategy
to construct the bicyclo framework.5 Pandey et al. presented a syn-
thesis of N-protected 7-azabicyclo[2.2.1]heptane derivatives via a
[3+2] cycloaddition of a nonstabilized cyclic azamethine ylide.6
Armstrong et al. developed the preparation of various substituted
ClCO2Ph
K2CO3
CO2Ph
N
N
CH3
toluene, 55 o
79%
C
CuBr2
EA, reflux
O
tropinone 2
O
3
CO2Ph
N
Cbz
Cbz
N
N
Br
BnONa
BnOH
NaOH
iPrOH
reflux
CO2Bn
CO2H
( )-1
rt
5
4
O
62% from 3
⇑
Corresponding author. Tel.: +886 4 22840411420; fax: +886 4 22862547.
E-mail address: wchiou@dragon.nchu.edu.tw (W.-H. Chiou).
Scheme 1. Preparation of racemic acid ( )-1.
0957-4166/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetasy.2013.11.010
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2
W.-H. Chiou et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
In order to separate the two enantiomers, we considered that
Fortunately, the separation of the two diastereomers was
the strategy of covalent modification with a chiral auxiliary fol-
lowed by removal of the auxiliary as a practical method.9 Thus,
racemic acid 1 was treated with SOCl2, followed by reaction with
various chiral auxiliaries. We found that the diastereomeric esters
achieved after condensation of racemic acid 1 with the Evans’ oxazo-
lidinone derivative,11 which was readily available from
L-valine
(Table 1, entry 1). Subsequent basic hydrolysis of the less polar oxa-
zolidinone derivative 7a with H2O2 in THF proceeded successfully to
yield enantiomerically pure (ꢀ)-acid 1, while the more polar one
gave enantiomerically pure (+)-acid 1. In order to determine the
absolute configuration, enantiomerically pure (ꢀ)-acid 1 was cou-
derived from either
effectively by flash chromatography. However, racemic acid 1 was
coupled with (S)- -methylbenzylamine, using SOCl2 activation to
L-menthol or L-borneol could not be separated
a
afford two diastereomeric products, the less polar 6a in 42% and
the more polar 6b in 44% isolated yield (Scheme 2). Recrystalliza-
tion of amide 6b from ethyl acetate and hexane provided crystals
suitable for an X-ray analysis, which confirmed the absolute con-
figuration as (1R,2S,4S)-7-azabicyclo[2.2.1]heptane carboxamide
pled with (S)-a-methylbenzylamine to yield the corresponding
amide with an [
a
]D value of ꢀ23.5 (c 1.0, CHCl3), essentially identical
to that of solid amide 6b {½a D25
¼ ꢀ22:9 (c 1.0, CHCl3)}. The (S)-meth-
ꢁ
ylbenzyl carboxamide derived from enantiomerically pure (+)-acid
1 showed an ½a 2D5
value of ꢀ4.0 (c 1.0, CHCl3). This value was closer
ꢁ
bearing an (S)-
a
-methylbenzylamine moiety (Fig. 2).10 The results
to that of oily amide 6a {½a D25
¼ ꢀ3:5 (c 1.0, CHCl3)}. These results
ꢁ
also suggested the absolute configuration of the other diastereo-
mer, the less polar amide 6a, to be a (1S,2R,4R)-7-azabicyclo frame-
work. In order to obtain enantiopure acid 1, hydrolysis of the
resulting amides 6a or 6b would provide both enantiopure acids.
A number of hydrolysis conditions of the carboxamides were
investigated, including hydrolysis using bases such as LiOH,
LiOH/H2O2, or acidic conditions using 6 M HCl. The formation of
the desired acid was not observed under any of above conditions,
even with refluxing or microwave-heating.
confirmed that the absolute configuration of (+)-acid 1 was
(1S,2R,4R), while (ꢀ)-acid 1 was (1R,2S,4S).
In order to find a better chiral auxiliary for the separation, we also
performed an investigation into other oxazolidinone derivatives
from natural amino acids; the results are summarized in Table 1.
The use of an oxazolidinone derived from alanine produced two sep-
arable compounds 8a in 42% and 8b in 33% yield but with a small Rf
difference of 0.04 (entry 2). Coupling with a leucine-derived oxazo-
lidinone also allowed for a practical separation to obtain two separa-
ble compounds 9a in 43% and 9b in 39% yield (entry 3), which was
easier than that using alanine. Using the oxazolidinone derived from
isoleucine 10 (entry 4) gave similar separation results to those of
leucine-derived oxazolidinone 9 (Rf = 0.07, entry 4).
The results showed that the 4-alkyloxazolidinone could serve as
an effective chiral auxiliary for the separation of enantiomeric acid
1. Among the 4 pairs of diastereomers, subsequent basic hydrolysis
of all of the less polar products 7a–10a produced enantiomerically
pure (ꢀ)-acid 1 in 84–98% yield, while the polar products 7b–10b
gave (+)-acid 1 in 89–94%.
