Development of highly enantioselective new Lewis basic N-formamide organocatalysts for hydrosilylation of imines with an unprecedented substrate profile

Article abstract of DOI:10.1016/j.tet.2008.09.034

l-Pipecolinic acid derived N-formamides have been developed as new Lewis basic organocatalysts that promote the asymmetric reduction of N-aryl ketimines using trichlorosilane as the reducing agent. The substituent on N4 of the piperazinyl backbone and the

Full text of DOI:10.1016/j.tet.2008.09.034

Tetrahedron 64 (2008) 11304–11312
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Development of highly enantioselective new Lewis basic N-formamide
organocatalysts for hydrosilylation of imines with an unprecedented
substrate profile
,
,
*
Pengcheng Wu a, Zhouyu Wang a b, Mounuo Cheng a, Li Zhou a, Jian Sun a
a Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
b Department of Chemistry, Xihua University, Chengdu 610039, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 April 2008
Received in revised form 2 September 2008
Accepted 5 September 2008
Available online 23 September 2008
L
-Pipecolinic acid derived N-formamides have been developed as new Lewis basic organocatalysts that
promote the asymmetric reduction of N-aryl ketimines using trichlorosilane as the reducing agent. The
substituent on N4 of the piperazinyl backbone and the 2-carboxamide group both proved to have pro-
found effects on the efficacy of the catalyst. The reductions of both N-aryl acyclic methyl ketimines and
non-methyl ketimines were catalyzed to afford the desired amines in good to high yield and enantio-
selectivity. In particular, catalyst 6e enabled the reduction of the difficult bulky ketimines to be highly
efficient and enantioselective, affording up to 99% yield and 97% ee. This catalyst proved to prefer the
relatively bulkier non-methyl acyclic ketimines to the methyl ketimines as substrate, which is so far
unprecedented in catalytic asymmetric reduction of imines.
Keywords:
Lewis basic organocatalysts
Acyclic ketimines
L-Pipecolinic acid
Ó 2008 Elsevier Ltd. All rights reserved.
Asymmetric reduction
1. Introduction
trichlorosilane (HSiCl3) as the reducing agent (Scheme 1).4–8
Matsumura et al. first disclosed that
L-proline derived
Chiral amines are fundamentally important structural motifs
of natural products, drugs, and agrochemicals. Catalytic asym-
metric reduction of imines is one of the most efficient and
straightforward methods for their preparation and has attracted
tremendous efforts in the past several decades.1,2 However, so far
only limited successes have been met with the development of
catalytic asymmetric reduction of imines,2 in contrast to the
extraordinary advances that have been made in asymmetric
reduction of olefins and ketones. The currently available enan-
tioselective catalytic methods for the reduction of imines mainly
rely on chiral transition metal catalysts, which often require
elevated pressures and/or additives to afford high yields and ee
values. On the other hand, all of these catalysts only tolerate
a narrow scope of substrates, which are mostly limited to either
cyclic ketimines or acyclic methyl ketimines.2 There have been
rare examples of catalysts that are tolerant to acyclic non-methyl
ketimines.3
N-formamides 3 (Fig. 1) catalyzed the reduction of N-aryl ketimines
in modest enantioselectivity (up to 66% ee).4a Later, Malkov et al.
reported that
the enantioselectivity (up to 92% ee).5a Very recently, our group
developed an -pipecolinic acid derived Lewis basic catalyst 5 that
L-valine derived catalysts 4 significantly improved
L
not only exhibited a high level of enantioselectivities (up to 96%
ee), but also displayed an unprecedented substrate spectrum.6a
Encouraged by these results, we continued to search for new
highly efficient and enantioselective Lewis basic catalysts with
structural diversity, particularly those with different substrate
preferences and thus complementing with the existing catalysts.
In a preliminary communication, we reported on an L-piperazine-
2-carboxylic acid derived new catalyst 6e (Fig. 2) that exhibited
high enantioselectivity in the hydrosilylation of N-aryl ketimines
with an interesting substrate profile.6b This catalyst prefers rela-
tively bulky acyclic non-methyl ketimines as the substrate, which
Recently, catalytic asymmetric reduction of imines has been
effected with chiral Lewis basic organocatalysts using
R3
R2
R3
R2
N
HN
HSiCl3
catalyst
R1
R1
*
2
1
* Corresponding author. Tel.: þ86 28 85211220; fax: þ86 28 85222753.
E-mail address: sunjian@cib.ac.cn (J. Sun).
Scheme 1. Asymmetric reduction of ketimines.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.034

P. Wu et al. / Tetrahedron 64 (2008) 11304–11312
11305
afford 16. The subsequent procedures for the deprotections and the
installations of R4 and N-formyl groups to produce the desired
catalysts 7 and 8 are similar to those shown in Scheme 2 for the
preparation of 6, 9, and 10.
H
N
H
N
H
N
Ph
Ph
Ar
N
N
Ar
N
O
O
O
H
O
H
O
H
O
O
Ac
3
4
5
2.2. Asymmetric reduction of ketimines with HSiCl3 catalyzed
by chiral formamides
Figure 1. Structures of the Lewis basic catalysts reported previously.
We first tested the catalytic efficacies of 6a–h bearing various
substituents R4 on N4 in the model reaction of 1a with HSiCl3 in
dichloromethane at 0 ꢀC. As shown in Table 1, R4 was indeed found
to have significant influences on both the reactivity and the enan-
tioselectivity of the catalyst. Catalyst 6a with an alkyl group (Bn) on
N4 gave only a moderate yield and ee value (entry 1). When this
group was changed to methanesulfonyl, the resulted catalyst 6b
is so far unprecedented. Herein, we wish to describe the details
related to the development of this catalyst.
2. Result and discussion
2.1. Catalyst design and synthesis
exhibited improved reactivity and enantioselectivity (entry 2).9
A
In our previous studies, it has been shown that the six-
membered cyclic 2S-piperdinyl backbone of 5 is preferable for the
structure of chiral Lewis basic N-formamide catalysts.6a We
envisioned that the analogous 2S-piperazinyl backbone could also
be a good one for the same type of catalysts. The additional sec-
ondary amino group on the 4-position (N4) of the piperazinyl
backbone should provide an excellent open site for introducing
diversity elements and thus an excellent handle for fine-tuning the
catalytic properties. Thus, we designed and synthesized a series of
new N-formamide catalysts (6–10, Fig. 2) based on 2S-piperazinyl
switch of the methanesulfonyl group to the benzenesulfonyl group
(catalyst 6c) led to further improvement of both reactivity and
enantioselectivity (entry 3). Interestingly, a para-alkyl substitution
on the benzene ring of the benzenesulfonyl group (6d and 6e) has
some beneficial effects on both the reactivity and the enantiose-
lectivity of the catalyst (entries 4 and 5). The bulkier the para-
substituent is, the stronger such effects seem to be. Compound 6e
bearing a bulky para-tert-butyl gave a high yield of 97% with 80% ee
(entry 5).
A carbonyl group on N4 of the piperazinyl backbone has similar
effects on the catalytic efficacies and similar substituent preference
as the sulfonyl group (entries 6–8). Compound 6h bearing a para-
tert-butyl benzoyl gave good results with 87% yield and 87% ee
(entry 8).
backbone starting from the commercially available
carboxylic acid.
L-piperazine-2-
The synthesis of 6, 9, and 10 began with the Boc- and Cbz-
protected -piperazine-2-carboxylic acid 11, which first reacted
L
with the corresponding amines in the presence of EDCI and HOBt to
afford amides 12 (Scheme 2). N-Boc deprotection of 12 with
trifluoroacetic acid (TFA) followed by treatment with the corre-
sponding chloride gave intermediate 13. After the N-Cbz group of
13 was removed with Pd/C, the resulting amine was subjected to
N-formylation with formic acid and acetic anhydride to afford the
desired N-formamide.
Catalysts 7 and 8 were prepared starting from the commercially
available chiral 1,2-diphenyl-2-aminoethanol 14 according to
Scheme 3. The coupling of 14 with 11 gave compound 15, of which
the hydroxy group was then acetylated with acetic anhydride to
As observed with the previously reported amino acid derived
diamide Lewis base catalysts,4a,5a,b,d,6a,b,d,e the 2-carboxlic amide
group also has profound impacts on both the reactivity and the
selectivity of this new catalyst system. While catalyst 10a bearing
a para-methoxyphenyl amide group led to slightly lowered yield
and ee value, significantly decreased yield and ee value were ach-
ieved with 10b bearing a 2-naphthyl amide group.
The (10S,20S)-20-acetoxy-10,20-diphenylethyl amide group, a crit-
ical structural motif of 5,6a was found to be unfavorable in the
structure of catalysts 7. Compound 7a catalyzed the reaction with
only 36% ee (entry 9). To check if the absolute stereochemistries in
COCH3
N
t
R4
N
SO2(p- BuPh)
N
H
4
H
H
N
Ph
2
N
Ph
N
N
N
N
Ph
1'
1'
2'
Ph
O
2'
Ph
O
O
H
O
O
H
O
H
O
O
6
7
8
Ac
Ac
6a, R4 = Bn; 6b, R4 = SO2Me
8a, (1'S, 2'S)
8b, (1'R, 2'S)
8c, (1'S, 2'R)
7a, (1'S, 2'S)
7b, (1'R, 2'S)
7c, (1'S, 2'R)
6c, R4 = SO2Ph; 6d, R4 = SO2(p-MeC6H4)
6e, R4 = SO2(p- BuC6H4); 6f, R4 = COMe
t
6g, R4 = COPh; 6h, R4 = CO(p- BuC6H4)
t
R4
N
SO2(p- BuPh)
t
N
H
H
N
Ph
N
N
N
R5
1'
O
O
H
O
9
H
O
10
t
9a, 1'R, R4 = COMe
9b, 1'S, R4 = COMe
9e, 1'R, R4 = CO(p- BuC6H4)
10a, R5 = p-MeOC6H4
10b, R5 = 2-Naphthyl
9f, 1'R, R4 = CO(p-ClC6H4)
9c, 1'R, R4 = SO2(p- BuC6H4) 9g, 1'R, R4 = COPh
t
9d, 1'S, R4 = SO2 (p- BuC6H4) 9h, 1'R, R4 = COEt
t
Figure 2. L-Piperazine-2-carboxylic acid derived organocatalysts.

