Synthesis and catalytic activities of (S)-1-formylpyrrolidine-2-carboxylic acid derivatives for the enantioselective reductions of both a ketone and a ketimine

Article abstract of DOI:10.3184/030823408X318433

A series of (S)-1-formylpyrrolidine-2-carboxylic acid derivatives (6a-t) have been synthesised and examined as chiral organocatalysts in the asymmetric reduction of both ketone 2 and ketimine 3. These organic activators afforded good to moderate enantiose

Full text of DOI:10.3184/030823408X318433

266 RESEARCH PAPER
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Synthesis and catalytic activities of (S)-1-formylpyrrolidine-2-carboxylic
acid derivatives for the enantioselective reductions of both a ketone and
a ketimine
Zhenfei Chena, Anjiang Zhang*a,b, Lixue Zhanga, Jing Zhanga and Xinxiang Leia
aCollege of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325027, P. R. China
bNingbo Institute of Material Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, P. R. China
A series of (S)-1-formylpyrrolidine-2-carboxylic acid derivatives (6a–t) have been synthesised and examined as chiral
organocatalysts in the asymmetric reduction of both ketone 2 and ketimine 3. These organic activators afforded
good to moderate enantioselectivities in the asymmetric reductions of both the ketone and the ketimine. Among
them, organic activator 6h displayed the best efficiency, affording a 84% yield and 41% ee in the reduction of the
ketone and 75% yield and 52% ee in the reduction of the ketimine.
Keywords: organic activators, ketone, ketimine, asymmetric reduction
During the past few decades, asymmetric reductions of
ketones and imines have emerged as one of the most important
¿HOGVꢀ LQꢀ RUJDQLFꢀ V\QWKHVLVꢁꢀ $OWKRXJKꢀ Dꢀ YDULHW\ꢀ RIꢀ FDWDO\WLFꢀ
methods have been used for the enantioselective reductions
of both ketones and imines, the transition metal complexes
which are commonly used, often require elevated pressures
and/or additives to afford high yields and ee values.1-5
Therefore, attention has been turned to the development of
chiral organocatalysts. Organic chiral activators are important
in the enantioselective reductions of both ketones and imines
by HSiCl3, which is an economical and easy to handle
reagent.6 Matsumura et al.6ꢀUHSRUWHGꢀWKHꢀ¿UVWꢀRUJDQRFDWDO\WLFꢀ
enantioselective reduction method applicable to both ketones
and imines. This employed a chiral organic Lewis base (1a,b)
as the catalyst and trichlorosilane (HSiCl3) as the reducing
agent. It gave low to moderate enantioselectivities.6,7 Until
now only a few new organic activators for the enantioselective
reductions of both ketones and imines have been reported
to work well and all the organocatalysts have narrow
substrate scope.8-10 &RQVHTXHQWO\ꢀWKHꢀVHDUFKꢀIRUꢀWKHꢀHI¿FLHQWꢀ
organocatalysts for enantioselective reductions of both ketones
and imines is still necessary. Herein, we report our studies on
the Lewis basic organocatalysts 6a–t (Fig. 1).
Results and discussion
,QꢀRUGHUꢀWRꢀ¿QGꢀVXLWDEOHꢀRUJDQLFꢀDFWLYDWRUVꢀIRUꢀHQDQWLRVHOHFWLYHꢀ
reductions of both ketones and ketimines by trichlorosilane, we
¿UVWꢀSUHSDUHGꢀDꢀVHULHVꢀRIꢀꢂS)-1-formylpyrrolidine-2-carboxylic
acid derivatives (6a–t, Fig. 1). The catalysts were examined
in the reduction of both paraꢃWULÀXRURPHWK\OSKHQ\Oꢀ PHWK\Oꢀ
ketone 2 and ketimine 3 with HSiCl3 at –20°C for 16 h with
dichloromethane as the solvent, affording low to moderate
enantioselectivities (Scheme 1). The results are shown in
Table 1. It was found that all of the catalysts exhibited better
enantioselectivities in the reduction of ketimine 3 than in
the reduction of ketone 2 except for catalysts 6a and 6f
(entries 1 and 6). Organic activator 6h displayed the best
HI¿FDF\ꢄꢀDIIRUGLQJꢀDQꢀꢅꢆꢇꢀ\LHOGꢀDQGꢀꢆꢈꢇꢀHHꢀLQꢀWKHꢀUHGXFWLRQꢀ
of ketone 2ꢀDQGꢀꢉꢊꢇꢀ\LHOGꢀDQGꢀꢊꢋꢇꢀHHꢀLQꢀWKHꢀUHGXFWLRQꢀRIꢀ
ketimine 3ꢀꢂHQWU\ꢀꢅꢌꢁꢀ$OWKRXJKꢀFDWDO\VWꢀ6oꢀJDYHꢀDQꢀꢅꢊꢇꢀ\LHOGꢀ
DQGꢀꢍꢋꢇꢀHHꢀIRUꢀWKHꢀUHGXFWLRQꢀRIꢀNHWLPLQHꢀ3, it showed very
O
O
N
CHO
HN
R
X
N
CHO
N
N
CHO
6b g
-
6a
1a
: X = CONHPh
1b: X = CONH-1-Naph
6b
6c
: R=(2-furyl)CH2; : R=4-FC6H4CH2;
6d: R=4-ClC6H4CH2; 6e:R=C6H5CH2CH2;
6f
6g
: R=4-CH3C6H4; : R=4-ClC6H4.
