Chiral primary amino alcohol organobase catalysts for the asymmetric Diels-Alder reactions of anthrones with maleimides

Article abstract of DOI:10.1016/j.tetasy.2015.10.022

Simple chiral triethylsilyl-amino alcohol organocatalysts containing a bulky triethylsilyl group on the oxygen atom at the γ-position were designed and synthesized as new organocatalysts for enantioselective Diels-Alder reactions of anthrones with maleimides to produce chiral hydroanthracene Diels-Alder adducts in up to 99% yield and with up to 94% ee.

Full text of DOI:10.1016/j.tetasy.2015.10.022

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral primary amino alcohol organobase catalysts for the
asymmetric Diels–Alder reactions of anthrones with maleimides
Jun Kumagai a, Teppei Otsuki a, U. V. Subba Reddy a, Yoshihito Kohari a, Chigusa Seki a, Koji Uwai a,
Yuko Okuyama b, Eunsang Kwon c, Michio Tokiwa d, Mitsuhiro Takeshita d, 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 Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
c Research and Analytical Center for Giant Molecules, Graduate School of Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
d 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:
Simple chiral triethylsilyl-amino alcohol organocatalysts containing a bulky triethylsilyl group on the
oxygen atom at the c-position were designed and synthesized as new organocatalysts for enantioselec-
tive Diels–Alder reactions of anthrones with maleimides to produce chiral hydroanthracene Diels–Alder
adducts in up to 99% yield and with up to 94% ee.
Received 19 September 2015
Accepted 29 October 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
R1
N
R3
Asymmetric organocatalysis has emerged as an important and
rapidly growing area of synthetic organic chemistry, and excellent
covalent and non-covalent organocatalysts have been developed
for use in a wide range of reactions.1 The base catalyzed asymmet-
ric Diels–Alder reaction is one of the most straightforward and
atom economical method to construct chiral six-membered carbo-
cyclic compounds in synthetic organic chemistry.1 Among the
dienes, anthrone is considered to be one of the most powerful
diene components and can react with a variety of dienophiles.2
Particularly, the Diels–Alder reaction of anthrone with N-substi-
tuted maleimide3 to construct cage anthrone derivatives, which
are key intermediates for the preparation of some unsaturated lac-
tams with antipsoriatic and antiproliferative biological activities,
have been studied extensively.4 Several efficient chiral organo-
bases, such as cinchona alkaloids,5 pyrrolidine derivatives,6 cyclic
guanidines,7 bisoxazolines,8 and tertiary amine thioureas9 have
been used to promote these reactions (Scheme 1).10 However, to
the best of our knowledge, the effectiveness of primary b-amino
alcohol11 organocatalysts as organobases in this reaction has not
been shown yet.
+
R4
R2
biologically active
compounds
O
anthrones
maleimides
asymmetric
chiral
organobase
Diels-Alder
reaction
catalyst
R3
R3
O
R4
R5
N
N
O
R6
O
R2
R1
R4
α,β-unsaturated
HO
hydroanthracenes
lactams
Scheme 1. The asymmetric Diels–Alder reaction of anthrones with maleimides and
its application.
state X (Fig. 1). Thus, anionic anthracene is formed by the reaction
with amino alcohol acting as a base. Next both the anionic
diene and maleimide dienophile are fixed by hydrogen bondings
with the ammonium alcohol and might react stereoselectively
to afford the Diels–Alder adduct in good chemical yields and
enantioselectivity.