11306
P. Wu et al. / Tetrahedron 64 (2008) 11304–11312
Boc
N
Boc
N
R4
N
R4
N
d, e
CONHR5
a
b, c
CONHR5
N
Cbz
CO2H
N
Cbz
N
CHO
CONHR5
N
Cbz
13
11
12
6, 9, 10
Scheme 2. Preparation of organocatalysts 6, 9, and 10. Reagents and conditions: (a) EDCI, HOBt, DIEA, R5NH2, rt, 80–95%; (b) TFA (20% v/v in DCM), 0 ꢀC; (c) TEA, R4Cl, rt, two steps
85–95%; (d) Pd/C, H2 (g), rt, 83–96%; (e) HCO2H, Ac2O, rt, 60–95%.
this amide group could make any significant difference, the di-
astereomers 7b and 7c were examined. In agreement with the
observation in the case of 5, an (S)-configuration is distinctly pre-
ferred for C10. Compound 7b with (R)-C10 afforded a nearly racemic
product (entry 10). Interestingly, while the absolute configuration
of C20 has marginal influence on the selectivity of 5, 7c with (R)-C20
exhibited much higher selectivity than 7b with (S)-C20 (entries 10
and 11). Thus, catalyst 7c with the (10S, 20R)-20-acetoxy-10,20-
diphenylethyl amide group has the best-match stereochemistries.
Nevertheless, the performance of 7c is still not as good as that of 6e
bearing the same para-tert-butyl benzenesulfonyl group on N4 but
a simple phenyl amide group on C2 (entries 5 and 11), which means
the use of the chiral 20-acetoxy-10,20-diphenylethyl amide group has
no beneficial effect on the stereoselectivity of the catalysts.
When the para-tert-butyl benzenesulfonyl group on N4 was
changed to a less bulky acetyl, catalysts 8 displayed similar C10 and
C20 stereochemistry preferences as 7 (entries 12–14).
enantioselective among these three catalysts at ꢁ20 ꢀC, in contrast
to being the most enantioselective at 0 ꢀC.
These catalysts were next examined with a challenging sub-
strate, the non-methyl ketimine 1b, at ꢁ20 ꢀC. Similar to all the
other currently available catalysts, 9g gave no better ee value for
this ketimine than for its methyl analogue 1a (entry 9 vs 6). In
contrast, substantially higher enantioselectivities were obtained for
1b than 1a under the catalysis of both 6e and 6h (entries 7 and 8 vs
4 and 5). This unprecedented observation prompted us to explore
the potential of the present catalyst system for the asymmetric
reduction of other relatively bulky non-methyl substrates such as
1b–n (Table 3), which so far still remains a big challenge in asym-
metric catalysis.
As illustrated in Table 3, in the presence of catalyst 6e, N-phenyl
aromatic ethyl ketimines 1b–g and aliphatic ethyl ketimine 1h all
underwent smooth reductions to afford the corresponding amines
in high yield and enantioselectivity (83–92% yield, 84–95% ee, en-
tries 1–7). Moreover, ketimines 1j–n with even bulkier R2 groups
were also reduced well, affording high yields and ee values (75–88%
yield, 89–97% ee, entries 9–13).
Trimming off the substituents on C20 in 8 led to catalysts 9a and
9b that exhibited improved enantioselectivities (entries 15 and 16).
Without the chirality of C20, an (R)-configuration is preferred for
C10, with which the phenyl group virtually remains in the same
To have a better picture of the substrate profile of catalyst 6e,
some other methyl ketimines 1o–y besides 1a were also examined.
The results are summarized in Table 3 (entries 14–25). Although
b
-orientation as in 7a, 7c, 8a, and 8c. As expected, such C10
stereochemistry preference remains unchanged when R4 was
replaced with para-tert-butyl benzenesulfonyl (9c vs 9d, entry 17 vs
18). With the trimmed (R)-configured amide group, the other
substituents were also examined as R4 (9e–h). The obtained results
showed that R4 prefers a benzoyl group (9g, entry 21). A para-
substituent, either tert-butyl (9e) or chloro (9f), on the benzene ring
of this group has no obvious impact on the catalytic efficacies
(entries 19 and 20).
We then selected the three catalysts 6e, 6h, and 9g that dis-
played relatively high enantioselectivity in their classes for further
study. These catalysts were first tested for the reduction of 1a under
a lowered reaction temperature at ꢁ20 ꢀC. Interestingly, while both
6e and 9g gave substantially improved ee values (entries 4 and 6 vs
1 and 3, respectively, Table 2), 6h gave slightly decreased enan-
Table 1
Asymmetric hydrosilylation of ketimine 1aa
Ph
Ph
HN
Ph
N
10 mol % catalyst
HSiCl3, CH2Cl2, 0 °C
48 h
*
Ph
1a
2a
Entry
Catalyst
Yieldb (%)
eec (%)
Config.
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
7a
7b
7c
8a
8b
8c
9a
9b
9c
9d
9e
9f
65
64
77
82
97
77
80
87
80
71
63
57
52
56
71
69
79
82
76
77
75
84
92
68
40
70
74
77
80
66
78
87
36
5
R
R
R
R
R
R
R
R
R
S
tioselectivity (entry
5
vs 2). Thus, 6h became the least
Boc
N
Boc
N
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H2N
HO
Ph
Ph
71
62
6
R
R
S
H
N
H
N
a
b
Ph
Ph
Ph
Ph
N
N
Cbz O
Cbz O
68
80
77
74
54
83
83
84
72
73
56
R
R
R
R
R
R
R
R
R
R
R
HO
O
14
15
Ac
16
R4
N
R4
N
H
e, f
c, d
H
N
N
Ph
Ph
Ph
Ph
N
N
9g
9h
10a
10b
Cbz O
O
O
Ac
H
O
O
Ac
17
7, 8
a
Scheme 3. Preparation of organocatalysts 7 and 8. Reagents and conditions: (a) 11,
EDCI, HOBt, DIEA, rt, 80–93%; (b) Ac2O, DIEA, CHCl3, reflux, 90–96%; (c) TFA (20% in
DCM), 0 ꢀC; (d) TEA, R4Cl, rt, two steps 85–92%; (e) Pd/C, rt; (f) HCO2H, Ac2O, rt, two
steps 60–95%.
Unless specified otherwise, reactions were carried out with 2.0 equiv of HSiCl3
on a 0.2 mmol scale in 1.0 mL of CH2Cl2.
b
Isolated yield based on the imine.
The ee values were determined using chiral HPLC.
c

P. Wu et al. / Tetrahedron 64 (2008) 11304–11312
11307
Table 2
entries 15, 16, 18–22, 24, and 25), only low to moderate enantio-
selectivities (entries 1 and 9–13) were attained for the non-methyl
ones, with only one exception of 92% ee for cyclopropanyl ketimine
1l (entry 11).6a Thus, 6e complements well with 5 and the other
previously reported catalysts, which are limited to methyl keti-
mines for highly enantioselective reduction.
Asymmetric hydrosilylation of ketimine 1a
Ph
R2
Ph
HN
R1
N
10 mol % catalyst
HSiCl3, CH2Cl2, -20 °C
48 h
R1
R2
1
2
Entry
Catalyst
Imine
R1
R2
Temp
Yieldb (%)
eec (%)
2.3. Mechanistic consideration
1
2
3
4
5
6
7
8
9
6e
6h
9g
6e
6h
9g
6e
6h
9g
1a
1a
1a
1a
1a
1a
1b
1b
1b
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Ethyl
0
0
0
97
87
75
95
92
90
90
91
80
80
87
84
89
85
91
93
90
61
Although detailed structural and mechanistic studies remain to
be carried out, on the basis of the available experimental data, we
propose a transition state model I for the present catalytic reaction
system, which could reasonably explain the absolute configuration
of the product and the profound effects of the substituent on N4
due to its steric shielding effects.
ꢁ20
ꢁ20
ꢁ20
L20
ꢁ20
ꢁ20
Ethyl
Ethyl
O
N
O
a
Unless specified otherwise, reactions were carried out with 2.0 equiv of HSiCl3
on a 0.2 mmol scale in 1.0 mL of CH2Cl2.
S
b
Isolated yield based on the imine.
The ee values were determined using chiral HPLC.
c
N
N
H
O
O
H
RL
RS
Ar
H
Si
Cl
Cl
moderate to high yields and ee values were obtained for these
methyl ketimines, it is quite clear that these ketimines are not as
good substrates as those bulkier non-methyl ketimines for the 6e
catalyzed reduction. To the best of our knowledge, such a substrate
profile has not been previously reported for the asymmetric re-
duction of N-aryl ketimines. As a matter of fact, when our previous
analogous catalyst 5 was used as the catalyst, a dramatically dif-
ferent scenario was observed (see data in parentheses in Table 3):
while most of the methyl ketimines gave high ee values (89–95%,
Cl
N
I
3. Conclusion
We have developed
L-pipecolinic acid derived N-formamides as
new Lewis basic organocatalysts that promote the asymmetric re-
duction of N-aryl ketimines using trichlorosilane as the reducing
agent. The substituents on N4 of the piperazinyl backbone and the
2-carboxamide group both proved to have profound effects on the
efficacy of the catalyst. The reductions of both N-aryl acyclic methyl
ketimines and non-methyl ketimines were catalyzed to afford the
desired amines in good to high yield and enantioselectivity. Most
remarkably, catalyst 6e promoted the reduction of the relatively
bulky non-methyl ketimines in high yields with high ee values. The
preference of 6e for the relatively bulkier non-methyl ketimines
over the methyl ketimines as substrate is so far unprecedented in
catalytic asymmetric reduction of imines. This feature renders the
present catalyst system a good complement to the existing catalyst
systems for the high enantioselective reduction of imines in terms
of the substrate spectrum.
Table 3
Asymmetric hydrosilylation of ketimine 1 with catalyst 6ea
R3
R3
R2
N
10 mol % catalyst 6e
HSiCl3, CH2Cl2, -20 °C
48h
HN
R1
R1
R2
1
2
Entry
Imine
R1
Ph
R2
R3
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1a
1o
1p
1q
1r
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
92
87
83
89
83
87
84
75
88
75
85
84
86
95
81
99
71
40
63
64
84
66
73
33
86
94 (67)
95
94
95
90
88
84
74
90 (45)
92 (50)
97 (92)
89 (29)
91 (7)
89 (95)
89 (95)
90 (95)
85
62 (93)
88 (93)
85 (90)
75 (93)
55 (92)
56
4-FPh
4-ClPh
4-BrPh
4-MeOPh
4-MePh
c-C6H11
4. Experimental
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeOPh
4.1. General methods
9
nPr
iPr
cPr
nBu
iBu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
All starting materials were of the highest commercially available
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 chromatography was performed
using silica gel HG/T2354-92. 1H and 13C NMR (300 or 600 and 75 or
150 Hz, respectively) spectra were recorded in CDCl3 or DMSO. 1H
4-BrPh
4-NO2Ph
4-MePh
4-MeOPh
Naphth
2-(6-MeO)-Naphth
1s
1t
NMR chemical shifts are reported in parts per million (
tetramethylsilane (TMS) with the solvent resonance employed as
the internal standard (CDCl3, 7.26 ppm; DMSO, 2.36 ppm). Data
d) relative to
1u
1v
1w
1x
1y
Ph
Ph
Ph
Ph
4-ClPh
4-MeOPh
4-NO2Ph
2-MeOPh
Ph
d
d
are reported as follows: chemical shift, multiplicity (s¼singlet,
d¼doublet, q¼quartet, m¼multiplet), coupling constants (Hz), and
integration. 13C NMR chemical shifts are reported in parts per
million from tetramethylsilane (TMS) with the solvent resonance as
58 (89)
82 (95)
c-C6H11
a
Unless specified otherwise, reactions were carried out with 2.0 equiv of HSiCl3
on a 0.2 mmol scale in 1.0 mL of CH2Cl2.
the internal standard (CDCl3,
d 77.0 ppm; DMSO, d 40.0 ppm).
b
Isolated yield based on the imine.
