L-Pipecolinic acid derived Lewis base organocatalyst for asymmetric reduction of N-aryl imines by trichlorosilane: Effects of the side amide group on catalytic performances

Article abstract of DOI:10.1039/c2ob26772a

A series of N-formamides derived from pipecolinic acid have been synthesized and tested as Lewis base catalysts for the enantioselective reduction of N-aryl imines by trichlorosilane. Through the investigation of the structure-efficacy relationship between the side amide group and catalytic performance, several highly effective catalysts were discovered. In particular, arylamido-type catalyst 5i and non-arylamido-type catalyst 6c exhibited high reactivity and enantioselectivity, furnishing the reduction of a wide variety of N-aryl imines with high isolated yields (up to 98%) and ee values (up to 96%) under mild conditions. Moreover, these two catalysts complement each other in terms of their tolerances to nonaromatic ketimines and non-methyl ketimines. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2ob26772a

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L-Pipecolinic acid derived Lewis base organocatalyst for
asymmetric reduction of N-aryl imines by
trichlorosilane: effects of the side amide group on
catalytic performances†
Cite this: Org. Biomol. Chem., 2013, 11,
787
Zhouyu Wang,*a Chao Wang,b Li Zhoub and Jian Sun*b
A series of N-formamides derived from pipecolinic acid have been synthesized and tested as Lewis base
catalysts for the enantioselective reduction of N-aryl imines by trichlorosilane. Through the investigation
of the structure–efficacy relationship between the side amide group and catalytic performance, several
highly effective catalysts were discovered. In particular, arylamido-type catalyst 5i and non-arylamido-type
catalyst 6c exhibited high reactivity and enantioselectivity, furnishing the reduction of a wide variety of
N-aryl imines with high isolated yields (up to 98%) and ee values (up to 96%) under mild conditions.
Moreover, these two catalysts complement each other in terms of their tolerances to nonaromatic
ketimines and non-methyl ketimines.
Received 8th September 2012,
Accepted 11th November 2012
DOI: 10.1039/c2ob26772a
www.rsc.org/obc
stoichiometric pyridine type byproduct could sometimes com-
plicate the product separation. The other one uses chiral Lewis
Introduction
Chiral amines are an important class of organic compounds bases as catalyst and trichlorosilane (HSiCl3) as reducing
that serve as building blocks and precursors for many natural agent. This method seems to be quite attractive since the cata-
products and pharmaceutical and agrochemical products. lyst is cheap and easy to prepare, while the reducing agent is a
Catalytic asymmetric reduction of imines represents a most cheap industrial raw material and readily available in bulky
straightforward and efficient method to synthesize chiral quantity.
amines.1 However, effective catalysts for the enantioselective
Since the first report of enantioselective imine reduction by
reduction of imines had long been limited to chiral transition trichlorosilane using N-formyl proline amide as a Lewis base
metal complexes, which often require elevated pressures and/ catalyst in 2001,4a great efforts have been focused on this field
or additives to afford high yields and ee values. Besides, the and significant progress has been made.4–13 Up to now, quite a
relatively high loading and the high cost of these catalysts number of highly efficient chiral Lewis base organocatalysts
retarded their practical applications. Recently, great attention have been developed for the reduction of imines by trichlorosi-
started to focus on the development of reductions promoted lane. Besides N-formyl proline amide,4a,b,6e,8,12,13 some other
by metal-free chiral organocatalysts, which are relatively easy to carboxamide type catalysts have also been developed, including
operate, cost efficient, and environmentally benign. So far quite a few highly efficient catalysts derived from valine,5a,c–i
there have been two main types of effective organocatalytic pipecolinic acid,6a,d,11 and piperazine-2-carboxylic acid.6b,f
reduction system reported in the literature.2,3 One employs Recently, several new types of catalysts including sulfin-
chiral phosphoric acids as catalyst and Hantzsch esters as amide,6c,g–k oxazoline,5b,j picolinamide4c,7,9 and imidazole
reducing agent, which proved to be high yielding and highly derivatives10 have also emerged. With the development of
enantioselective although the unavoidable production of the these catalysts, the applications of the Lewis base–trichlorosi-
lane catalytic system have been extended from initially the
reduction of N-aryl ketimines only to currently the reduction of
N-alkyl ketimines,6h α-imino esters,7b β-enamino esters,6j
aDepartment of Pharmaceutics Engineering, Xihua University, Chengdu, China.
γ-imino esters,7f β-nitroenamines,6k indoles,6i benzoxazino-
E-mail: zhouyuwang77@gmail.com; Fax: +86-028-8772-0552; Tel: +86-028-8772-0552
bNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy
nes,7c quinoxalinones,7c and so on.
of Sciences, Chengdu, China. E-mail: sunjian@cib.ac.cn; Fax: (+86) 28-85222753;
In our preliminary communication,6a we developed a
Tel: (+86) 28-85222753
L-pipecolinic acid derived Lewis base catalyst 6c that afforded
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c2ob26772a
high level of enantioselectivity (up to 96% ee) with a broad
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than its congeners 3a and 4a in the reduction of imine 1a
under identical conditions. Greatly encouraged by this prelimi-
nary observation, we prepared compounds 6a–c and examined
their catalytic efficiencies (Table 1). In the test reaction of
imine 1a in the presence of 10 mol% catalyst in CH2Cl2 at 0 °C
for 16 h, 6c afforded the highest yield and ee (97% yield and
94% ee, entry 14). Its diastereomer 6b gave the same yield and
marginally lower ee (entries 13 and 14), indicating that the
absolute configuration of C2 (see 6 for labeling) has little
impact on the reactivity and selectivity. In contrast, 6a was
found to be much less selective and reactive than 6b and 6c,
affording only 71% yield and 47% ee under identical con-
ditions (entry 12). Thus an (S)-configuration proved to be dis-
tinctly preferred for C1. To explore the role of each structural
element of catalyst 6c, the reconstructive and truncated mole-
cules 7–10 were synthesized. Replacement of the acetoxyl
group with hydroxyl (7a), methoxyl (7b) and para-methyl
benzene sulfonamido (7c) all decreased the enantioselectivity
to some extent (entries 15, 16, 17 vs. 14). Retaining the acetoxyl
group and trimming off the C2 phenyl group, catalyst 8a dis-
played slightly lowered yield and ee (entry 18). Further chan-
ging the C1 phenyl to benzyl (8b) and isopropyl (8c) led to
significantly decreased yield and enantioselectivity (entries
19–20). These results indicated that the existence of a phenyl
group at C1 is crucial for both the reactivity and the enantio-
selectivity of the catalyst. Interestingly, removing the acetoxyl
group (9a) or further trimming off the phenyl (9b) had only
a marginal effect on the enantioselectivity (entries 21, 22 vs.
14). Without the chirality of C2, an (R)-configuration is pre-
ferred for C1, with which the phenyl group virtually remains
in the same β-orientation as in 6b, 6c and 7a–c. We further
altered the phenyl of 9b to para-chlorophenyl (10a), para-
methoxylphenyl (10b) and 1-naphthyl (10c), but found no
apparent differences in catalytic efficiency (entries 22, 23,
24 vs. 22).
At the same time, we also prepared a set of N-formyl L-pipe-
colinic amides bearing different arylamido groups (5, Fig. 1)
and tested their catalytic efficacies. While 5b–d and 5f bearing
different substituents on the phenyl ring, either electron-
donating or electron-withdrawing, did not show apparent
differences in selectivity and reactivity compared with 5a
(entries 4–6 and 8 vs. 3), 5e with a 2-hydroxyphenyl and 5g
with a 2-pyridinyl group displayed significantly decreased
enantioselectivities (36% and 12% ee, respectively, entries 7
and 9). The competitive binding of the hydroxy oxygen and the
pyridine nitrogen with the central silicon atom of HSiCl3 may
be responsible for the loss of the enantioselectivity. Interest-
ingly, catalyst 5i bearing a 1-naphthyl group exhibited excellent
enantioselectivity, while its regiomer 5h gave mediocre
enantioselectivity. Apparently, the different steric nature of 1-
and 2-naphthyl plays a critical role.
Fig. 1 Structures of the catalysts evaluated in this study.
substrate spectrum. Initially, we speculated that a six-mem-
bered pipecolinyl backbone might be better than either the
five-membered prolinyl backbone of 3 or the acyclic valinyl
backbone of 4 for the N-formamide type Lewis base catalysts
because it has a better balance of rigidity and flexibility. Thus,
we prepared L-pipecolinic acid derived amides 5a and 6 (Fig. 1)
and tested their catalytic efficacies. 6c proved to be an excellent
catalyst and promoted the reduction of a broad range of N-aryl
ketimines 1 with excellent enantioselectivity and reactivity.