N
Cbz
1. SOCl2, DMF, CH2Cl2
2. (S)-(_)-α-methylbenzylamine
Et3N, CH2Cl2, rt
CO2H
( )-1
Cbz
Cbz
N
O
Me
N
(4R)
O
Me
(1R)
N
H
(S) Ph
(2S)
N
H
Ph
+
(S)
(1S)
(2R)
(4S)
3. Conclusion
6a : 42% [α]D25 = - 3.5
6b: 44% [α]D25 = - 22.9
In conclusion, we have developed an effective preparation for
both enantiopure 7-benzyloxycarbonyl-7-azabicyclo[2.2.1]heptan-
Scheme 2. Separation of carboxamide 6a and 6b.
Figure 2. X-ray crystallography of carboxamide 6b.
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W.-H. Chiou et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
Table 1
Separation of racemic acid 1 using oxazolidinone derivatives
O
O
Cbz
N
Cbz
Cbz
N
H2O2, LiOH
CO2H
N
O
Cbz
N
THF/H2O, rt
84~98%
1. SOCl2, DMF, CH2Cl2
(-)-1, [α]D25 = - 8.6
7a - 10a
R
O
CO2H 2.
Li N
THF, CH2Cl2,
-40 ~ -50 o
N
C
O
( )-1
O
Cbz
N
O
H2O2, LiOH
THF/H2O, rt
N
O
CO2H
(+)-1, [α]D25 = + 8.8
R
R
7b - 10b
89~94%
Entry
Compd
R
7a–10a
7b–10b
Yielda
%
Rfb
Yielda
%
Rfb
1
2
3
4
7
8
9
CH(CH3)2
CH3
CH2CH(CH3)2
41
42
43
45
0.38
0.23
0.47
0.42
41
33
39
42
0.30
0.19
0.40
0.35
10
(S)-CH(CH3)CH2CH3
a
Isolated yield.
Eluant of EtOAc/n-hexane = 1/2.
b
ecarboxylic acids. The applications of these acids in the synthesis of
natural products are currently underway.
12 h. Upon completion of the reaction as monitored by TLC analy-
sis, the reaction mixture was concentrated under reduced pressure
to afford a residue. The crude residue was portioned with CH2Cl2
(150 mL) and water (150 mL). After separation of the organic layer,
the resulting aqueous layer was extracted with CH2Cl2 (80 mL, five
times). The combined organic layers were dried over anhydrous
Na2SO4. After removal of the solid dehydrating agent, the organic
layer was concentrated under reduced pressure to give a gray
white crude solid product. Recrystallization of the crude product
using EtOAc/n-heptane afforded a white solid as the title product
(31.7 g, 129 mmol, 79%): mp 120–121 °C, [lit.: 122–123 °C];13
Rf = 0.63, EtOAc/n-hexane = 1:2; 1H NMR (400 MHz, 25 °C, CDCl3,
d): 1.70–1.79 (m, 2H, H-6 and H-7), 2.17–2.19 (m, 2H, H-6 and
H-7), 2.35–2.46 (m, 2H, H-2 and H-4), 2.79 (br s, 2H, H-2 and
H-4), 4.63–4.74 (m, 2H, H-1 and H-5), 7.14 (d, J = 8.4 Hz, 2H, H-2
in Ph), 7.20 (t, J = 7.6 Hz, 1H, H-4 in Ph), 7.36 (t, J = 7.6 Hz, 1H,
H-3 in Ph); 13C NMR (100 MHz, 25 °C, CDCl3, d): 28.9⁄ (t, C-6 and
C-7), 48.8⁄ (t, C-2 and C-4), 53.4⁄ (d, C-1 and C-5), 121.4 (d, C-2
in Ph), 125.4 (d, C-4 in Ph), 129.2 (d, C-3 in Ph), 150.8 (s, C-1 in
Ph), 151.6 (s, –N–CO–O), 207.4 (s, C-3); EI-HRMS (m/z): [M]+ calcd
4. Experimental
4.1. Preparation of racemic acid ( )-1
4.1.1. Tropinone 2
A
mixture of a solution of 2,5-dimethoxytetrahydrofuran
(30.0 mL, 231 mmol, 1.0 equiv), concentrated HCl (12 M, 3.0 mL),
and water (70 mL) was stirred at 70 °C for 30 min. Another acetate
buffer solution was prepared as followed: to a 1-L flask charged
with NaOH (36.2 g, 905 mmol, 3.9 equiv) in an ice bath, was added
water (170 mL), followed by AcOH (51.8 mL, 906 mmol, 3.9 equiv),
acetonedicarboxylic acid (37.3 g, 255 mmol, 1.1 equiv), methyl-
amine hydrochloride salt (17.2 g, 255 mmol, 1.1 equiv). To the buf-
fer solution in an ice bath, was added slowly the acidic solution.
The pH value of the combined solution was kept at 5.1. After stir-
ring at 40 °C for 1 h, the cooled reaction mixture was added to an
NaOH solution (50%, 18.0 mL) and NaCl (60.0 g) in an ice bath.