The ee values were determined using chiral HPLC; the data in parentheses are for
c
ESIMS spectra were recorded on BioTOF Q. HPLC analyses were
performed on PerkinElmer (Series 200 UV/VIS Detector and Series
catalyst 5.

11308
P. Wu et al. / Tetrahedron 64 (2008) 11304–11312
200 Pump). Chiralpak OD-H, AD-H, and OJ-H columns were pur-
chased from Daicel Chemical Industries, Ltd. All enantiomeric ratios
have been controlled by co-injections of the pure sample with the
racemic substrates. All imines were prepared according to the
general procedure. Imines 1a, 1b, 1j, 1k, and 1o–1y are known
compounds.4,5,6a,10 Amines 2a–2g and 2j–2y are also known com-
pounds.4,5,6a,10,11 Chemical yields refer to pure isolated substances.
4.2.6. Imine 1h
Light yellow oil; yield: 61%; 1H NMR (300 MHz, CDCl3):
d¼1.0 (t,
J¼7.7 Hz, 3H), 1.17–1.92 (m, 10H), 2.37 (m, 1H), 2.45 (q, J¼7.3 Hz, 2H),
6.65 (d, J¼7.3 Hz, 2H), 6.99 (t, 1H), 7.26 (t, J¼7.7 Hz, 2H); minor iso-
mer: 2.14 (q, J¼7.7 Hz, 2H); 13C NMR (150 MHz, CDCl3):
¼11.8, 25.2,
d
26.4, 28.6, 30.8, 46.0, 119.2, 122.4, 128.7, 151.7, 179.7; ESI HRMS exact
mass calcd for C15H22N requires m/z 216.1747, found m/z 216.1736.
4.2. General procedure for the synthesis of imines
4.2.7. Imine 1l
Light yellow oil; yield: 62%; 1H NMR (300 MHz, CDCl3):
d
¼1.02–
1.07 (m, 2H), 1.22–1.28 (m, 2H), 2.67 (m, 1H), 6.56–7.57 (m, 8H),
8.00–8.04 (m, 2H); 13C NMR (150 MHz, CDCl3):
120.1, 122.6, 128.0, 128.5, 132.7, 138.1, 151.1, 172.9; ESI HRMS exact
mass calcd for C16H16N requires m/z 222.1277, found m/z 222.1275.
A mixture of NaHCO3 (50 mmol), amine (10 mmol), ketone
(10 mmol), and activated 4 Å molecular sieves (8.0 g) in anhydrous
toluene (10 mL) was heated at 80 ꢀC for 12 h under an argon at-
mosphere. The mixture was filtered through Celite. The filtrate was
then evaporated in vacuo and the product was crystallized from
appropriate solvents or purified by distillation to give pure imine.
d
¼9.5, 11.6, 17.1,
4.2.8. Imine 1m
Light yellow oil; yield: 70%; a 12/1 mixture of E/Z isomers; 1H
4.2.1. Imine 1c
NMR (300 MHz, CDCl3):
d
¼0.77 (t, J¼7.2 Hz, 3H), 1.19–1.25 (m, 2H),
Light yellow solid; yield: 70%; mp 69–72 ꢀC; a 15/1 mixture of E/
1.40–1.60 (m, 2H), 2.64 (t, J¼7.9 Hz, 3H), 6.78 (d, J¼8.4 Hz, 2H), 7.07
(t, J¼7.42 Hz,1H), 7.34 (t, J¼8.0 Hz, 2H), 7.44–7.46 (m, 3H), 7.89–7.92
Z isomers; 1H NMR (300 MHz, CDCl3):
d¼1.08 (t, J¼7.7 Hz, 3H), 2.64
(q, J¼7.7 Hz, 2H), 6.78 (d, J¼8.4 Hz, 2H), 7.08–7.16 (m, 3H), 7.35 (t,
(m, 2H); minor isomer:
d
¼2.76 (t, J¼7.88 Hz, 2H); 13C NMR
J¼7.9 Hz, 2H), 7.91–7.96 (m, 2H); minor isomer:
d
¼1.23 (t, J¼7.4 Hz,
(150 MHz, CDCl3):
128.9, 130.2, 138.6, 151.6, 169.9; ESI HRMS exact mass calcd for
d
¼13.6, 22.7, 30.3, 38.3, 119.2, 122.9, 127.5, 128.4,
3H), 2.77 (q, J¼7.5 Hz, 2H); 13C NMR (150 MHz, CDCl3):
d
¼12.9, 23.4,
115.4,115.5,119.1,123.1, 129.0, 129.8,134.2, 151.4, 163.4, 165.0, 169.5;
ESI HRMS exact mass calcd for C15H15FN requires m/z 228.1183,
found m/z 228.1176.
C17H20N requires m/z 238.1590, found m/z 238.1592.
4.2.9. Imine 1n
Light yellow oil; yield: 55%; an 8/1 mixture of E/Z isomers; 1H
4.2.2. Imine 1d
NMR (300 MHz, CDCl3):
d
¼0.78 (d, J¼6.7 Hz, 6H), 1.86–1.93 (m, 1H),
Light yellow solid; yield: 75%; mp 57–59 ꢀC; a 12/1 mixture of E/
2.59 (d, J¼7.4 Hz, 2H), 6.78–6.79 (m, 2H), 7.04–7.11 (m, 1H), 7.26–
Z isomers; 1H NMR (300 MHz, CDCl3):
d¼1.07 (t, J¼7.7 Hz, 3H), 2.64
7.56 (m, 5H), 7.84–7.98 (m, 2H); minor isomer:
d¼1.00 (d, J¼6.7 Hz,
(q, J¼7.7 Hz, 2H), 6.78 (d, J¼8.1 Hz, 2H), 7.09 (t, J¼7.4 Hz, 1H), 7.35 (t,
6H), 2.68 (d, J¼7.4 Hz, 2H); 13C NMR (150 MHz, CDCl3):
¼22.5,
d
J¼7.7 Hz, 2H), 7.42 (d, J¼6.8 Hz, 2H), 7.87 (d, J¼6.7 Hz, 2H); minor
22.8, 27.0, 38.9, 119.5, 122.9, 127.6, 128.4, 128.8, 130.1, 139.1, 151.4,
169.8; ESI HRMS exact mass calcd for C17H20N requires m/z
238.1590, found m/z 238.1600.
isomer:
(150 MHz, CDCl3):
d
¼1.23 (t, J¼7.3 Hz, 3H), 2.77 (q, J¼7.5 Hz, 2H); 13C NMR
d
¼12.87, 23.4, 119.0, 120.8, 123.2, 128.7, 129.0,
129.4, 136.5, 151.3, 169.6; ESI HRMS exact mass calcd for C15H15ClN
requires m/z 244.0888, found m/z 244.0882.
4.3. General procedure for catalytic hydrosilylation of imines
4.2.3. Imine 1e
Under an argon atmosphere, trichlorosilane (40 mL, 0.4 mmol)
Light yellow solid; yield: 75%; mp 37–39 ꢀC; a 14/1 mixture of E/
was added dropwise to a stirred solution of imine 1 (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 48 h. The reaction
was quenched with a saturated aqueous solution of NaHCO3 (5 mL)
and was extracted with EtOAc. The combined extracts were washed
with brine and dried over anhydrous MgSO4. Solvents were evap-
orated. The crude product was purified by column chromatography
(silica gel, hexane/EtOAc) to afford pure amine. The ee values were
determined by using established HPLC techniques with chiral
stationary phases.
Z isomers; 1H NMR (300 MHz, CDCl3):
d
¼1.07 (t, J¼7.7 Hz, 3H), 2.63
(q, J¼7.7 Hz, 2H), 6.77 (d, J¼7.3 Hz, 2H), 7.10 (t, J¼7.4 Hz, 1H), 7.35 (t,
J¼7.7 Hz, 2H), 7.58 (d, J¼8.6 Hz, 2H), 7.81 (d, J¼8.7 Hz, 2H); minor
isomer:
(150 MHz, CDCl3):
d
¼1.22 (t, J¼7.2 Hz, 3H), 2.77 (q, J¼7.4 Hz, 2H); 13C NMR
d
¼12.87, 23.3, 118.8, 122.6, 125.0, 129.5, 129.6,
131.7, 136.9,151.3, 169.7; ESI HRMS exact mass calcd for C15H15BrN
requires m/z 288.0382, found m/z 288.0383.
4.2.4. Imine 1f
Light yellow solid; yield: 65%; mp 51–52 ꢀC; 1H NMR (300 MHz,
CDCl3):
d
¼1.09 (t, J¼7.6 Hz, 3H), 2.63 (q, J¼7.7 Hz, 2H), 3.87 (s, 3H),
4.3.1. Amine 2a
6.78 (d, J¼7.6 Hz, 2H), 6.96 (d, J¼6.8 Hz, 2H), 6.96 (t, J¼6.9 Hz, 1H),
Light yellow oil; yield: 95%, purification by flash chromatogra-
7.34 (t, J¼7.5 Hz, 2H), 7.90 (d, J¼6.8 Hz, 2H); 13C NMR (150 MHz,
phy (hexane/EtOAc¼98/2); 1H NMR (300 MHz, CDCl3):
¼1.54 (d,
d
CDCl3):
d
¼13.1, 23.3, 55.4, 113.8, 119.3, 122.8, 129.0, 129.3, 130.6,
J¼6.72 Hz, 3H), 4.05 (br s, 1H), 4.51 (q, J¼6.72 Hz, 1H), 6.53 (m, 2H),
6.66 (m, 1H), 7.08–7.14 (m, 2H), 7.26–7.40 (m, 5H) in agreement
with the literature data.4,5a The enantiomers were analyzed by
HPLC using a chiral OD-H column (n-heptane/2-propanol¼99/1,
flow rate¼1.0 mL/min, wavelength¼254 nm); minor enantiomer:
tR¼11.82 min, major enantiomer: tR¼16.05 min; 89% ee.