Besides the pipecolinyl backbone, the other key structural
feature of catalyst 6c is the bulky 1,2-diphenyl-2-acetoxyethyl
amide fragment that bears two extra chiral carbon centers. To
reveal the role of this fragment and explore the possibility of
simplifying the structure of this catalyst, we carried out a survey
on the structure–efficacy relationship between the side amide
group and catalytic performances. We synthesized and tested a
series of new catalysts 5b–i and 7–10 (Fig. 1). Catalysts 11 and
12 were also prepared and tested for comparisons. As a result,
three more highly effective analogous new catalysts (5i, 9a, and
9b in Fig. 1) with simpler structures than 6c were discovered.
Herein, we wish to report a full account of our studies.
Results and discussions
We firstly designed novel formamide-based Lewis basic cata-
Catalysts 11 and 12 with a five-membered ring framework
lysts for asymmetric hydrosilylation of imines with HSiCl3 were also synthesized and tested for the hydrosilylation. Not
using the commercially available L-pipecolinic acid as the tem- surprisingly, they both showed significantly lower enantio-
plate. In our initial work, we observed that compound 5a selectivities than their six-membered ring congeners 6 and 9b
(Fig. 1) exhibited significantly higher selectivity and reactivity (entries 28–31 vs. 12–14 and 22).
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Table 1 Asymmetric hydrosilylation of imine 1a
Entry
Catalyst
Yielda (%)
eeb (%)
Config.c
Entry
Catalyst
Yielda (%)
eeb (%)
Config.c
1
2
3
4
5
6
7
8
3a
4a
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
7a
7b
75
38
94
94
89
89
71
94
66
71
96
71
97
97
93
97
59
73
73
70
73
72
36
64
12
70
93
47
93
94
71
90
R
S
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
7c
8a
8b
8c
9a
9b
9c
9d
10a
10b
10c
11a
11b
11c
12
92
92
64
77
92
81
80
79
86
88
94
81
80
84
70
82
85
44
43
93
91
65
73
89
90
92
26
70
76
73
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
9
10
11
12
13
14
15
16
a Isolated yield based on the imine. b Determined using chiral HPLC. c Identified by comparison of the HPLC data with the literature data.
On the basis of the data obtained in the test reaction of range of ketimines were reduced with HSiCl3 in the presence
imine 1a, the four catalysts 6b, 6c, 9a and 9b stood out as the of 10 mol% of catalyst in CH2Cl2 at 0 °C. As illustrated in
top-class players that exhibited the same high level of selectiv- Table 3, N-phenyl aromatic methyl ketimines 1a–j, either elec-
ity and reactivity.
tron-rich or electron-deficient, all reacted well to give the
We thus selected catalysts 5i and 6c for further studies. To desired products in high yield and high to excellent enantios-
optimize the reaction conditions, effects of the solvent, temp- electivity (72–97% yield, 83–96% ee, entries 1–10) with both
erature, catalyst loading and reaction concentration were exam- catalysts. Substrates 1q–v derived from arylamines other than
ined (Table 2). Compared with chloroform, dichloroethane, aniline also underwent the reduction to afford high yields and
and toluene, dichloromethane was found to be a more compe- excellent ee values (entries 17–22). In particular, the sterically
tent solvent to maintain the high reactivity and enantioselec- hindered N-o-MeOPh ketimine 1r (entry 18), which is a
tivity of both catalysts 5i and 6c (entries 1–4 and entries 11–14, difficult substrate for many other catalytic reduction systems,
Table 2). When the reaction temperature was lowered from 0 to was well tolerated in this system. Furthermore, high yields
−20 °C, the enantioselectivity of either catalyst was almost (70–86%) and enantioselectivities (88–95% ee) were achieved
unchanged, but their reactivities were significantly decreased for the challenging aliphatic ketimines 1l–p with catalyst 6c
(entries 5 and 15, Table 2). Further lowering the temperature despite these imines all being used as E/Z isomeric mixtures
to −40 °C and −78 °C caused a substantial decrease in enan- (entries 12–16). Additionally, in the presence of catalyst 6c,
tioselectivity and an unacceptable loss of reactivity (entries 16 α,β-unsaturated imine 1k (E/Z = 2/1) was chemo- and enantio-
and 17, Table 2). Raising the temperature to room temperature selectively reduced to afford allylic amine in 81% yield and
also caused a slight drop of the enantioselectivity (entry 18 vs. 86% ee (entries 11).
14, Table 2). The lowest effective catalyst loading was found to
The non-methyl ketimines 1w–1a′, for which so far only a
be 10 mol%. Enhancing the loading to 20 mol% has little few catalytic reduction systems have been shown to be highly
effect on the selectivity and reactivity (entries 7 and 21, effective, also proved to be good substrates for the present
Table 2). When the catalyst loading was reduced from 10 mol reaction system. Under the catalysis of 5i, good to high yields
% to 5 mol%, the ee value remains at almost the same level, (65–90%) and excellent enantioselectivities (83–96% ee) were
but the reaction slowed down significantly (entries 6 and 20, obtained (entries 23–27).
Table 2). Further lowering the catalyst loading to 1 mol% of 6c
We also investigated the imines derived from tetralone and
caused unacceptable loss of reactivity and selectivity (entry 19, indanone (Fig. 2, 1b′ and 1c′). Unfortunately, with the catalysis
Table 2). The best reaction concentration proved to be at 0.2 of 6c, the two ketimines were found to give significantly
M. Either increasing or decreasing the concentration had unfa- lowered yields and poor ee values. However, with the catalysis
vorable effects on the reactivity and enantioselectivity (entries of 5i, the hydrosilylation of imine 1b′ proceeded well with 77%
8–10 and 22–24, Table 2).
yield and 80% ee.
Having established the optimal reaction conditions, we
According to the obtained data as shown in Table 2, it
next examined the generality of catalysts 5i and 6c. A broad should be noted that the two catalysts 5i and 6c are different to
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Table 2 Effects of reaction conditions in the reduction of 1a with 5i and 6c
Entry
Catalyst
Solvent
Temp. (°C)
Cat. (eq)
[C] (mol L−1
)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
5i
5i
5i
5i
5i
5i
5i
5i
CH2Cl2
CHCl3
0
0
0
0
−20
0
0
0
0
0
0
0
0
0
−20
−40
−78
r.t.
0
0.1
0.1
0.1
0.1
0.1
0.05
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.01
0.05
0.2
0.1
0.1
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.4
0.8
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.4
0.8
96
90
93
94
63
70
90
96
91
93
97
97
91
80
77
51
26
97
61
71
94
96
94
94
93
92
91
89
93
91
91
93
91
88
94
92
94
94
95
69
66
90
85
95
92
94
91
89
ClCH2CH2Cl
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
ClCH2CH2Cl
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
5i
5i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
6c
6c
6c
6c
6c
6c
6c
6c
6c
6c
6c
6c
6c
6c
0
0
0
0
0
a Isolated yield based on the imine. b Determined using chiral HPLC.
some extent in terms of substrate scope. Aromatic methyl keti- thorough investigation on the catalyst structure–efficacy
mines proved to be good substrates for both 5i and 6c (e.g. relationship (SER) was presented in this full account, which
entries 1–9 and 17–20). However, while nonaromatic ketimines revealed a significant amount of valuable information missed
are well tolerated by 6c, 5i seems much less tolerant to these in the communication. (2) On the basis of the SER studies,
substrates (entries 11–15). Moreover, for non-methyl ketimines, three structurally simpler highly efficient new catalysts (5i, 9a,
5i proved to be much more competent than 6c (entries 23–27). and 9b) were discovered. (3) In particular, the new catalyst 5i,
Thus, 5i and 6c are complementary to each other for the non- which is structurally simpler, easier to synthesize and much
aromatic ketimines and the non-methyl ketimines, which more cost efficient than the original catalyst 6c, shows almost
enables the present reaction system to be broadly applicable.
equal efficiency compared to 6c, and meanwhile, proved to be
To illustrate the practicality of the present catalytic system, applicable for the challenging substrates bearing a relatively
a gram-scale reaction was conducted for the reduction of 1q bulky alkyl group that are hardly tolerable to 6c. (4) The appli-
using 10 mol% of 5i (Scheme 1). As expected, it retained the cation scope and limitation of the catalytic system was fully
excellent yield and enantioselectivity.
explored and thus a full picture was presented, which should
be valuable to the readers.
Experimental section
General methods
All starting materials were of the highest commercially avail-
able grade and used without further purification. All solvents
used in the reactions were distilled from appropriate drying
agents prior to use. Reactions were monitored by thin layer
chromatography using silica gel HSGF254 plates. Flash chrom-
atography was performed using silica gel HG/T2354-92. 1H and
13C NMR (300 or 600 and 75 or 150 MHz, respectively) spectra
Scheme 1 Hydrosilylation of imine 1q on gram-scale.