The mixture was stirred at room temperature for 1 h, and then ex-
tracted with CH2Cl2 (150 mL). The aqueous layer was then ex-
tracted with CH2Cl2 (100 mL, five times). The combined organic
layer was dried over anhydrous Na2SO4, and then concentrated un-
der reduced pressure to give a crude brown product. The crude oil
was purified by vaccum distillation, to afford a colorless oil (bp 60–
65 °C, 0.8 mm Hg). While standing at room temperature under nor-
mal pressure, the colorless liquid became a white solid (22.7 g,
163 mmol, 70%): mp 41–42 °C, [lit.: 40–42 °C];12 Rf = 0.19, EtOAc/
n-hexane = 1:2; 1H NMR (400 MHz, 25 °C, CDCl3, d): 1.27–1.33
(m, 2H, H-6 and H-7), 1.80–1.83 (m, 2H, H-6 and H-7), 1.88 (d,
J = 16.0 Hz, 2H, H-2 and H-4), 2.20 (s, 3H, –NCH3), 2.39 (dd,
J = 4.8 and 16.0 Hz, 2H, H-2 and H-4), 3.15 (br s, 2H, H-1 and
H-5); 13C NMR (100 MHz, 25 °C, CDCl3, d): 27.1 (t, 2C, C-6 and
C-7), 37.7 (q, –NCH3), 46.9 (t, 2C, C-2 and C-4), 60.1 (d, 2C, C-1
and C-5), 208.7 (s, C-3); EI-HRMS (m/z): [M]+ calcd for C8H13NO+,
for C14H15NOþ, 245.1052; found, 245.1044 (
D
= 3.3 ppm). ⁄Means
3
the average values of two peaks have been reported since a strong
rotamer effect was observed.
4.1.3. 7-Benzyloxycarbonyl-7-azabicyclo[2.2.1]heptane-2-carbox-
ylic acid ( )-1
A mixure of tropinone derivative 3 (7.36 g, 30 mmol, 1.0 equiv),
CuBr2 (13.4 g, 60 mmol, 2.0 equiv), and EtOAc (150 mL) was re-
fluxed for 2 h. The suspension was then filtered off, and the result-
ing filtrate was washed with water (113 mL), NaHCO3 (5%,
113 mL), and then dried over anhydrous Na2SO4. After filtration
to remove the solid dehydrating agent, the organic layer was con-
centrated under reduced pressure to give a crude bromide product
as a dark brown oil (ꢂ12.8 g). The crude bromide product 4 was
then diluted with toluene (15 mL).
To the benzyl alcohol (52 mL) in an ice bath under argon, was
added Na metal (1.79 g, 78 mmol, 2.6 equiv) in small portions.
When all of the metal had disappeared, the crude product in the
toluene solution was slowly cannulated to the benzyl alkoxide
solution. The resulting mixture was then stirred at room tempera-
ture for 1 h. Upon completion of the reaction as monitored by TLC
analysis, the reaction mixture was diluted with toluene (46 mL)
and heptane (46 mL), and then washed with HCl (10%, 150 mL),
139.0997; found, 139.0990 (
D = 5.0 ppm).
4.1.2. 8-Phenoxycarbonyl-8-azabicyclo[3.2.1]octan-3-one 3
To a toluene solution (226 mL) of tropanone (22.7 g, 163 mmol,
1.0 equiv) and K2CO3 (2.25 g, 16.3 mmol, 10 mol %) in an ice bath,
was slowly added phenyl chloroformate (27 mL, 215 mmol,
1.3 equiv). The reaction mixture was then stirred at 55 °C for
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W.-H. Chiou et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
KOH solution (5%, 46 mL, twice), brine (20 mL), and dried over
anhydrous Na2SO4. After filtration to remove the solid dehydrating
agent, the organic layer was concentrated under reduced pressure
to remove volatile substances to yield crude ester 5 product as a
dark brown oil.
(m, 1H, H-4), 4.41 (br s, 1H, H-1), 5.00 (quintet, J = 7.2 Hz, 1H,
–CHCH3), 5.05 (d, J = 12.4 Hz, 1H, –OCH2Ph), 5.12 (d, J = 12.4 Hz,
1H, –OCH2Ph), 6.63 (br s, 1H, –NH), 7.16–7.25 (m, 5H, –Ph),
7.27–7.34 (m, 5H, –OBn); 13C NMR (100 MHz, 25 °C, CDCl3, d):
21.8 (q, –CHCH3), 28.4 (t, C-5), 29.2 (t, C-6), 35.6 (t, C-3), 48.3 (d,
–CHCH3), 48.9 (d, C-2), 55.7 (d, C-4), 59.3 (d, C-1), 67.0 (t, –OCH2-
Ph), 125.8 (d, C-2 in Ph), 126.9 (d, C-4 in Ph), 127.7(d, C-2
in –OBn), 128.0 (d, C-4 in –OBn), 128.3 (d, C-3 in –OBn), 128.4
(d, C-3 in Ph), 136.2 (s, C-1 in –OBn), 143.3 (s, C-1 in Ph), 155.4
(s, –N–CO–O), 172.6 (s, –CONH); EI-HRMS (m/z): [M]+ calcd for
