New procedure for the preparation of (1 R,2 R)-2-[(R)-3-(benzyloxy)pyr- rolidin-1-yl]cyclohexanol

Article abstract of DOI:10.1055/s-0031-1289619

A novel route to an intermediate of vernakalant, (1R,2R)-2-[(R)-3- (benzyloxy)pyrrolidin-1-yl]cyclohexanol from ethyl (R)-4-chloro-3- hydroxybutanoate is described. It was found that the key intermediate (R)-4-(benzyloxy)-1-[(1R,2R)-2-(tert-butyldimethylsiloxy)cyclohexyl] pyrrolidin-2-one could be isolated with high dia-stereomeric excess (up to 99% de) from its isomer by column chromatography alone, without further chemical resolution. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289619

PAPER
51
New Procedure for the Preparation of (1R,2R)-2-[(R)-3-(Benzyloxy)pyr-
rolidin-1-yl]cyclohexanol
(
1
R
,2
R
)-2-[(
R
)-3-(
a
Benzyloxy
i
w
din-1-yl]cyclohexa
e
nol i Ye, Chuanming Yu,* Weihui Zhong
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Fax +86(571)88320867; E-mail: ycm@zjut.edu.cn
Received 19 October 2011; revised 3 November 2011
O
N
OMe
OMe
OH
N
Abstract: A novel route to an intermediate of vernakalant, (1R,2R)-
2-[(R)-3-(benzyloxy)pyrrolidin-1-yl]cyclohexanol from ethyl (R)-
4-chloro-3-hydroxybutanoate is described. It was found that the key
intermediate (R)-4-(benzyloxy)-1-[(1R,2R)-2-(tert-butyldimethyl-
siloxy)cyclohexyl]pyrrolidin-2-one could be isolated with high dia-
stereomeric excess (up to 99% de) from its isomer by column
chromatography alone, without further chemical resolution.
OH
vernakalant (1)
OBn
2
Figure 1
Key words: (1R,2R)-2-[(R)-3-(benzyloxy)pyrrolidin-1-yl]cyclo-
hexanol, vernakalant, enantioselectivity
istry based route started from (R)-3-hydroxypyrrolidine,
which was converted into the corresponding (R)-3-(benz-
yloxy)pyrrolidine by selective protection and deprotec-
tion, followed by ring-opening reaction with
epoxycyclohexane to afford the diastereomer of 2, which
finally led to 2 through a chemical resolution process.7,8
However, several problems still remain, such as the re-
quirement for multiple chiral resolutions. An alternative
route using asymmetric catalysis utilized chiral ligands or
boranes that were hard to recycle.7,8 Here we wish to de-
velop a new and efficient procedure for the preparation of
2 outlined in Scheme 1.
Vernakalant (Kynapid/RSD1235, 1) (Figure 1) is an anti-
arrhythmic agent that affects cardiac Na+ and K+ currents,
including the atrial-selective currents IKur and IK,ACh.
1,2 In
animal models of atrial fibrillation and in initial clinical
studies, vernakalant significantly prolonged the atrial re-
fractory period without significantly affecting ventricular
refractoriness.1,2 It was discovered by Cardiome Pharma-
ceutical Company and Astellas Pharmaceutical Company
and developed by Merck & Co., Inc.3 At present, clinical
data have shown that vernakalant has advantages over
other atrial fibrillation drugs, including fewer side ef-
fects.3–7 In September 2010, vernakalant was granted mar-
keting authorization by the European Commission for the
rapid conversion of recent-onset atrial fibrillation to sinus
rhythm under the trade name ‘Brinavess’ (Cardiome/
Merck).7
As shown in Scheme 1, our initial experiment involve the
synthesis of 2-(trialkylsiloxy)cyclohexanamines rac-
5a–c. Firstly, 2-(Cbz-amino)cyclohexanol rac-4, pre-
pared by treatment of commercially available epoxycy-
clohexane (3) with aqueous ammonia,9 followed by
addition of benzyl chloroformate in the presence of sodi-
um hydroxide.8a Subsequently, the hydroxy-protected de-
rivatives were achieved by using trialkylchlorosilane in
the presence of imidazole in N,N-dimethylformamide.