Conclusions
1
In summary, we have developed a series of L-pipecolinic acid
derived N-formamides as Lewis basic organocatalysts for the
enantioselective reduction of N-aryl ketimines with trichloro-
silane as the reducing agent. Compared with the previous
work, the advances of this work are the following: (1) A
were recorded in CDCl3. H NMR chemical shifts are reported
in ppm (δ) relative to tetramethylsilane (TMS) with the solvent
resonance employed as the internal standard (CDCl3,
δ
7.26 ppm). Data are reported as follows: chemical shift, multi-
plicity (s = singlet, d = doublet, q = quartet, m = multiplet),
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Table 3 Asymmetric reduction of ketimines 1 with 5i and 6ca
Cat 5i ee (%) Cat 6c ee (%)
Entry Imines R8, R9, R10
(Yield%)
(Yield%)
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph, Me, Ph
91 (94)
90 (92)
94 (88)
92 (95)
91 (90)
—
—
—
93 (90)
—
94 (97)
93 (95)
96 (85)
95 (96)
95 (98)
94 (82)
83 (72)
87 (86)
93 (92)
90 (91)
4-MeOPh, Me, Ph
4-CF3Ph, Me, Ph
4-NO2Ph, Me, Ph
4-BrPh, Me, Ph
3-BrPh, Me, Ph
2-BrPh, Me, Ph
2-ClPh, Me, Ph
2-Naphthyl, Me, Ph
6-MeONaphthyl, Me,
Ph
Scheme 2 The synthesis of 5a.
injections of the pure sample with the racemic substrates. All
imines were prepared according to the general procedure.
Some imines and amines are known compounds and their H
NMR data matched the literature data. Chemical yields refer to
pure isolated substances.
1
1j
11b
12c
13d
1k
1l
1m
Phenylethenyl, Me, Ph 79 (74)
87 (81)
95 (81)
87 (75)
Cyclohexyl, Me, Ph
Cyclohexyl, Me,
2-MeOPh
Cyclohexyl, Me,
4-BrPh
81 (74)
—
14e
1n
—
95 (80)
Procedure for the synthesis of 5a (Scheme 2)
15f
16g
17
18
19
20
21
22
23
24
25
26
27
1o
1p
1q
1r
1s
1t
1u
1v
1w
1x
1y
1z
1a′
i-Propyl, Me, Ph
i-Propyl, Me, 4-MeOPh
Ph, Me, 4-MeOPh
Ph, Me, 2-MeOPh
Ph, Me, 4-MePh
Ph, Me, 4-BrPh
Ph, Me, 4-ClPh
Ph, Me, 2-ClPh
Ph, ethyl, Ph
Ph, n-propyl, Ph
Ph, i-propyl, Ph
Ph, c-propyl, Ph
Ph, n-butyl, Ph
12 (86)
—
93 (84)
—
—
93 (94)
—
91 (86)
87 (78)
92 (98)
89 (92)
95 (90)
93 (91)
93 (98)
90 (93)
67 (90)
45 (88)
50 (66)
92 (92)
29 (90)
To a solution of L-pipecolinic acid (2.6 g, 20.0 mmol) in a
mixture of dioxane (40 mL), water (20 mL) and 1 N NaOH
(20 mL) was added di-tert-butyl dicarbonate (4.8 g, 22 mmol)
at 0 °C. The mixture was stirred and warmed to room tempera-
ture in 1 h, and then was extracted with ether (2 × 40 mL). The
aqueous phase was separated and concentrated in vacuo. Ethyl
acetate (50 mL) was added and the mixture was cooled down
with an ice-water bath. A dilute aqueous solution of KHSO4
was added to adjust the pH to 2–3. The aqueous layer was
separated and extracted with ethyl acetate. The combined
extracts was washed with brine, dried over anhydrous Na2SO4
and evaporated in vacuo. The residue was purified through
column chromatography on silica gel (eluent: hexane/EtOAc =
10/1) to give Boc-L-pipecolinic acid.
—
91 (90)
86 (86)
83 (65)
96 (70)
87 (88)
a Isolated yield based on the imine. Enantiomeric excess determined
using chiral HPLC. b E/Z = 2/1. c E/Z = 10/1. d E/Z = 8/1. e E/Z = 10/1. f E/Z
= 6/1. g E/Z = 6/1.
To a solution of Boc-L-pipecolinic acid (458 mg, 2.0 mmol)
in DCM (20 mL) was added aniline (221 μL, 2.4 mmol), HOBt
(350 mg, 2.4 mmol), DIEA (700 μL, 2.4 mmol) and EDCI
(460 mg, 2.4 mmol) at 0 °C. The reaction mixture was stirred at
25 °C for 12 h, and then concentrated under reduced pressure.
The resulting mixture was diluted with ethyl acetate (20 mL).
The organic layer was separated and washed with saturated
aqueous NaHCO3 (10 mL), aqueous HCl (1.0 N, 10 mL) and
brine (10 mL), and dried over anhydrous Na2SO4. After
removal of solvents under reduced pressure, the residue was
purified through column chromatography on silica gel (eluent:
hexane/EtOAc = 10/1) to give (S)-2-phenylcarbamoyl-piperidine-
1-carboxylic acid tert-butyl ester.
(S)-2-Phenylcarbamoyl-piperidine-1-carboxylic acid tert-
butyl ester (559 mg, 1.84 mmol) was dissolved in 20 v% TFA in
CH2Cl2 (20 mL) for an hour and then concentrated under
reduced pressure. The residue was dissolved in formic acid
(1.5 mL) and the resulting solution was cooled to 0 °C. Acetic
anhydride (1 mL, 10.66 mmol) was added dropwise and the
mixture was allowed to stir at room temperature overnight.
After concentration under reduced pressure, the crude product
Fig. 2 The results of hydrosilylation of imines 1b’ and 1c’.
coupling constants (Hz) and integration. 13C NMR chemical
shifts are reported in ppm from tetramethylsilane (TMS) with
the solvent resonance as the internal standard (CDCl3, δ
77.0 ppm). ESIMS spectra were recorded on BioTOF Q. HPLC
analyses were performed on PerkinElmer (Series 200 UV/VIS
Detector and Series 200 Pump). Chiralpak OD-H, AD-H and
OJ-H columns were purchased from Daicel Chemical Indus-
tries, Ltd. All enantiomer ratios have been controlled by co-
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was purified by column chromatography on silica gel (eluent: ESI HRMS exact mass calcd for (C13H16N2O3 + Na)+ requires m/
hexane/EtOAc = 10/1) to afford pure 5a.
(S)-1-Formyl-piperidine-2-carboxylic
z 271.1053, found m/z 271.1047.
acid
phenylamide
(S)-1-Formyl-piperidine-2-carboxylic acid 3,5-dimethyl-phe-
(5a). White solid; yield: 72%; [α]2D0 = −139.20 (c = 0.12, EtOH); nylamide (5f). Viscous liquid; yield: 68%; [α]D20 = −112.10 (c =
1
mp 129.0–130.0 °C; H NMR (600 MHz, CDCl3): δ = 1.43–1.61 0.12, CH3CH2OH); 1H NMR (600 MHz, CDCl3): δ = 1.43–1.58
(m, 2H), 1.79 (d, J = 11.76 Hz, 2H), 1.89–1.96 (m, 1H), 2.35 (m, 2H), 1.78–1.79 (m, 1H), 1.88–1.96 (m, 1H), 2.28 (s, 6H),
(d, J = 13.86 Hz, 1H), 3.29 (dt, J = 2.7, 13.32 Hz, 1H), 3.60 (d, J = 2.30 (m, 1H), 2.32–2.34 (m, 1H), 3.26–3.31 (m, 1H), 3.58–3.60
11.94 Hz, 1H), 5.12 (d, J = 5.94 Hz, 1H), 7.10 (t, J = 7.32 Hz, (d, J = 11.76 Hz, 1H), 5.09–5.10 (d, J = 5.76 Hz, 1H), 6.74 (s,
1H), 7.30 (t, J = 8.28 Hz, 2H), 7.50 (d, J = 8.28 Hz, 2H), 8.11 1H), 7.14 (s, 2H), 7.94 (s, 1H), 8.04 (s, 1H); 13C NMR (150 MHz,
(brs, 1H), 8.18 (s, 1H); 13C NMR (150 MHz, CDCl3,): δ = 20.9, CDCl3): δ = 20.87, 21.33, 24.82, 25.59, 44.54, 58.47, 117.59,
24.7, 25.6, 44.6, 51.5, 119.9, 120.2, 124.4, 128.9, 137.7, 163.1, 126.08, 137.52, 138.70, 163.01, 168.23; ESI HRMS exact mass
168.3; ESI HRMS exact mass calcd for (C13H16N2O2 + Na)+ calcd for (C15H20N2O2 + Na)+ requires m/z 283.1417, found m/z
requires m/z 255.1104, found m/z 255.1095.