A mixture of the crude ester product in NaOH (30%, 3.2 mL) and
2-propanol (80 mL) was allowed to be refluxed for 1 h. The reac-
tion mixture was then concentrated under reduced pressure to
yield a crude residue. The crude residue was partitioned with
EtOAc (80 mL) and water (80 mL). The resulting EtOAc solution
was extracted with water (25 mL, three times). After the addition
of EtOAc (30 mL) to the combined aqueous layers, the bilayer solu-
tion was acidified with an HCl solution (3 M) in an ice bath until
the pH was approximately 2. A white precipitate was observed
during the acidification. After separation of the organic layer, the
resulting aqueous layer was extracted with EtOAc (30 mL, five
times). The combined organic layers were washed with brine
(10 mL), dried over Na2SO4, and then concentrated to give a crude
acid. Purification of the crude acid product by flash chromatogra-
phy on silica gel, using EtOAc/n-hexane as the eluent gave the title
product as a white solid (5.12 g, 18.6 mmol, 62% over three steps):
mp 110–111 °C, Rf = 0.24, EtOAc/n-hexane = 4:1; 1H NMR
(400 MHz, 25 °C, CDCl3, d): 1.37–1.50 (m, 2H, H-5 and H-6), 1.64
(dd, J = 9.2 and 12.4 Hz, 1H, H-3 exo), 1.77–1.84 (m, 2H, H-5 and
H-6), 2.20-2.23 (m, 1H, H-3 endo), 2.57 (dd, J = 4.8 and 8.8 Hz,
1H, H-2), 4.39 (br s, 1H, H-4), 4.64 (br s, 1H, H-1), 5.02 (br s, 1H,
–OCH2Ph), 5.09 (d, J = 12.4 Hz, 1H, –OCH2Ph), 7.24–7.33 (m, 5H,
–OCH2Ph), 10.92 (br s, 1H, –COOH); 13C NMR (100 MHz, 25 °C,
CDCl3, d): 28.6 (t, C-5), 29.2 (t, C-6), 33.3 (t, C-3), 47.1 (d, C-2),
55.8 (d, C-4), 59.1 (d, C-1), 66.8 (t, –OCH2Ph), 127.6 (d, C-2 in
Ph), 127.8 (d, C-4 in Ph), 128.3 (d, C-3 in Ph), 136.3 (s, C-1 in Ph),
155.0 (s, –N–CO–O), 178.5 (d, –COOH); EI-HRMS (m/z): [M]+ calcd
C
23H26N2Oþ, 378.1943; found, 378.1949 (
D
= 1.6 ppm).
3
4.2.2. N-[(1S)-Phenylethyl]-(1R,2S,4S)-7-benzyloxycarbonyl-7-
azabicyclo[2.2.1]heptane-2-carboxamide (6b)
Light yellow solid (1.330 g, 3.514 mmol, 44%); mp 100–102 °C;
Rf = 0.29, EtOAc/n-hexane = 1:1; ½a D25
ꢁ
¼ ꢀ23:5 (c 1.0, CHCl3); 1H
NMR (400 MHz, 25 °C, CDCl3, d): 1.32–1.42 (m, 2H, H-5 and H-6),
1.37 (d, J = 7.2 Hz, 3H, –CHCH3), 1.65–1.75 (m, 3H, H-3, H-5 and
H-6), 1.92–2.02 (m, 1H, H-3), 2.42 (dd, J = 4.8 and 9.2 Hz, 1H, H-
2), 4.28–4.34 (m, 1H, H-4), 4.42 (br s, 1H, H-1), 4.94–5.06 (m, 3H,
–CHCH3 and –OCH2Ph), 6.75 (br s, 1H, –NH), 7.14–7.32 (m, 10H,
–Ph ꢃ 2); 13C NMR (100 MHz, 25 °C, CDCl3, d): 21.6 (q, –CHCH3),
28.3 (t, C-5), 29.1 (t, C-6), 35.0 (t, C-3), 48.1 (d, –CHCH3), 48.5 (d,
C-2), 55.5 (d, C-4), 59.2 (d, C-1), 66.6 (t, –OCH2Ph), 125.7 (d, C-2
in Ph), 126.7 (d, C-4 in Ph), 127.6 (d, C-2 in –OBn), 127.7 (d, C-4
in –OBn), 128.1 (d, C-3 in –OBn), 128.2 (d, C-3 in Ph), 136.1
(s, C-1 in –OBn), 143.2 (s, C-1 in Ph), 155.1 (s, –N–CO–O), 172.4
(s, –CONH); EI-HRMS (m/z): [M]+ calcd for C23H26N2Oþ, 378.1943;
3
found, 378.1947 (D = 1.1 ppm).
4.3. General procedure for the preparation and separation of
oxazolidinone derivatives
for C15H17NOþ, 275.1158; found, 275.1154 (
D = 1.5 ppm).
4
Racemic acid 1 (1.0 equiv) was dissolved in CH2Cl2 (ꢂ5 M). To
the solution in an ice bath, was added SOCl2 (3.0 equiv) followed
by a drop of DMF under argon. Upon completion of the addition,
the ice bath was removed and the reaction mixture was stirred
at room temperature for 16 h. The reaction mixture was concen-
trated under reduced pressure to remove the volatile substances,
to yield a crude residue. The crude residue was diluted with CH2Cl2
to give a crude acid chloride solution. To a THF solution of the oxa-
zolidinone derivative11 (1.2 equiv, ꢂ0.3 M) at ꢀ50 °C under argon,
BuLi (1.3 equiv, 1.6 M in hexane) was added slowly by an addi-
tional funnel. The reaction mixture was stirred at ꢀ50 °C for 1 h.
