Diastereoselective arylation of l-proline derivatives at the 5-position

Article abstract of DOI:10.1016/j.tet.2008.06.004

Diastereoselective introduction of nucleophiles into l-proline derivatives at the 5-position was achieved with suitable selection of N-protecting group. N-Methoxycarbonylated or benzyloxycarbonylated l-proline derivatives reacted with arene to give cis-ar

Full text of DOI:10.1016/j.tet.2008.06.004

Tetrahedron 64 (2008) 7498–7503
Contents lists available at ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
Diastereoselective arylation of -proline derivatives at the 5-position
L
*
Osamu Onomura , Peter G. Kirira, Toshimitsu Tanaka, Shinsuke Tsukada,
Yoshihiro Matsumura, Yosuke Demizu
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2008
Received in revised form 3 June 2008
Accepted 3 June 2008
Available online 6 June 2008
Diastereoselective introduction of nucleophiles into L-proline derivatives at the 5-position was achieved
with suitable selection of N-protecting group. N-Methoxycarbonylated or benzyloxycarbonylated
L-proline derivatives reacted with arene to give cis-arylated products. On the other hand, N-benzoylated
L-proline derivative preferentially gave trans-arylated product, which could be easily transformed into
optically active C2-symmetrical pyrrolidine derivative. Such derivative 5 worked well as an organic
activator in the asymmetric reduction of aromatic imines by Cl3SiH.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Diastereoselective
Organocatalysis
Asymmetric reduction of imines
C2-symmetrical pyrrolidine
Proline derivative
O
OH
1. Introduction
Cl3SiH (3.0 equiv)
ð2Þ
4 (0.1 equiv)
Ar
R
Ar
R
Optically active 2,5-disubstituted pyrrolidines are key in-
termediates for preparation of pharmaceuticals or natural prod-
ucts1 as well as organocatalysts for asymmetric reactions.2
up to 99% ee
Me
N
Me
Me
Electrochemical oxidation of
L-proline derivatives 1 is a useful tool
Et
Me
for their synthesis (Eq. 1).3
N
CO2H
Me
N
Me
Et
O
-2e
MeOH
NuH
Lewis acid
CHO
Et
Nu
N
PG
3
N
PG
1
CO2Me
N
PG
2
CO2Me
CO Me
MeO
2
4
5
ð1Þ
2. Results and discussion
Recently, we have reported that cis-5-arylated N-formyl-
L-pro-
line 44 worked well as an organic activator in the enantioselective
reduction of ketones with Cl3SiH5 in high enantioselectivities (Eq.
2). However, it was difficult to prepare 4 for practical use because
diastereoselectivity in arylation reaction of 2a (PG¼CHO) was very
low. We wish herein to report diastereoselective introduction of
2.1. Diastereoselective introduction of nucleophiles into
-proline derivatives at the 5-position
L
First, we investigated introduction of trimethylbenzene and
triethylbenzene into 5-methoxylated
-proline derivatives 2a–d7
L
protected with various N-acyl groups in the presence of Lewis acids
(Eq. 3). The results are shown in Table 1. N-Formylated proline 2a
gave the corresponding arylated product 3a as a diastereomeric
mixture (cis/trans¼43:57, entry 1),4 while N-methoxycarbonylated
2b and N-benzyloxycarbonylated 2c gave compounds 3b and 3c as
a single isomer (cis/trans¼100:0, entries 2 and 3). In the case of
N-benzoylated 2d, trans-3d8 was mainly obtained along with small
amount of cis-3d (cis/trans¼11:89, entry 4). Using SnCl4 instead of
TiCl4 did not affect the diastereoselectivity though the former had
relatively poor yield (entry 5). Triethylbenzene as a nucleophile
nucleophiles into L-proline derivatives at the 5-position. In addi-
tion, synthesis of compound 4 and C2-symmetrical pyrrolidine
derivative 5 derived from cis- and trans-arylated products, and its
application to asymmetric reduction of aromatic imines with
Cl3SiH6 are presented.
* Corresponding author. Tel.: þ81 95 819 2429; fax: þ81 95 819 2476.
E-mail address: onomura@nagasaki-u.ac.jp (O. Onomura).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.004

O. Onomura et al. / Tetrahedron 64 (2008) 7498–7503
7499
Table 1
Nu
(Carbamate)
CO2Me
CO2Me
OR
Arylation of proline derivative 2a–d at the 5-position
>>
N
N
Entry
PG
Lewis acid
R
Yield (%)
cis/trans
O
1
2
3
4
5
6
7
8
9
10
CHO
CO2Me
Cbz
Bz
Bz
CHO
CO2Me
Cbz
Cbz
Bz
2a
2b
2c
2d
2d
2a
2b
2c
2c
2d
TiCl4
TiCl4
TiCl4
TiCl4
SnCl4
SnCl4
SnCl4
SnCl4
TiCl4
SnCl4
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
3a
3b
3c
3d
3d
6a
6b
6c
6c
6d
61
51
68
65
43
71
55
36
31
0
43:57
100:0
100:0
11:89
11:89
52:48
100:0
100:0
100:0
d
O
OR
Lewis Acid
Lewis Acid
(Amide)
carbenium ion
iminium ion
CO2Me
CO2Me
N
N
<<
Nu
Ph
iminium ion
Scheme 1. Plausible stereochemical course.
O
Ph
O
carbenium ion
gave similar results to that of trimethylbenzene (entries 6–9), but in
the case of N-benzoylated proline 2d did not afford 5-arylated
product 6d (entry 10).
