2-Azanorbornane-based amine organocatalyst for enantioselective aldol reaction of isatins with ketones

Article abstract of DOI:10.1016/j.tetasy.2016.08.013

Optically active 2-azanorbornane-based organocatalysts were designed and synthesized, and the catalytic activity of these catalysts in enantioselective aldol reactions of isatins with ketones was investigated. Among these catalysts, 2-azanorbornylmethanol

Full text of DOI:10.1016/j.tetasy.2016.08.013

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
2-Azanorbornane-based amine organocatalyst for enantioselective
aldol reaction of isatins with ketones
Ayumi Ogasawara a, U. V. Subba Reddy a, Chigusa Seki a, Yuko Okuyama b, Koji Uwai a, Michio Tokiwa c,
Mitsuhiro Takeshita c, Hiroto Nakano a,
⇑
a Division of Sustainable and Environmental Engineering, Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto, Muroran 050-8585, Japan
b Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
c Tokiwakai Group, 62 Numajiri, Tsuduri-chou, Uchigo, Iwaki 973-8053, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Optically active 2-azanorbornane-based organocatalysts were designed and synthesized, and the cat-
alytic activity of these catalysts in enantioselective aldol reactions of isatins with ketones was investi-
gated. Among these catalysts, 2-azanorbornylmethanol showed the best catalytic activity to afford the
corresponding aldol product in excellent chemical yield (up to 95%) and with moderate stereoselectivity
(up to 64% ee, up to syn:anti = 36:64).
Received 2 June 2016
Accepted 10 August 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
use of an organocatalyst with a cage structure such as 2-
azanorbornane has never been reported in aldol reactions except
for the use of a cinchonidine–thiourea type catalyst.3 For these rea-
sons, we decided to explore the catalytic efficiency of 2-azanorbor-
nane-based organocatalysts B in the aldol reaction of isatins with
acyclic or cyclic ketones.4 The aldol reaction of isatins with acyclic
or cyclic ketones is a versatile reaction for affording chiral 3-hydro-
xyl-2-oxindoles containing a stereogenic quaternary carbon center
at the 3-position, which are useful intermediates for the synthesis
of various biologically active compounds and pharmaceuticals.5
We hypothesized that the designed organocatalyst B having steric
and electric control elements on both the 2-azabicyclo[2.2.1]oc-
tane backbone and at the side chain, could effectively control the
stereoselective reaction course in the transition state X of this reac-
tion (Scheme 2). Thus, the enamine intermediate, which is formed
from the condensation of catalyst B with acyclic or cyclic ketones,
could be fixed by both the hydrogen bonding of the nitrogen atom
in the enamine part with the hydrogen atom of hydroxyl group on
the side chain, and the two sterically bulky phenyl groups on the
side chain. The enamine moiety might selectively attack the isatins
to afford the corresponding aldol product in good chemical yield
and stereoselectivity (Scheme 2).
The development of new optically active organocatalysts for
their use in asymmetric synthesis has attracted considerable inter-
est in the scientific community over the past 10 years. Excellent
covalent and non-covalent organocatalysts have been developed
in a wide range of reactions.1 In recent years, we have developed
various b-amino alcohols, which were utilized effectively as
organocatalysts in different enantioselective reactions.2 2-Azanor-
bornane 1 with a cage type structure, could be synthesized from
the Diels–Alder reaction of cyclopentadiene with chiral imino-
dienophiles, which could find use as excellent synthetic intermedi-
ates, for deriving various biologically active compounds.3
2-Azanorbornane-based cage compound A, with a bulky 2-azanor-
bornane backbone and an amino nitrogen atom in the cage struc-
ture for the formation of an enamine moiety as a covalent site,
could be synthesized from compound 1 (Scheme 1). Furthermore,
compound A has the side chain at the 3-position on the 2-azanor-
bornane backbone, which can show strong electronic and steric
effects through the formation of a hydrogen bond with the sub-
strate and through steric control for the stereoselective reaction
course. Considering these structural characteristics, it is expected
that this cage type compound A might show an efficient function-
ality as an organocatalyst. However, only a few studies of the
asymmetric reactions using compound A as an organocatalyst have
been reported.3b,c Furthermore, to the best of our knowledge, the
Herein we report that the prepared 2-azanorbornane-based
organocatalysts showed asymmetric catalytic activity in the aldol
reactions of isatins with acyclic or cyclic ketones to afford the cor-
responding aldol products in excellent chemical yield (up to 95%)
and with moderate stereoselectivity (up to 64% ee, up to syn:
anti = 36:64).