The acid chloride solution was then slowly cannulated to the oxa-
zolidinone solution. The addition rate of the acid chloride solution
was controlled so that the internal temperature was between ꢀ40
and ꢀ50 °C. The resulting reaction mixture was stirred at the same
temperature for 6 h. Upon completion of the reaction, as monitored
by TLC analysis, chilled saturated NH4Cl solution (about one-thirds
volume of the resulting reaction mixture) was added to quench the
reaction, and the solution mixture was concentrated under re-
duced pressure to remove the excess organic solvent. The residue
was then partitioned with CH2Cl2 (approximately an equal volume
to the reaction mixture) and water. The resulting aqueous layer
was extracted with an equal amount of CH2Cl2 (five times). The
combined organic layers were dried over anhydrous Na2SO4, and
then concentrated to give a crude product. Purification of the crude
product by flash chromatography14 on silica gel, using EtOAc/n-
hexane as the eluent afforded the title product.
4.2. General method for the preparation of (S)-methylbenzylcar-
bamide derivatives
Racemic acid 1 (2.20 g, 7.99 mmol, 1.0 equiv) was dissolved in
CH2Cl2 (1.7 mL, ꢂ5 M). To the solution in an ice bath, was added
SOCl2 (1.7 mL, 23.4 mmol, 3.0 equiv) followed by a drop of DMF
under argon. Upon completion of the addition, the ice bath was re-
moved and the reaction mixture was stirred at room temperature
for 16 h. The reaction mixture was concentrated under reduced
pressure to remove the volatile substances, to yield a crude resi-
due. The crude residue was diluted with one part of CH2Cl2
(1.7 mL) to give the crude acid chloride solution. To a solution of
(S)-a-methylbenzylamine (1.1 mL, 8.6 mmol, 1.1 equiv) and Et3N
(1.2 mL, 8.6 mmol, 1.1 equiv) in CH2Cl2 (4.2 mL) in an ice bath,
was slowly cannulated the crude acid chloride solution. The result-
ing reaction mixture was stirred at room temperature for 12 h.
Upon completion of the reaction as monitored by TLC analysis,
chilled saturated NH4Cl solution (20 mL) was added to quench
the reaction. After separation of the organic layer, the aqueous
layer was extracted with CH2Cl2 (8 mL, four times). The combined
organic layers were dried over anhydrous Na2SO4, and then con-
centrated to give a crude product. Purification of the crude product
by flash chromatography on silica gel, using EtOAc/n-hexane as the
eluent afforded two products.
4.2.1. N-[(1S)-Phenylethyl]-(1S,2R,4R)-7-benzyloxycarbonyl-7-
azabicyclo[2.2.1]heptane-2-carboxamide 6a
Light yellow oil (1.280 g, 3.382 mmol, 42%); Rf = 0.37, EtOAc/n-
4.3.1. 3-[(1R,2S,4S)-7-Benzyloxycarbonyl-7-azabicyclo[2.2.1]-
heptane-2-carbonyl]-(4S)-[1-methylethyl]-2-oxazolidinone 7a
41%; white solid, mp 110–112 °C; Rf = 0.38, EtOAc/n-hex-
hexane = 1/1; ½a 2D5
ꢁ
¼ ꢀ4:0 (c 1.0, CHCl3); 1H NMR (400 MHz,
25 °C, CDCl3, d): 1.33 (d, J = 7.2 Hz, 3H, –CHCH3), 1.36–1.42 (m,
2H, H-5 and H-6), 1.68–1.82 (m, 3H, H-3, H-5 and H-6), 1.96–
2.02 (m, 1H, H-3), 2.42 (dd, J = 4.8 and 8.8 Hz, 1H, H-2), 4.34-4.39
ane = 1:2; ½a 2D5
ꢁ
¼ þ20:0 (c 1.0, CHCl3); 1H NMR (400 MHz, 25 °C,
CDCl3, d): 0.80 (br s, 6H), 1.40–1.50 (m, 1H), 1.56–1.70 (m, 2H),
Please cite this article in press as: Chiou, W.-H.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.11.010

W.-H. Chiou et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
5
1.75–1.88 (m, 2H), 2.16–2.35 (m, 1H), 2.36–2.48 (m, 1H), 3.64 (t,
J = 6.0 Hz, 1H), 3.70–3.90 (m, 1H), 3.95–4.20 (m, 1H), 4.40 (br s,
3H), 5.00 (br s, 2H), 7.24–7.32 (m, 5H); 13C NMR (100 MHz,
25 °C, CDCl3, d): 14.3 (q), 17.9 (q), 27.9 (d), 28.9⁄ (t), 29.5⁄ (t),
32.3⁄ (t), 47.7⁄ (d), 56.2 (d), 58.6 (d), 60.0 (d), 63.2 (t), 66.7 (t),
127.9 (d, 3C), 128.4 (d, 2C), 136.6 (s), 154.1 (s), 155.0 (s), 172.2
0.76–1.00 (m, 6H), 1.38–1.62 (m,4H), 1.64–1.88 (m, 4H), 2.42 (br
s, 1H), 3.55 (dd, J = 5.2 and 8.0 Hz, 1H), 4.08 (d, J = 6.8 Hz, 1H),
4.32–4.45 (m, 3H), 4.49 (br s, 1H), 4.80–5.28 (m, 2H), 7.27–7.32
(m, 5H); 13C NMR (100 MHz, 25 °C, CDCl3, d): 21.3 (q), 23.2 (q),
24.6 (d), 28.7⁄ (t), 29.3⁄ (t), 31.8 (t), 40.9 (t), 47.4 (d), 53.1 (d),
55.9 (d), 60.0 (d), 66.4 (t), 67.7 (t), 127.7 (d, 3C), 128.2 (d, 2C),
136.6 (s), 153.6 (s), 154.7 (s), 171.9 (s); EI-HRMS (m/z): [M]+ calcd
(s); EI-HRMS (m/z): [M]+ calcd for C21H26N2Oþ, 386.1842; found,
5
386.1847 (
D
= 1.3 ppm).