R
R = Me, Et (3.0 equiv)
R
R
R
ð3Þ
Lewis acid (1.0 equiv)
N
PG
N
CO2Me
CO2Me
MeO
CH2Cl2, -78 °C to 0 °C, 12h
PG
R
R
3a-d, 6a-d
2a-d
Allylation of 5-methoxylated
L-proline derivatives 2b and 2d
2.2. Synthesis of an organic activator 4 and C2-symmetrical
showed similar tendency to their arylation (Eq. 4). That is,
N-methoxycarbonylated 2b mainly gave cis-allylated proline 7b
(cis/trans¼73:27),7c while N-benzoylated proline 2d preferentially
changed into trans-allylated proline 7d (cis/trans¼13:87).9
pyrrolidine derivative 5
An organic activator 4 for the enantioselective reduction of ke-
tones was synthesized from 6c after hydrogenation, N-formylation
followed by alkaline hydrolysis in 58% yield (Eq. 5).10
C2-symmetrical pyrrolidine derivative 5 was prepared from
N-benzoylated proline 3d as follows (Scheme 2): alkaline hydro-
lysis of 3d followed by recrystallization from CHCl3/hexane affor-
ded carboxylic acid 8 in 54% yield as a single isomer (cis/
trans¼0:100). Electrochemical decarboxylative methoxylation11 of
8 in methanol afforded methoxylated compound 9, which reacted
with mesitylene in the presence of TiCl4 to exclusively afford
allyl-SiMe3 (3.0 equiv for 2b,
1.0 equiv for 2d)
N
PG
N
PG
CO2Me
TiCl4 (1.0 equiv)
CO2Me
MeO
CH2Cl2, -78 °C to 0 °C, 12h
PG = CO2Me 7b : 80% (cis/trans = 73/27)
2b,d
= Bz
7d : 53% (cis/trans = 13/87)
ð4Þ
Et
Et
1) Pd-C, H2, Et3N, MeOH
2) Ac2O, HCO2H
CO2Me
CO2H
N
CHO
N
Cbz
Et
3) NaOH, H2O/THF
Et
ð5Þ
Et
Et
6c
4
58% yield
Key intermediates in these reactions are carbenium and imi-
nium ions illustrated in Scheme 1. Since the carbonyl group of
carbamates (PG¼CO2Me or Cbz) can coordinate to Lewis acid,
carbenium ion will be preferable to iminium ion. On the other
hand, carbonyl group of amide (PG¼Bz) might not coordinate to
Lewis acid. Therefore, the iminium ion will be predominantly
generated. The cis-selectivity in the carbenium ion intermediate
is illustrated in Scheme 1 (Carbamate) in which PG (CO2Me or
Cbz) is oriented in trans position with respect to 2-CO2Me
substituent. Nucleophiles may approach the intermediate prefer-
entially from the trans direction with respect to PG.7c The trans-
selectivity (PG¼Bz) in the iminium ion intermediate is illustrated
in Scheme 1 (Amide) in which Bz and iminium groups exist on
the same plane. Nucleophiles can approach the intermediate
preferentially from the trans direction with respect to 2-CO2Me
substituent.
trans-2,5-biarylated pyrrolidine 10 in high yield. By reduction of
N-benzoyl group of 10, successive deprotection of N-benzyl group
of 11, and N-picolynoylation of 12, desired pyrrolidine 5 was
obtained in good yield.
2.3. Asymmetric reduction of aromatic imines catalyzed by
5 with Cl3SiH
Catalytic activation of Cl3SiH with compound 5 was applicable
to asymmetric reduction of aromatic imines 13a–f (Eq. 6). The re-
sults are summarized in Table 2, which also shows the results of
asymmetric reduction using 156c for comparison. In all cases,
compound 5 could play the role of an activator to afford (S)-amines
14a–f6 with good yield and enantioselectivity comparable to that of
15 (entries 1–6).

7500
O. Onomura et al. / Tetrahedron 64 (2008) 7498–7503
2,6-lutidine (1.3 equiv),
1) NaOH (2.0 equiv),
H2O/THF, rt
C(+)−Pt(-), -2e
3d
Ar
CO2H
N
Bz
2) Recrystallization
from CHCl3/hexane
MeOH, 0 °C
Ar = 1,3,5-trimethylbenzene
8, 54% yield
cis/trans = 11/89
cis/trans = 0/100
TiCl4 (1.0 equiv)
Mesitylene (3.0 equiv)
CH2Cl2, -78 °C to rt
BH3-THF (2.0 equiv),
THF, reflux
Ar
Ar
OMe
Ar
N
Bz
N
Bz
9, 73% yield
10, 88% yield
(cis/trans=0/100)
Picolinic acid
Pd(OH)2, aq.HCl
MeOH, H2, rt
Ar
Ar
(1.1 equiv),
N
Ar
Ar
CDI (1.5 equiv)
N
Ar
Ar
N
H
O
CH2Cl2, rt
Bn
N
11
12, 81% yield (from 10)
5, 93% yield
Scheme 2.
Table 2
standard. IR spectra were obtained on a Shimadzu FTIR-8100A.
Mass spectra were obtained on a JEOL JMS-DX 303 instrument.
Elemental analyses were performed on Perkin Elmer 2400II.
All reagents and solvents were used as supplied without further
purification.
Asymmetric reduction of imines 13a–f
Entry Imine R1
R2
(S)-
Amine
Activator 5
Activator 15
Yield (%) eea (%) Yield (%) eea (%)
1
2
3
4
5
6
13a
13b
13c
13d
13e
13f
H
H
OMe
H
H
H
14a
92
84
87
88
60
74
77
78
76
73
64
85
86
90
90
73
24
84
73
71
75
71
67
73
OMe 14b
H
Cl
Ac
NO2
14c
14d
14e
14f
4.2. Methyl N-protected 5-methoxy-
L
-prolinates 2a–d
-prolinates 2a,7c 2b,7a 2c,7d and 2d7b
H
N-Protected 5-methoxy-
L
a
were known compounds.
Determined by HPLC.