We designed a series of chiral primary amino alcohols 1a–f,
2a–h, and 3–5 with several substituent groups at the b-position
as organobase catalysts (Scheme 2). The reaction using these
designed amino alcohol catalysts might proceed through transition
Herein we report that a newly designed primary amino alcohol
containing a bulky silyl group on the oxygen atom at the
is an efficient organobase catalyst for the asymmetric Diels–Alder
c-position
⇑
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.2015.10.022
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kumagai, J.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.022

2
J. Kumagai et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
R2 = TIPS12
2a
2b
:
:
52%
65%
50%
86%
72%
69%
69%
53%
(R2')R2O
R2OTf or R2'Cl
Et3N
Ph
R2' = TBDMS12
OH
Ph
Ph
2c : R2' = DPMS
Ph
Ph
Ph
R1
2' = TPS
R2 = TES12
2d
2e
:
:
R
OH
OH
OH
CHCl3
NH2
2a-h
-40 °C to rt
24 h
NH2
2f : R2' = TPrS
NH2
1a-f
2' = THS
R2' = TTMSS11c
1f
2g
2h
:
:
R
1 = Ph
1b : R1 = Bn
:
1a
R
2e
1 = i-Pr
1c
:
R
:
1d R1 = t-Bu
1e : R1 = i-Bu
CHCl3
PhCH2Br
K2CO3
Me-I
EtOH
CHCl3
rt, 72 h
TMSOTf
Et3N
-40 °C to rt
24 h
R1
:
=
CH2OH
K2CO3
rt, 24 h
1f
Ph
Ph
Ph
Ph
Ph
TESO
TESO
TESO
Ph
OH
OTMS
OH
NH2
NMe2
HN
Bn
4
5
3
27%
41%
46%
Scheme 2. Preparations of amino alcohol organocatalysts.
organobase catalysts (Table 1). The reaction of 6 (1 equiv) with 7
(1.2 equiv.) was carried out at room temperature in CH2Cl2 in the
presence of 10 mol % of catalysts 1a–f, respectively (entries 1–6).
The obtained Diels–Alder adducts 8 (8a and/or 8b) were isolated
and the absolute configurations were determined on the basis of
both literature values of the specific rotation and retention times
on HPLC chiral column.9 Catalysts 1a–e did not show satisfactory
catalytic activity and afforded the Diels–Alder adduct 8 in only
low chemical yields (14–29%) and enantioselectivities (3–23%
ee). Furthermore, amino diol catalyst 1f afforded 8 in a good chem-
ical yield (76%), but the enantioselectivity was low (9%). Consider-
ing the above results, we next examined the same Diels–Alder
reaction using amino alcohols 2a–h containing bulkier substituted
steric
hydrogen bonding
site
steric
Ph
O
influence
Ph
influence
H
hydrogen
bond
Ph
O
H
Ph
R
H2N
H
R
O
OH
basic site
basic
site
Ph
N
NH2
O
hydrogen
bond
amino alcohol
organocatalyst
transition state X
Figure 1. Concept for catalyst design.
silyl groups on the oxygen atom at the c-position in the catalyst.
reaction of anthrone with maleimides to afford chiral hydroan-
thracene as a Diels–Alder adduct in good chemical yields (up to
99%) and with excellent enantioselectivity (up to 94% ee).
The reaction of 6 (1 equiv) with 7 (1.2 equiv) was carried out at
room temperature in CH2Cl2 in the presence of catalysts 2a–h
(10 mol %), respectively (entries 7–14). From the results of these
reactions, it can be seen that all of the catalysts showed a catalytic
activity and afforded the Diels–Alder adduct 8 in moderate to fairly
good chemical yields (32–92%). Furthermore, enantioselectivity
also increased in the reaction using almost all catalysts 2a–c,e–g
(32–43% ee), other than TPS-2d (16% ee) and TTMSS-2h (25% ee),
although satisfactory enantioselectivities were not observed under
these reaction conditions. The best chemical yield and enantiose-
lectivity were 92% and 42% ee when using the catalyst 2e, which
2. Results and discussion
Primary b-amino alcohol catalysts 1a–f,11 2a–h and 3–5 con-
taining several substituent groups at the b-position were prepared
as follows (Scheme 2). Amino alcohols 1a–f containing aliphatic or
aromatic substituent groups at the b-position were easily prepared
by the well-known Grignard reaction with the corresponding
a
-amino acid esters. The bulkier b-amino alcohol catalysts 2a–g
containing several silyl groups on the oxygen atom at the
-position were also easily prepared11b by the reactions of the
has a triethylsilyl moiety on the oxygen atom at the c-position in
the molecule (entry 11). From these results, it was indicated that
the use of an amino alcohol catalyst bearing a considerably bulky
silyl substituent on the oxygen atom at the c-position might not
c
amino alcohol 1f with R2OTf [R2 = triisopropylsilyl (TIPS),
0
0
triethylsilyl (TES)] or R2 Cl [R2 = tert-butyldimethylsilyl (TBDMS),
diphenylmethylsilyl (DPMS), triphenylsilyl (TPS), tripropylsilyl
(TPrS), trihexylsilyl (THS)] in moderate to good yields (50–86%).