⇑
Corresponding author. Tel.: +81 143 46 5727.
E-mail address: catanaka@mmm.muroran-it.ac.jp (H. Nakano).
http://dx.doi.org/10.1016/j.tetasy.2016.08.013
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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2
A. Ogasawara et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Diels–Alder adduct 5 gave hydrogenated compound 1. The Grig-
R1
R1
R2
nard reaction of the obtained product 1 with phenyl magnesium
bromide, followed by catalytic hydrogenolysis with palladium
hydroxide afforded the desired compound 7 in good yield. 2-
Azanorbornyltrimethylsilyldiphenylether 8 with a trimethylsilyl
(TMS) protected hydroxyl group was obtained by the protection
of 7 with TMSOTf in moderate yield. 2-Azanorbornyldiphenylami-
nes 10 and 11 bearing a primary amino group in the side chain
were prepared as a separable mixture from the reaction of 6 with
NaN3, followed by catalytic hydrogenolysis of 9 with palladium
hydroxide. Isoquinuclidine-based catalyst 15 with a 2-azabicyclo
[2.2.2]octane ring system was also synthesized via the same route
as 7 using the Diels–Alder reaction of cyclohexadiene with 4, cat-
alytic hydrogenation of 12, Grignard reaction of 13 with phenyl
magnesium bromide, followed by the catalytic hydrogenolysis of
14 with palladium hydroxide sequence in a moderate yield.
Initially, we examined the aldol reaction of isatin 16 with cyclo-
hexanone 17 using the synthesized cage type amine organocata-
lysts 7, 8, 10, 11 and 15 (20 mol %) in the presence of
trifluoroacetic acid (TFA) (10 mol %) as a co-catalyst at room tem-
perature for 24 h (Table 1). All of the catalysts showed asymmetric
catalytic activities (7–38% ee) and the corresponding aldol prod-
ucts, 18 (syn) and 180 (anti), were obtained in low to good chemical
yields (10–84%) and with low to moderate diastereoselectivities
(syn:anti = 48:52–86:14). The absolute configuration and syn:anti
stereoselectivity of the aldol products, 18 and 180, were deter-
mined by comparison with the literature data.4c,4g,4j,4r,4u The
reaction using catalyst 7 with diphenyl hydroxyl group afforded
the product 18 in good chemical yield and enantioselectivity
(84%, 38% ee, entry 1). On the other hand, the use of catalyst 8,
in which the hydroxyl group was protected by a TMS group, gave
the product 180 in low chemical yield and enantioselectivity
(10%, 24% ee, entry 2). These results indicate that the presence of
a free hydroxyl group at the side chain in the catalyst might be
necessary to realize satisfactory results. Although catalyst 10
with a diphenyl amino group as a hydrogen bonding site gave
the corresponding product 180 in moderate chemical yield and
diastereoselectivity (46%, syn:anti = 62:38), the enantioselectivity
was low (18% ee) (entry 3). The use of catalyst 11 with a primary
cyclopentadiene
+
CO2Et
Ph
H
N
N
R3
steric and
electronic
steric
influence
Ph
N
influences
A
compound
2-azanorbornane
1
CO2Et
imino dienophile
Scheme 1. Functional of 2-azanorbornanes.