R1
R1
Cl3SiH (1.5 equiv)
Ph
N
5 or 15 (0.1 equiv)
HN
N
Ph
ð6Þ
CH2Cl2, rt, 4h
OH
Me
O
Me
R2
N
R2
13a-f
14a-f
15
3. Conclusion
4.3. General procedure for arylation or allylation of methyl
N-protected-5-methoxy- -prolinate 2a–d
L
We have accomplished diastereoselective introduction of
nucleophiles into -proline derivatives at the 5-position. N-Meth-
oxycarbonylated or N-benzyloxycarbonylated -proline 2b or 2c
was exclusively transformed into cis-arylated products 3b,c or 6b,c,
while N-benzoylated -proline derivative 2d mainly gave trans-
arylated product 3d. C2-symmetrical pyrrolidine derivative 5 de-
rived from 3d worked well as an organic activator in the reduction
of aromatic imines to the corresponding optically active amines
with high enantioselectivity by Cl3SiH.
L
Under an argon atmosphere, TiCl4 (55 mL, 0.5 mmol) was added
L
dropwise to the solution of 2a (109 mg, 0.5 mmol) and 1,3,5-tri-
methylbenzene (209
m
L, 1.5 mmol) in CH2Cl2 (5 mL) at ꢀ78 ꢁC. The
L
resulting mixture was stirred for 12 h and allowed to stand until it
warmed to room temperature. The solution was poured in ice water
(10 mL) and extracted with CHCl3 (10 mLꢂ3). The combined or-
ganic layer was dried over MgSO4 and the solvent removed under
reduced pressure. The residue was purified by silica gel column
chromatography (n-hexane/AcOEt¼10:1) to afford 3a as a colorless
oil (93 mg, 61%). Arylation with 1,3,5-triethylbenzene and allylation
with allyltrimethylsilane were carried out according to this same
procedure.
4. Experimental section
4.1. General
Electrochemical reactions were carried out using DC Power
Supply (GP 050-2) of Takasago Seisakusho, Inc. 1H NMR spectra
were measured on a Varian Gemini 300 and 400 spectrometer with
TMS as an internal standard. 13C NMR spectra were measured on
a Varian Gemini 400 spectrometer with TMS as an internal
4.3.1. Methyl cis-N-formyl-5-(2,4,6-trimethylphenyl)-L-prolinate
(cis-3a)4
Colorless oil; 1H NMR (300 MHz, CDCl3)
d 7.85 (s, 1H), 6.88 (s,
2H), 5.04 and 5.06 (d, J¼11.0 Hz, 1H), 4.53 (t, J¼5.4 Hz, 1H), 3.80 (s,
3H), 2.55–1.95 (m, 13H).

O. Onomura et al. / Tetrahedron 64 (2008) 7498–7503
7501
4.3.2. Methyl trans-N-formyl-5-(2,4,6-trimethylphenyl)-
L
-prolinate
14.8; HR-EI(þ) m/z calcd for C20H29NO4 [M]þ 347.2097, found
(trans-3a)4
347.2081.
Colorless oil; 1H NMR (300 MHz, CDCl3)
d 7.81 (s, 1H), 6.85 (s,
2H), 5.37 (t, J¼8.0 Hz, 1H), 4.56 (t, J¼7.5 Hz, 1H), 3.75 (s, 3H), 2.42–
4.3.9. Methyl trans-N-benzyloxycarbonyl-5-(2,4,6-triethylphenyl)-
1.99 (m, 13H).
L
-prolinate (6c)
28
Colorless oil; [
a]
ꢀ42.3 (c 1.0, CHCl3); IR (neat)
n
¼2965, 1755,
D
4.3.3. Methyl N-methoxycarbonyl-5-(2,4,6-trimethylphenyl)-
L
-
1705, 1408, 1339, 1198, 1175, 1080, 696 cmꢀ1 1H NMR (300 MHz,
;
prolinate (3b)
CDCl3)
3.77 (s, 3H), 3.10–1.95 (m, 10H), 1.32–0.86 (m, 9H); 13C NMR
(100 MHz, CDCl3) (a mixture of rotamers) 172.6, 156.7, 142.4,
d 7.40–6.80 (m, 7H), 5.20–4.80 (m, 3H), 4.60–4.50 (m, 1H),
27
Colorless crystal; mp 48–50 ꢁC; [
a
]
ꢀ49.1 (c 1.0, CHCl3); IR
D
(neat)
851, 781 cmꢀ1
(t, J¼9.0 Hz, 1H), 4.59–4.51 (m, 1H), 3.78 (s, 3H), 3.55 (s, 3H),
2.44–2.07 (m, 13H); 13C NMR (100 MHz, CDCl3)
172.5, 157.1,
135.8, 135.6, 133.1, 130.0, 60.4, 52.6, 51.9, 30.2, 27.9, 20.5;
n
¼2953, 1754, 1701, 1612, 1447, 1348, 1198, 1123, 1078,
d
;
1H NMR (300 MHz, CDCl3)
d
6.80 (s, 2H), 5.10
142.3, 142.1, 135.7, 132.3, 128.1, 127.9, 127.7, 127.4, 126.5, 67.0, 61.0,
60.8, 59.9, 57.7, 52.2, 52.1, 33.3, 32.7, 28.9, 28.2, 27.8, 27.5, 27.1, 26.3,
25.1, 25.0, 24.8, 15.9, 15.7, 15.4, 15.3, 15.2; HR-EI(þ) m/z calcd for
d
C
26H33NO4 [M]þ 423.2410, found 423.2394.
HR-EI(þ) m/z calcd for
C
17H23NO4 [M]þ 305.1627, found
305.1623.