283.1423.
The procedures for the synthesis of 5b–i are similar to 5a.
(S)-1-Formyl-piperidine-2-carboxylic acid 2-pyridinylamide
(S)-1-Formyl-piperidine-2-carboxylic acid 4-fluorophenyl- (5g). Viscous liquid; yield: 46%; [α]2D0 = −67.50 (c = 0.10,
amide (5b). White solid; yield: 69%; [α]2D0 = −102.20 (c = 0.23, CH3OH); 1H NMR (600 MHz, CDCl3): δ = 1.38–1.82 (m, 5H),
MeOH); mp 118.0–120.0 °C; 1H NMR (600 MHz, CDCl3): δ = 2.40 (d, J = 13.56 Hz, 1H), 3.30 (td, J = 2.7 Hz, 13.2 Hz, 1H),
1.45–1.58 (m, 2H), 1.79–1.81 (m, 2H), 1.89–1.96 (m, 1H), 2.33 3.63 (dd, J = 3.49 Hz, 13.32 Hz, 1H), 5.21 (d, J = 5.58 Hz, 1H),
(d, J = 13.86 Hz, 1H), 3.26 (td, J = 2.82 Hz, 13.2 Hz, 1H), 3.60 7.04 (td, J = 0.96 Hz, 6.6 Hz, 1H), 7.70 (td, J = 1.8 Hz, 8.52 Hz,
(d, J = 13.08 Hz, 1H), 5.08 (d, J = 5.82 Hz, 1H), 6.98–7.05 1H), 8.18 (d, J = 8.34 Hz, 1H), 8.26–8.28 (m, 1H), 8.38 (brs, 1H);
(m, 2H), 7.43–7.47 (m, 2H), 8.07 (s, 1H), 8.18 (s, 1H); 13C NMR 13C NMR (150 MHz, CDCl3): δ = 21.0, 24.9, 25.7, 44.5, 51.8,
(150 MHz, CDCl3): δ = 20.8, 24.6, 25.5, 44.5, 51.5, 115.8, 115.7, 113.9, 120.0, 138.3, 148.0, 151.0, 162.7, 168.5; ESI HRMS exact
121.6, 133.7, 163.1, 168.2; ESI HRMS exact mass calcd for mass calcd for (C12H15N3O2 + Na)+ requires m/z 256.1056,
(C13H15FN2O2
273.1024.
+
Na)+ requires m/z 273.1010, found m/z found m/z 256.1047.
(S)-1-Formyl-piperidine-2-carboxylic acid 2-naphthylamide
(S)-1-Formyl-piperidine-2-carboxylic acid 4-methoxylphenyl- (5h). Viscous liquid; yield: 56%; [α]2D0 = −126.00 (c = 0.10,
amide (5c). Viscous liquid; yield: 74%; [α]2D0 = −117.30 (c = EtOAc); 1H NMR (600 MHz, CDCl3): δ = 1.47–1.56 (m, 1H),
0.10, CH3CH2OH); 1H NMR (600 MHz, CDCl3): δ = 1.47–1.58 1.61–1.65 (m, 1H), 1.73–1.84 (m, 2H), 1.95–2.04 (m, 1H), 2.39
(m, 3H), 1.79–1.81 (d, J = 11.7 Hz, 1H), 1.89–1.94 (m, 1H), (d, J = 13.56 Hz, 1H), 3.30 (t, J = 13.2 Hz, 1H), 3.62 (d, J =
2.34–2.36 (d, J = 13.5 Hz, 1H), 3.25–3.30 (m, 1H), 3.59–3.61 12.9 Hz, 1H), 5.16 (d, J = 5.7 Hz, 1H), 7.38–7.50 (m, 3H),
(d, J = 10.56 Hz, 1H), 3.79 (s, 3H), 5.10–5.11 (d, J = 5.7 Hz, 1H), 7.76–7.82 (m, 2H), 8.20–8.26 (m, 3H); 13C NMR (150 MHz,
6.84–6.86 (d, J = 9.06 Hz, 2H), 7.40–7.41 (d, J = 9.06 Hz, 2H), CDCl3): δ = 20.9, 24.7, 25.6, 44.6, 51.6, 116.6, 119.9, 125.0,
8.19 (s, 1H); 13C NMR (150 MHz, CDCl3): δ = 20.91, 24.73, 126.5, 127.5, 127.6, 128.7, 130.7, 133.8, 135.1; ESI HRMS exact
25.61, 44.54, 51.42, 55.49, 114.13, 121.63, 130.76, 156.46, mass calcd for (C17H18N2O2 + Na)+ requires m/z 305.1260,
163.00, 167.98; ESI HRMS exact mass calcd for (C14H18N2O3 + found m/z 305.1256.
Na)+ requires m/z 285.1210, found m/z 285.1199.
(S)-1-Formyl-piperidine-2-carboxylic acid 1-naphthylamide
(S)-1-Formyl-piperidine-2-carboxylic acid 2-methoxylphenyl- (5i). Viscous liquid; yield: 68%; [α]2D0 = −104.20 (c = 0.12,
amide (5d). Viscous liquid; yield: 54%; [α]2D0 = −103.23 (c = EtOAc); 1H NMR (600 MHz, CDCl3): δ = 1.43–1.57 (m, 1H),
0.12, CH3OH); 1H NMR (600 MHz, CDCl3): δ = 1.25–1.85 1.60–1.66 (m, 1H), 1.84 (t, J = 13.08 Hz, 2H), 1.98–2.06 (m, 1H),
(m, 5H), 2.39 (d, J = 13.62 Hz, 1H), 3.31 (dt, J = 2.92 Hz, 2.43 (d, J = 13.86 Hz, 1H), 3.31 (t, J = 13.14 Hz, 1H), 3.66 (d, J =
13.2 Hz, 1H), 3.66 (dd, J = 3.48 Hz, 13.02 Hz, 1H), 3.86 (s, 3H), 13.68 Hz, 1H), 5.28 (d, J = 5.82 Hz, 1H), 7.45–7.51 (m, 2H), 7.54
4.09–4.14 (m, 1H), 5.19 (d, J = 5.88 Hz, 1H), 6.87 (d, J = 8.16 (t, J = 8.1 Hz, 1H), 7.66 (d, J = 8.28 Hz, 1H), 7.85 (d, J = 8.82 Hz,
Hz, 1H), 6.94–6.97 (m, 1H), 7.04 (dt, J = 1.42 Hz, 7.82 Hz, 1H), 2H), 8.12 (d, J = 7.5 Hz, 1H), 8.27 (s, 1H); 13C NMR (150 MHz,
8.22 (s, 1H), 8.32 (s, 1H); 13C NMR (150 MHz, CDCl3): δ = 21.0, CDCl3): δ = 21.0, 24.5, 25.6, 44.6, 51.7, 125.2, 125.7, 126.0,
25.1, 25.7, 44.4, 51.8, 55.9, 110.1, 119.8, 121.0, 124.0, 127.3, 126.1, 126.5, 128.1, 132.4, 134.0; ESI HRMS exact mass calcd
148.2, 162.4, 167.8; ESI HRMS exact mass calcd for for (C17H18N2O2 + Na)+ requires m/z 305.1260, found m/z
(C14H18N2O3
285.1207.
+
Na)+ requires m/z 285.1210, found m/z 305.1265.
Procedure for the synthesis of 6a (Scheme 3)
(S)-1-Formyl-piperidine-2-carboxylic acid 2-hydroxyphenyl-
amide (5e). Viscous liquid; yield: 54%; [α]2D0 = −116.00 (c = To a solution of Boc-L-pipecolinic acid (458 mg, 2.0 mmol) in
0.10, CH3OH); 1H NMR (300 MHz, CDCl3): δ = 1.23–1.28 (m, DCM (20 mL) was added (1S,2S)-2-amino-1,2-diphenylethanol
2H), 1.48–1.63 (m, 3H), 2.35 (d, J = 14.2 Hz, 1H), 3.23 (t, J = (511 mg, 2.4 mmol), HOBt (350 mg, 2.4 mmol), DIEA (700 μL,
12.78 Hz, 1H), 3.60 (d, J = 10.74 Hz, 1H), 5.21 (d, J = 5.7 Hz, 2.4 mmol) and EDCI (460 mg, 2.4 mmol) at 0 °C. The reaction
1H), 6.81–7.08 (m, 3H), 7.26–7.54 (m, 1H), 8.17 (s, 1H), 8.59 mixture was stirred at 25 °C for 12 h, and then concentrated
(brs, 1H); 13C NMR (150 MHz, CDCl3): δ = 20.8, 25.2, 25.5, under reduced pressure. After the resulting mixture was
44.7, 51.5, 118.1, 120.4, 121.8, 125.7, 126.3, 147.7, 163.2, 169.3; diluted with EtOAc (20 mL), the organic phase was washed
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Scheme 4 The synthesis of 7a.