The key intermediate in the preparation of vernakalant,
(1R,2R)-2-[(R)-3-(benzyloxy)pyrrolidin-1-yl]cyclohexanol
(2) has three chiral centers. The original medicinal chem-
OR
OH
1. RCl, Imidazole
1. NH4OH
O
Cbz
2. ClCbz
2. Pd/C, H2
NH2
N
H
3
rac-4
rac-5
R = TBS, TES, TBDPS
OH
N
OR
Ag2O
rac-5
O
Cl
CO2Et
Cl
CO2Et
OH
OBn
BnBr
N
6
7
OBn
OBn
8
2
Scheme 1
SYNTHESIS 2012, 44, 51–56
x
x.
x
x
.
2
0
1
1
Advanced online publication: 23.11.2011
DOI: 10.1055/s-0031-1289619; Art ID: H98711SS
© Georg Thieme Verlag Stuttgart · New York

52
H. Ye et al.
PAPER
OR
N
OH
N
O
1. H+
2. LiAlH4
R = TBS
OBn
(–)-8 (R,R,R)
OBn
OR
2
1. KI
1. NaOH
Cl
CO2Et
2. DCC, DMAP
2. rac-5
OBn
N
H
CO2Et
7
OR
O
OBn
column
chromatography
9
N
OBn
(+)-8' (S,S,R)
Scheme 2
The derivatives could be readily converted into 2-(tri- ed 7 in 68% yield, and the byproduct silver bromide could
alkylsiloxy)cyclohexanamines rac-5a–c, for example, be recycled. Unfortunately, attempts to synthesize the dia-
rac-5a was obtained in 63% yield (from 3), through amino stereomer of 8 from the reaction of O-benzyl-substituted
deprotection in the presence of palladium on carbon cata- 7 with rac-5 failed. Actually, we obtained (–)-8 (R,R,R) in
lyst under a hydrogen atmosphere.
three steps as shown in Scheme 2. Thus, we focused our
efforts on the nucleophilic substitution of ethyl (R)-3-
(benzyloxy)-4-chlorobutanoate (7) with 2-(trialkylsil-
oxy)cyclohexanamines rac-5a–c to afford ethyl (3R)-3-
(benzyloxy)-4-{[2-(trialkylsiloxy)cyclohexyl]amino}bu-
tanoates 9a–c under different conditions. We were de-
lighted to find that the yield of 9a could be improved to
83% when the combination of sodium carbonate and N,N-
dimethylformamide was employed at 105 °C (Table 1, en-
try 4). However, unsatisfactory results were obtained
when 2-(trialkylsiloxy)cyclohexanamines 5b,c were used
(Table 1, entries 13, 14).
Secondly, commercially available ethyl (R)-4-chloro-3-
hydroxybutanoate (6) was treated with benzyl bromide, in
the presence of silver oxide, to obtain O-benzyl-substitut-
Table 1 Preparation of 9 from 7 under Various Conditions
OR
1. KI, solvent
Cl
CO2Et
OBn
7
2. base, rac-5
N
CO2Et
H
OBn
9
Entry R
Solvents Basea
Temp Time ProductYieldb
We then converted 9a into the corresponding lactam prod-
ucts 8a via saponification with sodium hydroxide in tet-
rahydrofuran–water (2:1), and successively condensation
in the presence of N,N¢-dicyclohexylcarbodiimide and 4-
(dimethylamino)pyridine. As expected, the two isomers
(–)-8a (R,R,R) and (+)-8a¢ (S,S,R) were easy to separate
by column chromatography without further chemical res-
olution to afford the target compound (–)-8a (R,R,R) with
high diastereomeric excess. Moreover, we also investigat-
ed the synthesis of other analogues from 9. The reaction
conditions were optimized and the results are listed in
Table 2. Unfortunately, the results indicated that the yield
of the corresponding (–)-8b and (–)-8c decreased to some
extent when triethylsilyl or tert-butyldiphenylsilyl were
used to protect the hydroxy group of 9 instead of tert-bu-
tyldimethylsilyl (Table 2, entries 4 and 5).