151.9, 161.4, 169.8; ESI HRMS exact mass calcd for C16H18NO
requires m/z 240.1383, found m/z 240.1378.
4.2.5. Imine 1g
Light yellow solid; yield: 60%; mp 47–48 ꢀC; an 11/1 mixture of
E/Z isomers; 1H NMR (300 MHz, CDCl3):
d
¼1.08 (t, J¼7.6 Hz, 3H),
2.41 (s, 3H), 2.64 (q, J¼7.6 Hz, 2H), 6.79 (d, J¼8.4 Hz, 2H), 7.10
4.3.2. Amine 2b
(t, J¼7.5 Hz, 1H), 7.24–7.31 (m, 2H), 7.34 (t, J¼7.6 Hz, 2H), 7.83
Light yellow oil; yield: 92%, purification by flash chromatogra-
(d, J¼8.2 Hz, 2H); minor isomer:
d
¼1.23 (t, J¼7.4 Hz, 3H), 2.78 (q,
phy (2% EtOAc in hexane); 1H NMR (600 MHz, CDCl3):
d
¼0.93–0.96
J¼7.5 Hz, 2H); 13C NMR (150 MHz, CDCl3):
d
¼13.1, 21.4, 23.4, 119.2,
(t, J¼7.4 Hz, 3H), 1.79–1.83 (q, J¼7.3 Hz, 4H), 4.20–4.22 (t, J¼6.7 Hz,
1H), 6.50 (t, J¼7.8 Hz, 2H), 6.60 (t, J¼7.3 Hz, 1H), 7.05 (t, J¼8.5 Hz,
2H), 7.20–7.33 (m, 5H) in agreement with the literature data.10a The
enantiomers were analyzed by HPLC using a chiral OD-H column
120.9, 122.9, 127.6, 128.9, 129.2, 135.3, 140.6, 151.8, 170.5; ESI HRMS
exact mass calcd for C16H18N requires m/z 224.1434, found m/z
224.1433.

P. Wu et al. / Tetrahedron 64 (2008) 11304–11312
11309
(n-heptane/2-propanol¼99/1, flow rate¼1.0 mL/min, wave-
(300 MHz, CDCl3):
d
¼0.93 (t, J¼7.4 Hz, 3H), 1.11–1.22 (m, 5H), 1.65–
length¼254 nm); minor enantiomer: tR¼8.15 min, major enantio-
mer: tR¼10.27 min; 94% ee.
1.77 (m, 8H), 3.10–3.16 (m, 1H), 3.44 (br s, 1H), 6.56–6.65 (m, 3H),
7.12–7.26 (m, 2H); 13C NMR (150 MHz, CDCl3):
d¼10.8, 24.7, 26.5,
26.6, 26.7, 29.0, 29.5, 41.6, 59.2, 112.7, 116.2, 129.3, 148.9; ESI HRMS
exact mass calcd for C15H24N requires m/z 218.1903, found m/z
218.1912. Compound 2h was N-formylated and the resulted
N-formyl-2h enantiomers were successfully analyzed using a chiral
OJ-H column (n-heptane/2-propanol¼98/2, flow rate¼1.0 mL/min,
wavelength¼254 nm); minor enantiomer: tR¼8.28 min, major en-
antiomer: tR¼9.98 min; 84% ee.
4.3.3. Amine 2c
Light yellow oil; yield: 87%, purification by flash chromatogra-
20
phy (hexane/EtOAc¼98/2); [
a
]
ꢁ4.85 (c 0.676, EtOAc); 1H NMR
D
(300 MHz, CDCl3):
d
¼0.95 (t, J¼7.4 Hz, 3H), 1.72–1.89 (m, 2H), 4.06
(s,1H), 4.21 (t, J¼6.5 Hz,1H), 6.50 (d, J¼8.3 Hz, 2H), 6.67 (t, J¼7.3 Hz,
1H), 7.01 (t, J¼8.7 Hz, 2H), 7.10 (t, J¼7.7 Hz, 2H), 7.28–7.33 (m, 2H);
13C NMR (150 MHz, CDCl3):
d
¼10.8, 31.8, 59.2, 113.3, 115.3, 115.4,
N-Formyl-2h: 1H NMR (300 MHz, CDCl3):
d¼0.91 (t, J¼7.3 Hz,
117.4, 128.0, 129.2, 139.7, 147.4, 161.0, 162.7; ESI HRMS exact mass
calcd for C15H17FN requires m/z 230.1340, found m/z 230.1345. The
enantiomers were analyzed by HPLC using a chiral OD-H column
(n-heptane/2-propanol¼99/1, flow rate¼1.0 mL/min, wave-
length¼254 nm); minor enantiomer: tR¼9.13 min, major enantio-
mer: tR¼13.30 min; 95% ee.
3H), 1.03–1.25 (m, 6H), 1.72–2.04 (m, 7H), 4.09 (dt, J¼3.1, 10.7 Hz,
1H), 7.16 (d, J¼8.0 Hz, 2H), 7.21–7.42 (m, 3H), 8.43 (s, 1H).
4.3.9. Amine 2i
Light yellow oil; yield: 75%, purification by flash chromatogra-
25
phy (hexane/EtOAc¼95/5); [
a]
þ11.9 (c 0.74, EtOAc); 1H NMR
D
(300 MHz, CDCl3):
d
¼0.96 (t, J¼7.4 Hz, 3H), 1.82 (m, 2H), 3.69 (s,
4.3.4. Amine 2d
3H), 4.17 (t, J¼6.7 Hz, 1H), 6.49 (d, J¼9.0 Hz, 2H), 6.70 (d, J¼9.0 Hz,
2H), 7.24 (m, 1H), 7.31 (m, 4H) in agreement with the literature
data.6a,10a The enantiomers were analyzed by HPLC using a chiral
AD-H column (n-heptane/2-propanol¼98/2, flow rate¼1.0 mL/min,
wavelength¼254 nm); minor enantiomer: tR¼11.05 min, major
enantiomer: tR¼12.17 min; 74% ee.
Light yellow oil; yield: 83%, purification by flash chromatogra-
phy (hexane/EtOAc¼98/2); [
a
]
ꢁ7.89 (c 0.57, EtOAc); 1H NMR
20
D
(300 MHz, CDCl3):
d
¼0.95 (t, J¼7.4 Hz, 3H), 1.74–1.86 (m, 2H), 4.05
(s, 1H), 4.21 (t, J¼6.6 Hz, 1H), 6.48 (d, J¼7.7 Hz, 2H), 6.65 (t, J¼7.3 Hz,
1H), 7.09 (t, J¼7.5 Hz, 2H), 7.26–7.34 (m, 4H) in agreement with the
literature data.11a–c The enantiomers were analyzed by HPLC using
a
chiral OD-H column (n-heptane/2-propanol¼99/1, flow
4.3.10. Amine 2j
rate¼1.0 mL/min, wavelength¼254 nm); minor enantiomer:
Light yellow oil; yield: 88%, purification by flash chromatography
25
tR¼9.95 min, major enantiomer: tR¼15.12 min; 94% ee.
(hexane/EtOAc¼98/2); [
a]
þ14.1 (c 0.34, EtOAc); 1H NMR (600 MHz,
D
CDCl3):
d¼0.93 (t, J¼7.3 Hz, 3H),1.31–1.49 (m, 2H),1.75 (m,1H), 4.07
4.3.5. Amine 2e
(br s, 1H), 4.30 (t, J¼6.8 Hz, 1H), 6.50 (d, J¼7.7 Hz, 2H), 6.62 (t,
J¼7.1 Hz, 1H), 7.07 (t, J¼7.5 Hz, 2H), 7.21 (m, 1H), 7.31 (m, 4H) in
agreement with the literature data.10b,c The enantiomers were an-
alyzed by HPLC using a chiral OD-H column (n-heptane/2-prop-
anol¼99/1, flow rate¼1.0 mL/min, wavelength¼254 nm); minor
enantiomer: tR¼7.30 min, major enantiomer: tR¼9.17 min; 90% ee.
Light yellow oil; yield: 89%, purification by flash chromatogra-
20
phy (hexane/EtOAc¼98/2); [
a]
ꢁ2.31 (c 0.736, EtOAc); 1H NMR
D
(300 MHz, CDCl3):
d
¼0.95 (t, J¼7.4 Hz, 3H), 1.75–1.85 (m, 2H), 4.05
(s, 1H), 4.18 (br s, 1H), 6.47 (d, J¼7.7 Hz, 2H), 6.67 (t, J¼7.3 Hz, 1H),
7.08 (t, J¼7.4 Hz, 2H), 7.24 (t, J¼8.8 Hz, 2H), 7.43 (d, J¼6.5 Hz, 2H) in
agreement with the literature data.11c The enantiomers were ana-
lyzed by HPLC using a chiral OD-H column (n-heptane/2-prop-
anol¼95/5, flow rate¼1.0 mL/min, wavelength¼254 nm); minor
enantiomer: tR¼7.72min, major enantiomer: tR¼11.02min; 95% ee.
4.3.11. Amine 2k
Light yellow oil; yield: 75%, purification by flash chromatog-
raphy (hexane/EtOAc¼98/2); 1H NMR (300 MHz, CDCl3):
¼0.92
d
(d, J¼6.8 Hz, 3H), 0.98 (d, J¼6.8 Hz, 3H), 2.03–2.05 (m, 1H), 4.11 (s,
2H), 6.50 (d, J¼7.9 Hz, 2H), 6.60 (t, J¼7.3 Hz, 1H), 7.07 (t, J¼7.7 Hz,
2H), 7.20–7.30 (m, 5H) in agreement with the literature data.10c
The enantiomers were analyzed by HPLC using a chiral OD-H
column (n-heptane/2-propanol¼99/1, flow rate¼1.0 mL/min,
wavelength¼254 nm); minor enantiomer: tR¼6.22 min, major
enantiomer: tR¼7.26 min; 92% ee.
4.3.6. Amine 2f
Light yellow oil; yield: 83%, purification by flash chromatogra-
20
phy (hexane/EtOAc¼98/2); [
a
]
ꢁ10.94 (c 0.384, EtOAc); 1H NMR
D
(300 MHz, CDCl3):
d
¼0.95 (t, J¼7.4 Hz, 3H), 1.75–1.85 (m, 2H), 3.79
(s, 3H), 4.19 (t, J¼6.68 Hz, 1H), 6.53 (d, J¼7.7 Hz, 2H), 6.64 (t,
J¼7.3 Hz, 1H), 6.87 (d, J¼8.6 Hz, 2H), 7.10 (t, J¼7.5 Hz, 2H), 7.27 (d,
J¼8.6 Hz, 2H) in agreement with the literature data.6a,11b The
enantiomers were analyzed by HPLC using a chiral OD-H column
(n-heptane/2-propanol¼99/1, flow rate¼1.0 mL/min, wave-
length¼254 nm); minor enantiomer: tR¼10.74 min, major enan-
tiomer: tR¼13.92 min; 90% ee.