for C22H28N2Oþ, 400.1998; found, 400.1989 (
D
= 2.2 ppm).
5
4.3.2. 3-[(1S,2R,4R)-7-Benzyloxycarbonyl-7-azabicyclo[2.2.1]-
heptane-2-carbonyl]-(4S)-[1-methylethyl]-2-oxazolidinone 7b
4.3.7. 3-[(1R,2S,4S)-7-Benzyloxycarbonyl-7-azabicyclo[2.2.1]-
heptane-2-carbonyl]-(4S)-[(1S)-methyl propyl]-2-oxazolidinone 10a
41%;
colorless
oil,
Rf = 0.30;
EtOAc/n-hexane = 1/2;
45%;
colorless
oil;
Rf = 0.42,
EtOAc/n-hexane = 1/2;
½
a 2D5
ꢁ
¼ þ77:7 (c 1.0, CHCl3); 1H NMR (400 MHz, 25 °C, CDCl3, d):
½
a 2D5
ꢁ
¼ þ24:6 (c 1.0, CHCl3); 1H NMR (400 MHz, 25 °C, CDCl3, d):
0.55–0.88 (m, 6H), 1.35–1.48 (m, 2H), 1.62–1.82 (m, 3H), 2.06–
2.30 (m, 1H), 2.43 (t, J = 6.0 Hz, 1H), 3.55 (br s, 1H), 4.02–4.23 (m,
2H), 4.26–4.50 (m, 3H), 4.80–5.12 (m, 2H), 7.10–7.50 (m, 5H);
13C NMR (100 MHz, 25 °C, CDCl3, d): 13.9 (q), 17.5 (q), 27.8 (d),
28.9 (t), 29.8 (t), 32.1 (t), 47.1 (d), 55.8 (d), 58.2 (d), 60.3 (d),
63.1 (t), 66.3 (t), 127.4 (d, 2C), 127.5 (d), 128.0 (d, 2C), 136.4 (s),
153.8 (s), 154.4 (s), 171.7 (s); EI-HRMS (m/z): [M]+ calcd for
0.70 (br s, 3H) 0.84 (br, 3H), 0.94–1.26 (m, 2H), 1.35–1.42 (m,
1H), 1.50–1.62 (m, 2H), 1.65–1.82 (m, 2H), 1.88–2.14 (m, 1H),
2.36 (dd, J = 5.2 and 11.6 Hz, 1H), 3.56–3.61 (m, 1H), 3.67 (br s,
0.5H), 3.94 (br s, 1H), 4.05–4.15 (br, 0.5H), 4.28–4.50 (m, 3H),
4.86–5.06 (m, 2H), 7.05–7.45 (m, 5H); 13C NMR (100 MHz, 25 °C,
CDCl3, d): 11.29 (q), 11.34 (q), 25.1 (t), 28.6⁄ (t), 29.2⁄ (t), 31.9 (t),
34.2 (d), 47.4 (d), 56.0 (d), 57.4 (d), 59.8 (d), 62.9 (t), 66.4 (t),
127.5 (d, 2C), 127.6 (d), 128.1 (d, 2C), 136.4 (s), 153.9 (s), 154.8
C
21H26N2Oþ, 386.1842; found, 386.1848 (
D
= 1.6 ppm).
5
(s), 171.9 (s); EI-HRMS (m/z): [M]+ calcd for C22H28N2Oþ,
5
4.3.3. 3-[(1R,2S,4S)-7-Benzyloxycarbonyl-7-azabicyclo[2.2.1]-
heptane-2-carbonyl]-(4S)-methyl-2-oxazolidinone 8a
400.1998; found, 400.2049 (D = 12.7 ppm).