(°C)
(h)
(%)
1
2
3
4
5
6
7
8
9
TBS
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
EtOAc
acetone
DMF
Na2CO3 105
Cs2CO3 105
6
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9b
9c
5c
TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
8
40
61
83
79
40
30
15
11
55
29
32
67
65
K2CO3
105
6
Na2CO3 105
Na2CO3 125
DIPEA 105
6
5
12
12
12
12
12
12
12
6
Et3N
105
125
DBU
t-BuOK 125
10 TBS
11 TBS
12 TBS
13 TES
Na2CO3
Na2CO3
Na2CO3
85
80
65
Finally, (–)-8a was treated with a solution of dilute acid to
give the silyl-deprotected intermediate which was reacted
with the reducing agent to afford the target product 2. The
amount of reducing agent and the reaction temperature
were carefully optimized (Table 3). The best result was
obtained when the reaction was performed with 2 molar
equivalents of lithium aluminum hydride at room temper-
ature, achieving the desired product 2 with 99% de in 78%
yield (Table 3, entry 4).
Na2CO3 105
Na2CO3 105
14 TBDPS DMF
8
a Base molar ratio with 1.2 equiv of 7.
b Isolated yields of 9 based on 7.
c Without treatment of 7 with KI.
Synthesis 2012, 44, 51–56
© Thieme Stuttgart · New York

PAPER
(1R,2R)-2-[(R)-3-(Benzyloxy)pyrrolidin-1-yl]cyclohexanol
53
Table 2 Preparation of (–)-8 from 9 under Various Conditions
OR
N
OR
N
OR
1. NaOH, THF–H2O
O
O
+
2. DCC, DMAP
N
CO2Et
H
OBn
OBn
(–)-8 (R,R,R)
OBn
9
(+)-8' (S,S,R)
Entry
R
Solvents
Time (h)
Yielda (%)
de (%)b (–)-8
(–)-8
(+)-8¢
1
2
3
4
5
TBS
DMF
10
12
7
8a (41)
8a (40)
8a (43)
8b (37)
8c (30)
8a¢ (42)
8a¢ (40)
8a¢ (41)
8b¢ (35)
8c¢ (31)
>99
>99
>99
87
TBS
toluene
CH2Cl2
CH2Cl2
CH2Cl2
TBS
TES
8
TBDPS
8
97
a Isolated yields based on 9.
b Diastereomeric excess was determined by HPLC on a chiral stationary phase.
Table 3 Preparation of 2 from (–)-8a under Various Conditions
ternal standard. Mass spectra were measured with a Finni-
gan Trace DSQ instrument. HRMS was performed on a
Micromass LCT. Optical rotations were measured on a
AUTOPOL V Polarimeter. Chiral HPLC analysis was
performed on Agilent 1100 HPLC (Chromatographic
Column: Daicel Chiralcel AY-H or OD-H column and
eluting with n-hexane–i-PrOH) with DAD UV detector.
PE = petroleum ether.
OTBS
O
OH
1. H+
N
N
2. reducing agent
OBn
OBn
(–)-8a
2
Entry Reducing agent (equiv) Temp (°C) Time (h) Yielda (%)
2-[(Benzyloxycarbonyl)amino]cyclohexanol (rac-4)
1
2
3
4
5
BF3·THF (4)
Red-Al (4)
LiAlH4 (4)
LiAlH4 (2)
LiAlH4 (2)
60
80
25
25
5
10
10
5
5
30
76
78
70
Epoxycyclohexane 3 (50.0 g, 0.51 mol) was added to a magnetically
stirred 25% aq NH3 soln (407.9 g, 2.91 mol). The oily suspension
was stirred for 12 h at r.t. and then evaporated to dryness. A soln of
NaOH (20.0 g, 0.50 mol) in H2O (250 mL) was added to the residue
and the mixture was cooled to 0 °C, CbzCl (85.0 g, 0.50 mol) was
added over 0.5 h. The mixture was stirred for 3 h at r.t. then the solid
was separated, washed successively with H2O, and dried to afford
rac-4 (81.3 g, 64% from 3) as a white solid; mp 104–105 °C.
6
8
a Isolated yields of 2 based on (–)-8a.