4.3.10. Methyl N-methoxycarbonyl-5-allyl-L
-prolinate (7b)7c
1H NMR (400 MHz, CDCl3) (cis/trans¼73:27)
d 5.83–5.65 (m,
4.3.4. Methyl N-benzyloxycarbonyl-5-(2,4,6-trimethylphenyl)-
prolinate (3c)
L
-
1H), 5.12–5.03 (m, 2H), 4.40–4.27 (m, 1H), 4.15–3.91 (m, 1H), 3.77–
3.63 (m, 6H), 2.80–2.42 (m, 1H), 2.25–1.72 (m, 5H).
27
Colorless oil; [
a
]
ꢀ49.6 (c 1.0, CHCl3); IR (neat)
n
¼2960, 1753,
1H NMR
7.35–7.10 (m, 5H), 6.79 (s, 2H), 5.15–4.90 (m,
3H), 4.63–4.55 (m, 1H), 3.74 (s, 3H), 2.45–2.05 (m, 13H); 13C NMR
(100 MHz, CDCl3) 172.5, 156.4, 135.8, 135.7, 133.2, 131.3, 130.1,
D
1701, 1456, 1338, 1197, 1174, 1120, 851, 735 cmꢀ1
(300 MHz, CDCl3)
;
4.3.11. Methyl N-benzoyl-5-allyl-
L
-prolinate (7d)
20
d
Colorless oil; [
1750, 1644, 1603, 1446, 1410, 1277, 1203, 1174, 1076 cmꢀ1
7.53–7.28 (m, 5H), 5.97–5.80
a
]
D
ꢀ26.9 (c 1.0 CHCl3); IR (neat)
n
¼2977, 2953,
;
1H NMR
d
(400 MHz, CDCl3) (cis/trans¼13:87)
d
129.3, 128.2, 127.9, 127.8, 127.4, 127.2, 67.0, 60.4, 52.0, 30.4, 27.8,
20.6, 20.5; HR-EI(þ) m/z calcd for C23H27NO4 [M]þ 381.1940, found
381.1938.
(m, 0.5H), 5.55–5.38 (m, 0.5H), 5.16–4.72 (m, 2H), 4.44–4.17 (m,1H),
3.96 (br s, 0.5H), 3.77–3.60 (m, 3H), 3.06 (br s, 0.5H), 2.23–1.18 (m,
6H); 13C NMR (100 MHz, CDCl3) (cis/trans¼13:87, a mixture of
rotamers) d 173.0, 171.5, 134.7, 133.5, 129.7, 128.3, 128.2, 126.7, 126.5,
4.3.5. Methyl trans-N-benzoyl-5-(2,4,6-trimethylphenyl)-
L
-
118.1, 117.6, 62.1, 59.6, 59.3, 58.9, 52.2, 39.1, 38.4, 37.7, 28.9, 28.5,
26.8; HR-FAB(þ) m/z calcd for C16H20NO3 [MþH]þ 274.1443, found
274.1444.
prolinate (3d)
18
Colorless crystal; mp 112–114 ꢁC; [
a
]
ꢀ133.5 (c 1.0, CHCl3); IR
D
(neat)
1279, 1202, 1175, 1127, 1028, 853 cmꢀ1
7.50–7.00 (m, 5H), 6.80 (br s, 0.11H), 6.64 (s,
n
¼2953, 1755, 1745, 1659, 1641, 1632, 1580, 1444, 1414,
;
1H NMR (300 MHz, CDCl3)
4.4. Synthesis of cis-N-formyl-5-(2,4,6-triethylphenyl)-L-
proline (4)
(cis/trans¼11:89)
d
0.89H), 6.60 (br s, 0.11H), 6.39 (s, 0.89H), 5.64 (t, J¼8.7 Hz,
0.11H), 5.40 (t, J¼8.7 Hz, 0.89H), 4.77 (t, J¼9.0 Hz, 1H), 3.83–3.76
Pd–C (5%, 30 mg) was added to the solution of 6c (2.0 mmol,
847 mg) and triethylamine (279 L, 2.0 mmol) in MeOH (5.0 mL).
(m, 3H), 2.58–1.95 (m, 13H); 13C NMR (100 MHz, CDCl3)
d
170.8,
m
169.5, 134.3, 133.3, 132.1, 129.6, 127.2, 127.0, 125.4, 123.5, 59.3,
58.0, 50.3, 30.4, 26.8, 18.4, 18.3; HR-EI(þ) m/z calcd for C22H25NO3
[M]þ 351.1834, found 351.1832. HPLC: Daicel Chiralcel OJ-H
column, n-hexane/isopropanol¼20:1, wavelength: 254 nm, flow
rate: 1.0 ml/min, retention time: 19.1 min (cis-3d), 23.3 min
(trans-3d).
The mixture was then stirred under 1 atm of H2 for 12 h. Upon
completion of reaction, the mixture was then filtered through
Celite and solvent was removed in vacuo to obtain methyl cis-5-
(2,4,6-triethylphenyl)-L-prolinate, which was used for next reaction
28
without further purification. Colorless oil; [
a]
þ13.4 (c 1.1, CHCl3);
D
IR (neat)
n
¼3350, 2963, 1734, 1458, 1210, 874, 669 cmꢀ1
;
1H NMR
(300 MHz, CDCl3)
d
6.89 (s, 2H), 4.57 (t, J¼8.7 Hz, 1H), 3.87 (t,
4.3.6. Methyl cis-N-formyl-5-(2,4,6-triethylphenyl)-
L
-prolinate
J¼7.8 Hz, 1H), 3.76 (s, 3H), 2.90–2.50 (m, 6H), 2.35–2.00 (m, 4H),
(cis-6a)4
1.78 (br s, 1H), 1.23 (t, J¼7.5 Hz, 9H); HR-EI(þ) m/z calcd for
Colorless oil; 1H NMR (300 MHz, CDCl3)
d
7.87 (s, 1H), 7.10–6.82
C
18H27NO2 [M]þ 289.2042, found 289.2027.