7.01 (m, 2H), 7.07 (m, 2H), 7.11–7.14 (m, 1H), 7.24–7.26 (m,
4H), 7.29 (m, 1H), 8.12 (s, 1H); 13C NMR (150 MHz, CDCl3): δ =
20.8, 21.0, 24.9, 25.5, 26.7, 44.3, 50.8, 56.7, 127.1, 127.4, 127.8,
128.2, 128.3, 128.4, 135.8, 137.4, 162.6, 169.3; ESI HRMS exact
mass calcd for (C23H26N2O4 + Na)+ requires m/z 417.1785,
found m/z 417.1791.
Scheme 3 The synthesis of 6a.
(2S,1′S,2′S)-Acetic acid 2-[(1-formyl-piperidine-2-carbonyl)-
amino]-1,2-diphenyl ethyl ester (6c). White solid; yield: 68%;
[α]2D0 = −28.60 (c = 0.17, EtOH); mp 69–72 °C; 1H NMR
(600 MHz, CDCl3): δ = 1.36–1.58 (m, 3H), 1.66 (t, J = 12.90 Hz,
2H), 2.10 (s, 3H), 2.14 (d, J = 13.32 Hz, 1H), 3.12 (dt, J = 2.88,
12.90 Hz, 1H), 3.53 (d, J = 9.84 Hz, 1H), 4.98 (d, J = 5.58 Hz,
1H), 5.32 (dd, J = 6.96, 8.28 Hz, 1H), 6.02 (d, J = 6.54 Hz, 1H),
7.01–7.28 (m, 11H), 8.17 (s, 1H); 13C NMR (150 MHz, CDCl3): δ
= 20.9, 21.2, 25.1, 25.5, 26.9, 44.4, 50.9, 58.1, 126.9, 127.0,
127.7, 128.3, 128.5, 128.6, 136.8, 138.5, 162.6, 169.4; ESI HRMS
exact mass calcd for (C23H26N2O4 + Na)+ requires m/z 417.1785,
found m/z 417.1800.
with saturated aqueous NaHCO3 (10 mL), aqueous HCl (1.0 N,
10 mL) and brine (10 mL), and dried over anhydrous Na2SO4.
After removal of solvents under reduced pressure, the residue
was purified through column chromatography on silica gel
(eluent: hexane/EtOAc = 5/1) to give 6a-1.
To a solution of 6a-1 (678 mg, 1.60 mmol) in CHCl3 was
added acetic anhydride (1 mL, 10.66 mmol). The mixture was
refluxed for 5 h and then concentrated under reduced
pressure. Purification using column chromatography on silica
gel (eluent: hexane/EtOAc = 10/1) gave 6a-2.
Procedure for the synthesis of 7a (Scheme 4)
6a-2 (699 mg, 1.5 mmol) was treated with 20 v% TFA in
CH2Cl2 (20 mL) and stirred for 1 h, and then concentrated
under reduced pressure. The residue was dissolved in formic
acid (1.5 mL) and the resulting solution was cooled to 0 °C.
Acetic anhydride (1 mL, 10.66 mmol) was added dropwise and
the mixture was allowed to stir at room temperature overnight.
After concentration under reduced pressure, the crude product
was purified by column chromatography on silica gel (eluent:
hexane/EtOAc = 1/1) to afford pure 6a.
(2S,1′R,2′S)-Acetic acid 2-[(1-formyl-piperidine-2-carbonyl)-
amino]-1,2-diphenyl ethyl ester (6a). White solid; yield: 69%,
[α]2D0 = −62.10 (c = 0.12, EtOH), mp 63–66 °C; 1H NMR
(600 MHz, CDCl3): δ = 1.31–1.89 (m, 5H), 1.99 (s, 3H), 2.16 (d, J
= 14.0 Hz, 1H), 2.65 (dt, J = 2.88, 13.20 Hz, 1H), 3.32 (d, J =
13.4 Hz, 1H), 4.84 (d, J = 5.7 Hz, 1H), 5.43 (dd, J = 6.84, 8.94
Hz, 1H), 6.06 (d, J = 6.72 Hz, 1H), 6.88 (d, J = 9.18 Hz, 1H),
7.10–7.22 (m, 4H), 7.26–7.33 (m, 6H), 7.96 (s, 1H); 13C NMR
(150 MHz, CDCl3): δ = 20.8, 21.0, 24.4, 25.4, 26.6, 44.1, 50.6,
56.4, 127.4, 127.6, 127.9, 128.3, 128.4, 128.5, 136.7, 137.4,
To a solution of potassium carbonate in methanol (2 mL) was
added 6c (78.8 mg, 0.2 mmol). The reaction mixture was
stirred at 25 °C for 12 h, and then filtered. The filtrate was con-
centrated under reduced pressure and purified through
column chromatography on silica gel (eluent: hexane/EtOAc =
1/1) to give 7a.
(2S,1′S,2′S)-2-[(1-Formyl-piperidine-2-carbonyl)-amino]-1,2-
diphenylethanol (7a). White solid; yield: 65%; [α]2D0 = −60.00
1
(c = 0.10, MeOH); mp 62–65 °C; H NMR (600 MHz, DMSO): δ
= 1.19–1.23 (m, 1H), 1.36–1.50 (m, 3H), 1.93 (t, J = 13.98 Hz,
1H), 2.72 (s, 1H), 3.21 (td, J = 3.18 Hz, 12.9 Hz, 1H), 3.46 (d, J =
9.42 Hz, 1H), 4.87–4.88 (m, 2H), 5.02–5.06 (m, 1H), 5.54 (d, J =
4.98 Hz, 1H), 7.17–7.21 (m, 2H), 7.25–7.29 (m, 4H), 7.35 (t, J =
7.38 Hz, 4H), 8.0 (s, 1H), 8.12 (d, J = 8.94 Hz, 1H); 13C NMR
(150 MHz, DMSO): δ = 20.9, 25.6, 27.8, 43.9, 50.4, 56.4, 59.1,
75.4, 126.7, 127.0, 127.2, 127.8, 128.1, 128.2, 142.1, 143.7,
162.5, 170.0; ESI HRMS exact mass calcd for (C21H24N2O3
+
Na)+ requires m/z 375.1679, found m/z 375.1673
162.8, 169.0; ESI HRMS exact mass calcd for (C23H26N2O4
Na)+ requires m/z 417.1785, found m/z 417.1801.
+
Procedure for the synthesis of 7b (Scheme 5).
The procedures for the synthesis of 6b–c are similar to 6a.
To a solution of (1S,2S)-2-amino-1,2-diphenylethanol (2.13 g,
(2S,1′S,2′R)-Acetic acid 2-[(1-formyl-piperidine-2-carbonyl)- 10 mmol) in ethanol (20 mL) was added benzaldehyde (1.06 g,
amino]-1,2-diphenyl ethyl ester (6b). White solid; yield: 66%;
10 mmol). The reaction mixture was stirred at room tempera-
ture for 3 h, sodium borohydride (0.57 g, 15 mmol) was then
[α]2D0 = −31.40 (c = 0.14, EtOH), mp 62–64 °C; 1H NMR
(600 MHz, CDCl3): δ = 1.33–1.74 (m, 5H), 2.07 (s, 3H), 2.15 added. After the resulting solution was stirred at room temp-
(d, J = 13.62 Hz, 1H), 3.01 (dt, J = 2.70, 13.02 Hz, 1H), 3.43 (dd,
J = 3.06, 13.26 Hz, 1H), 4.98 (d, J = 5.82 Hz, 1H), 5.43 (dd, J =
erature for 1 h, aqueous HCl (2.0 N) was added at 0 °C to
adjust the pH to 1. The volatiles were removed under reduced
5.1 Hz, 8.88 Hz, 1H), 6.07 (d, J = 5.28 Hz, 1H), 6.84 (m, 1H), pressure. Aqueous NaOH (2.0 N) solution was then added to
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Scheme 6 The synthesis of 7c.
HRMS exact mass calcd for (C22H26N2O3 + Na)+ requires m/z
389.1836, found m/z 389.1845.