42%; colorless oil, Rf = 0.23; EtOAc/n-hexane = 1/2; ½a D25
ꢁ
¼ þ3:7
4.3.8. 3-[(1S,2R,4R)-7-Benzyloxycarbonyl-7-azabicyclo[2.2.1]-
heptane-2-carbonyl]-(4S)-[(1S)-methyl propyl]-2-oxazolidinone 10b
(c 1.0, CHCl3); 1H NMR (400 MHz, 25 °C, CDCl3, d): 1.15–1.46 (m,
4H), 1.52–1.57 (m, 1H), 1.60–1.83 (m, 3H), 2.37–2.44 (m, 1H), 3.57
(dd, J = 5.2 and 8.4 Hz, 1H), 3.70–4.08 (m, 2H), 4.28–4.56 (m, 3H),
4.92–5.08 (m, 2H), 7.23–7.30 (m, 5H); 13C NMR (100 MHz, 25 °C,
CDCl3, d): 18.9 (q), 28.7⁄ (t), 29.3⁄ (t), 31.8 (t), 47.5⁄ (d), 50.5 (d),
56.1 (d), 59.9 (d), 66.6 (t), 68.9 (t), 127.6 (d, 2C), 127.7 (d), 128.2
(d, 2C), 136.4 (s), 153.4 (s), 154.9 (s), 172.0 (s); EI-HRMS (m/z):
42%;
colorless
oil,
Rf = 0.35;
EtOAc/n-hexane = 1/2;
½
a 2D5
ꢁ
¼ þ74:2 (c 1.0, CHCl3); 1H NMR (400 MHz, 25 °C, CDCl3, d):
0.61 (br s, 3H) 0.86 (br, 3H), 1.00–1.28 (m, 2H), 1.38–1.45 (m,
1H), 1.49 (dd, J = 8.8 and 12.0 Hz, 1H), 1.67–1.85 (m, 3H), 1.95–
2.11 (m, 1H), 2.44 (ddd, J = 5.6, 5.6 and 11.2 Hz, 1H), 3.57 (dd,
J = 5.2 and 8.0 Hz, 1H), 4.08–4.24 (m, 2H), 4.37 (br s, 1H), 4.42–
4.57 (m, 2H), 4.76–5.20 (m, 2H), 7.00–7.25 (m, 5H); 13C NMR
(100 MHz, 25 °C, CDCl3, d): 11.5 (q, 2C), 25.2 (t), 28.6⁄ (t), 29.5⁄
(t), 31.4 (t), 34.3 (d), 47.3 (d), 55.9 (d), 57.2 (d), 60.4 (d), 63.1 (t),
66.5 (t), 127.5 (d, 2C), 127.7 (d), 128.2 (d, 2C), 136.5 (s), 154.0
(s), 154.6 (s), 171.9 (s); EI-HRMS (m/z): [M]+ calcd for
[M]+ calcd for C19H22N2Oþ, 358.1529; found, 358.1521
5
(D = 2.2 ppm).
4.3.4. 3-[(1S,2R,4R)-7-Benzyloxycarbonyl-7-azabicyclo[2.2.1]-
heptane-2-carbonyl]-(4S)-methyl-2-oxazolidinone 8b
33%;
colorless
oil,
Rf = 0.19;
EtOAc/n-hexane = 1/2;
C
22H28N2Oþ, 400.1998; found, 400.1986 (
D
= 3.0 ppm).
5
½
a 2D5
ꢁ
¼ þ66:2 (c 1.0, CHCl3); 1H NMR (400 MHz, 25 °C, CDCl3, d):
1.08–1.22 (m, 1H), 1.32–1.44 (m, 3H), 1.46–1.58 (m, 1H), 1.62–
1.72 (m, 1H), 1.74–1.88 (m, 2H), 2.42 (br s, 1H), 3.53–3.57 (m,
1H,), 3.92 (br s, 1H), 4.36 (br s, 2H), 4.45 (br s, 2H), 4.80–5.22 (m,
2H), 7.00–7.60 (m, 5H); 13C NMR (100 MHz, 25 °C, CDCl3, d): 18.7
(q), 28.7⁄ (t), 29.7⁄ (t), 31.6 (t), 47.5 (d), 50.5 (d), 55.9 (d), 60.0
(d), 66.5 (t), 69.0 (t), 127.6 (d, 2C), 127.7 (d), 128.2 (d, 2C), 136.5
(s), 153.4 (s), 154.6 (s), 172.0 (s); EI-HRMS (m/z): [M]+ calcd for
4.4. General procedure for the hydrolysis of the oxazolidinone
derivatives
To
a THF solution (48 mL) of oxazolidinone derivative
(9.5 mmol, 1.0 eq.) in an ice bath, LiOHꢄH2O (639 mg, 15.2 mmol,
1.6 eq.) was added followed by H2O2 (35%, 3.9 mL, 44 mmol,
4 equiv). The reaction mixture was stirred at room temperature
for 2 h. Upon completion of the reaction monitored by TLC analysis,
an Na2SO3 solution (4.8 g dissolved in 30 mL) was added to quench
the reaction, and the reaction mixture was concentrated under re-
duced pressure to remove the excess organic solvent. Next, H2O
(10 mL) was added to the aqueous solution. The resulting aqueous
solution was washed with CH2Cl2 (5 mL, five times), and covered
with EtOAc (30 mL). The bilayer solution was acidified with an
HCl solution (3 M) until the pH was approximately 2. A white pre-
cipitate was observed during acidification. After separation of the
organic layer, the resulting aqueous layer was extracted with
EtOAc (10 mL, five times). The combined organic layers were
washed with brine (30 mL), and dried over anhydrous Na2SO4,
and then concentrated to give a crude acid. Purification of the
crude acid product by flash chromatography on silica gel, using
EtOAc/n-hexane/AcOH as the eluant gave the acid as a colorless
oil, Rf = 0.24; EtOAc/n-hex = 1/4. HPLC condition: CHIRACEL
C
19H22N2Oþ, 358.1529; found, 358.1539 (
D
= 2.8 ppm).