(br s, 2H), 5.03 and 5.01 (d, J¼12.0 Hz, 1H), 4.58–4.50 (m, 1H), 3.80
Under an argon atmosphere, acetic anhydride (2.0 mL) was
(s, 3H), 2.95–2.05 (m, 10H), 1.30–1.10 (m, 9H).
added dropwise to a solution of methyl cis-5-(2,4,6-triethyl-
phenyl)- -prolinate in formic acid (6.0 mL) and stirred at room
L
4.3.7. Methyl trans-N-formyl-5-(2,4,6-triethylphenyl)-
L
-prolinate
temperature for 9 h. Upon completion of reaction, the solvent was
removed under reduced pressure, then the residue was purified by
silica gel column chromatography (n-hexane/AcOEt¼3:1) to afford
(trans-6a)4
Colorless oil; 1H NMR (300 MHz, CDCl3)
d 7.79 (s, 1H), 6.99 (s,
1H), 6.88 (s, 1H), 5.34 and 5.33 (d, J¼9.9 Hz, 1H), 4.62 (t, J¼7.8 Hz,
1H), 3.80 (s, 3H), 2.74 (q, J¼7.8 Hz, 2H), 2.65–2.40 (m, 5H), 2.38–2.01
(m, 3H), 1.30–1.10 (m, 9H).
methyl cis-N-formyl-5-(2,4,6-triethylphenyl)-L
-prolinate4 as a col-
orless crystals (372 mg, 58% for two steps). Then, aqueous 1 M
NaOH (2.0 mL) was added to the stirred solution of methyl cis-N-
formyl-5-(2,4,6-triethylphenyl)-L-prolinate (1.0 mmol, 317 mg) in
4.3.8. Methyl trans-N-methoxycarbonyl-5-(2,4,6-triethylphenyl)-
L
-
MeOH (4.0 mL), and the solution was stirred at room temperature
for 12 h. The solution was neutralized with 3% aqueous HCl, and
then MeOH was evaporated. The residue was diluted with brine,
extracted with AcOEt, and dried over MgSO4. Removal of the sol-
prolinate (6b)
28
Colorless oil; [
a]
ꢀ41.3 (c 1.1, CHCl3); IR (neat)
n
¼2963, 1755,
1H NMR
6.86 (m, 2H), 5.10 (t, J¼8.7 Hz, 1H), 4.60–4.50
(m, 1H), 3.80–3.50 (m, 6H), 2.80–2.11 (m, 10H), 1.30–1.10 (m, 9H);
13C NMR (100 MHz, CDCl3) (a mixture of rotamers)
172.8,
D
1709, 1445, 1348, 1198, 1150, 1125, 1080, 874, 781 cmꢀ1
(300 MHz, CDCl3)
;
d
vent afforded compound 44 (303 mg, quant.) as colorless crystals.
25
Mp 132–133 ꢁC; [
CDCl3) d 7.96 (s, 1H), 6.98 (s, 1H), 6.89 (s, 1H), 5.21 and 5.19 (d,
a]
ꢀ135.5 (c 0.5, CHCl3); 1H NMR (300 MHz,
D
d
157.1, 142.5, 142.1, 141.9, 141.7, 132.0, 127.0, 125.5, 60.5, 59.8,
52.1, 51.8, 32.6, 28.2, 28.0, 26.5, 25.6, 24.9, 24.7, 15.9, 15.5, 15.4, 15.2,
J¼11.0 Hz, 1H), 4.75 (q, J¼9.3 Hz, 1H), 2.90 and 2.88 (d, J¼10 Hz, 1H),
2.85–2.05 (m, 9H), 1.30–1.10 (m, 9H).

7502
O. Onomura et al. / Tetrahedron 64 (2008) 7498–7503
4.5. Synthesis of N-picolinoyl (2S,5S)-[2,5-bis-(2,4,6-
(2S,5S)-10. EA calcd for C29H33NO: C, 84.63; H, 8.08; N, 3.40. Found:
trimethylphenyl)]pyrrolidine (5)
C, 84.43; H, 8.15; N, 3.02.
4.5.1. trans-N-Benzoyl-5-(2,4,6-trimethylphenyl)-
L
-proline (8)
4.5.4. N-Benzyl-(2S,5S)-[2,5-bis-(2,4,6-trimethylphenyl)]-
pyrrolidine (11)
NaOH (12.9 mmol, 516 mg) was added to the stirred solution of
3d (6.5 mmol, 2.27 g) in THF/H2O¼1:1 (60 mL), and the solution
was stirred at room temperature for 4 h. The solution was then
neutralized with 10% aqueous HCl, and extracted with AcOEt
(150 mLꢂ3), and dried over MgSO4. After removal of the solvent
BH3/THF (1.03 M, 17.4 mL, 18.0 mmol) was added to the solution
of 10 (3.6 g, 8.7 mmol) in THF (70 mL) and refluxed at 80 ꢁC for 17 h.