The bulkiest b-amino alcohol catalyst 2h containing our explored
super tris(trimethylsilyl)silyl (TTMSS) group11c on the oxygen
be effective for obtaining satisfactory enantioselectivity in this
reaction. The same reaction using triethylsilyl-amino silyl ether
catalyst 3, in which the hydroxyl group was protected by a
trimethylsilyl (TMS) group brought about a great decrease in the
chemical yield and enantioselectivity (74%, 6% ee, entry 15) in
comparison with the result of the reaction using the corresponding
amino alcohol catalyst 2e with a free hydroxyl group (92%, 42% ee,
entry 11). This difference may be due to the loss of the ability for
hydrogen bonding to maleimide dienophile 7 or the steric influ-
ence of the bulkier TMS group on the molecule, although the rea-
sons are not clear. Furthermore, the catalytic abilities of both
catalyst 4 with tertiary amino group and catalyst 5 with secondary
amino group in the molecules were also examined (entries 16 and
17). However, these catalysts did not afford Diels–Alder adduct 8a
with satisfactory enantioselectivities despite having stronger basic
properties than primary catalyst 2e.
atom at the
of 1f with tris(trimethylsilyl)chloride in 53% yield.11c In addition,
catalyst masked the hydroxy group at the -position by
trimethylsilyl group prepared from the reaction of 2e with
TMSOTf in 27% yield. Moreover, catalyst 4 containing the tertiary
amino group was obtained by the reaction of 2e with MeI in
moderate yield (41%). Catalyst 5 containing a secondary amino
group was also prepared by the reaction of 2e with benzyl
bromide in 46% yield.
c-position was also easily obtained by the reaction
3
a
We first examined the Diels–Alder reaction of anthrone 6 with
N-phenylmaleimide 7 using the common amino alcohols 1a–f as
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J. Kumagai et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
Table 1
The asymmetric Diels–Alder reaction of anthrone 6 with N-phenylmaleimide 7
O
O
Ph
Ph
O
O
O
N
N
catalyst
(10 mol%)
O
+
N
Ph
CH2Cl2
rt
24 h
O
HO
8a
OH
8b
6
7
ee (%)b
entry
catalyst
yield (%)a
8a
8b
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
2g
2h
3
4
5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
23
17
28
14
29
76
68
69
32
40
92
65
57
66
74
84
37
12
23
17
7
3
9
34
42
32
16
42
43
41
25
6
21
11
In order to optimize the reaction conditions using the superior
triethylsilyl-amino alcohol organocatalyst 2e, we next examined
the effect of the molar ratio of catalyst 2e, the effect of the solvent,
the reaction temperature, and the reaction time (Table 2). Increas-
ing the catalytic loading of 2e to 20 mol % resulted in a slight
increase in both the chemical yield (93%) and enantioselectivity
(46% ee) (entry 1) when compared to the reaction containing
10 mol % of 2e (Table 1, entry 11). However, decreasing the cat-
alytic loading of 2e to 5 mol % resulted in a substantial decrease
in the chemical yield (50%) and enantioselectivity (28% ee) (entry
2). To further improve the enantioselectivity, the reactions using
2e were examined at lower temperatures of both 0 °C and ꢀ30 °C
(entries 3 and 4). However, satisfactory results were not observed
in terms of chemical yield and enantioselectivity under either tem-
perature. Next, we examined the solvent effects on this reaction.