Scheme 5 The synthesis of 7b.
Procedure for the synthesis of 7c (Scheme 6)
To
a
solution of (1S,2S)-1,2-diphenylethane-1,2-diamine
adjust the pH to 10. The resulting mixture was extracted with
CH2Cl2 (3 × 20 mL) was washed with brine (10 mL), dried over
anhydrous Na2SO4, and removal of solvent under reduced
pressure. The residue was subjected to crystallization from
ethanol to afford pure (1S,2S)-2-benzylamino-1,2-diphenyletha-
nol as white crystals.
To an anhydrous THF (10 mL) solution of (1S,2S)-2-benzyl-
amino-1,2-diphenylethanol (700 mg) obtained above was
added sodium hydride (500 mg) at 0 °C, followed by the
addition of iodomethane (3 mL) dropwise. The reaction
mixture was allowed to warm to room temperature and stir for
0.5 h. Upon completion, the reaction was quenched with satu-
rated aqueous ammonium chloride and diluted with EtOAc.
The organic layer was separated, washed with brine, and dried
over anhydrous Na2SO4. After removal of solvents under
reduced pressure, the residue was purified through column
chromatography on silica gel (eluent: hexane/EtOAc = 5/1) to
give pure (1S,2S)-2-benzylamino-1,2-diphenylethyl methyl
ether as a white solid.
(212 mg, 1 mmol) in CH2Cl2 (5 mL) were added tosyl chloride
(92 mg, 0.48 mmol) and triethylamine (140 μL, 1 mmol). The
reaction mixture was stirred at room temperature for 12 h.
After removal of solvents under reduced pressure, the residue
was purified through column chromatography on silica gel
(eluent: CH2Cl2/MeOH = 20/1) to give pure N-((1S,2S)-2-amino-
1,2-diphenylethyl)-4-methylbenzenesulfonamide. The follow-
ing steps to synthesize 7c are similar to 5a.
N-(2S,1′S,2′S)-2-[(1-Formyl-piperidine-2-carbonyl)-amino]-
1,2-diphenyl-ethyl 4-methylbenzenesulfonamide (7c). White
solid; yield: 68%; [α]D20 = −58.90 (c = 0.15, EtOAc); mp
1
97–100 °C; H NMR (600 MHz, CDCl3): δ = 1.41–1.43 (m, 1H),
1.53–1.58 (m, 1H), 1.67–1.73 (m, 2H), 2.26 (d, J = 13.98 Hz,
1H), 2.30 (s, 3H), 3.26 (t, J = 13.2 Hz, 1H), 3.49 (d, J = 13.2 Hz,
1H), 4.57 (t, J = 8.58 Hz, 1H), 5.02 (d, J = 5.58 Hz, 1H), 5.14
(d, J = 8.22 Hz, 1H), 6.24 (d, J = 7.86 Hz, 1H), 6.81 (d, J =
7.26 Hz, 2H), 6.95–6.99 (m, 1H), 7.00–7.06 (m, 5H), 7.11–7.16
(m, 3H), 7.23 (d, J = 7.68 Hz, 1H), 7.41 (d, J = 8.22 Hz, 2H), 8.08
(s, 1H); 13C NMR (150 MHz, CDCl3): δ = 20.9, 21.4, 25.6, 25.7,
44.5, 51.9, 58.8, 63.3, 126.8, 127.3, 127.5, 127.8, 128.1, 128.5,
129.3, 137.7, 137.9, 162.8, 171.1; ESI HRMS exact mass calcd
for (C28H31N3O4S + Na)+ requires m/z 528.1927, found m/z
528.1940.
A methanol solution of (1S,2S)-2-benzylamino-1,2-diphenyl-
ethyl methyl ether (659 mg, 2.1 mmol) and 10% Pd(OH)2/C
were charged in a two-neck flask. The mixture was stirred
under hydrogen (1 atm) at 45 °C for 12 h, and was then filtered
through Celite®. The filtrate was concentrated to dryness to
give white solid (1S,2S)-2-amino-1,2-diphenylethyl methyl
ether.
Procedure for the synthesis of 8a (Scheme 7)
With the (1S,2S)-2-amino-1,2-diphenylethyl methyl ether in
hand, the synthesis of 7b is similar to 5a.
To a solution of (S)-methyl 2-amino-2-phenylacetate (330 mg,
2.0 mmol) in methanol (10 mL) was added sodium borohy-
dride (114 mg, 3.0 mmol) at 0 °C. After the resulting solution
was stirred at room temperature for 1 h, aqueous HCl (2.0 N)
was added at 0 °C to adjust the pH to 1. The volatiles were
removed under reduced pressure. Aqueous NaOH (2.0 N) sol-
ution was then added to adjust the pH to 10. The resulting
mixture was extracted with CH2Cl2 (3 × 20 mL) was washed
with brine (10 mL), dried over anhydrous Na2SO4, and removal
of solvent under reduced pressure. The residue was purified
through column chromatography on silica gel (eluent: DCM/
MeOH = 10/1) to give (S)-2-amino-2-phenylethanol. The follow-
ing steps to synthesize 8a are similar to 6a.
(2S,1′S,2′S)-2-[(1-Formyl-piperidine-2-carbonyl)-amino]-1,2-
diphenyl-ethyl methyl ether (7b). White solid; yield: 67%;
[α]2D0 = −29.00 (c = 0.10, MeOH); mp 145–146 °C; 1H NMR
(600 MHz, CDCl3): δ = 1.25–1.65 (m, 5H), 2.14 (d, J = 13.56 Hz,
1H), 3.09 (dt, J = 2.96 Hz, 13.16 Hz, 1H), 3.21 (s, 3H), 3.49 (dd,
J = 3.06 Hz, 12.90 Hz, 1H), 4.42 (d, J = 3.72 Hz, 1H), 4.99 (d, J =
5.82 Hz, 1H), 5.06 (dd, J = 3.66 Hz, 8.40 Hz, 1H), 6.90 (d, J =
7.92 Hz, 1H), 7.19–7.24 (m, 4H), 7.28 (d, J = 7.50 Hz, 3H), 7.32
(d, J = 7.62 Hz, 2H), 8.18 (s, 1H); 13C NMR (150 MHz, CDCl3):
δ = 20.9, 25.1, 25.7, 29.7, 44.3, 50.8, 57.5, 58.7, 85.5, 126.9,
127.0, 127.3, 128.0, 128.3, 128.4, 138.4, 140.4, 162.4, 169.3; ESI
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J = 3.84 Hz, 13.02 Hz, 1H), 4.91 (d, J = 5.7 Hz, 1H), 5.20
(q, J = 7.68 Hz, 15.12 Hz, 1H), 6.44 (d, J = 7.8 Hz, 1H),
7.04–7.07 (m, 2H), 7.13 (d, J = 7.26 Hz, 2H), 7.17–7.21 (m, 1H),
7.22–7.29 (m, 5H), 8.09 (s, 1H); 13C NMR (150 MHz, CDCl3):
δ = 20.8, 24.9, 25.5, 42.9, 44.3, 50.8, 54.6, 126.4, 126.6, 127.3,
128.3, 128.5, 129.4, 137.1, 141.7, 162.4, 169.2; ESI HRMS exact
mass calcd for (C21H24N2O2 + Na)+ requires m/z 359.1730,
found m/z 359.1713.
(2S,1′R)-2-[(1-Formyl-piperidine-2-carbonyl)-amino]-2-phenyl-
ethane (9b). Viscous liquid; yield: 75%; [α]2D0 = −74.19 (c =
0.25, EtOAc); 1H NMR (600 MHz, CDCl3): δ = 1.39–1.45
(m, 1H), 1.46 (d, J = 6.96 Hz, 3H), 1.48–1.50 (m, 1H), 1.61–1.79
(m, 3H), 2.30 (d, J = 13.68 Hz, 1H), 3.05 (td, J = 12.90 Hz, 1H),
3.46 (d, J = 10.20 Hz, 1H), 5.0 (d, J = 5.76 Hz, 1H), 5.07–5.12
Scheme 7 The synthesis of 8a.
(2S,1′S)-Acetic
acid
2-[(1-formyl-piperidine-2-carbonyl)- (m, 1H), 6.38 (brs, 1H), 7.24–7.36 (m, 5H), 8.09 (s, 1H);
amino]-2-phenyl ethyl ester (8a). Viscous liquid; yield: 51%; 13C NMR (75 MHz, CDCl3): δ = 20.8, 21.8, 25.1, 25.5, 44.3, 48.7,
[α]2D0 = −47.58 (c = 0.14, EtOAc); 1H NMR (600 MHz, CDCl3): δ = 50.7, 125.8, 127.1, 128.5, 143.3, 162.4, 168.8; ESI HRMS exact
1.25–1.76 (m, 5H), 2.06 (s, 3H), 2.28 (d, J = 12.96 Hz, 1H), mass calcd for (C15H20N2O2 + Na)+ requires m/z 283.1417,
3.11–3.15 (td, J = 13.2 Hz, 1H), 3.53–3.59 (dd, J = 13.02 Hz, 9.96 found m/z 283.1412.