O
R1
N
CHO
HN
*
R2
O
R3
6h q
-
N
HN
*
R4
CHO
1
2
1
2
6h
6j
6i
: R =CH2OAc, R =CH(CH3)2; : R =CH2OAc, R =CH2OAc;
1
2
1
2
6r t
-
6k
: R =CH2OAc, R =CH3; : R =COOCH3, R =CH3;
6l: R1=COOCH3, R2=CH2COOCH3;
3
4
6m: R1=COOCH3, R2=CH2CH2COOCH3;
6r
: R =CH2OAc, R =CH3;
: R =COOCH3, R =CH3;
3
4
6n: R1=COOCH3, R2=Ph; 6o: R1=COOCH3, R2=CH2Ph;
6s
6t: R3=COOCH3, R4=CH2Ph.
1
2
6p
6q
: R =COOCH3, R =CH2(4-CH3COOC6H4);
: R =COOCH3, R =CH2(3H- indol-3-yl).
1
2
Fig. 1 The structures of organic activators 6a–t.
* Correspondent. E-mail: anjiangzhang@gmail.com

JOURNAL OF CHEMICAL RESEARCH 2008 267
Table 1 Asymmetric reduction of ketone 2 and ketimine 3a
Entry
Catalyst
Yield of 4/%b
ee of 4/%d
Yield of 5/%c
ee of 5/%d
1
2
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
70
30
42
44
35
60
47
84
96
28
82
70
93
32
50
17
20
91
45
51
39
7
92
68
70
81
80
70
81
75
85
82
86
80
91
71
85
80
60
90
70
61
11
23
40
41
37
32
48
52
44
34
39
34
45
40
62
45
55
52
48
47
3
0
4
0
0
45
5
41
28
13
1
5
5
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
25
7
9
3
8
6s
6t
23
37
aUnless specified otherwise, reactions were carried out with 2.0 equiv of HSiCl3 on a 0.2 mmol scale in 1.0 ml of dichloromethane
at –20°C for 16 h. bIsolated yield based on the ketone 2. cIsolated yield based on the ketimine 3. dThe ee values were determined
using chiral HPLC.
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observed in the reduction of ketimine 3 XVLQJꢀRUJDQRFDWDO\VWVꢀ
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2–5). The existence of an electron donating group on the
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reactivities in the reductions of both ketone and ketimine.
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Rudolph AuTo Pol IV automatic polarimeter. 1H NMR and 13C NMR
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silica gel (hexane/acetone = 3:1) to give 9.
General procedure of synthesis of 6a–t
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(10 ml) and stirred for 1 h, and then concentrated under reduced
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CH2Cl2/CH32+ꢀ§ꢀꢆꢎꢀꢒꢀꢈꢌꢀWRꢀDIIRUGꢀSXUHꢀ6a–t.
General procedure of synthesis of 7a–b
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2.4 mmol), N, NꢃGLLVRSURS\OHWK\ODPLQHꢀ ꢂ',($ꢄꢀ ꢉꢎꢎꢀ —Oꢌꢀ DQGꢀ ꢈꢃꢂꢐꢃ
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ZHUHꢀLQꢀWXUQꢀDGGHGꢀWRꢀDꢀVROXWLRQꢀRIꢀ%RFꢃL-pipecolinic acid (458 mg,
2.0 mmol) in dichloromethane DCM (20 ml) at 0°C. The reaction
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(S)-2-(piperidine-1-carbonyl)pyrrolidine-1-carbaldehyde
(6a):
<HOORZꢀ VROLGꢀ ꢂꢍꢈꢇꢀ \LHOGꢌꢄꢀ PꢁSꢁꢀ ꢉꢋ±ꢉꢆ°&ꢁꢀ >Į@D = – 45.1° (c 0.130,
1
EtOAc). H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.22 (s, 1H),
4.78 (s, 1H), 3.61–3.44 (m, 6H), 2.17–1.60 (m, 10H). 13C NMR (75
MHz, CDCl3) G: 169.1, 160.4, 54.0, 46.6, 30.1, 29.3, 25.4, 24.4, 24.3,
OH
HSiCl3
O
HSiCl3
N
HN
*
10%Catalyst
*
10%Catalyst
F3C
F3C
2
5
4
3
Scheme 1 Asymmetric reductions of ketone 2 and ketimine 3.