IR (KBr): 3375, 2965, 1735, 1565, 1120 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.39–7.28 (m, 5 H), 5.12 (d,
J = 11.6 Hz, 1 H), 5.08 (d, J = 11.6 Hz, 1 H), 4.84 (s, 1 H), 3.41–
3.35 (m, 1 H), 3.32–3.26 (m, 1 H), 2.79 (s, 1 H), 2.06–1.97 (m, 2 H),
1.73–1.66 (m, 2 H), 1.36–1.09 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 157.1, 136.1, 128.4 (2 C), 128.0
(3 C), 74.9, 67.0, 57.1, 34.2, 31.8, 24.7, 24.1.
In conclusion, we have developed a new and efficient
route for the preparation of (1R,2R)-2-[(R)-3-(benzyl-
oxy)pyrrolidin-1-yl]cyclohexanol (2) with a total yield of
19% from ethyl (R)-4-chloro-3-hydroxybutanoate (6). It
is worth mentioning that the key intermediate (R)-4-(ben-
zyloxy)-1-[(1R,2R)-2-(tert-butyldimethylsiloxy)cyclo-
hexyl]pyrrolidin-2-one [(–)-8a] could be isolated in high
diastereomeric excess (up to 99% de) from its isomer
(S,S,R)-(+)-8a¢ by column chromatography alone.
MS (ESI): m/z = 250.1 [M + H]+.
HRMS (ESI): m/z [M] calcd for C14H19NO3: 249.1385; m/z [M +
H]+ found: 250.1377.
2-(tert-Butyldimethylsiloxy)cyclohexanamine (rac-5a); Typical
Procedure
A soln of TBSCl (57.3 g, 0.38 mol) in DMF (250 mL) was added
dropwise to a soln of rac-4 (80.0 g, 0.32 mol) and imidazole (25.9
g, 0.38 mol) in DMF (250 mL) at 5 °C. The mixture was stirred for
8 h at r.t., then cold H2O (250 mL) and petroleum ether (400 mL)
were added. The organic layer was separated, washed successively
with H2O, and evaporated to dryness. Then MeOH (300 mL) and
5% Pd/C (4.0 g, 5 wt% of the rac-4) were added, the reaction was
stirred under a H2 atmosphere (1 atm) for 5 h at r.t. The Pd/C was
All solvents and reagents were purchased from commer-
cial sources and were used without additional purification.
Melting points were determined with a Büchi B-540 cap-
illary melting point apparatus and are uncorrected. IR
spectra were recorded on a Nicolet Avatar 370 instrument.
1H and 13C NMR spectra were recorded on a Varian (400
MHz) instruments in CDCl3 or DMSO-d6 with TMS as in-
© Thieme Stuttgart · New York
Synthesis 2012, 44, 51–56

54
H. Ye et al.
PAPER
filtered and recycled, and the organic layer was evaporated in vacuo
to afford rac-5a (71.8 g, 98% from rac-4) as a pale-yellow oil.
Ethyl (3R)-3-(Benzyloxy)-4-{[2-(tert-butyldimethylsiloxy)cyclo-
hexyl]amino}butanoate (9a); Typical Procedure
A mixture of 7 (51.2 g, 0.20 mol) and KI (83.0 g, 0.50 mol) in DMF
(200 mL) was stirred for 2 h at r.t. Then rac-5a (45.8 g, 0.20 mol)
and Na2CO3 (25.4 g, 0.24 mol) were added and the mixture was
stirred for a further 6 h at 105 °C. Then the mixture was cooled, cold
H2O (150 mL) and EtOAc (150 mL) were added; the organic layer
was separated and dried (Na2SO4), filtered, and evaporated in vacuo
to afford 9a (74.5 g, 83% from 7).
IR (KBr): 2935, 2869, 1555, 1460, 1125 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.20–3.14 (m, 1 H), 2.55–2.49 (m,
1 H), 1.86–1.83 (m, 2 H), 1.70–1.64 (m, 4 H), 1.28–1.21 (m, 3 H),
1.15–1.08 (m, 1 H), 0.90 (s, 9 H), 0.09 (d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 78.2, 57.0, 34.5, 33.2, 26.0 (3 C),
24.9, 24.8, 18.2, –3.8, –4.4.