O
O
cage type amine
O
HO
*
organocatalysts
+
R1
*
R1
O
O
asymmetric
N
R2
isatins
N
aldol reaction
R2
3-hydroxy-2-oxindoles
ketones
steric influence
steric
influence
Ph
;
Ph
X
+
1
H
N
H
X : OH, NH2
2
non-covalent
hydrogen
bonding site
covalent
enamine
formation site
2
1
R1
transition state
2-azanorbornane-based
organocatalyst B
R2
X
Scheme 2. Concept of catalyst design.
2. Results and discussion
Cage type amine organocatalysts 7, 8, 10, 11 and 15 with 2-
azanorbornane or isoquinuclidine backbones were prepared as fol-
lows (Scheme 3).1,6 First, our previously reported 2-azanorbornyl-
methanol 5 with a diphenyl methanol moiety in the side chain was
synthesized by the Diels–Alder reaction of cyclopentadiene with
chiral imino dienophile 4, which was obtained by the condensation
of aldehyde 2 with chiral amine 3. The catalytic hydrogenation of
(4S)
EtO2C
CO2Et
H
CO2Et
)
H
Ph
(3
S
CO2Et
i
ii
iii
+
N
Ph
(1R)N
N
66%
53%
CHO
NH2
3
Ph
Ph
(R)
2
4
5
1
(1R,3S,4S)-
Ph
Ph
Ph
Ph
Ph
Ph
(3S) OTMS
(4S)
(4S)
OH
iv
44%
v
87%
vi
67%
(3
) OH
S
1
H
N
H
N
H
N
(1R) H
(1R) H
Ph
7
8
(1R,3S,4S)-
(1R,3S,4S)-
6
Ph
Ph
Ph
Ph
Ph
N3
Ph
(4S)
(4S)
(3S)
NH2
vii
(3S)
v
NH2
+
6
H
H
(1R)N
N
H
N
10: 20%
11
(1R)H
(R) Ph
Ph
: 43%
(1R,3S,4S)-10
9
(1R,3S,4S)-11
Ph
Ph
OH
Ph
Ph
CO2Et
CO2Et
(3S)
(3S)OH
H
viii
42%
ix
35%
x
29%
xi
40%
H
H
4
H
N
N
N
N
H
(R) Ph
Ph
Ph
(3R)-15
13
12
14
(3S)-
Scheme 3. Preparations of cage type organocatalysts 7, 8, 10, 11, 15. Reagents. (i) MS 4 Å, CH2Cl2, 0 °C, 1 h; (ii) cyclopentadiene, CF3CO2H, BF3ꢀEt2O, ꢁ50 °C to rt, 16 h; (iii) H2,
10% Pd–C, EtOAc, rt, 24 h; (iv) PhMgBr, THF, 0 °C to rt, 24 h; (v) H2, 20% Pd(OH)2, EtOAc, 45 °C, 48 h; (vi) TMSOTf, Et3N, CH2Cl2, ꢁ30 °C to rt, 24 h; (vii) NaN3, H2SO4, toluene, rt,
2 h; (viii) cyclohexadiene, CF3CO2H, BF3ꢀEt2O, ꢁ78 °C to rt, 16 h; (ix) H2, 10% Pd–C, EtOAc, rt, 12 h; (x) PhMgBr, 1,4-dioxane, reflux, 24 h; (xi) H2, 20% Pd(OH)2, EtOAc, 45 °C,
72 h.
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A. Ogasawara et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 1
Enantioselective aldol reaction of 16 with 17 using organocatalysts 7, 8, 10, 11, 15 and 19
Ph
Ph
Ph
Ph
Ph
Ph
OH
OTMS
NH2
H
H
H
N
H
N
H
N
H
8
7
10
Ph
Ph
Ph
Ph
Ph
Ph
OH
19
OH
NH2
(2S)
H
N
H
N
H
15
H2N
Ph
(2S)-
11
O
catalysts 7,8,
10,11,15,19
(20 mol%)
O
HO
*
O
*
+
O
O
TFA (10 mol%)
N
H
16
N
toluene
rt
H
(syn)
(anti)
(2S,3R)-18
17
24 h
18'
Entry
Cat.