The solution was poured in water (100 mL) and extracted with
AcOEt (100 mLꢂ3). The combined organic layer was dried over
MgSO4 and the solvent removed in vacuo to obtain 11 (3.45 g,
and recrystallization from CHCl3/hexane, compound
8 was
19
obtained as colorless crystals (1.27 g, 58%). Mp 204–207 ꢁC; [
ꢀ82.3 (c 0.3, CHCl3); IR (neat) ¼3640, 1727, 1642, 1620, 1445,
1354, 1123 cmꢀ1 1H NMR (300 MHz, CDCl3)
7.20–7.00 (m, 5H),
a
]
quant.), which was used for next reaction without further purifi-
D
23
n
cation. Colorless crystal; mp 109–110 ꢁC; [
a
]
D
ꢀ124.5 (c 1.0, CHCl3);
;
d
IR (neat)
n
¼2947, 1611, 1480, 1372, 1312, 1213, 1188, 1165, 1105, 1075,
6.66 (s, 1H), 6.41 (s, 1H), 5.38 (t, J¼8.4 Hz, 1H), 4.83 (t, J¼7.8 Hz,
1028, 851, 741, 700 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
7.00–6.89 (m,
1H), 4.20 (br s, 1H), 2.58–1.90 (m, 13H); 13C NMR (100 MHz, CDCl3)
3H), 6.78 (s, 2H), 6.63 (s, 2H), 6.38 (dd, J¼2.1, 7.8 Hz, 2H), 4.95 (t,
(a mixture of rotamers)
d 176.1, 171.4, 136.2, 136.0, 135.7, 135.1,
J¼7.2 Hz, 2H), 3.37 (q, J¼12.9 Hz, 2H), 2.41–2.11 (m, 22H); 13C NMR
134.5, 134.1, 134.0, 131.2, 130.2, 129.2, 128.9, 128.1, 127.6, 127.4,
125.6, 63.1, 61.4, 60.3, 59.4, 32.3, 31.0, 29.9, 28.6, 20.6, 20.4,
20.3; HR-EI(þ) m/z calcd for C21H23NO3 [M]þ 337.1678, found
337.1674. EA calcd for C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found:
C, 74.41; H, 6.92; N, 3.93.
(100 MHz, CDCl3) d 140.9, 138.8, 136.9, 136.3, 135.8, 131.2, 129.5,
129.2, 127.3, 125.9, 60.9, 51.7, 31.0, 21.5, 20.9; HR-EI(þ) m/z calcd for
C
29H35N [M]þ 397.2769, found 397.2766.
4.5.5. (2S,5S)-[2,5-Bis-(2,4,6-trimethylphenyl)]pyrrolidine (12)
Pd(OH)2 (20%, 80 mg, 0.12 mmol) was added to the solution of
11 (228 mg, 0.57 mmol) and three drops of concentrated aqueous
HCl in MeOH (5.0 mL). The mixture was then stirred under 1 atm of
H2 for 3 h. Upon completion of reaction, the mixture was then fil-
tered through Celite and solvent was removed in vacuo. The residue
was poured into saturated aqueous NaHCO3 (10 mL) and extracted
with CHCl3 (20 mLꢂ3). The combined organic layer was dried over
MgSO4 and the solvent removed in vacuo to afford 12 (142 mg, 81%
4.5.2. N-Benzoyl-2-methoxy-(5S)-(2,4,6-trimethylphenyl)-
pyrrolidine (9)
Anodic oxidation of 8 was carried out using graphite cathode
(10 cmꢂ5 cm) and platinum anode (12 cmꢂ5 cm) in an undivided
beaker-type cell. 8 (29.4 mmol, 9.9 g), and 2,6-lutidine (38.2 mmol,
4.5 mL) was added into MeOH (200 mL). After passing through
2.0 F/mol of electricity at constant voltage (18 V) at 0 ꢁC, MeOH
was evaporated, then the residue was poured in water, and
extracted with AcOEt (200 mLꢂ3). The combined organic layer
was dried over MgSO4 and the solvent removed under reduced
pressure. The residue was purified by silica gel column chroma-
from 10), which was used for next reaction without further puri-
22
fication. Colorless oil; [
a
]
ꢀ107.1 (c 0.5, CHCl3); IR (neat)
n
¼2951,
6.81 (s,
4H), 5.04 (t, J¼7.2 Hz, 2H), 2.46 (s, 12H), 2.23 (s, 6H), 2.13–2.08 (m,
D
1611, 1462, 1084, 849 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d
tography (n-hexane/AcOEt¼3:1) to afford 9 (6.9 g, 73% yield) as
4H), 1.68 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d 134.8, 134.2, 133.5,
24
colorless oil. [
a
]
D
þ17.8 (c 1.0, CHCl3); IR (neat)
n
¼2732, 1765, 1727,
128.2, 56.4, 31.0, 18.7, 18.6; HR-EI(þ) m/z calcd for C22H29N [M]þ
1692, 1642, 1613, 1582, 1547, 1503, 1468 cmꢀ1
CDCl3) 7.83 (br s, 2H), 7.37 (br s, 3H), 6.77 (s, 2H), 5.23 (br s, 1H),
4.72 (br s, 1H), 3.14 (s, 3H), 2.60–2.03 (m, 13H); 13C NMR (100 MHz,
CDCl3) (a mixture of diastereomers and rotamers) 171.3, 169.2,
;
1H NMR (300 MHz,
307.2300, found 307.2281.
d
4.5.6. N-Picolinoyl-(2S,5S)-[2,5-bis-(2,4,6-trimethylphenyl)]-
pyrrolidine (5)
d
135.8, 133.8, 133.4, 132.6, 132.0, 130.7, 129.7, 129.5, 127.8, 126.5,
125.9, 125.6, 125.2, 123.2, 92.7, 90.0, 60.2, 58.1, 54.5, 31.5, 31.1, 30.6,
28.6, 20.6, 20.5; HR-EI(þ) m/z calcd for C21H25NO2 [M]þ 323.1885,
found 323.1866.
A solution of picolinic acid (68.9 mg, 0.55 mmol) and CDI
(122 mg, 0.75 mmol) in CH2Cl2 (2.5 mL) was stirred at 0 ꢁC for
30 min. Then, a solution of 12 (153 mg, 0.50 mmol) in CH2Cl2
(2.5 mL) was added at 0 ꢁC, and the mixture was stirred at room
temperature for 24 h. The solution was poured into saturated
aqueous NaHCO3 (10 mL) and extracted with AcOEt (20 mLꢂ3). The
combined organic layer was dried over MgSO4 and the solvent re-
moved under reduced pressure. The residue was purified by silica
4.5.3. N-Benzoyl-(2S,5S)-[2,5-bis-(2,4,6-trimethylphenyl)]-
pyrrolidine (10)
Under an argon atmosphere, TiCl4 (140 mL, 1.0 mmol) was added
dropwise to the solution of 9 (313 mg, 0.97 mmol) and 1,3,5-tri-
gel column chromatography (n-hexane/AcOEt¼5:1) to afford 5
20
methylbenzene (400
m
L, 2.9 mmol) in CH2Cl2 (10 mL) at ꢀ78 ꢁC.