IR (KBr): 2929, 1731, 1573, 1483, 1129 cm–1.
MS (ESI): m/z = 230.2 [M + H]+.
1H NMR (400 MHz, CDCl3): d = 7.30–7.25 (m, 5 H), 4.59 (d,
J = 11.6 Hz, 1 H), 4.55 (d, J = 11.6 Hz, 1 H), 4.15–4.07 (m, 2 H),
4.02–3.97 (m, 1 H), 3.50–3.37 (m, 1 H), 2.78–2.77 (m, 2 H), 2.70–
2.55 (m, 2 H), 2.38–2.31 (m, 1 H), 1.92–1.83 (m, 2 H), 1.68–1.62
(m, 2 H), 1.32–1.17 (m, 7 H), 1.0 (s, 1 H), 0.85 (s, 9 H), 0.07 (d,
J = 1.6 Hz, 6 H).
HRMS (ESI): m/z [M] calcd for C12H27NOSi: 229.1940; m/z [M +
H]+ found: 230.1947.
2-(Triethylsiloxy)cyclohexanamine (rac-5b)
Following the typical procedure for rac-5a gave rac-5b as a pale-
yellow oil; yield: 90% from rac-4.
13C NMR (100 MHz, CDCl3): d = 171.5, 138.2, 128.1 (2 C), 127.6
(2 C), 127.3, 75.3, 74.8, 71.5, 62.8, 60.4, 49.0, 38.2, 34.6, 29.6, 26.0
(3 C), 24.5, 24.3, 18.1, 14.3, –3.9, –4.4.
IR (KBr): 2933, 2875, 1576, 1456, 1091 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.19–3.14 (m, 1 H), 2.54–2.48 (m,
1 H), 1.86–1.82 (m, 2 H), 1.70–1.62 (m, 2 H), 1.54 (s, 2 H), 1.33–
1.21 (m, 3 H), 1.13–1.07 (m, 1 H), 0.99–0.95 (m, 9 H), 0.66–0.60
(m, 6 H).
13C NMR (100 MHz, CDCl3): d = 78.2, 57.0, 34.6, 33.4, 25.0, 24.8,
7.1 (3 C), 5.3 (3 C).
MS (ESI): m/z = 450.4 [M + H]+.
HRMS (ESI): m/z [M] calcd for C25H43NO4Si: 449.3040; m/z [M +
H]+ found: 450.3041.
Ethyl (3R)-3-(Benzyloxy)-4-{[2-(triethylsiloxy)cyclohexyl]ami-
no}butanoate (9b)
Following the typical procedure for 9a gave 9b as a yellow viscous
MS (ESI): m/z = 230.2 [M + H]+.
HRMS (ESI): m/z [M] calcd for C12H27NOSi: 229.1865; m/z [M +
H]+ found: 230.1860.
oil; yield: 67% from 7.
IR (KBr): 2931, 1735, 1573, 1477, 1120 cm–1.
2-(tert-Butyldiphenylsiloxy)cyclohexanamine (rac-5c)
Following the typical procedure for rac-5a gave rac-5c as a pale-
white solid; yield: 71% from rac-4; mp 243–245 °C.
IR (KBr): 2928, 2857, 1635, 1573, 1103 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.89 (s, 2 H), 7.68–7.65 (m, 4
H), 7.47–7.39 (m, 6 H), 3.80–3.75 (m, 1 H), 3.04–2.98 (m, 1 H),
2.06–2.02 (m, 1 H), 1.54–1.50 (m, 1 H), 1.41–1.29 (m, 3 H), 1.25–
1.15 (m, 2 H), 0.99 (s, 9 H), 0.90–0.80 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 135.1 (2 C), 135.1 (2 C),
133.6, 132.6, 129.7 (2 C), 129.5 (2 C), 127.6, 127.4, 73.0, 54.4,
32.2, 27.9, 26.8 (3 C), 22.6, 22.3, 18.9.