Commonly used aprotic (CHCl3, ClCH2CH2Cl, Et2O, MeCN, benzene,
toluene), polar aprotic (DMF, DMSO) and protic (EtOH, MeOH) sol-
vents were screened, respectively (entries 5–14). Only ClCH2CH2Cl
afforded an excellent chemical yield (99%) (entry 6), but the other
solvents gave chiral Diels–Alder adduct 8a in moderate to good
yields (60–84%) (entries 5–10). Unfortunately, no improvements
in enantioselectivity were observed in these solvents in compar-
ison with the use of CH2Cl2 (Table 1, entry 11). Furthermore, the
reactions did not proceed when using polar aprotic (DMF, DMSO)
and protic (EtOH, MeOH) solvents (entries 11–14). Under the best
reaction conditions (CH2Cl2, 2e: 20 mol %, rt), extending the reac-
tion time from 24 to 48 h led to an increase in the chemical yield
(98%) with 47% ee (entry 15).
Under the optimized reaction conditions, a wide range of Diels–
Alder reactions with anthrones 6, 9a,b2 and maleimides 7, 10a–f3–9
were investigated using superior triethylsilyl-catalyst 2e and the
results are shown in Table 3. The obtained Diels–Alder adducts
11a–h were isolated and their absolute configurations were deter-
mined on the basis of the literature values of the specific rotation
and retention times on HPLC chiral columns.7,9,10a The use of N-
methylmaleimide 10a afforded the corresponding Diels–Alder
adduct 11a10a in an excellent chemical yield (97%), although the
enantioselectivity was low (39% ee) (entry 1). The reaction with
N-(4-methylphenyl)maleimide 10b also afforded the Diels–Alder
adduct 11b10a in a reasonably good chemical yield (91%) and the
enantioselectivity also increased to 32% ee (entry 2). Although
the bulkier N-benzylmaleimide 10c also did not afford the 11c9
Table 2
Optimization of the reaction conditions using catalyst 2e
catalyst 2e
+
8a
6
7
solvent
temp.
time
entry
2e (mol%)
solvent
yield (%)a
ee (%)b
temp. (°C)
time (h)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
ClCH2CH2Cl
Et2O
MeCN
benzene
toluene
DMF
DMSO
MeOH
rt
rt
0
-30
rt
rt
rt
rt
rt
rt
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
93
50
65
24
76
99
81
60
84
76
--
46
28
27
11
43
27
10
7
17
18
--
--
--
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
20
5
20
20
20
20
20
20
20
20
20
20
20
20
20
rt
rt
rt
rt
--
--
--
98
EtOH
CH2Cl2
--
47
rt
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4
J. Kumagai et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 3
The asymmetric Diels–Alder reaction of anthrones 6, 9a,b with maleimides 7, 10a–f using catalyst 2e
O
O
R3
R2
O
R2
R1
N
N
O
NO2
catalyst 2e
1
R1
O
O
R
(20 mol%)
R3
+
N
CH2Cl2
rt, 48 h
HO
OH
11d
R1
R2
O
R2
11a-c,e-h
6, 9a,b
7, 10a-f
11a : R1 = R2 = H, R3 = Me
: R3 = Ph
6 : R1 = R2 = H
7
: R3 = Me
11b : R1 = R2 = H, R3 = 4-Me-Ph
11c : R1 = R2 = H, R3 = Bn
: R1 = Cl, R2 = H
: R1 = H, R2 = Cl
10a
9a
9b
10b : R3 = 4-Me-Ph
: R3 = Bn
11d : R1 = R2 = H, R3 = 2-NO2-Ph
10c
10d : R3 = 2-NO2-Ph
10e : R3 = 3-NO2-Ph