Yield (%)a
syn:antib
ee (%)c
18
180
1
2
3
4
5
6
7
8
10
11
15
19
84
10
46
12
39
17
40:60
54:46
62:38
86:14
44:56
48:52
38
10
Racemic
17
19
7
30
24
18
20
33
22
a
b
c
Isolated yield.
Diastereoselectivity was determined by HPLC of the reaction mixture.
The ee of the isomer was determined by HPLC using CHIRALCEL OJ-H column.
amino group as an enamine formation site at the side chain
afforded product 180 in low chemical yield and enantioselectivity
(12%, 20% ee, entry 4). In addition, the catalytic activity of 15
with a 2-azabicyclo[2.2.2]octane ring system was also examined
(entry 5). However, the catalyst 15 did not show better catalytic
activity than that of catalyst 7 having 2-azabicyclo[2.2.1]heptane
ring system. Similarly, the simple b-amino alcohol catalyst 19
was also not effective in this reaction (entry 6). From these
results, it was indicated that the use of catalyst 7 bearing
diphenyl hydroxyl group as the substituent group on the side
chain is effective for this reaction to obtain the aldol product in
satisfactory chemical yield and stereoselectivity.
In order to optimize the reaction conditions using superior 2-
azanorbornylmethanol organocatalyst 7, we next examined the
effect of the solvent, the molar ratio of catalyst, co-catalyst, the
reaction temperature and the reaction time (entries 1–24, Table 2).
From the results, it can be seen that the aldol products 18 and 180
were obtained in good chemical yield (84%) and with moderate
diastereoselectivity (syn/anti = 40:60) and enantioselectivity (38%
ee), when the reaction was carried out in toluene by using
20 mol % of catalyst 7 and 10 mol % of TFA as co-catalyst at room
temperature for 24 h (Table 2, entry 16).
yields (210b: 54%, 21c: 62%) and enantioselectivities (210b: 49% ee,
21c: 47% ee), respectively, but syn:anti diastereoselectivity was poor
(syn:anti = 50:50) (entries 2, 3). However, the same reaction using
N-Boc-isatin 20d did not proceed, although the reason for this was
not clear (entry 4). Isatin 20e bearing electron donating methyl
group on aromatic ring afforded the product 21e in moderate chem-
ical yield and enantioselectivity (32%, 30% ee, entry 5). Isatins 20f–h
bearing halogen atoms on the aromatic ring also afforded the corre-
sponding products 210f–h, respectively, in good chemical yields and
enantioselectivities (64–79%, 35–39% ee, entries 6–8). The reaction
of isatin 20i bearing a strong electron withdrawing NO2 group on
the aromatic ring also afforded product 21i in moderate chemical
yield and enantioselectivity (40%, 44% ee, entry 9). These results
showed the catalytic activity of 7 to the aldol reaction of different
substituted isatins.