1H NMR (400 MHz, CDCl3): d = 7.31–7.25 (m, 5 H), 4.62 (d,
J = 11.2 Hz, 1 H), 4.58 (d, J = 11.2 Hz, 1 H), 4.11 (q, J = 7.2 Hz, 2
H), 4.01–3.99 (m, 1 H), 3.39–3.35 (m, 1 H), 2.81–2.75 (m, 1 H),
2.70–2.53 (m, 3 H), 2.33–2.27 (m, 1 H), 1.97–1.83 (m, 3 H), 1.68–
1.62 (m, 2 H), 1.37–1.17 (m, 7 H), 0.95–0.89 (m, 9 H), 0.62–0.53
(m, 6 H).
13C NMR (100 MHz, CDCl3): d = 171.2, 138.2, 128.1 (2 C), 127.5
(2 C), 127.3, 75.4, 71.8, 63.5, 60.5, 50.9, 49.1, 38.6, 34.7, 30.1,
24.7, 24.3, 14.3, 7.1 (3 C), 5.3 (3 C).
MS (ESI): m/z = 450.2 [M + H]+.
HRMS (ESI): m/z [M] calcd for C25H43NO4Si: 449.2972; m/z [M +
MS (ESI): m/z = 354.0 [M + H]+.
H]+ found: 450.2977.
HRMS (ESI): m/z [M] calcd for C22H31NOSi: 353.2177; m/z [M +
H]+ found: 354.2181.
Ethyl (3R)-3-(Benzyloxy)-4-{[2-(tert-butyldiphenylsiloxy)cyclo-
hexyl]amino}butanoate (9c)
Following the typical procedure for 9a gave 9c as a yellow viscous
Ethyl (R)-3-(Benzyloxy)-4-chlorobutanoate (7)
A mixture of 6 (50.5 g, 0.3 mol), BnBr (59.9 g, 0.35 mol), and Ag2O
(74.2 g, 0.32 mol) in CH2Cl2 (300 mL) was stirred for 12 h at r.t. The
suspension was filtered to recycle AgBr (45.7 g), and the combined
filtrates were concentrated under vacuum and purified by column
chromatography (silica gel, PE–EtOAc, 12:1) to give 7 (52.2 g,
68% from 6) as a colorless oil.
oil; yield: 65% from 7.
IR (KBr): 2937, 1742, 1565, 1456, 1151 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.70–7.65 (m, 4 H), 7.40–7.22 (m,
11 H), 4.57 (s, 1 H), 4.55 (d, J = 5.6 Hz, 1 H), 4.14–4.07 (m, 2 H),
3.99–3.90 (m, 1 H), 3.58–3.51 (m, 1 H), 2.76–2.58 (m, 3 H), 2.56–
2.44 (m, 3 H), 2.14 (s, 1 H), 1.95–1.88 (m, 1 H), 1.58–1.50 (m, 3 H),
1.30–1.12 (m, 6 H), 0.99 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 171.3, 137.9, 135.7 (4 C), 134.8,
133.9, 129.4, 129.3, 128.1 (2 C), 127.5 (2 C), 127.4 (2 C), 127.3,
127.2 (2 C), 76.4, 75.8, 71.8, 62.3, 60.4, 50.5, 38.7, 33.6, 29.7, 27.1
(3 C), 23.9, 23.8, 19.5, 14.3.
IR (KBr): 2929, 1731, 1568, 1374, 1071 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.34–7.24 (m, 5 H), 4.65 (d,
J = 11.6 Hz, 1 H), 4.60 (d, J = 11.6 Hz, 1 H), 4.17–4.08 (m, 3 H),
3.66–3.58 (m, 2 H), 2.75–2.61 (m, 2 H), 1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.5, 137.5, 128.3 (2 C), 127.7,
127.6 (2 C), 75.5, 72.4, 60.7, 45.4, 38.0, 14.3.
MS (ESI): m/z = 574.3 [M + H]+.
MS (EI): m/z (%) = 256 (10) [M+], 222 (15), 221 (100).
HRMS (ESI): m/z [M] calcd for C35H47NO4Si: 573.3278; m/z [M +
HRMS (EI): m/z [M]+ calcd for C13H17ClO3: 256.0869; m/z [M +
H]+ found: 574.3288.
H]+ found: 256.0879.