10f : R3 = 4-NO2-Ph
: R1 = R2 = H, R3 = 3-NO2-Ph
: R1 = R2 = H, R3 = 4-NO2-Ph
11e
11f
11g : R1 = Cl, R2 = H, R3 = Ph
11h : R1 = H, R2 = Cl, R3 = Ph
ee (%)b
11a-c,e-h 11d
Diels-Alder
adduct
yield (%)a
entry
diene
dienophile
1
2
3
4
5
6
7
8
6
6
6
6
6
6
9a
9b
10a
10b
10c
10d
10e
10f
7
39
32
46
66
32
35
25
38
11a
11b
11c
11d
11e
11f
97
91
93
97
97
95
98
98
11g
11h
7
Table 4
in a satisfactorily enantioselectivity (46% ee), the chemical yield
was reasonably good (93%) (entry 3). Based on the results of the
reaction using maleimides 7, 10a–c, the Diels–Alder reaction of 6
with N-(2-nitrophenyl)maleimide 10d with a polar and bulkier
strong electron-withdrawing nitro group at the 2-position on the
phenyl group using triethylsilyl catalyst-2e (20 mol %) was exam-
ined at rt for 48 h (entry 4). The reaction proceeded smoothly
and afforded the Diels–Alder adduct 11d7 in an excellent chemical
yield (97%) and with better enantioselectivity (66% ee) in compar-
ison to the result obtained using other maleimides 7, 10a–c (entry
4). However, the reactions using both N-(3-nitrophenyl)maleimide
10e and N-(4-nitrophenyl)maleimide 10f also afforded the corre-
sponding Diels–Alder adducts 11e10a,f10a respectively, in
excellent chemical yields (11e: 97%, 11f: 95%), but satisfactory
enantioselectivities (11e: 32% ee, 11f: 35% ee) were not obtained
under the optimized reaction conditions (entries 5, 6).
Furthermore, the reactions of dichloroanthrones 9a,b with 7
were also examined in the same reaction conditions (entries 7
and 8). Although, that reactions also afforded the corresponding
Diels–Alder adducts 11g,10ah10a in excellent chemical yields (11g:
98%, 11h: 98%), satisfactory enantioselectivities were not
obtained (11g: 25% ee, 11h: 38% ee).
Optimization of the reaction conditions using catalyst 2e
catalyst 2e
11d
+
6
10d
CH2Cl2
temp.
time
entry
ee (%)b
temp. (°C)
time (h)
2e (mol%)
yield (%)a
48
48
48
48
72
1
2
3
4
5
20
20
10
5
0
-20
0
0
0
65
21
39
24
83
94
86
91
89
94
20
decrease in the chemical yield (10 mol %: 39%, 5 mol %: 24%),
respectively, although those enantioselectivities were good
(10 mol %: 91% ee, 5 mol %: 89% ee) (entries 3 and 4). In the reac-
tion using catalyst 2e (20 mol %), extending the reaction time from
48 to 72 h led to an increase in their chemical yield (83%) with 94%
ee (entry 5).
To further improve the enantioselectivity in the reaction of 6
with 10d using 2e, we next examined the effect of the molar ratio
of catalyst 2e, the reaction temperature and the reaction time
(Table 4). The reaction was examined at lower temperatures of
both 0 °C and ꢀ20 °C (entries 1 and 2). The best enantioselectivity
(94% ee) with a good chemical yield (65%) were obtained when the
reaction was carried out at 0 °C (entry 1). However, when the reac-
tion was carried out at ꢀ20 °C, it led to a decrease in both the
chemical yield and the enantioselectivity (21%, 86% ee) (entry 2).