Next, we examined the scope of the aldol reaction of isatin 16
with several acyclic or cyclic ketones 22a–f using catalyst 7 under
the same reaction conditions (entries 1–6, Table 4). The reaction
with acetone 22a afforded the corresponding aldol product 23a with
moderate chemical yield and poor enantioselectivity (43%, 13% ee,
entry 1).4c,b,g,k,m,n,r,s,u The use of cyclopentanone 22b gave the aldol
product 230b in good chemical yield (74%) with moderate
enantioselectivities (43% ee) and moderate diastereoselectivity
(syn:anti = 36:63) (entry 2).4c,7 Although bulkier cycloheptanone
22c provided the product 230c with moderate enantioselectivity
(46% ee), the reaction hardly proceeded (8%) (entry 3). The use of
heterocyclic ketones 22d–f also afforded the corresponding
products, 230d,e and 23f, respectively, but the syn:anti
stereoselectivity was poor (entries 4–6). The reaction using
tetrahydropyran-4-one 22d afforded product 230d with moderate
chemical yield and low enantioselectivity (37%, 14% ee, entry 4).4c
Although, tetrahydrothipyran-4-one 22e furnished product 230e
with good chemical yield (82%), the enantioselectivity was low
(23% ee, entry 5).4c The reaction with piperidin-4-one 22f led to an
After optimizing the reaction conditions, we investigated the
generality of the reaction of isatins 20a–i with different substitution
patterns and electronic properties with cyclohexanone 17 using cat-
alyst 7 under the best reaction conditions (entries 1–9, Table 3).4c,j,7
As can be seen from the results, they all afforded the corresponding
aldol products 21a–i (syn) and 210a–i (anti), although the products
were obtained as
a mixture of syn/anti diastereomers (syn:
anti = 42:58–43:57). The reaction using synthetically useful
N-Me-isatin 20a5 afforded the aldol product 21a in good chemical
yield and enantioselectivity (86%, 64% ee), although it took a long
reaction time (entry 1). The use of N-benzyl-20b and N-allyl-20c isa-
tins also gave the aldol products 210b and 21c in moderate chemical
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A. Ogasawara et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 2
Optimization of the reaction conditions of 16 with 17 using organocatalyst 7
O
HO
*
catalyst 7
*
+
16
17
O
co-cat.(10 mol%)
N
solvent
temp.
time
H
18 (syn)
18' (anti)
(2S,3R)-
a
b
c
Isolated yield.
Diastereoselectivity was determined by HPLC.
The ee of the isomer was determined by HPLC using CHIRALCEL OJ-H column.
Table 3
Enantioselective aldol reactions of 20a–I with 17 using organocatalyst 7
O
HO
*
R1
O
catalyst 7
R1
*
(20 mol%)
O
+
17
O
N
N
TFA (10 mol%)
R2
(2S,3R)-21c-i (syn)
toluene
rt
R2
20a-i
time
21a b (syn)
,
(2R,3S)-
21'a i
-
(anti)
Entry
20
R1
R2
21
Time (h)
Yield (%)a
syn:antib
ee (%)c
21c–i
21a,b
210a–i
1
2
3
4
5
6
7
8
9
20a
20b
20c
20d
20e
20f
20g
20h
20i
H
H
H
H
Me
F
Cl
Br
NO2
Me
21a
21b
21c
21d
21e
21f
21g
21h
21i
120
120
120
120
24
24
24
24
24
86
54
62
—
32
79
64
71
40
43:57
50:50
50:50
—
56:44
42:58
45:55
49:51
52:48
64
24
32
49
25
—
22
35
39
35
22
Bn
Allyl
Boc
H
H
H
47
—
30
32
31
28
44
H
H
a
b
c
Isolated yield.
Diastereoselectivity was determined by HPLC of the reaction mixture.
The ee of isomer was determined by HPLC using DAICEL CHIRAL column.
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A. Ogasawara et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
Table 4
Enantioselective aldol reactions of 16 with 22a–f using organocatalyst 7
R2
R1
O
HO
*
O
7
catalyst
*
(20 mol%)
O
+
16
N
H
TFA (10 mol%)
R1 R2
toluene
rt
(2S,3R)-23a,d-f(syn)
22a-f
23b c (syn)
,
(2R,3S)-
time
(anti)
23'b-f
Entry
22
R1
H
R2
H
23
Time (h)
Yield (%)a
syn:antib
ee (%)c
23a,d–f
23b,c
230b–f
1
2
22a
22b
23a
23b
72
48
43
74
—
13
36:64
16
24
43
3
4
22c
22d
23c
23d
144
72
8
37
38:62
55:45
46
14
5
O
S
5
22e
22f
23e
23f
48
24
82
91
57:43
55:45
20
23
5
N
6
37
Boc
a
b
c
Isolated yield.