268 JOURNAL OF CHEMICAL RESEARCH 2008
23.9, 22.7. MS–ESI (m/z): 212.1 (M+ + 2), 211.1 (M+ + 1), 210.2
(M+), 150.1. Anal. Calcd. for C11H18N2O2: C, 62.8; H, 8.6; N, 13.3.
Found: C, 62.9; H, 8.5; N, 13.2%.
J = 6.78 Hz, 1H), 4.46–4.42 (m, 1H), 4.36–4.27 (m, 1H), 4.21–4.04
(m, 2H), 3.62–3.48 (m, 2H), 2.46–2.16 (m, 1H), 2.07–1.84 (m, 6H),
1.17 (m, 3H). 13C NMR (75 MHz, CDCl3) G: 171.2, 169.9, 162.2,
66.7, 57.8, 46.9, 44.5, 27.1, 24.1, 20.8, 17.1. MS–ESI (m/z, relative
LQWHQVLW\ꢄꢇꢌꢒꢀꢋꢆꢐꢁꢈꢀꢂ0+ + 1), 225.1, 215.1 (20), 201.0, 184.1, 183.1
(100), 165.3, 153.9. Anal. Calcd. for C11H18N2O4: C, 54.5; H, 7.5; N,
11.6. Found: C, 54.8; H, 7.4; N, 11.6%.
(S)-1-formyl-N-(furan-2-ylmethyl)pyrrolidine-2-carboxamide
(6bꢌꢒꢀ&RORXUOHVVꢀOLTXLGꢀꢂꢆꢊꢇꢀ\LHOGꢌꢄꢀ>Į@D = – 87.4° (c 0.123, EtOAc).
1H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.25 (s, 1 H), 7.33 (m,
2H), 6.28 (t, J = 1.4 Hz, 1H), 6.18 (d, J = 3.1 Hz, 1H), 4.50–4.36
(m, 3H), 3.58–3.51 (m, 2H), 2.50–1.84 (m, 4H). 13C NMR (75 MHz,
CDCl3) G: 170.2, 162.2, 151.2, 142.0, 110.3, 107.1, 57.8, 46.9, 36.6,
27.1, 24.1. MS–ESI (m/z): 224.1 (M+ + 2), 223.2 (M+ + 1), 217.4,
211.2, 204.5, 195.1, 190.2, 174.0. Anal. Calcd. for C11H14N2O3: C,
59.45; H, 6.35; N, 12.6. Found: C, 59.6; H, 6.2; N, 12.8%.
(S)-methyl-2-((S)-1-formylpyrrolidine-2-carbonyl-amino)
propanoate (6kꢌꢒꢀ &RORXUOHVVꢀ OLTXLGꢀ ꢂꢆꢅꢇꢀ \LHOGꢌꢄꢀ >Į@D = –97.8° (c
0.100, EtOAc). 1H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.30 (s,
1H), 7.40 (s, 1H), 4.62–4.37 (m, 1H), 4.19–4.11 (m, 1H), 3.74 (s,
3H), 3.64–3.50 (m, 2H), 2.38–1.82 (m, 4H), 1.43 (m, 3H). 13C NMR
(75 MHz, CDCl3) G: 170.4, 166.4, 162.0, 59.2, 51.1, 46.8, 45.4, 28.1,
22.7, 17.8. MS–ESI (m/zꢄꢀUHODWLYHꢀLQWHQVLW\ꢄꢇꢌꢒꢀꢋꢋꢑꢁꢋꢀꢂ0+ + 1, 100),
228.1 (M+), 197.2, 183.2, 169.9, 154.1. Anal. Calcd. for C10H16N2O4:
C, 52.6; H, 7.1; N, 12.3. Found: C, 52.5; H, 7.2; N, 12.2%.
ꢀ6ꢁꢂ1ꢂꢀꢃꢂÀXRUREHQ]\OꢁꢂꢄꢂIRUP\OS\UUROLGLQHꢂꢅꢂFDUER[DPLGH (6c):
/LJKWꢀ \HOORZꢀ VROLGꢀ ꢂꢊꢊꢇꢀ \LHOGꢌꢄꢀ PꢁSꢁꢀ ꢈꢐꢉ±ꢈꢐꢑ°&ꢁꢀ >Į@D = –73.8°
(c 0.106, EtOAc). 1H NMR (300 MHz, CDCl3, 25°C, TMS)
G: 8.25 (s, 1H), 7.44 (s, 1H), 7.28–7.20 (m, 2H), 7.01–6.95 (m, 2H),
4.51–4.35 (m, 3H), 3.59–3.52 (m, 2H), 2.45–1.85 (m, 4H). 13C NMR
(75 MHz, CDCl3) G: 170.4, 162.2, 160.4, 133.9, 129.2, 115.5, 57.8,
46.9, 42.8, 27.3, 24.1. MS–ESI (m/z): 251.2 (M+ + 1), 246.5, 235.0,
217.1, 212.2, 204.6. Anal. Calcd. for C13H15FN2O2: C, 62.4; H, 6.0;
N, 11.2. Found: C, 62.6; H, 5.9; N, 11.1%.