Synthesis 2012, 44, 51–56
© Thieme Stuttgart · New York

PAPER
(1R,2R)-2-[(R)-3-(Benzyloxy)pyrrolidin-1-yl]cyclohexanol
55
(R)-4-(Benzyloxy)-1-[(1R,2R)-2-(tert-butyldimethylsiloxy)cyclo-
hexyl]pyrrolidin-2-one [(–)-8a]; Typical Procedure
13C NMR (100 MHz, CDCl3): d = 172.1, 137.4, 135.7 (2 C), 135.5
(2 C), 133.9, 133.7, 129.5 (4 C), 128.3 (2 C), 127.7 (2 C), 127.5 (2
C), 127.4, 71.9, 70.9, 70.8, 56.1, 48.8, 38.8, 35.5, 28.8, 26.9 (3 C),
24.6, 24.5, 19.2.
A soln of 9a (80.8 g, 0.18 mol) and NaOH (14.4 g, 0.36 mol) in
THF–H2O (2:1, 300 mL) was stirred for 8 h at r.t. Then cold H2O
(300 mL) and EtOAc (300 mL) were added and the organic layer
was separated, washed successively with H2O, dried (Na2SO4), and
concentrated under vacuum. Then DCC (41.3 g, 0.20 mol), DMAP
(2.4 g, 0.02 mol), and CH2Cl2 (300 mL) were added and the mixture
was stirred at r.t. for 10 h. The formed precipitates were filtered off,
washed successively with H2O, and concentrated under vacuum.
The residue was purified by flash column chromatography (silica
gel, PE–EtOAc, 4:1) to afford (–)-8a (31.2 g, 43% from 9a) as a yel-
low viscous oil; >99% de [HPLC (Chiralpak OD-H column, hex-
ane–i-PrOH, 98:2, flow rate 0.5 mL/min, l = 206 nm): tR = 30.8
(major), 37.6 min (minor)].
MS (ESI): m/z = 528.0 [M + H]+.
HRMS (ESI): m/z [M] calcd for C33H41NO3Si: 527.2846; m/z [M +
H]+ found: 528.2857.
(1R,2R)-2-[(R)-3-(Benzyloxy)pyrrolidin-1-yl]cyclohexanol (2)
To a soln of (–)-8a (28.2 g, 0.07 mol) in MeOH (200 mL) was added
3 M HCl (50 mL) and the soln stirred for 0.5 h at r.t. The soln was
concentrated under reduced pressure and the residue redissolved in
EtOAc (200 mL) and washed successively with H2O, dried
(Na2SO4), and concentrated under vacuum to give a yellow oil res-
idue. Then a soln of the oil residue in THF (50 mL) was added drop-
wise to a soln of LiAlH4 (5.32 g, 0.14 mol) in THF (150 mL) at 0
°C under a N2 atmosphere. The mixture was stirred for 6 h at r.t. The
soln was cooled to 0 °C and quenched with H2O (150 mL) and
EtOAc (100 mL). The resulting slurry was filtered, then filtrate was
acidified with 10% HCl (45 mL) until pH ~1 was obtained. The up-
per organic phase was separated and the lower aqueous phase was
washed with EtOAc (2 × 50 mL). The pH of aqueous phase was ad-
justed to ~12 using 10% NaOH (80 mL) and extracted with EtOAc
(3 × 50 mL). The combined organic phases were dried (Na2SO4)
and concentrated under vacuum to give 2 [15.0 g, 78% from (–)-8a]
as a pale-yellow oil; >99% de [HPLC (Chiralpak AY-H column,
hexane–i-PrOH–Et2NH, 90:10:0.5, flow rate 1.0 mL/min, l = 220
nm): tR = 9.0 (major), 7.8 min (minor).
[a]D20 –39.1 (c 0.16, CHCl3).
IR (KBr): 3373, 1638, 1577, 1558, 1116 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.34–7.25 (m, 5 H), 4.49 (d,
J = 11.6 Hz, 1 H), 4.45 (d, J = 11.6 Hz, 1 H), 4.12–4.07 (m 1 H),
3.65 (s, 1 H), 3.36–3.30 (s, 1 H), 2.99 (dd, J = 10.0, 6.4 Hz, 1 H),
2.89 (q, J = 8.0 Hz, 1 H), 2.66–2.57 (m, 2 H), 2.45–2.39 (m, 1 H),
2.11–2.02 (m, 2 H), 1.87–1.82 (m, 1 H), 1.79–1.77 (m, 2 H), 1.71–
1.70 (m, 1 H), 1.27–1.16 (m, 4 H).