Furthermore, the decrease in the catalytic loading of 2e to
Based on the observed enantiopurities (Diels–Alder adduct 8a:
47% ee, Table 2, entry 15, Diels–Alder adduct 11d: 94% ee, Table 4,
entry 5) of optically active Diels–Alder adducts 8a and 11d, which
were obtained from the reactions of 6 with 7, or with 10d, the
models of the enantioselective reaction courses were proposed as
follows (Scheme 3). The reaction of
6 with 7 afforded the
Diels–Alder adduct 8a, which might go through transition state
Ts-A-1 since it has less steric interaction between the triethylsilyl
group on the ammonium alcohol and maleimide 7 than that of the
transition state Ts-A-2 in Ts-A. Thus, in Ts-A-1, the diene and the
dienophile are fixed by the two hydrogen bonding interactions
10 mol % and 5 mol %, respectively, resulted in
a significant
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J. Kumagai et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
transition state A
O
Ts-A
N
H
H2N
H
H
H2N
H
O
O
H
H
7
O
O
O
O
O
Si
Si
O
O
N
N
O
O
Ts-A-1
Ts-A-2
47% ee
O
O
N
NO2
O
O
Ph
O
N
OH
11d'
6
HO
8a
94% ee
transition state B
Ts-B
H
H
O
H
O
H2N
H
H2N
H
O
O
O
O
Si
O
O
O
O
H
O
Si
O
N
O
N
N
N
N
O
NO2
10d
O
O
Ts-B-1
Ts-B-2
Scheme 3. Plausible reaction courses.
between the ammonium site on the ammonium alcohol intermedi-
ate and the oxygen atom on the anionic anthracene 6, and between
the hydroxy group on the ammonium alcohol intermediate and the
carbonyl group on maleimide 7, and then, might react stereoselec-
tively from the one reaction site (i.e. Ts-A-1). On the other hand,
the reaction of 6 with 10d affording Diels–Alder adduct 11d might
go through the different transition state Ts–B, since the reaction
proceeded with high enantioselectivity (94% ee) and the obtained
Diels–Alder adduct 11d have an opposite absolute stereochemistry
in comparison with the reactions using other anthrones 6,9a,b and
maleimides 7, 10a–c,e,f. Thus, the reaction proceeded through
transition state Ts-B-2 in which the diene and dienophile were
fixed by two hydrogen bonding interactions between the ammo-
nium site, the hydroxy site of the ammonium alcohol and the anio-
nic oxygen atom on anthrone 6, or the strong ionic nitro group on
maleimide 10d. Also, Ts-B-2 shows less steric interaction between
the triethylsilyl group on the ammonium alcohol and the malei-
mide part in dienophile 10d when compared with Ts-B-1, although
the reason is not clear.
enantioselectivity (up to 94% ee). Further studies, including cata-
lyst design modifications and mechanistic investigations, are cur-
rently in progress.
4. Experimental
4.1. General
All reactions were carried out under an argon atmosphere in
flame-dried glassware with magnetic stirring. Thin layer
chromatography (TLC) was performed on silica gel 60 F254 and
analytes were detected using UV light (254 nm) and iodine vapor.
Column chromatography was carried out on silica gel 60N
(40–100 lm) and preparative TLC was carried out on silica gel
60 F254. Melting points were measured using a micro-melting
point apparatus. Infrared (IR) spectra were measured with a
FT/IR spectrophotometer (JASCO FT/IR-400). 1H NMR (500 MHz)
and 13C NMR (125 MHz) spectra were measured in CDCl3 on a
JEOL JNM-ECA 500 spectrometer. 1H NMR data are reported as
follows: chemical shifts in ppm from tetramethylsilane
(0.0 ppm), integration, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, dd = double-doublet, m = multiplet and
br = broad), coupling constants (Hz), and assignment. 13C NMR
spectra were measured with complete proton decoupling.
Chemical shifts are reported in ppm from the residual solvent
as an internal standard (CDCl3; 77.16 ppm). High performance
liquid chromatography (HPLC) was performed using the chiral
columns AD-H 4.6 mm ꢁ 25 cm column. Optical rotations were
measured with JASCO DIP-360 digital polarimeter. HRMS spectra
were measured by EI using sector instruments on Hitachi
RMG-6MG and JEOL-JNM-DX 303 spectrometers.