Diastereoselectivity was determined by HPLC of the reaction mixture.
The ee of isomer was determined by HPLC using DAICEL CHIRAL column.
increase in both the chemical yield (91%) and the enantioselectivity
(37% ee) (entry 6).4c
as organocatalysts. Among all of these catalysts, 2-azanorbor-
nanemethanol 7 provided the corresponding aldol products in
excellent chemical yields (up to 95%) and with moderate stereose-
lectivities (up to 64% ee, syn:anti = 36:64). Further studies, includ-
ing catalyst design modifications to improve the stereoselectivity
and mechanistic investigations are in progress.
Unfortunately, although satisfactory enantioselectivities and
syn:anti diastereoselectivities were not observed in this reaction
using a cage type organocatalyst, a model of the enantioselective
reaction course was proposed based on the observed enantiopurity
(38% ee, entry 16, Table 1) of chiral aldol product (2S,3R)-18, which
was obtained from the reaction of 16 with 17, as follows
(Scheme 4). The combination of catalyst 7, cyclohexanone 17 and
TFA forms an enamine intermediate I. The conformation of inter-
mediate I is fixed by the hydrogen bonding interaction between
the amine nitrogen atom at the enamine part and the hydroxyl
hydrogen atom at the side chain, and it might exist as intermediate
I-1, which has less steric interaction between the cage structure
and the methylene part in the cyclohexene ring at the enamine
part than that of I-2. The reaction could then proceed through tran-
sition state Ts-1 in Ts-A, which has a smaller steric interaction
between intermediate I-1 and isatin 16 than Ts-2, which could
experience a more severe repulsive interaction between intermedi-
ate I-1 and 16. Furthermore, the syn:anti stereochemistry in the
reaction might depend on the steric interaction between 2-azanor-
bornane ring system in I-1 and 16. Thus, Ts-1 (syn) has less steric
interaction between the 2-azanorbornane ring system and 16,
rather than through Ts-3 (anti), which has greater steric interaction
between I-1 and 16. Furthermore, considering the results that the
use of bulkier N-methylisatin 20a afforded the product 21a (syn)
with the best enantioselectivity (64% ee, entry 1, Table 3) in all
reactions, the reaction could proceed through the Ts-4 in Ts-B,
which has less steric interaction between both the cage structure
and the methylene parts in the enamine intermediate and isatin
21a, rather than that of Ts-10, Ts-20 and Ts-30.
4. Experimental
4.1. General
All commercial reagents were purchased and used without fur-
ther purification. All reactions were carried out under argon in
flame-dried glassware with magnetic stirring. Thin layer chro-
matography was performed on silica gel 60 F254, and then detected
by using UV light (254 nm) and iodine vapor. Column chromatogra-
phy was carried out on silica gel 60 N (40–100 lm), and preparative
TLC was carried out on silica gel 60 F254. Infrared (IR) spectra were
measured with a FT/IR spectrophotometer (JASCO FT/IR-400). Melt-
ing points were measured using a micro melting point apparatus.
NMR spectra were measured using a JEOL JNM-ECA500. 1H NMR
(500 MHz) and 13C NMR (125 MHz) spectra were measured in CDCl3
and DMSO-d6 as solvent and given in ppm from tetramethylsilane
(0.0 ppm) or the residual solvents as a internal standard (DMSO-
d6; 2.50 ppm from 1H NMR, CDCl3; 77.16 ppm from 13C NMR). Mul-
tiplicity of chemical shift are reported as s = singlet, d = doublet,
t = triplet, q = quartet, dd = doublet of doublets, m = multiplet and
br = broad and coupling constants J are given in Hz. Diastereo ratio
and enantiomeric excess were determined by high performance liq-
uid chromatography (HPLC) with DAICEL CHIRALPAK AD-H, CHIR-
ALPAK AS-H, CHIRALPAK IC and CHIRALCEL OJ-H.