4.3.12. Amine 2l
Light yellow oil; yield: 85%, purification by flash chromatogra-
20
phy (hexane/EtOAc¼98/2); [
a
]
ꢁ80.10 (c 0.412, EtOAc); 1H NMR
D
(300 MHz, CDCl3):
d
¼0.40–0.60 (m, 4H), 1.18–1.29 (m, 1H), 3.65 (d,
J¼8.4 Hz,1H), 4.41 (br s, 1H), 6.48 (d, J¼7.6 Hz, 2H), 6.64 (t, J¼7.4 Hz,
1H), 7.09 (t, J¼7.4 Hz, 2H), 7.25–7.43 (m, 5H) in agreement with the
literature data.11e The enantiomers were analyzed by HPLC using
4.3.7. Amine 2g
Light yellow oil; yield: 87%, purification by flash chromatogra-
20
phy (hexane/EtOAc¼98/2); [
a
]
ꢁ6.16 (c 0.406, EtOAc); 1H NMR
a
chiral OD-H column (n-heptane/2-propanol¼99/1, flow
D
(300 MHz, CDCl3):
d
¼0.96 (t, J¼7.4 Hz, 3H), 1.76–1.87 (m, 2H), 2.33
rate¼1.0 mL/min, wavelength¼254 nm); minor enantiomer:
tR¼9.08 min, major enantiomer: tR¼10.42 min; 97% ee.
(s, 3H), 4.20 (t, J¼6.7 Hz,1H), 6.51 (d, J¼8.6 Hz, 2H), 6.63 (t, J¼7.3 Hz,
1H), 7.06–7.26 (m, 6H) in agreement with the literature data.6a,11d
The enantiomers were analyzed by HPLC using a chiral OD-H col-
umn (n-heptane/2-propanol¼99/1, flow rate¼1.0 mL/min, wave-
length¼254 nm); minor enantiomer: tR¼6.71 min, major
enantiomer: tR¼8.60 min; 88% ee.
4.3.13. Amine 2m
Light yellow oil; yield: 84%, purification by flash chromatogra-
20
phy (hexane/EtOAc¼98/2); [
a
]
ꢁ23.86 (c 0.352, EtOAc); 1H NMR
D
(600 MHz, CDCl3):
d
¼0.88 (t, J¼7.7 Hz, 3H), 1.25–1.43 (m, 4H), 1.73–
1.83 (m, 2H), 4.07 (br s, 1H), 4.28 (t, J¼6.8 Hz, 1H), 6.50 (d, J¼7.7 Hz,
2H), 6.61 (t, J¼7.3 Hz, 1H), 7.07 (t, J¼7.1 Hz, 2H), 7.21 (t, J¼6.9 Hz,
1H), 7.29–7.34 (m, 4H) in agreement with the literature data.10c,11f
The enantiomers were analyzed by HPLC using a chiral OD-H
4.3.8. Amine 2h
Light yellow oil; yield: 84%, purification by flash chromatogra-
phy (hexane/EtOAc¼98/2); [
20
a
]
þ10.53 (c 0.38, EtOAc); 1H NMR
D

11310
P. Wu et al. / Tetrahedron 64 (2008) 11304–11312
column (n-heptane/2-propanol¼99/1, flow rate¼1.0 mL/min,
wavelength¼254 nm); minor enantiomer: tR¼6.73 min, major en-
antiomer: tR¼8.23 min; 89% ee.
and 4.20 (d, J¼12.2 Hz,1H), 4.12 and 4.26 (d, J¼12.5 Hz,1H), 4.74 and
5.01 (s, 1H), 7.10 (t, J¼7.5 Hz,1H), 7.34 (t, J¼7.5 Hz, 2H), 7.56 and 7.60
(d, J¼7.7 Hz, 2H), 8.18 and 8.23 (s, 1H), 10.01 and 10.05 (s, 1H); 13C
NMR (150 MHz, DMSO):
d
¼35.3, 43.3, 45.8, 47.0, 51.0, 120.4, 124.3,
4.3.14. Amine 2n
129.2, 138.8, 163.4, 167.2; ESI HRMS exact mass calcd for
Light yellow oil; yield: 86%, purification by flash chromatogra-
(C13H17N3O4SþNa)þ requires m/z 334.0832, found m/z 334.0835.
20
phy (hexane/EtOAc¼98/2); [
a
]
D
ꢁ18.78 (c 0.362, EtOAc); 1H NMR
(300 MHz, CDCl3):
d
¼0.94 (d, J¼6.2 Hz, 3H), 0.99 (d, J¼6.1 Hz, 3H),
4.4.3. Catalyst 6c
20
1.57–1.62 (m, 1H), 1.65–1.74 (m, 2H), 4.04 (br s, 1H), 4.38 (t,
J¼7.5 Hz, 1H), 6.52 (d, J¼7.6 Hz, 2H), 6.63 (t, J¼7.3 Hz, 1H), 7.06–7.11
(m, 2H), 7.22–7.37 (m, 5H) in agreement with the literature data.11g
The enantiomers were analyzed by HPLC using a chiral OD-H col-
umn (n-heptane/2-propanol¼99/1, flow rate¼1.0 mL/min, wave-
length¼254 nm); minor enantiomer: tR¼6.68min, major
enantiomer: tR¼7.55min; 91% ee.
White solid; yield: 70%; [
a]
ꢁ62.0 (c 0.11, CHCl3); mp 211.0–
D
212.0 ꢀC; 1H NMR (600 MHz, CDCl3/CD3OD):
d
¼2.44–2.51 (m, 1H),
2.61 and 2.71 (dd, J¼4.3, 12.5 Hz, 1H), 3.66 and 3.72 (d, J¼11.5 Hz,
1H), 3.80–3.85 (m, 2H), 4.38–4.41 (m, 1H), 5.09 (s, 1H), 7.12–7.17 (m,
1H), 7.31–7.36 (m, 2H), 7.51–7.57 (m, 4H), 7.62–7.66 (m, 1H), 7.77 (d,
J¼7.6 Hz, 2H), 8.12 and 8.08 (s, 1H); 13C NMR (150 MHz, CDCl3/
CD3OD):
d
¼37.7, 43.2, 45.6, 51.1, 120.5, 124.6, 127.4, 128.7, 129.2,
133.3, 135.5, 137.4, 162.8, 165.8; ESI HRMS exact mass calcd for
4.4. General procedure for the synthesis of catalysts 6, 9,
and 10
(C18H19N3O4SþNa)þ requires m/z 396.0988, found m/z 396.0972.
4.4.4. Catalyst 6d
20
To a solution of 11 (10 g, 27.4 mmol) in CH2Cl2 (70 mL) were
added amine (32.9 mmol), DIEA (5.8 mL, 32.9 mmol), HOBt (4.8 g,
32.9 mmol), and EDCI (6.3 g, 32.9 mmol) at 0 ꢀC. The reaction
mixture was stirred at room temperature for 12 h and then con-
centrated under reduced pressure. The residue was diluted with
EtOAC (200 mL) and the solution was washed with saturated
aqueous NaHCO3 (40 mL), aqueous HCl (1.0 M, 20 mL), and brine
(20 mL) and dried over anhydrous Na2SO4 After removal of solvents
under reduced pressure, the residue was purified through column
chromatography on silica gel to give pure amide 12.
White solid; yield: 86%; [
a]
ꢁ61.2 (c 0.15, CHCl3); mp 96.0–
D
100.0 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼2.43 (s, 3H), 2.37–2.48 (m,
1H), 2.52 and 2.57 (dd, J¼12.6, 3.7 Hz, 1H), 3.61 (m, 1H), 3.80 (d,
J¼9.0 Hz, 1H), 4.38 (m, 1H), 4.26 and 5.14 (s, 1H), 7.12 and 7.16 (t,
J¼7.4 Hz, 1H), 7.29–7.36 (m, 4H), 7.51 and 7.66 (d, J¼7.6 Hz, 2H), 7.66
(d, J¼7.4 Hz, 2H), 7.97 and 8.33 (s,1H), 8.17 (s,1H); 13C NMR (150 MHz,
CDCl3):
d
¼21.6, 37.7, 43.2, 45.8, 51.4, 120.2, 124.8, 127.8, 129.0, 130.0,
132.6, 137.2, 144.4, 162.3, 165.0; ESI HRMS exact mass calcd for
(C19H21N3O4SþNa)þ requires m/z 410.1145, found m/z 410.1139.
Compound 12 (2.28 mmol) was dissolved in 20 v/v% TFA in
CH2Cl2 (40 mL) and stirred at room temperature for an hour, and
then concentrated under reduced pressure. The residue was dis-
solved in CH2Cl2 and the resulting solution was cooled to 0 ꢀC. TEA
4.4.5. Catalyst 6e
20
White solid; yield: 90%; [
a
]
ꢁ48.0 (c 0.10, CHCl3); mp 212.0–
D
214.0 ꢀC; 1H NMR (600 MHz, CDCl3):
d¼1.34 (s, 9H), 2.43 and 2.50
(td, J¼3.1, 11.5 Hz, 1H), 2.54 and 2.60 (dd, J¼3.7, 12.7 Hz, 1H), 3.61–
3.64 (m, 1H), 3.80–3.84 (m,1H), 4.39–4.43 (m, 2H), 4.27 and 5.16 (br
s, 1H), 7.12 and 7.16 (d, J¼7.3 Hz, 1H), 7.31 and 7.35 (d, J¼7.9 Hz, 2H),
7.52–7.63 (m, 4H), 7.70 (d, J¼8.3 Hz, 2H), 7.97 and 8.35 (s, 1H), 8.18
(480 m
L, 3.42 mmol) was added followed by the addition of R4Cl.
The mixture was allowed to stir at room temperature overnight.
After removal of solvents under reduced pressure, the residue was
purified through column chromatography on silica gel to afford
pure intermediate 13.
(s, 1H); 13C NMR (150 MHz, CDCl3/CD3OD):
d¼30.9, 35.2, 37.7, 43.3,
45.7, 51.3, 57.1, 120.3, 124.7, 126.3, 127.5, 128.9, 129.0, 132.4, 137.4,
157.3, 162.6; ESI HRMS exact mass calcd for (C22H27N3O4SþNa)þ
requires m/z 452.1614, found m/z 452.1619.