(S)-dimethyl-2-((S)-1-formylpyrrolidine-2-carbonyl-amino)
succinate (6lꢌꢒꢀ:KLWHꢀVROLGꢀꢂꢊꢐꢇꢀ\LHOGꢌꢄꢀPꢁSꢁꢀꢉꢑ±ꢅꢈ°&ꢁꢀ>Į@D = –60.2°
1
(c 0.156, EtOAc). H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.30
(s, 1H), 7.49 (d, J = 7.80 Hz, 1H), 4.85 (m, 1H), 4.47 (m, 1H), 3.77
(s, 3H), 3.71 (s, 3H), 6.60 (m, 2H), 2.92 (m, 2H), 2.40–1.82 (m, 4H).
13C NMR (75 MHz, CDCl3) G: 171.2, 170.9, 170.5, 161.8, 57.8, 52.8,
52.1, 48.7, 46.8, 34.0, 27.8, 24.1. MS–ESI (m/zꢄꢀUHODWLYHꢀLQWHQVLW\ꢄꢇꢌꢒꢀ
288.0 (M+ + 2, 14), 287.0 (M+ + 1, 100), 259.0, 255.0 (19), 243.0,
227.0, 183.1, 160.1. Anal. Calcd. for C12H18N2O6: C, 50.35; H, 6.3;
N, 9.8. Found: C, 50.6; H, 6.2; N, 9.7%.
(S)-N-(4-chlorobenzyl)-1-formylpyrrolidine-2-carboxamide (6d):
:KLWHꢀVROLGꢀꢂꢊꢈꢇꢀ\LHOGꢌꢄꢀPꢁSꢁꢀꢈꢈꢆ±ꢈꢈꢍ°&ꢁꢀ>Į@D = –66.4° (c 0.106,
1
EtOAc). H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.27 (s, 1H),
7.42 (s, 1H), 7.33–7.24 (m, 2H), 7.19–7.15 (m, 2H), 4.59–4.36 (m,
3H), 3.60–3.53 (m, 2H), 2.50–1.86 (m, 4H). 13C NMR (75 MHz,
CDCl3) G: 170.3, 162.2, 136.7, 133.0, 128.7, 127.4, 57.9, 46.9, 42.9,
27.0, 24.1. MS–ESI (m/z): 267.2 (M+ + 1), 246.3, 239.1, 233.3, 231.1,
211.0, 198.1, 150.4. Anal. Calcd. for C13H15ClN2O2: C, 58.5; H, 5.7;
N, 10.5. Found: C, 58.6; H, 5.5; N, 10.6%.
(S)-dimethyl-2-((S)-1-formylpyrrolidine-2-carbonyl-amino)
pentanedioate (6mꢌꢒꢀ:KLWHꢀVROLGꢀꢂꢐꢉꢇꢀ\LHOGꢌꢄꢀPꢁSꢁꢀꢍꢑ±ꢉꢈ°&ꢁꢀ>Į@D
=
1
–44.4° (c 0.120, EtOAc). H NMR (300 MHz, CDCl3, 25°C, TMS)
G: 8.29 (s, 1H), 7.39 (d, J = 7.47 Hz, 1H), 4.55–4.45 (m, 2H), 3.72
(s, 3H), 3.64 (s, 3H), 3.58 (m, 2H), 2.40–1.87 (m, 8H). 13C NMR
(75 MHz, CDCl3) G: 173.0, 171.8, 170.4, 161.9, 57.7, 52.4, 51.9,
51.6, 46.8, 29.7, 27.4, 27.0, 24.1. MS–ESI (m/zꢄꢀUHODWLYHꢀLQWHQVLW\ꢄꢇꢌꢒꢀ
302.1 (M+ + 2, 27), 301.1 (M+ + 1, 100), 279.1 (21), 258.4, 242.4
(31), 194.9, 169.0, 150.3. Anal. Calcd. for C13H20N2O6: C, 52.0; H,
6.7; N, 9.3. Found: C, 52.1; H, 6.6; N, 9.2%.
(S)-1-formyl-N-phenethylpyrrolidine-2-carboxamide
(6e):
&RORXUOHVVꢀ OLTXLGꢀ ꢂꢊꢆꢇꢀ \LHOGꢌꢄꢀ >Į@D = –75.2° (c 0.104, EtOAc).