Hz, 1H), 4.23–4.42 (m, 2H), 5.02 (t, J = 7.62 Hz, 1H), 5.22–5.31
(2S,1′S)-2-[(1-Formyl-piperidine-2-carbonyl)-amino]-1,2-
(m, 1H), 7.24–7.37 (m, 4H), 8.15 (s, 1H); 13C NMR (150 MHz, diphenyl-ethane (9c). Light yellow solid; yield: 77%; [α]2D0
=
1
CDCl3): δ = 20.9, 24.9, 25.6, 44.4, 50.9, 52.8, 53.4, 66.1, 126.6, −108.40 (c = 0.50, EtOAc); mp 98–102 °C; H NMR (600 MHz,
128.0, 128.9, 138.4, 162.6, 169.6, 171.3; ESI HRMS exact mass CDCl3): δ = 1.25–1.64 (m, 5H), 2.16 (d, J = 14.1 Hz, 1H), 2.38
calcd for (C17H22N2O4 + Na)+ requires m/z 341.1472, found m/z (dt, J = 2.94 Hz, 13.08 Hz, 1H), 2.88 (q, J = 10.62 Hz, 14.28 Hz,
341.1461.
1H), 3.15 (d, J = 13.44 Hz, 1H), 3.20 (dd, J = 5.22 Hz, 14.28 Hz,
The procedures for the synthesis of 8b and 8c are similar to 1H), 3.15 (d, J = 13.44 Hz, 1H), 3.20 (dd, J = 5.22 Hz, 14.28 Hz,
1H), 5.26–5.30 (m, 1H), 6.35 (d, J = 7.74 Hz, 1H), 7.16 (d, J =
8a.
(2S,1′S)-Acetic
acid
2-[(1-formyl-piperidine-2-carbonyl)- 7.68 Hz, 2H), 7.18–7.23 (m, 2H), 7.27–7.35 (m, 6H), 7.91
amino]-2-benzyl ethyl ester (8b). Viscous liquid; yield: 60%; (s, 1H); 13C NMR (150 MHz, CDCl3): δ = 20.9, 24.4, 25.5, 42.9,
[α]2D0 = −98.57 (c = 0.14, CH3OH); H NMR (600 MHz, CDCl3): δ 43.9, 50.7, 53.9, 126.3, 126.7, 127.4, 128.4, 128.7, 129.1, 137.8,
1
= 1.28–1.42 (m, 2H), 1.50–1.60 (m, 2H), 1.63–1.65 (m, 2H), 2.24 141.9, 169.2, 175.0; ESI HRMS exact mass calcd for
(d, J = 13.5 Hz, 1H), 2.46 (dt, J = 3.12 Hz, 10.08 Hz, 1H), (C21H24N2O2
2.96–3.00 (m, 2H), 3.19 (d, J = 13.56 Hz, 1H), 3.60–3.64 (m, 359.1744.
+
Na)+ requires m/z 359.1730, found m/z
1H), 3.71–3.74 (m, 1H), 4.27 (brs, 1H), 4.91 (d, J = 5.52 Hz, 1H),
(2S,1′S)-2-[(1-Formyl-piperidine-2-carbonyl)-amino]-2-phenyl-
6.10–6.18 (m, 1H), 7.19–7.30 (m, 5H), 7.91 (s, 1H); 13C NMR ethane (9d). White solid; yield: 72%; [α]2D0 = −115.50 (c = 0.20,
(150 MHz, CDCl3): δ = 20.8, 24.7, 25.5, 37.0, 44.0, 51.0, 52.7, EtOAc); mp 128–132 °C; 1H NMR (600 MHz, CDCl3): δ =
64.8, 126.6, 128.6, 129.2, 137.8, 162.6, 170.2; ESI HRMS exact 1.35–1.57 (m, 5H), 1.68–1.82 (m, 3H), 2.24 (d, J = 13.44 Hz,
mass calcd for (C16H22N2O3 + Na)+ requires m/z 313.1523, 1H), 3.27 (dt, J = 13.08 Hz, 1H), 3.56 (d, J = 13.08 Hz, 1H), 4.96
found m/z 313.1533.
(2S,1′S)-Acetic acid
(d, J = 5.76 Hz, 1H), 5.05–5.17 (m, 1H), 6.36 (brs, 1H),
2-[(1-formyl-piperidine-2-carbonyl)- 7.24–7.35 (m, 5H), 8.14 (s, 1H); 13C NMR (150 MHz, CDCl3): δ
amino]-2-iso-propanyl ethyl ester (8c). Viscous liquid; yield: = 21.0, 22.0, 25.2, 25.7, 44.4, 48.9, 50.9, 126.0, 127.4, 128.7,
56%; [α]2D0 = −102.00 (c = 0.10, EtOAc); 1H NMR (600 MHz, 143.0, 162.6, 168.3, 169.0; ESI HRMS exact mass calcd for
CDCl3): δ = 0.88 (d, J = 6.72 Hz, 3H), 0.93 (d, J = 6.66 Hz, 3H), (C15H20N2O2
1.42–1.52 (m, 2H), 1.75–1.86 (m, 4H), 2.05 (s, 3H), 2.26 (d, J = 283.1405.
+
Na)+ requires m/z 283.1417, found m/z
13.74 Hz, 1H), 3.22 (t, J = 13.2 Hz, 1H), 3.56 (d, J = 13.38 Hz,
1H), 3.96–4.18 (m, 3H), 4.95 (d, J = 5.94 Hz, 1H), 6.12 (d, J =
The procedure for the synthesis of 10 is similar to 5a.
(2S,1′R)-2-[(1-Formyl-piperidine-2-carbonyl)-amino]-2-(4-chloro-
8.76 Hz, 1H), 8.14 (s, 1H); 13C NMR (150 MHz, CDCl3): δ = phenyl)-ethane (10a). Viscous liquid; yield: 70%; [α]2D0
=
17.6, 19.4, 20.8, 21.0, 25.0, 25.7, 29.5, 44.4, 51.0, 53.3, 162.5, −47.20 (c = 0.47, EtOAc); 1H NMR (600 MHz, CDCl3): δ =
170.1, 171.1; ESI HRMS exact mass calcd for (C14H24N2O4
+
1.31–1.41 (m, 1H), 1.43 (d, J = 6.84 Hz, 3H), 1.46–1.50 (m, 2H),
1.70–1.73 (m, 2H), 2.27 (d, J = 13.74 Hz, 1H), 3.05 (t, J = 12.96
Hz, 1H), 3.48 (d, J = 13.38 Hz, 1H), 4.98 (d, J = 5.7 Hz, 1H),
Na)+ requires m/z 307.1628, found m/z 307.1612.
The procedure for the synthesis of 9 is similar to 5a.
(2S,1′R)-2-[(1-Formyl-piperidine-2-carbonyl)-amino]-1,2- 5.02–5.07 (m, 1H), 6.50 (brs, 1H), 7.18–7.31 (m, 4H), 8.07 (s,
diphenyl-ethane (9a). Light yellow solid; yield: 88%; [α]D20
=
1H); 13C NMR (150 MHz, CDCl3): δ = 20.9, 21.9, 25.0, 25.6,
−34.40 (c = 0.16, EtOAc); mp 95–98 °C; 1H NMR (600 MHz, 44.4, 48.3, 50.8, 127.3, 128.8, 132.9, 142.1, 162.5, 169.1; ESI
CDCl3): δ = 1.25–1.65 (m, 5H), 2.12 (d, J = 13.62 Hz, 1H), 2.99 HRMS exact mass calcd for (C15H19ClN2O2 + Na)+ requires m/z
(dt, J = 2.64 Hz, 15.84 Hz, 1H), 3.0–3.09 (m, 2H), 3.42 (dd, 317.1027, found m/z 317.1018.