Compound 13 (1.0 mmol), 5% Pd/C (50 mg), and methanol
(15 mL) were charged in a two-neck flask (100 mL). The mixture
was stirred under hydrogen (1 atm) until the starting material
completely disappeared (monitored by TLC), and then filtered
through Celite. The filtrate was concentrated under reduced pres-
sure. The residue was dissolved in formic acid (1.5 mL) and the
resulting solution was cooled to 0 ꢀC. Acetic anhydride (1 mL) was
added dropwise and the mixture was allowed to stir at room
temperature overnight. After removal of solvents under reduced
pressure, the residue was purified through column chromatogra-
phy on silica gel to give pure catalyst.
4.4.6. Catalyst 6f
20
White solid; yield: 91%; [
a
]
ꢁ167.0 (c 0.10, CHCl3); mp 79–
D
81 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼2.34 (s, 3H), 2.68–2.73 (dt,
J¼3.3, 13.0 Hz, 1H), 3.22–3.25 (dd, J¼4.4, 13.8 Hz, 1H), 3.33–3.38 (dt,
J¼3.4, 12.9 Hz, 1H), 3.63–3.65 (m, 1H), 4.58–4.60 (d, J¼13.7 Hz, 1H),
4.72–4.74 (d, J¼13.7 Hz, 1H), 5.09 (d, J¼3.9 Hz, 1H), 7.14 (t, J¼7.3 Hz,
1H), 7.30–7.64 (m, 4H), 8.02 (s, 1H), 8.30 (s, 1H); 13C NMR (150 MHz,
CDCl3):
d
¼21.3, 40.2, 43.6, 45.0, 51.9, 120.4, 124.9, 129.0, 137.1, 163.1,
166.1, 170.4; ESI HRMS exact mass calcd for (C14H17N3O3þNa)þ re-
quires m/z 298.1162, found m/z 298.1154.
4.4.1. Catalyst 6a
20
White solid; yield: 80%; [
a]
ꢁ83.0 (c 0.10, CHCl3); mp 54.0–
D
55.0 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼2.15–2.20 (m, 1H), 2.23 and
4.4.7. Catalyst 6g
20
2.42 (dd, J¼4.0, 12.2 Hz, 1H), 3.03–3.09 (m, 1H), 3.38 and 3.46 (d,
J¼12.2 Hz, 1H), 3.55–3.68 (m, 3H), 4.13 and 5.09 (s, 1H), 4.34 (dd,
J¼2.7,12.6 Hz,1H), 7.11–7.15 (m,1H), 7.28–7.40 (m, 7H), 7.48–7.51 (m,
2H), 8.20 and 8.26 (s, 1H), 8.58 and 9.90 (s, 1H); 13C NMR (150 MHz,
White solid; yield: 78%; [
a
]
ꢁ220.0 (c 0.10, CHCl3); mp 33–
D
35 ꢀC; 1H NMR (600 MHz, CHCl3):
d¼2.70–2.74 (dt, J¼3.7, 12.5 Hz,
1H), 3.02–3.26 (m, 1H), 3.70–3.73 (m, 1H), 4.30–4.35 (m, 2H), 4.67–
4.71 (m, 1H), 4.94–4.97 (m, 1H), 7.05–7.11 (m, 2H), 7.29–7.34 (m,
4H), 7.51–7.59 (m, 4H), 8.21 (s, 1H), 10.08 (m, 1H); 13C NMR
CDCl3):
d
¼37.4, 43.7, 52.2, 53.4, 63.0, 120.2, 124.8, 128.2, 128.9, 129.1,
129.4, 136.1, 137.2, 161.9, 166.9; ESI HRMS exact mass calcd for
(150 MHz, CDCl3):
d
¼38.1, 43.2, 50.6, 52.1, 120.3, 124.7, 127.4, 128.6,
(C19H21N3O2þNa)þ requires m/z 346.1526, found m/z 346.1506.
128.9, 130.2, 137.6, 163.0, 166.3, 171.7; ESI HRMS exact mass calcd
for (C19H19N3O3þNa)þ requires m/z 360.1319, found m/z 360.1318.
4.4.2. Catalyst 6b
20
White solid; yield: 70%; [
a]
ꢁ42.1 (c 0.12, MeOH); mp 198.0–
4.4.8. Catalyst 6h
D
20
202.0 ꢀC; 1H NMR (600 MHz, DMSO):
d
¼2.71 and 2.83 (td, J¼3.4,
White solid; yield: 74%; [
a
]
ꢁ43.0 (c 0.10, MeOH); mp 90–
D
11.8 Hz, 1H), 2.90 (s, 3H), 3.05 and 3.10 (dd, J¼4.6, 12.7 Hz, 1H), 3.17
and 3.66 (td, J¼3.6,12.7 Hz,1H), 3.54 and 3.58 (d, J¼11.6 Hz,1H), 3.82
92 ꢀC; 1H NMR (600 MHz, CDCl3):
3.59–4.02 (m, 2H), 4.24–4.35 (m, 2H), 5.23 (m, 1H), 7.09–7.13 (t,
d
¼1.30 (s, 9H), 3.13–3.26 (m, 2H),

P. Wu et al. / Tetrahedron 64 (2008) 11304–11312
11311
J¼7.4 Hz, 1H), 7.26–7.48 (m, 8H), 8.26 (s, 1H); 13C NMR (150 MHz,
1H), 1.64 (s, 1H), 3.16–3.20 (m, 2H), 3.41–3.44 (m, 1H), 4.11–4.14 (m,
1H), 5.06–5.29 (m, 2H), 7.26–7.49 (m, 9H), 8.17 (s, 1H); 13C NMR
CDCl3):
d
¼30.1, 34.2, 43.1, 56.9, 124.0, 125.2, 126.5, 128.5, 163.6,
167.6, 172.0; ESI HRMS exact mass calcd for (C23H27N3O3þNa)þ
requires m/z 416.1945, found m/z 416.1947.
(150 MHz, MeOD):
d
¼20.7, 42.9, 49.1, 51.4, 56.5, 125.7, 126.7, 128.2,
129.9, 133.5, 134.9, 135.9, 143.6, 163.5, 168.4; 171.6; ESI HRMS exact
mass calcd for (C21H22Cl1N3O3þNa)þ requires m/z 422.1242, found
m/z 422.1256.
4.4.9. Catalyst 9a
20
White solid; yield: 67%; [
a
]
ꢁ7.6 (c 0.9, MeOH); mp 187–
D
189 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼1.47 (d, J¼6.8 Hz, 3H), 2.25 (s,
4.4.15. Catalyst 9g
20
3H), 2.58–2.63 (dt, J¼3.3, 12.8 Hz, 1H), 2.93–3.12 (dt, J¼3.5, 13.6 Hz,
1H), 3.13–3.16 (dd, J¼4.4, 13.6 Hz, 1H), 3.49–3.52 (m, 1H), 4.56–4.58
(d, J¼13.6 Hz, 1H), 4.63–4.65 (d, J¼13.2 Hz, 1H), 4.96–4.98 (d,
J¼3.9 Hz, 1H), 5.04–5.14 (m, 1H), 6.28 (d, J¼7.8 Hz, 1H), 7.20–7.36
White solid; yield: 81%; [
a
d
]
þ45 (c 0.1, MeOH); mp 62–64 ꢀC;
D
1H NMR (600 MHz, CDCl3):
¼1.52 (d, J¼4.6 Hz, 3H), 1.77–1.83 (m,
1H), 3.18–3.21 (q, J¼3.7 Hz, 2H), 3.43 (m, 1H), 3.84 (m, 1H), 4.17 (m,
1H), 5.09–5.16 (m, 1H), 7.26–7.43 (m, 10H), 8.18 (s, 1H); 13C NMR
(m, 5H), 8.19 (s, 1H); 13C NMR (150 MHz, MeOD):
46.2, 49.1, 51.8, 56.9, 125.6, 126.7, 128.2, 143.4, 163.8, 168.0, 170.7;
ESI HRMS exact mass calcd for (C16H21N3O3þNa)þ requires m/z
326.1475, found m/z 326.1480.
d
¼19.7, 41.3, 42.9,
(150 MHz, MeOD):
d
¼22.4, 43.0, 48.8, 50.9, 126.4, 127.1, 128.7, 130.1,
136.0, 144.8, 163.0, 168.1, 170.0; ESI HRMS exact mass calcd for
(C21H23N3O3þNa)þ requires m/z 388.1632, found m/z 388.1629.
4.4.16. Catalyst 9h
20
4.4.10. Catalyst 9b
White solid; yield: 60%; [
a]
þ9.3 (c 0.9, MeOH); mp 179–
D
20
White solid; yield: 73%; [
a
]
ꢁ8.3 (c 0.1, MeOH); mp 182–
181 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼0.90–0.89 (q, J¼7.0 Hz, 3H),
D
184 ꢀC; 1H NMR (600 MHz, CDCl3)
d
¼1.50 (d, J¼6.9 Hz, 3H), 2.26 (s,
1.30–1.33 (dd, J¼6.6, 15.6 Hz, 3H), 2.26–2.30 (m, 1H), 2.65 (m, 1H),
2.85–3.08 (m, 1H), 3.25–3.27 (q, J¼14.8 Hz, 2H), 3.78–3.84 (m, 1H),
3.92–4.05 (m, 1H), 4.25–4.32 (m, 1H), 4.35–4.44 (m, 1H), 4.66–4.71
(m, 1H), 4.81–4.89 (m, 1H), 7.20–7.26 (m, 5H), 8.21 (s, 1H); 13C NMR
3H), 2.59–2.63 (dt, J¼3.3, 12.9 Hz, 1H), 3.06–3.12 (dt, J¼3.5, 12.9 Hz,
1H), 3.13–3.16 (dd, J¼4.6, 13.7 Hz, 1H), 3.50 (d, J¼11.9 Hz, 1H), 4.58
(d, J¼13.6 Hz, 1H), 4.99 (d, J¼4.1 Hz, 1H), 5.06–5.13 (m, 1H), 6.25 (d,
J¼7.1 Hz, 1H), 7.21–7.36 (m, 5H), 8.20 (s, 1H); 13C NMR (150 MHz,
(150 MHz, MeOD):
d
¼20.2, 25.3, 37.9, 43.1, 45.3, 49.3, 51.9, 56.9,
CDCl3):
d
¼22.3, 41.4, 43.4, 47.1, 47.8, 56.2, 126.4, 127.1, 127.8, 144.6,
125.8, 126.8, 128.2, 143.4, 163.8, 168.0, 173.9; ESI HRMS exact mass
calcd for (C17H23N3O3þNa)þ requires m/z 340.1632, found m/z
340.1639.
163.3, 168.7, 169.1; ESI HRMS exact mass calcd for
(C16H21N3O4þNa)þ requires m/z 326.1475, found m/z 326.1473.