1H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.21 (s, 1H), 7.34–
7.15 (m, 5H), 6.94 (s, 1H), 4.53–4.42 (m, 1H), 3.58–3.43 (m, 4H),
2.86–2.78 (m, 2H), 2.51–1.86 (m, 4H). 13C NMR (75 MHz, CDCl3)
G: 170.4, 162.1, 139.9, 128.7, 128.4, 126.3, 57.8, 46.7, 40.7, 35.5,
26.9, 24.0. MS–ESI (m/z): 245.2 (M+ –1), 235.1, 221.1, 217.1, 200.3,
185.3, 169.2, 157.3. Anal. Calcd. for C14H18N2O2: C, 68.3; H, 7.4; N,
11.4. Found: C, 68.5; H, 7.2; N, 11.25%.
(S)-methyl-2-((S)-1-formylpyrrolidine-2-carbonyl-amino)-2-
phenylacetate (6nꢌꢒꢀ :KLWHꢀ VROLGꢀ ꢂꢆꢋꢇꢀ \LHOGꢌꢄꢀ PꢁSꢁꢀ ꢍꢍ±ꢍꢅ°&ꢁꢀ >Į@D
=
1
+ 40.1° (c 0.156, EtOAc). H NMR (300 MHz, CDCl3, 25°C, TMS)
G: 8.29 (s, 1H), 8.01 (d, J = 5.91 Hz, 1H), 7.35 (m, 5H), 5.49 (d,
J = 6.93 Hz, 1H), 4.63–4.60 (m, 1H), 3.73 (s, 3H), 3.60–3.48 (m, 2H),
2.48–1.86 (m, 4H). 13C NMR (75 MHz, CDCl3) G: 170.9, 169.8, 162.2,
140.0, 128.9, 128.5, 127.1, 57.7, 56.9, 52.8, 46.9, 27.0, 24.1. MS–ESI
(m/zꢄꢀUHODWLYHꢀLQWHQVLW\ꢄꢇꢌꢒꢀꢋꢑꢋꢁꢎꢀꢂ0+ + 2, 14), 291.0 (M+ + 1, 100),
259.0 (18), 243.0 (85), 231.0 (38), 183.1 (100), 180.9, 160.1. Anal.
Calcd. for C15H18N2O4: C, 62.1; H, 6.25; N, 9.65. Found: C, 62.3; H,
6.1; N, 9.6%.
(S)-1-formyl-N-p-tolylpyrrolidine-2-carboxamide (6f): White solid
ꢂꢍꢍꢇꢀ \LHOGꢌꢄꢀ PꢁSꢁꢀ ꢈꢊꢎ±ꢈꢊꢋ°&ꢁꢀ >Į@D = –128.4° (c 0.102, EtOAc).
1H NMR (300 MHz, CDCl3, 25°C, TMS) G: 9.28 (s, 1H), 8.33 (s, 1H),
7.38 (d, J = 8.40 Hz, 2H), 7.07 (d, J = 8.13 Hz, 2H), 4.76–4.65 (m,
1H), 3.64–3.56 (m, 2H), 2.62–2.58 (m, 1H), 2.28 (s, 3H), 2.13–1.82
(m, 3H). 13C NMR (75 MHz, CDCl3) G: 167.9, 162.6, 135.5, 133.6,
129.3, 119.7, 60.3, 47.0, 26.5, 24.1, 20.7. MS–ESI (m/z): 233.0 (M+
+ 1), 230.2, 212.2, 197.2, 187.2, 174.3. Anal. Calcd. for C13H16N2O2:
C, 67.2; H, 6.9; N, 12.1. Found: C, 67.3; H, 6.9; N, 12.1%.
(S)-N-(4-chlorophenyl)-1-formylpyrrolidine-2-carboxamide (6g):
&RORXUOHVVꢀ OLTXLGꢀ ꢂꢐꢍꢇꢀ \LHOGꢌꢄꢀ >Į@D = –105.6° (c 0.10, EtOAc).
1H NMR (300 MHz, CDCl3, 25°C, TMS) G: 9.56 (s, 1H), 8.34 (s, 1H),
7.41 (d, J = 8.82 Hz, 2H), 7.18 (d, J = 8.82 Hz, 2H), 4.69–4.65 (m, 1H),
3.65–3.60 (m, 2H), 2.56–1.76 (m, 4H). 13C NMR (75 MHz, CDCl3) G:
168.2, 162.6, 136.7, 129.0, 128.7, 120.8, 58.8, 47.2, 26.8, 24.2. MS–
ESI (m/zꢄꢀUHODWLYHꢀLQWHQVLW\ꢄꢇꢌꢒꢀꢋꢊꢐꢁꢐꢀꢂ0+ + 1, 29), 251.2 (M+ –1, 100),
227.0 (10), 223.3, 220.1, 195.3, 167.1. Anal. Calcd. for C12H13ClN2O2:
C, 57.0; H, 5.2; N, 11.1. Found: C, 57.25; H, 5.25; N, 11.0%.