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(2S,1′R)-2-[(1-Formyl-piperidine-2-carbonyl)-amino]-2-(4- 3.55–3.59 (m, 1H), 4.50–4.52 (d, J = 7.98 Hz, 1H), 5.32–5.33
methoxyphenyl)-ethane (10b). Viscous liquid; yield: 68%; [α]2D0 (dd, J = 5.94 Hz, 8.70 Hz, 1H), 6.01–6.02 (d, J = 5.94 Hz, 1H),
= −45.50 (c = 0.38, EtOAc); 1H NMR (600 MHz, CDCl3): δ = 7.10–7.30 (m, 10H), 8.01–8.03 (d, J = 8.76 Hz, 1H), 8.34 (s, 1H);
1.30–1.40 (m, 1H), 1.41–1.51 (m, 5H), 1.69–1.75 (m, 2H), 2.30 13C NMR (150 MHz, CDCl3): δ = 21.00, 22.93, 26.84, 30.33,
(d, J = 13.38 Hz, 1H), 3.05 (t, J = 13.38 Hz, 1H), 3.46 (d, J = 46.90, 57.81, 58.10, 126.78, 127.10, 127.59, 128.20, 128.26,
12.96 Hz, 1H), 3.80 (s, 3H), 4.98 (d, J = 5.76 Hz, 1H), 5.03–5.07 128.40, 137.20, 138.54, 162.46, 169.60, 170.25; ESI HRMS exact
(m, 1H), 6.30 (d, J = 7.68 Hz, 1H), 6.85 (d, J = 8.76 Hz, 2H), 7.18 mass calcd for (C22H24N2O4 + Na)+ requires m/z 403.1628,
(d, J = 8.76 Hz, 2H), 8.08 (s, 1H); 13C NMR (150 MHz, CDCl3): δ found m/z 403.1621.
= 20.9, 21.8, 25.0, 25.7, 44.4, 48.3, 50.9, 55.3, 114.0, 127.1,
135.5, 158.8, 162.5, 168.8; ESI HRMS exact mass calcd for
The procedure for the synthesis of 12 is similar to 5a.
(2S,1′R)-1-Formyl-pyrrolidine-2-carboxylic acid 1-phenyl-ethyl-
(C16H22N2O3
313.1511.
+
Na)+ requires m/z 313.1523, found m/z amide (12). White solid; yield: 79%; [α]2D0 = −32.50 (c = 0.12,
EtOAc); mp 93.0–95.0 °C; 1H NMR (600 MHz, CDCl3): δ =
(2S,1′R)-2-[(1-Formyl-piperidine-2-carbonyl)-amino]-2-(1- 1.81–1.96 (m, 3H), 2.49–2.53 (m, 1H), 3.43–3.48 (m, 1H),
naphthyl)-ethane (10c). White solid; yield: 65%; [α]2D0 = +16.98 3.54–3.60 (m, 1H), 4.53–4.55 (m, 1H), 5.02–5.06 (m, 1H),
1
(c = 0.11, MeOH); mp 134–135 °C; H NMR (600 MHz, CDCl3): 7.22–7.50 (m, 5H), 8.28 (s, 1H); 13C NMR (75 MHz, CDCl3): δ =
δ = 1.35–1.42 (m, 2H), 1.55 (d, J = 6.96 Hz, 3H), 1.66–1.78 22.5, 23.9, 26.9, 46.7, 48.9, 57.7, 125.8, 126.8, 128.4, 143.3,
(m, 3H), 2.30 (d, J = 13.50 Hz, 1H), 3.02 (dt, J = 3 Hz, 13.02 Hz, 162.1, 169.2; ESI HRMS exact mass calcd for (C14H18N2O2
1H), 3.43 (d, J = 9.24 Hz, 1H), 5.01 (d, J = 5.76 Hz, 1H), Na)+ requires m/z 269.1260, found m/z 269.1249.
5.25–5.29 (m, 1H), 6.39 (d, J = 7.74 Hz, 1H), 7.37 (dd, J =
+
General procedure for the synthesis of imines
7.4 Hz, 8.64 Hz, 1H), 7.44–7.49 (m, 2H), 7.69 (s, 1H), 7.79–7.84
(m, 3H), 8.08 (s, 1H); 13C NMR (150 MHz, CDCl3): δ = 20.9,
21.8, 24.9, 25.6, 44.4, 48.9, 50.9, 124.4, 125.9, 126.3, 127.6,
127.9, 128.6, 132.7, 133.4, 140.7, 162.6, 169.0; ESI HRMS exact
mass calcd for (C19H22N2O2 + Na)+ requires m/z 333.1573,
found m/z 333.1581.
The procedure for the synthesis of 11 is similar to 6a.
(2S,1′R,2′S)-Acetic acid 2-[(1-formyl-pyrrolidine-2-carbonyl)-
amino]-1,2-diphenyl ethyl ester (11a). White solid; yield: 65%;
A mixture of NaHCO3 (50 mmol), amine (10 mmol), ketone
(10 mmol) and activated molecular 4 Å sieves (8.0 g) in anhy-
drous toluene (10 mL) was heated at 80 °C for 12 h under an
argon atmosphere. The mixture was filtered through Celite®.
The filtrate was then evaporated in vacuo and the product was
crystallized from appropriate solvents or purified by distilla-
tion to give pure imine.
mp 142.0–143.0 °C; [α]2D0 = −53.00 (c = 0.10, CH3CH2OH); 1H General procedure for the catalytic reduction of imines
NMR (600 MHz, CDCl3): δ = 1.77–1.90 (m, 3H), 2.05 (s, 3H),
2.48–2.53 (m, 1H), 3.32–3.36 (m, 1H), 3.46–3.49 (m, 1H), 4.48
Under an argon atmosphere, trichlorosilane (40 μL, 0.4 mmol)
was added dropwise to
a stirred solution of imine 1
(d, J = 6 Hz, 1H), 5.38 (dd, J = 3.18 Hz, 9 Hz, 1H), 6.07 (d, J = 6
Hz, 1H), 7.13–7.16 (m, 4H), 7.19–7.31 (m, 6H), 8.08 (d, J = 8.58
Hz, 1H), 8.19 (s, 1H); 13C NMR (150 MHz, CDCl3): δ = 20.9,
22.6, 23.9, 26.4, 46.7, 57.7, 57.8, 126.6, 126.9, 127.2, 127.7,
128.1, 128.5, 137.3, 138.2, 162.5, 169.6, 169.9; ESI HRMS exact
mass calcd for (C22H24N2O4 + Na)+ requires m/z 403.1628,
found m/z 403.1618.
(0.20 mmol) and catalyst (0.02 mmol) in anhydrous CH2Cl2 at
0 °C. The mixture was allowed to stir at the same temperature
for 16 h. The reaction was quenched with a saturated aqueous
solution of NaHCO3 (5 mL) and was extracted with EtOAc. The
combined extracts was washed with brine and dried over anhy-
drous MgSO4 and the solvents were evaporated. Purification by
column chromatography (silica gel, hexane/EtOAc) afforded
pure amine 2. The ee values were determined using esta-
blished HPLC techniques with chiral stationary phases.
(2S,1′S,2′R)-Acetic acid 2-[(1-formyl-pyrrolidine-2-carbonyl)-
amino]-1,2-diphenyl ethyl ester (11b). White solid; yield: 70%;
mp 178.0–181.0 °C; [α]2D0 = −39.00 (c = 0.10, CH3CH2OH); 1H
NMR (600 MHz, CDCl3): δ = 1.81–1.96 (m, 3H), 2.11 (s, 3H),
2.48–2.51 (m, 1H), 3.38–3.42 (m, 1H), 3.51–3.55 (m, 1H),
4.52–4.54 (d, J = 7.92 Hz, 1H), 5.37–5.39 (dd, J = 5.04 Hz, 9.06
Hz, 1H), 6.09–6.10 (d, J = 4.8 Hz, 1H), 7.02–7.30 (m, 10H),
8.05–8.07 (d, J = 9.06 Hz, 1H), 8.26 (s, 1H); 13C NMR (150 MHz,
CDCl3): δ = 21.04, 21.07, 24.08, 26.32, 46.95, 57.27, 57.87,
127.02, 127.60, 127.81, 128.07, 128.09, 128.20, 136.26, 137.12,
162.54, 169.30, 170.08; ESI HRMS exact mass calcd for
Acknowledgements
We are grateful for the financial supports from the National
Natural Science Foundation of China (Projects 20972152 and
21102115).
(C22H24N2O4
403.1616.
+
Na)+ requires m/z 403.1628, found m/z
Notes and references
(2S,1′S,2′S)-Acetic acid 2-[(1-formyl-pyrrolidine-2-carbonyl)-
amino]-1,2-diphenyl ethyl ester (11c). White solid; yield: 72%;
mp 61.0–65.0 °C; [α]D20 = −16.00 (c = 0.10, CH3CH2OH); 1H
NMR (600 MHz, CDCl3): δ = 1.80–1.88 (m, 1H), 1.91–1.96 (m,
2H), 2.11 (s, 3H), 2.32–2.36 (m, 1H), 3.45–3.49 (m, 1H),
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Org. Biomol. Chem., 2013, 11, 787–797 | 797