[a]D20 –18.6 (c 0.18, CHCl3).
IR (KBr): 2935, 1635, 1573, 1483, 1143 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.26 (m, 5 H), 4.55 (d,
J = 12.0 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 4.23–4.19 (m, 1 H),
3.86–3.90 (m, 1 H), 3.57–3.52 (m, 2 H), 3.39–3.36 (m, 1 H), 2.65–
2.51 (m, 2 H), 1.99–1.95 (m, 1 H), 1.73–1.70 (m, 4 H), 1.46–1.29
(m, 3 H), 0.81 (s, 9 H), 0.04 (s, 3 H), 0.00 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 171.9, 137.4, 128.3 (2 C), 127.7
(2 C), 127.5, 71.1, 70.8, 56.8, 49.8, 38.7, 35.4, 29.8, 28.7, 25.7 (3
C), 24.8, 24.6, 17.9, –3.2, –4.6.
MS (ESI): m/z = 404.3 [M + H]+.
HRMS (ESI): m/z [M] calcd for C23H37NO3Si: 403.2621; m/z [M +
H]+ found: 404.2614.
(R)-4-(Benzyloxy)-1-[(1R,2R)-2-(triethylsiloxy)cyclohexyl]pyr-
rolidin-2-one [(–)-8b]
Following the typical procedure for (–)-8a gave (–)-8b as a yellow
viscous oil; yield: 37% from 9b; 87% de [HPLC (Chiralpak OD-H
column, hexane–i-PrOH, 95:5, flow rate 1.0 mL/min, l = 206 nm):
tR = 9.0 (major), 10.8 min (minor)].
[a]D20 –10.6 (c 0.13, CHCl3).
IR (KBr): 2934, 1635, 1568, 1487, 1112 cm–1.
13C NMR (100 MHz, CDCl3): d = 138.1, 128.2 (2 C), 127.5 (2 C),
127.4, 77.9, 71.1, 70.6, 65.0, 52.8, 46.9, 33.4, 31.5, 25.3, 24.3, 24.6.
1H NMR (400 MHz, CDCl3): d = 7.36–7.28 (m, 5 H), 4.54 (d,
J = 12.0 Hz, 1 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.23–4.18 (m, 1 H),
3.83–3.74 (m, 1 H), 3.59–3.52 (m, 2 H), 3.39–3.36 (m, 1 H), 2.66–
2.51 (m, 2 H), 1.98–1.95 (m, 1 H), 1.72–1.68 (m, 3 H), 1.45–1.25
(m, 4 H), 0.99–0.89 (m, 9 H), 0.62–0.46 (m, 6 H).
MS (ESI): m/z = 276.2 [M + H]+.
HRMS (ESI): m/z [M] calcd for C17H25NO2: 275.1964; m/z [M +
H]+ found: 276.1960.
13C NMR (100 MHz, CDCl3): d = 172.3, 137.7, 128.6 (2 C), 127.9,
127.7 (2 C), 71.4, 71.3, 71.1, 57.2, 50.1, 38.9, 35.8, 29.0, 25.0, 24.9,
7.3 (3 C), 5.8 (3 C).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
MS (ESI): m/z = 404.1 [M + H]+.
Acknowledgment
HRMS (ESI): m/z [M] calcd for C23H37NO3Si: 403.2553; m/z [M +
We thank the National Natural Science Foundation of China (No.
21076194) for financial support.
H]+ found: 404.2550.
(R)-4-(Benzyloxy)-1-[(1R,2R)-2-(tert-butyldiphenylsiloxy)cyclo-
hexyl]pyrrolidin-2-one [(–)-8c]
Following the typical procedure for (–)-8a gave (–)-8c as a yellow
viscous oil; yield: 30% from 9c; 97% de; [HPLC (Chiralpak OD-H
column, hexane–i-PrOH, 95:5, flow rate 1.0 mL/min, l = 206 nm):
tR = 13.7 (major), 8.9 min (minor).
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