(S)-methyl-2-((S)-1-formylpyrrolidine-2-carbonyl-amino)-3-
phenylpropanoate (6oꢌꢒꢀ&RORXUOHVVꢀOLTXLGꢀꢂꢐꢑꢇꢀ\LHOGꢌꢄꢀ>Į@D = –37.3°
1
(c 0.126, EtOAc). H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.10
(s, 1H), 7.31–6.99 (m, 6H), 4.80 (m, 1H), 4.41 (m, 1H), 3.67 (s, 3H),
3.46–2.96 (m, 4H), 2.26–1.76 (m, 4H). 13C NMR (75 MHz, CDCl3)
G: 171.7, 170.2, 162.0, 136.0, 129.3, 129.0, 128.6, 128.2, 126.9, 57.5,
53.3, 52.3, 46.6, 37.8, 27.1, 23.9. MS–ESI (m/zꢄꢀUHODWLYHꢀLQWHQVLW\ꢄꢇꢌꢒꢀ
306.0 (M+ + 2, 7), 305.0 (M+ + 1, 42), 289.1, 277.1 (100), 257.3, 227.2
(10), 211.3, 199.3 (17). Anal. Calcd. for C16H20N2O4: C, 63.1; H, 6.6;
N, 9.2. Found: C, 63.3; H, 6.6; N, 9.2%.
(S)-2-((S)-1-formylpyrrolidine-2-carbonyl-amino)-3-methylbutyl
acetate (6hꢌꢒꢀ&RORXUOHVVꢀOLTXLGꢀꢂꢋꢉꢇꢀ\LHOGꢌꢄꢀ>Į@D = –101.5° (c 0.104,
EtOAc). 1H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.28 (s, 1H), 7.05
(d, J = 8.61 Hz, 1H), 4.46 (m, 1H), 4.11 (m, 2H), 4.08 (m, 1H), 3.55
(m, 2H), 2.50–1.81 (m, 8H), 0.89 (m, 6H). 13C NMR (75 MHz, CDCl3)
G: 172.0, 171.1, 163.0, 65.2, 58.8, 54.4, 47.8, 30.3, 27.9, 25.1, 23.8,
21.7, 19.6. MS–ESI (m/z): 272.0 (M+ + 2), 271.1 (M+ + 1), 267.3,
242.9, 225.4, 212.1, 211.2, 194.0. Anal. Calcd. for C13H22N2O4: C,
57.8; H, 8.2; N, 10.4. Found: C, 57.6; H, 8.35; N, 10.4%.
(S)-methyl-3-(4-acetoxyphenyl)-2-((S)-1-formylpyrrolidine-2-
carbonyl-amino) propanoate (6pꢌꢒꢀ&RORXUOHVVꢀOLTXLGꢀꢂꢆꢈꢇꢀ\LHOGꢌꢄꢀ>Į@D
= –37.4° (c 0.324, EtOAc). 1H NMR (300 MHz, CDCl3, 25°C, TMS)
G: 8.13 (s, 1H), 7.75 (s, 1H), 6.93 (m, 2H), 6.72 (m, 2H), 4.78 (m, 1H),
4.45 (m, 1H), 3.73 (m, 3H), 3.50–2.91 (m, 4H), 2.26–1.82 (m, 7H). 13
C
NMR (75 MHz, CDCl3) G: 172.8, 172.2, 171.3, 163.1, 156.6, 131.3,
127.8, 116.3, 58.6, 54.5, 53.2, 47.8, 37.9, 28.6, 24.9, 23.1. MS–ESI
(m/zꢄꢀUHODWLYHꢀLQWHQVLW\ꢄꢇꢌꢒꢀꢐꢍꢆꢁꢋꢀꢂ0+ + 2, 100), 355.1 (10), 333.2 (35),
319.2 (55), 279.9, 227.0, 185.2. Anal. Calcd. for C18H22N2O6: C, 59.7;
H, 6.1; N, 7.7. Found: C, 59.5; H, 6.2; N, 7.6%.
(S)-2-((1-formyl-pyrrolidine-2-carboyl)-amino)-propane-1,3-diyl
diacetate (6iꢌꢒꢀ&RORXUOHVVꢀOLTXLGꢀꢂꢈꢊꢇꢀ\LHOGꢌꢄꢀ>Į@D = –63.4° (c 0.142,
(S)-methyl-2-((S)-1-formylpyrrolidine-2-carbonyl-amino)-3-(1H-
indol-2-yl) propanoate (6qꢌꢒꢀ <HOORZꢀ VROLGꢀ ꢂꢆꢍꢇꢀ \LHOGꢌꢄꢀ PꢁSꢁꢀ ꢈꢋꢎ±
122°&ꢁꢀ>Į@D = –0° (c 0.156, EtOAc). 1H NMR (300 MHz, CDCl3,
25°C, TMS) G: 10.80 (s, 1H), 8.46 (s, 1H), 7.99 (s, 1H), 7.53 (d,
J = 7.74 Hz, 1H), 7.35 (m, 1H), 7.21–7.08 (m, 3H), 4.93–4.89 (m,
1H), 4.43 (m, 1H), 3.71 (s, 3H), 3.45–3.26 (m, 4H), 2.35–1.75 (m,
4H). 13C NMR (75 MHz, CDCl3) G: 172.2, 172.0, 161.8, 136.0,
127.6, 123.7, 121.7, 119.1, 118.4, 111.3, 109.5, 57.6, 53.1, 52.4, 46.6,
31.7, 29.2, 23.9. MS–ESI (m/zꢄꢀUHODWLYHꢀLQWHQVLW\ꢄꢇꢌꢒꢀꢐꢆꢊꢁꢈꢀꢂ0+ + 2,
5), 344.1 (M+ + 1, 35), 328.1 (16), 317.1 (24), 316.1 (100), 266.2,
219.0, 196.2. Anal. Calcd. for C18H21N3O4: C, 63.0; H, 6.2; N, 12.2.