3. Conclusion
4.2.
(1R,3S,4S)-2-Azabicyclo[2.2.1]heptane-3-exo-diphenyl
(trimethylsilyoxy)methane 8
In conclusion, we have reported on the first example of the
enantioselective aldol reaction of isatins with acyclic or cyclic
ketones using 2-azanorbornane-based amines 7, 8, 10, 11 and 15
To the solution of 7 (0.101 g, 0.4 mmol) in dry CH2Cl2 (6 mL)
were added trimethylsilyl triflate (0.1 mL, 0.48 mmol) and Et3N
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6
A. Ogasawara et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
2
2
2
+2
+2
+2
2
2
2
1
+
1
+
1
+
(2S,3R)-18 (syn)
(2R,3S)-18 (syn)
18'
(2S,3S)-
(anti)
38% ee
2
+
2
+
2
2
+
2
2
2
+
1
)
+
)
)
+
1
1
2
)
)
2
)
)
2
)
)
1+
2
1+
2
2
2
1+
2
Ts-2
Ts-3
Ts-1
isatin 16
Transition state A Ts-A
(
)
2
Ph
2
2
+
2
+
Ph
2
2
TFA
+
OH
+
)
+
)
1
1
H
N
H
)
2
)
+
+
)
+
)
+
7
17
catalyst
enamine
intermediate
I-1
I-2
20a
N-Me isatin
Transition state B Ts-B
(
)
2
+
2
)
+
1
2
2
)
)
0H
1
2
2
2
+
+
2
2
2
Ts-2'
)
+
)
+
1
1
)
2
)
0H
1
2
)
)
2
2
1
2
Ts-3'
0H
Ts-1'
2
+
+
2
2
)
1
)
2
2
)
2
+2
2
+2
1
0H
Ts-4
2
2
1
0H
64% ee
1
0H
(2S,3R)-21a (syn)
(2S,3S)-21'a (anti)
2
+2
2
1
0H
21a
(2R,3S)-
(syn)
Scheme 4. Plausible reaction course.
(0.7 mL, 0.48 mmol) simultaneously at ꢁ30 °C for 10 min under
argon. The solution was stirred at room temperature for 24 h and
quenched with H2O. The resulting mixture was extracted with
CHCl3 (3 ꢂ 10 mL), and the combined organic layers were washed
with brine and dried over Na2SO4. The solvent was then removed
under reduced pressure and the residue was purified by flash chro-
matography on silica gel (EtOAc) to give 8 (0.09 g, 67%) as a white
solid; mp 180–181 °C (ether/n-hexane).
CHCl3). IR (neat) cmꢁ1 3030, 1383, 1226. 1H NMR (CDCl3,
[a]
20 = +24.5 (c 1.06,
D
:
500 MHz) d: 7.41–7.32 (m, 8H), 7.27–7.26 (m, 2H), 4.26 (s, 1H),
4.03 (s, 1H), 2.61 (s, 1H), 2.16–2.13 (m, 1H), 1.79–1.72 (m, 3H),
1.21 (d, J = 11.7 Hz, 1H), 0.98 (d, J = 11.7 Hz, 1H), ꢁ0.11 (s, 9H).
13C NMR (CDCl3, 125 MHz) d: 141.9, 141.5, 128.8, 128.7, 128.4,
128.3, 81.4, 70.4, 58.5, 39.9, 35.2, 28.7, 25.6, 1.71. Ms m/z: 351
Please cite this article in press as: Ogasawara, A.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.013

A. Ogasawara et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
[M+H]. HRMS (EI) calcd for (C22H29NOSi): 351.2018, found:
References
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4.3. General procedure for the synthesis of cage type
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To a solution of NaN3 (0.456 g, 7 mmol) in toluene (14 mL) was
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10 min, after which the mixture was stirred for 15 min at room tem-
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toluene (15 mL) was added via syringe at ice-cold temperature
and the resulting mixture was stirred vigorously for 2 h at room
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NaHCO3 solution, and then organic layer was extracted with EtOAc
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pressure to give 9. A solution of 9 (0.323 g, 0.8 mmol) and Pd(OH)2
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chromatography on silica gel (MeOH:CHCl3 = 1:7) to give 10 and 11.