(192 mg, 93% yield) as colorless crystals. Mp 73–74 ꢁC; [
a
]
þ6.8 (c
D
The resulting mixture was stirred for 24 h and allowed to stand
until it warmed to room temperature. The solution was poured in
ice water (10 mL) and extracted with CHCl3 (10 mLꢂ3). The com-
bined organic layer was dried over MgSO4 and the solvent removed
under reduced pressure. The residue was purified by silica gel
0.3, CHCl3); IR (neat)
n
¼2963, 1738, 1639, 1503, 1443, 1408, 1356,
1287, 1242, 1183, 1107, 851 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
8.30
(d, J¼4.2 Hz, 1H), 7.32–7.26 (m, 2H) 6.91 (t, J¼4.8 Hz, 1H), 6.85 (s,
1H), 6.79 (s, 1H), 6.53 (s, 1H), 6.40 (s, 1H), 6.03 (t, J¼7.2 Hz, 1H), 5.67
(t, J¼7.2 Hz, 1H), 2.63–2.02 (m, 22H); 13C NMR (100 MHz, CDCl3) (a
column chromatography (n-hexane/AcOEt¼10:1) to afford 10
mixture of rotamers) d 167.1, 154.4, 146.7, 136.1, 135.9, 135.7, 135.5,
22
(351 mg, 88%) as colorless crystals. Mp 184–187 ꢁC; [
a
]
þ24.9 (c
135.4, 134.6, 134.5, 133.9, 131.1, 130.7, 129.0, 128.6, 123.7, 122.5, 60.0,
D
0.5, CHCl3); IR (neat)
n
¼2963, 1738, 1632, 1580, 1483, 1408, 1348,
59.8, 32.2, 29.9, 21.0, 20.6, 20.5, 20.3, 19.9; HR-EI(þ) m/z calcd for
1240, 1102, 849, 795 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
7.20–7.00
C
28H32N2O [M]þ 412.2515, found 412.2506. EA calcd for C28H32N2O:
(m, 5H), 6.85 (s, 1H), 6.81 (s, 1H), 6.60 (s, 1H), 6.35 (s, 1H), 5.65–5.59
C, 81.51; H, 7.82; N, 6.79. Found: C, 81.21; H, 7.84; N, 6.54.
(m, 2H), 2.61–2.20 (m, 22H); 13C NMR (100 MHz, CDCl3) (a mixture
of rotamers)
d
169.7, 137.3, 136.8, 136.0, 135.8, 134.9, 134.6, 134.5,
4.6. General procedure for asymmetric reduction of
imines 13a–f
133.6, 131.2, 131.0, 129.3, 129.2, 128.8, 127.1, 126.2, 60.3, 60.0, 32.4,
30.2, 21.2, 20.7, 20.6, 20.4, 20.1; HR-EI(þ) m/z calcd for C29H33NO
[M]þ 411.2562, found 411.2560. HPLC: Daicel Chiralcel OD-H
column, n-hexane/ethanol¼30:1, wavelength: 254 nm, flow rate:
1.0 mL/min, retention time: 8.9 min for (2R,5R)-10, 11.9 min for
Cl3SiH (0.45 mmol) was added into a solution of imine 13a
(0.3 mmol) and compound 5 (0.03 mmol) in CH2Cl2 (1.5 mL), and
the mixture was stirred at room temperature for 4 h. The mixture

O. Onomura et al. / Tetrahedron 64 (2008) 7498–7503
7503
was then poured into saturated aqueous NaHCO3 (10 mL) and
Acknowledgements
extracted with CHCl3 (10 mLꢂ3). The combined organic layer was
dried over MgSO4 and the solvent removed under reduced pres-
sure. The residue was purified by silica gel column chromatography
to afford amine 14a (159 mg, 77% yield).
This work was supported by a Grant-in-Aid for Scientific
Research (C) (19550109) from Japan Society for the Promotion of
Science, and a Grant-in-Aid for Young Scientists (B) (19790017)
from the Ministry of Education, Science, Sports and Culture, Japan.
4.6.1. (S)-N-Phenyl-N-(1-phenylethyl)amine (14a)6b
HPLC: Daicel Chiralcel OD-H column, n-hexane/isopropanol/
diethylamine¼10:1:0.01, wavelength: 254 nm, flow rate: 1.0 mL/
min, retention time: 7.2 min for (S)-14a, 8.6 min for (R)-14a.
References and notes
1. (a) Pichon, M.; Figade`re, B. Tetrahedron: Asymmetry 1996, 7, 927–964; (b)
Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron 2004, 60, 7301–7314;
(c) Esseveldt, B. C. J.; Vervoort, P. W. H.; van Delft, F. L.; Rutjes, P. J. T. J. Org. Chem.
2005, 70, 1791–1795; (d) Davis, F. A.; Song, M.; Augustine, A. J. Org. Chem. 2005,
71, 2779–2786.
2. (a) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J. Am.
Chem. Soc. 2004, 126, 4790–4791; (b) Simonini, V.; Benaglia, M.; Pignataro, L.;
Guizzetti, S.; Celentano, G. Synlett 2008, 1061–1065.
4.6.2. (S)-N-[1-(4-Methoxylphenyl)ethyl-N-phenylamine (14b)6b
HPLC: Daicel Chiralcel OD-H column, n-hexane/isopro-
panol¼99:1, wavelength: 254 nm, flow rate: 0.7 mL/min, retention
time: 13.1 min for (S)-14b, 14.4 min for (R)-14b.