Found: C, 62.9; H, 6.2; N, 12.4%.
1
EtOAc). H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.29 (s, 1H),
7.44 (d, J = 7.80 Hz, 1H), 4.51–4.47 (m, 1H), 4.43–4.36 (m, 1H),
4.24–4.13 (m, 4H), 3.58 (m, 2H), 2.52–2.47 (m, 1H), 2.10 (s, 6H),
2.06–1.86 (m, 3H). 13C NMR (75 MHz, CDCl3) G: 170.8, 170.2,
162.3, 62.7, 57.8, 47.5, 46.8, 26.8, 24.1, 20.7. MS–ESI (m/z, relative
LQWHQVLW\ꢄꢇꢌꢒꢀꢐꢎꢋꢁꢈꢀꢂ0+ + 2, 19), 301.1 (M+ + 1, 100), 279.0 (24),
259.0, 241.1, 216.1, 198.1, 157.8. Anal. Calcd. for C13H20N2O6: C,
52.0; H, 6.7; N, 9.3. Found: C, 51.8; H, 6.9; N, 9.25%.
(S)-2-((S)-1-formylpyrrolidine-2-carbonyl-amino)propyl acetate
(6jꢌꢒꢀ&RORXUOHVVꢀOLTXLGꢀꢂꢆꢊꢇꢀ\LHOGꢌꢄꢀ>Į@D = –85.6° (c 0.128, EtOAc).
1H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.29 (s, 1H), 7.09 (d,

JOURNAL OF CHEMICAL RESEARCH 2008 269
O
COOCH3
R1
COOCH3
COOH
+
N
Boc
N
Boc
HN
H2N
R1
7a
O
O
CH2OH
R1
CH2OAc
R1
N
Boc
HN
N
Boc
HN
O
9
N
CHO
HN
R
8
O
6a-t
COOH
R2NH2
+
HN R2
N
N
Boc
Boc
7b
Scheme 2 The synthesis of 6a–t.
(R)-2-((S)-1-formylpyrrolidine-2-carbonyl-amino)propyl
acetate
+3/&ꢀWHFKQLTXHVꢀZLWKꢀFKLUDOꢀVWDWLRQDU\ꢀSKDVHVꢀꢂ&KLUDOꢃSKDVHꢀ+3/&ꢀ
GDWDꢒꢀFKLUDOꢀ2-±+ꢀFROXPQꢄꢀQꢃKHSWDQHꢏꢋꢃSURSDQROꢀ ꢀꢑꢉꢏꢐꢄꢀÀRZꢀUDWHꢀ ꢀ
ꢈꢁꢎꢀPOꢏPLQꢄꢀZDYHOHQJWKꢀ ꢀꢋꢋꢎꢀQPꢄꢀWR = 10.29 min and 11.07 min).
(6rꢌꢒꢀ&RORXUOHVVꢀOLTXLGꢀꢂꢋꢍꢇꢀ\LHOGꢌꢄꢀ>Į@D = –81.5° (c 0.120, EtOAc).