4.4.11. Catalyst 9c
4.4.17. Catalyst 10a
20
20
White solid; yield: 85%; [
a]
þ51.4 (c 0.7, MeOH); mp 178–
White solid; yield: 80%; [
a]
ꢁ36.0 (c 0.10, MeOH); mp 126.0–
D
D
180 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼1.34 (s, 9H), 1.53–1.57 (dd,
127.0 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼1.35 (s, 9H), 2.40–2.45 (m,
J¼6.9, 8.2 Hz, 3H), 2.35–2.42 (dq, J¼3.4, 9.0 Hz, 1H), 2.53 and 2.56
(dd, J¼3.6,12.4 Hz,1H), 3.45–3.52 (m,1H), 3.76 (t, J¼10.8 Hz,1H), 4.31
(d, J¼12.5 Hz, 1H), 4.08 and 5.02 (s, 1H), 5.15 (q, J¼7.4 Hz, 1H), 6.25
and 6.75 (d, J¼7.7 Hz, 1H), 7.24–7.39 (m, 5H), 7.53–7.57 (m, 2H), 7.67
(d, J¼7.5 Hz, 2H), 8.07 (d, J¼2.8 Hz, 1H); 13C NMR (150 MHz, CDCl3):
1H), 2.53 and 2.53 (dd, J¼12.6, 3.8 Hz, 1H), 3.60–3.62 (m, 1H), 3.79
and 3.81 (s, 3H), 3.82–3.84 (m, 1H), 4.40 (d, J¼12.4 Hz, 1H), 5.14 and
4.25 (s, 1H), 6.85 and 6.88 (d, J¼8.8 Hz, 2H), 7.44 (d, J¼8.8 Hz, 1H),
7.52–7.58 (m, 3H), 7.70 (d, J¼8.4 Hz, 2H), 7.84 and 8.24 (s, 1H), 8.17
(s, 1H); 13C NMR (150 MHz, CDCl3):
d¼31.0, 35.3, 43.2, 45.4, 45.8,
d
¼22.7, 31.2, 35.4, 43.1, 46.2, 48.7, 50.2, 55.8, 126.6,126.8,127.2, 127.9,
51.3, 55.5, 114.2, 122.0, 126.4, 127.6, 130.3, 132.5, 157.3, 162.3, 164.8;
ESI HRMS exact mass calcd for (C23H29N3O5SþNa)þ requires m/z
482.1720, found m/z 482.1725.
128.7, 144.6, 156.9, 163.0 167.5; ESI HRMS exact mass calcd for
(C27H27N3O4þNa)þ requires m/z 480.1894, found m/z 480.1905.
4.4.12. Catalyst 9d
4.4.18. Catalyst 10b
20
20
White solid; yield: 75%; [
a]
ꢁ31.3 (c 0.9, MeOH); mp 95–97 ꢀC;
White solid; yield: 70%; [
a
]
ꢁ42.7 (c 0.10, MeOH); mp 129.0–
D
D
1H NMR (600 MHz, CDCl3):
d¼1.34 (s, 9H), 1.52–1.56 (dd, J¼7.0,
130.0 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼1.33 (s, 9H), 2.44–2.58 (m,
16.8 Hz, 3H), 2.31–2.39 (m, 1H), 2.49–2.52 (dd, J¼3.8, 12.4 Hz, 1H),
3.47–3.54 (m, 1H), 3.73–3.75 (d, J¼11.3 Hz, 1H), 4.33–4.36 (q,
J¼7.4 Hz, 1H), 4.08 and 5.02 (d, J¼2.5 Hz, 1H), 5.10–5.16 (m, 1H),
6.38 and 6.82 (d, J¼7.7 Hz, 1H), 7.23–7.28 (m, 1H), 7.33–7.35 (q,
J¼4.5 Hz, 4H), 7.53–7.57 (q, J¼8.6 Hz, 2H), 7.67 (d, J¼7.5 Hz, 2H),
2H), 3.63–3.80 (m, 3H), 4.49–4.53 (m, 1H), 5.26 and 4.48 (s, 1H),
7.42–7.56 (m, 5H), 7.66–7.87 (m, 6H), 8.17 and 8.18 (s, 1H), 8.37 and
8.64 (s, 1H); 13C NMR (150 MHz, CDCl3):
d
¼21.0, 31.0, 35.2, 43.2,
45.8, 45.8, 60.4, 120.9, 125.6, 126.1, 126.3, 126.5, 126.6, 127.7, 128.6,
131.9, 132.5, 134, 157.2, 162.5, 171.1; ESI HRMS exact mass calcd for
(C26H29N3O4SþNa)þ requires m/z 502.1771, found m/z 502.1759.
8.07 (d, J¼2.8 Hz, 1H); 13C NMR (150 MHz, CDCl3):
¼21.9, 31.0,
d
35.2, 43.1, 46.0, 49.3, 50.1, 56.2, 126.1, 126.3, 127.6, 128.7, 132.4,
142.9, 157.4, 162.0, 165.9; ESI HRMS exact mass calcd for
(C27H27N3O4þNa)þ requires m/z 480.1894, found m/z 480.1915.
4.5. General procedure for the synthesis of catalysts 7 and 8
To a solution of 11 (10 g, 27.4 mmol) in DCM (70 mL) were added
14 (7.0 g, 32.9 mmol), DIEA (5.8 mL, 32.9 mmol), HOBt (4.8 g,
32.9 mmol), and EDCI (6.3 g, 32.9 mmol) at 0 ꢀC. The reaction
mixture was stirred at room temperature for 12 h and then con-
centrated under reduced pressure. The residue was diluted with
EtOAC (200 mL) and the solution was washed with saturated
aqueous NaHCO3 (40 mL), aqueous HCl (1.0 M, 20 mL), and brine
(20 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/EtOAc¼5/1) to give
pure 15.
4.4.13. Catalyst 9e
20
White solid; yield: 75%; [
a]
þ43 (c 0.8, MeOH); mp 110–
D
112 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼1.35 (s, 9H), 1.46 (d, J¼7.0 Hz,
1H), 2.51–2.51–2.53 (m, 1H), 3.10–3.28 (m, 2H), 3.60–3.80 (m, 2H),
4.17–4.18 (t, J¼8.3 Hz, 1H), 4.95–5.10 (m, 2H), 7.22–7.36 (m, 7H),
7.50–7.52 (m, 2H), 8.17 (s, 1H); 13C NMR (150 MHz, MeOD):
d¼20.8,
30.2, 34.4, 43.0, 49.3, 51.4, 125.3, 125.7, 126.7, 128.1, 131.9, 163.5,
168.5, 171.9; ESI HRMS exact mass calcd for (C25H31N3O3þNa)þ
requires m/z 444.2258, found m/z 444.2265.
4.4.14. Catalyst 9f
Acetic anhydride (2 mL, 21.3 mmol) was added dropwise to
a solution of 15 (4.3 mmol) in chloroform. The mixture was refluxed
for 5 h and then concentrated under reduced pressure. The residue
20
White solid; yield: 75%; [
a
d
]
D
þ34 (c 0.9, MeOH); mp 78–90 ꢀC;
1H NMR (600 MHz, CDCl3):
¼1.44 (d, J¼6.0 Hz, 3H), 1.49–1.52 (m,

11312
P. Wu et al. / Tetrahedron 64 (2008) 11304–11312
was purified by column chromatography on silica gel (eluent:
hexane/EtOAc¼10/1) to give pure acetate 16.
4.5.6. Catalyst 8c
20
White solid; yield: 95%; [
a
d
]
D
ꢁ75 (c 0.7, MeOH); mp 93–95 ꢀC;
The rest of the procedures are similar to those for the synthesis
of 6, 9, and 10 from intermediates 12.
1H NMR (600 MHz, CDCl3):
¼2.04 (s, 3H), 2.16 (s, 3H), 2.60 and
2.75 (dt, J¼9.5, 12.8 Hz, 1H), 2.97–3.01 (dt, J¼3.2, 12.8 Hz, 1H), 3.12–
3.15 (dd, J¼4.6, 14.0 Hz, 1H), 3.46–3.49 (t, J¼13.8 Hz, 1H), 3.63 (m,
1H), 4.39–4.60 (t, J¼13.7 Hz, 2H), 5.30–5.34 (m, 1H), 6.08–6.16 (m,
1H), 6.90–7.16 (m, 5H), 7.24–7.33 (m, 5H), 8.15and 8.21 (s, 1H); 13C
4.5.1. Catalyst 7a
20
White solid; yield: 81%; [
a
]
þ38.0 (c 0.10, MeOH); mp 116.0–
D
118.0 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼1.35 and 1.36 (s, 9H), 2.03–
NMR (600 MHz, MeOD):
d
¼19.8, 37.2, 41.0, 42.6, 45.7, 51.3, 57.7,
2.06 (m, 1H), 2.159 and 2.164 (s, 3H), 2.24–2.48 (m, 3H), 3.40 and
4.10 (d, J¼13.7 Hz, 1H), 3.72 and 3.73 (d, J¼11.2 Hz, 1H), 3.94 and
4.98 (s, 1H), 4.20 (m, 1H), 5.46 and 5.54 (dd, J¼8.3, 5.64 Hz and 8.64,
3.7 Hz, 1H), 6.08 and 6.16 (d, J¼5.6, 3.6 Hz, 1H), 7.21–7.72 (m, 14H),
76.7, 127.1, 127.6, 127.9, 128.1, 163.4, 168.2, 170.0, 170.7; ESI HRMS
exact mass calcd for (C24H27N3O5þNa)þ requires m/z 460.1843,
found m/z 460.1826.
7.95 and 8.02 (s, 1H); 13C NMR (150 MHz, CDCl3):
d¼20.8, 31.0, 35.3,
Acknowledgements
42.5, 45.4, 50.6, 56.2, 58.3, 60.4, 125.9, 126.3, 126.6, 126.9, 127.0,
127.1, 127.7, 128.0, 128.2, 128.4, 128.6, 128.7, 131.3, 137.4, 157.9, 161.5,
166.4, 169.8; ESI HRMS exact mass calcd for (C32H37N3O6SþNa)þ
requires m/z 614.2295, found m/z 614.2291.
We are grateful for financial supports from National Natural
Science Foundation of China (Projects 20672107 and 20732006).
4.5.2. Catalyst 7b
20
Reference and notes
White solid; yield: 86%; [
a
]
þ14.7 (c 0.10, MeOH); mp 105.0–
D
107.0 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼1.35 and 1.36 (s, 9H), 2.09
1. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, NY,
1994; (b) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; Wiley: New York, NY,
2000; (c) James, B. R. Catal. Today 1997, 37, 209; (d) Kobayashi, S.; Ishitani, H.
Chem. Rev. 1999, 99, 1069.
2. For recent reviews, see: (a) Taratov, V. I.; Bo¨rner, A. Synlett 2005, 203; (b) Riant,
O.; Mostefai, N.; Courmarcel, J. Synthesis 2004, 2943; (c) Tang, W.; Zhang, X.