3. (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981, 103, 1172–1176;
(b) Shono, T.; Matsumura, Y.; Tsubata, K.; Uchida, K. J. Org. Chem. 1986, 51,
2590–2592; (c) Dhimane, H.; Vanucci-Bacque´, C.; Hamon, L.; Lhommet, G. Eur. J.
Org. Chem. 1998, 9, 1955–1963; (d) Kim, S.; Hayashi, K.; Kitano, Y.; Tada, M.;
Chiba, K. Org. Lett. 2002, 4, 3735–3737; (e) Onomura, O.; Ishida, Y.; Maki, T.;
Minato, D.; Demizu, Y.; Matsumura, Y. Electrochemistry 2006, 74, 645–648.
4. Matsumura, Y.; Ogura, K.; Kouchi, Y.; Iwasaki, F.; Onomura, O. Org. Lett. 2006, 8,
3789–3792.
5. Iwasaki, F.; Onomura, O.; Mishima, K.; Maki, T.; Matsumura, Y. Tetrahedron Lett.
1999, 40, 7507–7511.
6. (a) Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.; Maki, T.; Matsumura,
Y. Tetrahedron Lett. 2001, 42, 2525–2527; (b) Malkov, A. V.; Mariani, A.; Mac-
4.6.3. (S)-N-(4-Methoxylphenyl)-N-(1-phenylethyl)amine (14c)6b
HPLC: Daicel Chiralcel OD-H column, n-hexane/isopro-
panol¼99:1, wavelength: 254 nm, flow rate: 0.7 mL/min, retention
time: 17.5 min for (S)-14c, 19.3 min for (R)-14c.
4.6.4. (S)-N-[1-(4-Chlorophenyl)ethyl]-N-phenylamine (14d)6c
HPLC: Daicel Chiralcel OD-H column, n-hexane/isopro-
panol¼95:5, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 9.0 min for (S)-14d, 10.8 min for (R)-14d.
ˇ
´
Dougall, K. N.; Kocovsky, P. Org. Lett. 2004, 6, 2253–2266; (c) Onomura, O.;
Kouchi, Y.; Iwasaki, F.; Matsumura, Y. Tetrahedron Lett. 2006, 47, 3751–3754; (d)
Malkov, A. V.; Stewart Liddon, A. J. P.; Ramı´rez-Lo´pez, P.; Bendova´, L.; Haigh, D.;
4.6.5. (S)-N-[1-(4-Acetylphenyl)ethyl]-N-phenylamine (14e)
27
ˇ
´
Kocovsky, P. Angew. Chem., Int. Ed. 2006, 45, 1432–1435; (e) Wang, Z.; Wei, S.;
Wang, C.; Sun, J. Tetrahedron: Asymmetry 2007, 18, 705–709.
Pale yellow oil; [
a
]
D
ꢀ18.8 (c 0.7, CHCl3); IR (neat) ¼3390,
n
3054, 2980, 2926, 2869, 1678, 1603, 1506, 1429, 1360, 1320, 1269,
7. (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.; Yamane, S.; Kanazawa, T.;
Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697–6703; (b) Shono, T.; Matsumura, Y.;
Kanazawa, T.; Habuka, M.; Uchida, K.; Toyoda, K. J. Chem. Res., Synop. 1984, 320–
321; J. Chem. Res., Miniprint 1984, 2873–2889; (c) Shono, T.; Fujita, T.; Matsu-
mura, Y. Chem. Lett. 1991, 81–84; (d) Ce´lime`ne, C.; Dhimane, H.; Lhommet, G.
Tetrahedron 1998, 54, 10457–10468.
8. Stereoconfiguration of trans-3d was determined by the X-ray analysis. Crys-
tallographic data for this structure have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
686483. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB21EZ, UK; fax: þ44(0) 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk.
9. After hydrogenation of 7d, its stereoconfiguration was determined by com-
parison with authentic sample, see: Cossy, J.; Ce´cile, D.; Pardo, D. G. Synlett
1997, 905–906.
10. Deprotection of 6b with Me3SiI led to epimerization at the 5-position.
11. (a) Iwasaki, T.; Horikawa, H.; Matsumoto, K.; Miyoshi, M. J. Org. Chem. 1979, 44,
1552–1554; (b) Matsumura, Y.; Wanyoike, G. N.; Onomura, O.; Maki, T.
Electrochim. Acta 2003, 48, 2957–2966.
1210, 1181, 1144, 1015, 1015, 959 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
7.92 (d, J¼8.7 Hz, 2H), 7.47 (d, J¼8.7 Hz, 2H), 7.08 (t, J¼6.9 Hz, 2H),
6.65 (t, J¼6.3 Hz, 1H), 6.47 (d, J¼7.8 Hz, 2H), 4.53 (q, J¼8.2 Hz, 1H),
4.08 (br s, 1H), 2.58 (s, 3H), 1.53 (d, J¼6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d 197.7, 151.0, 146.8, 136.0, 129.2, 129.1, 128.9,
126.0, 113.2, 53.4, 26.6, 24.9; HR-EI(þ) m/z calcd for C16H17NO [M]þ
239.1310, found 239.1287. HPLC: Daicel Chiralcel OD-H column,
n-hexane/isopropanol¼5:1, wavelength: 254 nm, flow rate: 1.0 mL/
min, retention time: 11.1 min for (S)-14e, 13.2 min for (R)-14e.
4.6.6. (S)-N-[1-(4-Nitrophenyl)ethyl]-N-phenylamine (14f)6b
HPLC: Daicel Chiralcel OD-H column, n-hexane/isopro-
panol¼95:5, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 33.5 min for (S)-14f, 38.0 min for (R)-14f.