1H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.27 (s, 1H), 7.13 (d,
J = 6.51 Hz, 1H), 4.48–3.95 (m, 4H), 3.61–3.52 (m,2H), 2.49–2.44
(m, 1H), 2.06 (s, 3H), 2.04–1.86 (m, 3H), 1.18 (m, 3H). 13C NMR
(75 MHz, CDCl3) G: 171.1, 169.8, 162.2, 66.6, 57.8 46.8, 44.4, 26.9,
24.1, 20.8, 17.2. MS–ESI (m/z): 243.0 (M+ + 1), 241.9, 215.1, 197.1,
183.1, 181.1, 152.8. Anal. Calcd. for C11H18N2O4: C, 54.5; H, 7.5; N,
11.6. Found: C, 54.5; H, 7.4; N, 11.7%.
General procedure for the catalytic reduction of ketimine 3
7ULFKORURVLODQHꢀ ꢂꢆꢎꢀ ȝOꢄꢀ ꢎꢁꢆꢀ PPROꢌꢀ ZDVꢀ DGGHGꢀ GURSZLVHꢀ WRꢀ Dꢀ
stirred solution of ketimine 3 ꢂꢐꢑꢁꢎꢀ PJꢄꢀ ꢎꢁꢋꢎꢀ PPROꢌꢀ DQGꢀ FDWDO\VWꢀ
6a–t ꢂꢎꢁꢎꢋꢀPPROꢌꢀLQꢀDQK\GURXVꢀ'&0ꢀ ꢂꢈꢁꢎꢀPOꢌꢀDWꢀ±ꢋꢎƒ&ꢀXQGHUꢀDQꢀ
DUJRQꢀ DWPRVSKHUHꢁꢀ 7KHꢀ PL[WXUHꢀ ZDVꢀ DOORZHGꢀ WRꢀ VWLUꢀ DWꢀ WKHꢀ VDPHꢀ
WHPSHUDWXUHꢀIRUꢀ ꢈꢍꢀ Kꢁꢀ7KHꢀ UHDFWLRQꢀ ZDVꢀ TXHQFKHGꢀ ZLWKꢀ Dꢀ VDWXUDWHGꢀ
DTXHRXVꢀ VROXWLRQꢀ RIꢀ 1D+&23ꢀ ꢂꢊꢀ POꢌꢀ DQGꢀ H[WUDFWHGꢀ ZLWKꢀ (W2$Fꢁꢀ
7KHꢀFRPELQHGꢀH[WUDFWVꢀZHUHꢀGULHGꢀRYHUꢀDQK\GURXVꢀ0J624. The solvent
ZDVꢀHYDSRUDWHGꢀXQGHUꢀUHGXFHGꢀSUHVVXUHꢁꢀ7KHꢀUHVLGXHꢀZDVꢀSXUL¿HGꢀE\ꢀ
FROXPQꢀFKURPDWRJUDSK\ꢀꢂVLOLFDꢀJHOꢄꢀKH[DQHꢏ(W2$Fꢀ ꢀꢍꢎꢀꢒꢀꢈꢌꢀWRꢀDIIRUGꢀ
pure amine 5ꢁꢀ7KHꢀHHꢀYDOXHVꢀZHUHꢀGHWHUPLQHGꢀXVLQJꢀHVWDEOLVKHGꢀ+3/&ꢀ
WHFKQLTXHVꢀ ZLWKꢀ FKLUDOꢀ VWDWLRQDU\ꢀ SKDVHVꢀ ꢂ&KLUDOꢃSKDVHꢀ +3/&ꢀ GDWDꢒꢀ
FKLUDOꢀ2'±+ꢀFROXPQꢄꢀQꢃKHSWDQHꢏꢋꢃSURSDQROꢀ ꢀꢑꢑꢏꢈꢄꢀÀRZꢀUDWHꢀ ꢀꢈꢁꢎꢀPOꢏ
PLQꢄꢀZDYHOHQJWKꢀ ꢀꢋꢊꢆꢀQPꢄꢀWR = 8.32 min and 9.51 min).
(R)-methyl-2-((S)-1-formylpyrrolidine-2-carbonyl-amino)
propanoate (6sꢌꢒꢀ&RORXUOHVVꢀOLTXLGꢀꢂꢐꢅꢇꢀ\LHOGꢌꢄꢀ>Į@D = –83.1° (c 0.120,
EtOAc). 1H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.32 (s, 1H), 7.41
(d, J = 5.91 Hz, 1H), 4.56–4.47 (m, 1H), 4.19–4.13 (m, 1H), 3.73 (s,
3H), 3.61–3.55 (m, 2H), 2.04–1.97 (m, 4H), 1.41 (m, 3H). 13C NMR
(75 MHz, CDCl3) G: 172.6, 170.0, 162.3, 61.3, 57.7, 48.3, 46.8, 27.1,
24.0, 18.0. MS–ESI (m/z): 229.2, 227.5 (M+ – 1), 195.5, 181.3, 167.4,
154.1. Anal. Calcd. for C10H16N2O4: C, 52.6; H, 7.1; N, 12.3. Found:
C, 52.5; H, 7.1; N, 12.1%.
(R)-methyl-2-((S)-1-formylpyrrolidine-2-carbonyl-amino)-3-
phenylpropanoate (6tꢌꢒꢀ&RORXUOHVVꢀOLTXLGꢀꢂꢊꢎꢇꢀ\LHOGꢌꢄꢀ>Į@D = –54.0°
(c 0.304, EtOAc). 1H NMR (300 MHz, CDCl3, 25°C, TMS) G: 8.21 (s,
1H), 7.28–7.03 (m, 6H), 4.74 (m, 1H), 4.43 (m, 1H), 3.65 (s, 3H), 3.49
(m, 2H), 3.06 (m, 2H), 2.13–1.79 (m, 4H). 13C NMR (75 MHz, CDCl3)
G: 171.7, 170.2, 162.1, 135.9, 129.3, 129.0, 128.7, 128.5, 127.0, 57.6,
53.4, 52.2, 46.7, 37.7, 30.4, 23.9. MS–ESI (m/z): 306.0 (M+ + 2, 5),
305.0 (M+ + 1, 44), 289.1, 278.1 (15), 277.1 (100), 257.1, 211.2, 199.3.
Anal. Calcd. for C16H20N2O4: C, 63.1; H, 6.6; N, 9.2. Found: C, 63.3;
H, 6.4; N, 9.0%.
Received 18 March 2008; accepted 25 April 2008
Paper 08/5167 doi: 10.3184/030823408X318433
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