Chem. Rev. 2003, 103, 3029; (d) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.;
Steiner, H.; Studer, M. Adv. Synth. Catal. 2003, 345, 103; (e) Carpentier, J. F.;
Bette, V. Curr. Org. Chem. 2002, 6, 913; (f) Palmer, M. J.; Wills, M. Tetrahedron:
Asymmetry 1999, 10, 2045.
3. (a) Shang, G.; Yang, Q.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 6360; (b) Nolin,
K. A.; Ahn, R. W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 12462; (c) Verdaguer, X.;
Lange, U.; Buchwald, S. L. Angew. Chem., Int. Ed. 1998, 37, 1103; (d) Kang, Q.; Zhao,
Z.-A.; You, S.-L. Org. Lett. 2008, 10, 2031; (e) Kang, Q.; Zhao, Z.-A.; You, S.-L. Adv.
Synth. Catal. 2007, 349, 2075; (f) Li, G.; Liang, Y.; Antilla, J. C.; Kang, Q.; Zhao, Z.-A.;
You, S.-L. J. Am. Chem. Soc. 2007, 129, 5830.
4. (a) Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.; Maki, T.; Matsumura,
Y. Tetrahedron Lett. 2001, 42, 2525; (b) Onomura, O.; Kouchi, Y.; Iwasaki, F.;
Matsumura, Y. Tetrahedron Lett. 2006, 47, 3751.
5. (a) Malkov, A. V.; Mariani, A.; MacDougall, K. N.; Kocovsky, P. Org. Lett. 2004, 6,
2253; (b) Malkov, A. V.; Stoncius, S.; MacDougall, K. N.; Mariani, A.; McGeoch,
G. D.; Kocovsky, P. Tetrahedron 2006, 62, 264; (c) Malkov, A. V.; Liddon, A.;
Ramirez-Lopez, P.; Bendova, L.; Haigh, D.; Kocovsky, P. Angew. Chem., Int. Ed.
2006, 45, 1432; (d) Malkov, A. V.; Figlus, M.; Stoncius, S.; Kocovsky, P. J. Org.
Chem. 2007, 72, 1315; (e) Malkov, A. V.; Stoncius, S.; Kocovsky, P. Angew. Chem.,
Int. Ed. 2007, 46, 3722.
6. (a) Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett. 2006, 8, 999; (b)
Wang, Z.; Cheng, M.; Wu, P.; Wei, S.; Sun, J. Org. Lett. 2006, 8, 3045; (c) Pei, D.;
Wang, Z.; Zhang, Y.; Wei, S.; Sun, J. Org. Lett. 2006, 8, 5913; (d) Zhou, L.; Wang,
Z.; Wei, S.; Sun, J. Chem. Commun. 2007, 2977; (e) Wang, Z.; Wei, S.; Wang, C.;
Sun, J. Tetrahedron: Asymmetry 2007, 18, 705; (f) Pei, D.; Zhang, Y.; Wei, S.;
Wang, M.; Sun, J. Adv. Synth. Catal. 2008, 350, 619.
7. (a) Zheng, H.; Deng, J.; Lin, W.; Zhang, X. Tetrahedron Lett. 2007, 48, 7934; (b)
Baudequin, C.; Chaturvedi, D.; Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 2623.
8. For recent reviews on asymmetric Lewis base catalysis, see: (a) Denmark, S. E.;
Heemstra, J. R.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682; (b) Rendler,
S.; Oestreich, M. Synthesis 2005, 1727; (c) Koboyashi, S.; Sugiura, M.; Ogawa, C.
AdV. Synth. Catal. 2004, 346, 1023; (d) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103,
2763; (e) Denmark, S. E.; Fu, J. Chem. Commun. 2003, 167; (f) Denmark, S. E.;
Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.
and 2.13 (s, 3H), 2.20–2.54 (m, 2H), 3.00–3.01 (m, 1H), 3.39 and 4.18
(d, J¼13.9 Hz, 1H), 3.68 (d, J¼11.2 Hz, 1H), 4.24–4.30 (m, 1H), 4.91
and 4.05 (s, 1H), 5.42–5.46 (m, 1H), 6.10 and 6.17 (d, J¼5.40 Hz, 1H),
7.11–7.18 (m, 4H), 7.28–7.35 (m, 6H), 7.52–7.69 (m, 4H), 8.0 (s, 1H);
13C NMR (150 MHz, CDCl3):
d
¼21.0, 31.0, 35.2, 42.8, 44.8, 45.7, 50.9,
57.6, 60.4, 126.3, 126.4, 127.1, 127.6, 127.9, 128.2, 128.4, 128.5, 132.4,
136.8, 157.4, 162.0, 165.9, 170.7; ESI HRMS exact mass calcd for
(C32H37N3O6SþNa)þ requires m/z 614.2295, found m/z 614.2290.
4.5.3. Catalyst 7c
20
White solid; yield: 76%; [
a
]
þ43.8 (c 0.10, MeOH); mp 222.0–
D
223.0 ꢀC; 1H NMR (600 MHz, CDCl3):
d¼1.35 (s, 9H), 2.04 and 2.10
(s, 3H), 2.20–2.41 (m, 2H), 3.01–4.19 (m, 4H), 5.00 and 3.9 (s, 1H),
5.47–5.49 (m, 1H), 6.21 and 6.18 (d, J¼6.7 Hz, 1H), 7.15–7.18 (m, 2H),
7.26–7.36 (m, 8H), 7.53–7.57 (m, 2H), 7.65–7.68 (m, 2H), 8.01 and
8.05 (s,1H); 13C NMR (150 MHz, CDCl3):
d¼21.0, 31.1, 35.3, 36.7, 42.7,
45.2, 46.0, 50.7, 57.6, 126.4, 126.5, 127.3, 127.6, 127.8, 128.0, 128.2,
128.5, 131.6, 136.7, 157.6, 161.9, 166.0, 170.1; ESI HRMS exact mass
calcd for (C32H37N3O6SþNa)þ requires m/z 614.2295, found m/z
614.2301.
4.5.4. Catalyst 8a
20
White solid; yield: 87%; [
a
]
ꢁ37.5 (c 0.8, MeOH); mp 101–
D
103 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼1.97 (s, 3H), 2.12 (s, 3H), 2.64
(dt, J¼3.1, 12.8 Hz, 1H), 3.14 (dd, J¼4.7, 13.8 Hz, 1H), 3.22 (dt, J¼3.6,
16.2 Hz, 1H), 3.63 (d, J¼13.4 Hz, 1H), 4.40 (d, J¼13.8 Hz, 1H), 4.63 (d,
J¼13.4 Hz, 1H), 4.90 (d, J¼4.1 Hz, 1H), 5.23 (t, J¼7.5 Hz, 1H), 5.30 (t,
J¼7.3 Hz, 1H), 6.00 and 6.08 (d, J¼6.4 Hz, 1H), 7.00–7.29 (m, 10H),
8.31 and 8.2 (s, 1H); 13C NMR (150 MHz, MeOD):
d¼19.8, 41.3, 42.7,
45.8, 51.6, 56.6, 58.4, 77.3, 126.7, 127.1, 127.4, 128.0, 163.7, 168.9,
170.7; ESI HRMS exact mass calcd for (C24H27N3O5þNa)þ requires
m/z 460.1843, found m/z 460.1833.
9. The data for this catalyst in our preliminary communication (Ref. 6b) was
proven to be incorrect.
10. (a) Samec, J. S. M.; Ba¨ckvall, J. E. Chem.dEur. J. 2002, 8, 2955; (b) Gawinecki, R.
Pol. J. Chem. 1987, 61, 589; (c) Barluenga, A.; Aznar, F. Synthesis 1976, 704; (d)
Hansen, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 713; (e) Xiao, D. M.; Zhang, X.
4.5.5. Catalyst 8b
20
`
M. Angew. Chem., Int. Ed. 2001, 40, 3425; (f) Barluenga, J.; Fernandez, M. A.;
White solid; yield: 75%; [
a]
ꢁ46.2 (c 0.8, MeOH); mp 87–
D
Aznar, F.; Valdes, C. Chem.dEur. J. 2004, 10, 494; (g) Periasamy, M.; Srinivas, G.;
˙
89 ꢀC; 1H NMR (600 MHz, CDCl3):
d
¼2.04 (s, 3H), 2.16 (s, 3H), 2.58
Bharath, P. J. Org. Chem. 1999, 64, 4204; (h) Ozawa, F.; Okamoto, H.; Kawagishi,
S.; Yamamoto, S.; Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002, 124, 10968; (i)
Anna, T.; Jarle, S. D.; Pher, G. A. Chem.dEur. J. 2006, 12, 2318.
and 2.78 (dt, J¼3.2, 13.0 Hz, 1H), 3.04–3.08 (dd, J¼4.4, 13.7 Hz 1H),
3.12–3.15 (dd, J¼4.6, 14.0 Hz, 1H), 3.38 (d, J¼12.4 Hz, 1H), 4.39 (t,
J¼13.4 Hz, 1H) 4.60 (t, J¼13.7 Hz, 1H), 4.80 (d, J¼4.0 Hz, 1H), 5.30–
5.34 (m, 1H), 6.01 (d, J¼6.3 Hz, 1H), 6.86 (d, J¼9.0 Hz, 1H), 7.11–7.35
11. (a) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem. 1999, 64, 9189;
(b) Hou, X. L.; Zheng, X. L.; Dai, L. X. Tetrahedron Lett. 1998, 39, 6949; (c) Dmitry,
T.; Herbert, S.; Jochanan, B. Synthesis 2006, 1819; (d) Tsvelikhovsky, D.; Gelman,
D.; Molander, G. A.; Blum, J. Org. Lett. 2004, 6, 1995; (e) Yamauchi, Y.; Onodera,
G.; Sakata, K.; Yuki, M.; Miyake, Y.; Uemura, S.; Nishibayashi, Y. J. Am. Chem. Soc.
2007, 129, 5175; (f) Murahashi, S.; Tamba, Y.; Yamamura, M.; Yoshimura, N.
J. Org. Chem. 1978, 43, 4099; (g) Miyoshi, N.; Ikehara, D.; Kohno, T.; Matsui, A.;
Wada, M. Chem. Lett. 2005, 34, 760.
(m, 10H), 8.5 (s, 1H); 13C NMR (150 MHz, MeOD):
d¼21.0, 38.5, 42.2,
44.0, 46.8, 52.7, 57.5, 77.7, 129.0, 129.5, 130.0, 164.9, 169.0, 171.2,
172.0; ESI HRMS exact mass calcd for (C24H27N3O5þNa)þ requires
m/z 460.1843, found m/z 460.1853.