5
4.3.5. 3-[(1R,2S,4S)-7-Benzyloxycarbonyl-7-azabicyclo[2.2.1]-
heptane-2-carbonyl]-(4S)-[2-methylpropyl]-2-oxazolidinone 9a
43%; white solid, mp 112–114 °C; Rf = 0.47, EtOAc/n-hex-
ane = 1/2; ½a 2D5
ꢁ
¼ þ27:3 (c 1.0, CHCl3);1H NMR (400 MHz, 25 °C,
CDCl3, d): 0.92 (br s, 6H), 1.32–1.48 (m, 3H), 1.54–1.71 (m, 3H),
1.74–1.92 (m, 2H), 2.46 (t, J = 5.6 Hz, 1H), 3.61 (dd, J = 4.8 and
8.4 Hz, 1H), 3.78–4.14 (m, 2H), 4.43 (br s, 3H), 5.02 (br s, 2H),
7.27–7.35 (m, 5H); 13C NMR (100 MHz, 25 °C, CDCl3, d): 21.3 (q),
23.2 (q), 24.6 (d), 28.7⁄ (t), 29.4⁄ (t), 31.7 (t), 40.9 (t), 47.5⁄ (d),
53.2 (d), 56.1 (d), 60.0 (d), 66.6 (t), 67.4 (t), 127.7 (d, 2C), 127.8
(d), 128.2 (d, 2C), 136.5 (s), 153.6 (s), 154.9 (s), 171.8 (s); EI-HRMS
(m/z): [M]+ calcd for C22H28N2Oþ, 400.1998; found, 400.1991
5
(D = 1.7 ppm).
4.3.6. 3-[(1S,2R,4R)-7-Benzyloxycarbonyl-7-azabicyclo[2.2.1]-
heptane-2-carbonyl]-(4S)-[2-methylpropyl]-2-oxazolidinone 9b
OD-H, 4.6 mm ꢃ 250 mm, 5
lm; Mobile phase A: 0.5% TFA in
2-propanol alcohol /n-hexane solution (v/v = 1/10); mobile phase
B: 0.5% TFA in pure n-hexane; isocratic, 50% A:50% B; flow rate
1.0 mL per min; detection UV 215 nm, tR: 18.4 min for (+)-1,
39%;
colorless
oil,
Rf = 0.40;
EtOAc/n-hexane = 1/2;
½
a 2D5
ꢁ
¼ þ72:2 (c 1.03, CHCl3); 1H NMR (400 MHz, 25 °C, CDCl3, d):
Please cite this article in press as: Chiou, W.-H.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.11.010

6
W.-H. Chiou et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
4. Bai, D.; Xu, R.; Chu, G.; Zhu, X. J. Org. Chem. 1996, 61, 4600.
26.3 min for (-)-1. (+)-1: 93%; ½a D25
ꢁ
¼ þ8:8 (c 1.0, CHCl3); tR:
18.4 min; (ꢀ)-1: 95%; ½a D25
¼ ꢀ8:6 (c 1.0, CHCl3); tR: 26.5 min.
ꢁ
5. Zhang, C.; Trudell, M. L. J. Org. Chem. 1996, 61, 7189.
6. Pandey, G.; Laha, J. K.; Lakshmaiah, G. Tetrahedron 2002, 58, 3525.
7. Armstrong, A.; Shanahan, S. E. Org. Lett. 2005, 7, 1335.
8. Fevig, T. L.; Anjeh, T. E.; Lawson, J. P.; Walker, D. P.; Wishka, D. G. Pfizer Inc.: U.
S. Patents 0,173,063 A1. 2006.
Acknowledgments
9. The use of enantiopure fluorenylethylchloroformate (FLEC) in the chiral HPLC
analysis of 7-azabicyclo[2.2.1]heptane-2-carboxylic acid has been reported, see
Camerino, M. A.; Chalmers, D. K.; Thompson, P. E. Org. Biomol. Chem. 2013, 11,
2571.
The authors thank the National Science Council, Taiwan
(NSC101-2113-M-005-009-MY3) and the Nanotechnological Cen-
ter of National Chung Hsing University for support of this research.
10. CCDC number 954017.
11. Gages, J. R.; Evans, D. A. In Org. Synth. Coll.; Springer: Berlin, 1993; Vol. 8, p 339.
12. Burks, J. E.; Espinosa, L.; LaBell, E. S.; McGill, J. M.; Ritter, A. R.; Speakman, J. L.;
Williams, M.; Bradley, D. A.; Haehl, M. G.; Schmid, C. R. Org. Process Res. Dev.
1997, 1, 198.
13. Davis, C. R.; Johnson, R. A.; Cialdella, J. I.; Liggett, W. F.; Mizsak, S. A.; Marshall,
V. P. J. Org. Chem. 1997, 62, 2244.
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Please cite this article in press as: Chiou, W.-H.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.11.010