3. Conclusion
In conclusion, we have developed new chiral amino alcohols
2a–h, 3–5 bearing silyl groups on oxygen atom at the c-position.
The catalysts were easily prepared from the condensation of inex-
pensive and commercially available chiral amino alcohols in two or
three steps. The Diels–Alder reactions of anthrones with N-substi-
tuted maleimides using the explored catalysts were examined. In
these catalysts, triethylsilyl-amino alcohol catalyst 2e provided
the corresponding hydroanthracene Diels–Alder adducts 11d in
reasonably good chemical yields (up to 97%) and with moderate
Please cite this article in press as: Kumagai, J.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.022

6
J. Kumagai et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
4.2. General procedure for the preparation of amino alcohol
organocatalysts 2a–g
125.5, 125.1, 79.1, 64.1, 57.2, 6.64, 4.12; EI-MS m/z: 358 (M+H)+;
HRMS (EI) calcd for
21H32NO2Si (M+H)+: 358.2202, found:
C
358.2202. Anal. Calcd for (C21H31NO2Si): C, 70.54; H, 8.74; N,
3.92; Found: C, 70.61; H, 8.70; N, 3.87.
To a solution of amino alcohol 1f (1 mmol) in CH2Cl2 (15 mL)
were added substituted silyl trifluoromethane sulfonates (1 mmol)
or substituted silyl chlorides (1 mmol) and Et3N (1.2 mmol) at
ꢀ40 °C under argon. The mixture was stirred for 24 h at room tem-
perature. The reaction mixture was quenched with H2O and
extracted with CHCl3. The combined organic layer was washed
with brine and dried over anhydrous Na2SO4 and evaporated to
give crude products 2a–g. The residue was purified by column
chromatography on silica gel (n-hexane/ethyl acetate = 4:1) to give
products 2a–g (2a: 208 mg, 52%; 2b: 232 mg, 65%; 2c: 220 mg,
50%; 2d: 431 mg, 86%; 2e: 185 mg, 72%; 2f: 275 mg, 69%; 2g:
363 mg, 69%).
4.2.6. (S)-2-Amino-1,1-diphenyl-3-(tripropylsilyloxy)propanol 2f
Colorless oil; [
a
]
22 = ꢀ77.5 (c 1.02, CHCl3); IR (neat) cmꢀ1: 2953,
D
2867, 1449, 1204; 1H NMR (CDCl3) d: 7.59–7.57 (m, 2H), 7.49–7.48
(m, 2H), 7.33–7.14 (m, 6H), 3.91–3.89 (t, J = 4.6 Hz, 1H), 3.57–3.56
(m, 2H), 1.32–1.24 (m, 6H), 0.92–0.89 (t, J = 7.2 Hz, 9H), 0.52–0.50
(m, 6H); 13C NMR (CDCl3) d: 146.2, 145.1, 128.5, 128.2, 126.7,
126.5, 125.6, 125.1, 79.2, 64.2, 57.3, 18.4, 16.7, 16.1; EI-MS m/z:
400 (M+H)+; HRMS (EI) calcd for C24H38NO2Si (M+H)+: 400.2672,
found: 400.2675. Anal. Calcd for (C24H37NO2Si): C, 72.13; H, 9.33;
N, 3.50; Found: C, 72.19; H, 9.24; N, 3.42.