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4.3.1. (1R,3S,4S)-2-Azabicyclo[2.2.1]heptane-3-exo-
diphenylmethylamine 10
White solid; mp 148–149 °C (ether/n-hexane). [
a]
20 = +39.1 (c
D
0.23, CHCl3); IR (neat) cmꢁ1 1596, 1473. 1H NMR (CDCl3,
:
500 MHz) d: 7.49–7.42 (m, 4H), 3.97 (s, 1H), 3.45 (s, 1H), 2.40 (s,
1H), 1.68–1.57 (m, 3H), 1.50 (d, J = 10.6 Hz, 1H), 1.24 (s, 1H), 1.10
(d, J = 10.6 Hz, 1H). 13C NMR (CDCl3, 125 MHz) d: 128.6, 128.5,
127.1, 126.9, 126.8, 77.4, 77.1, 68.2, 63.0, 57.1, 38.8, 35.8, 30.8.
Ms m/z: 278 [M+H]. HRMS (EI) calcd for (C19H22N2): 278.1783,
found: 278.1788.
4.3.2. (1R,3S,4S)-2-[(R)-1-Phenylethyl]-2-azabicyclo[2.2.1]
heptane-3-exo-diphenylmethyl amine 11
White solid; mp 163–164 °C (ether/n-hexane). [a]
22 = +90.9
D
(c 0.11, CHCl3); IR (neat) cmꢁ1: 1596, 1190. 1H NMR (CDCl3,
500 MHz) d: 7.61–7.58 (m, 4H), 7.31–7.26 (m, 3H), 7.23–7.14 (m,
7H), 7.04–7.01 (m, 1H), 3.77 (s, 1H), 3.05 (s, 1H), 2.93 (q,
J = 7.2 Hz, 1H), 2.43 (s, 1H), 1.98–1.92 (m, 1H), 1.68–1.60 (m, 3H),
1.43–1.34 (m, 1H), 1.18 (d, J = 7.2 Hz, 3H), 0.85 (d, J = 9.2 Hz, 1H).
13C NMR (CDCl3, 125 MHz) d: 128.2, 128.1, 128.0, 127.9, 127.8,
126.4, 126.3, 126.2, 126.1, 125.9, 69.9, 63.6, 55.7, 55.2, 42.1, 39.1,
32.4, 30.8, 29.7, 13.8 Ms m/z: 382 [M+H]. HRMS (EI) calcd for
(C27H30N2): 382.2409, found: 382.2413.
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4.4. General procedure for the enantioselective aldol reaction of
isatins with ketones
To a stirred solution of catalyst 7 (0.02 mmol) in dry toluene
(0.2 mL) were added ketone (2 mmol), TFA (0.01 mmol) and isatin
(0.1 mmol) simultaneously at room temperature. The reaction mix-
ture was stirred at this temperature for the appropriate time and
then quenched with H2O. Toluene was then removed under
reduced pressure, and the residue was extracted with EtOAc
(3 ꢂ 2 mL). The combined organic layers were dried over Na2SO4
and the solvent was evaporated under reduced pressure. The result-
ing residue was purified by flash chromatography on silica gel
(n-hexane:EtOAc = 2:3) to give the corresponding aldol products.
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Acknowledgements
This research is partially supported by the Adaptable & Seam-
less Technology Transfer Program through Target-driven R&D from
Japan Science and Technology Agency, JST (AS231Z01382G).
Please cite this article in press as: Ogasawara, A.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.013