4.2.1. (S)-2-Amino-1,1-diphenyl-3-(triisopropyllsilyloxy)propa-
4.2.7. (S)-2-Amino-1,1-diphenyl-3-(trihexylsilyloxy)propanol 2g
nol 2a
Colorless oil; [
a
]
D
24 = ꢀ49.6 (c 1.27, CHCl3); IR (neat) cmꢀ1: 2920,
Colorless oil; [
a]
D
24 = ꢀ57.1 (c 0.63, EtOH); IR (neat) cmꢀ1: 2942,
2854, 1449, 1181; 1H NMR (CDCl3) d: 7.59–7.57 (m, 2H), 7.49–7.46
(m, 2H), 7.36–7.14 (m, 6H), 3.93–3.90 (m, 1H), 3.55–3.54 (m, 2H),
1.33–1.21 (m, 24H), 0.89–0.86 (t, J = 6.9 Hz, 9H), 0.51–0.48 (m, 6H);
13C NMR (CDCl3) d: 146.2, 145.0, 128.5, 128.2, 126.7, 126.5, 125.6,
125.1, 79.1, 64.1, 57.3, 33.3, 31.6, 31.5, 23.1, 23.0, 22.6, 15.1, 14.2,
13.3; EI-MS m/z: 526 (M+H)+; HRMS (EI) calcd for C33H56NO2Si (M
+H)+: 526.4080, found: 526.4074.
2889, 1449, 1248; 1H NMR (CDCl3) d: 7.60–7.59 (m, 2H), 7.51–7.47
(m, 2H), 7.34–7.14 (m, 6H), 3.95–3.93 (dd, J = 5.8 Hz, J = 3.8 Hz,
1H), 3.71–3.65 (m, 2H), 1.00–0.98 (m, 21H); 13C NMR (CDCl3) d:
146.1, 145.0, 128.5, 128.2, 126.7, 126.6, 125.6, 125.1, 79.1, 64.8,
57.4, 17.9, 11.7. EI-MS m/z: 399 (M+); HRMS (EI) calcd for
C
24H37NO2Si (M+): 399.2594, found: 399.2589.
4.2.2. (S)-2-Amino-1,1-diphenyl-3-(tert-butyldimethylsilyloxy)
4.3. Preparation of amino alcohol catalyst 3
propanol 2b
White solid (Et2O/hexane); mp 49–51 °C; [
a]
D
22 = ꢀ51.1 (c 0.45,
A solution of amino alcohol 2e (358 mg, 1 mmol) in CH2Cl2
(15 mL) was cooled down to ꢀ40 °C. To the solution were added
EtOH); IR (neat) cmꢀ1: 2951, 2882, 1468, 1307; 1H NMR (CDCl3)
d: 7.59–7.57 (m, 2H), 7.50–7.48 (m, 2H), 7.34–7.15 (m, 6H), 3.92–
3.90 (t, J = 4.6 Hz, 1H), 3.59–3.58 (d, J = 4.6 Hz 2H), 0.86 (s, 9H),
ꢀ0.02 (s, 3H), ꢀ0.05 (s, 3H); 13C NMR (CDCl3) d: 146.0, 145.1,
128.5, 128.2, 126.7, 126.6, 125.5, 125.3, 125.1, 79.3, 64.6, 57.1,
25.8, 18.1, ꢀ5.6, ꢀ5.1; EI-MS m/z: 358 (M+H)+; HRMS (EI) calcd
for C21H31NO2Si (M+H)+: 358.2202, found: 358.2202.
Et3N (166
lL, 1.2 mmol) and trimethylsilyl trifluoromethanesul-
fonate (217
lL, 1.2 mmol) and the reaction mixture was stirred
at room temperature for 24 h. The solution was quenched with
water and extracted with CHCl3. The combined organic layer was
washed with brine, dried over anhydrous Na2SO4, and filtered.
The filtrate was concentrated under reduced pressure to give a
residue. The residue was purified by column chromatography on
silica gel (n-hexane/ethyl acetate = 4:1) to afford 3 (116 mg, 27%).
4.2.3. (S)-2-Amino-1,1-diphenyl-3-(diphenylmethylsilyloxy)pro-
panol 2c
White solid (Et2O/hexane); mp 89–90 °C; [
a]
20 = ꢀ64.8 (c 1.05,
4.3.1. (S)-1,1-Diphenyl-3-(triethylsilyloxy)-1-(trimethylsilyloxy)
D
CHCl3); IR (neat) cmꢀ1: 2948, 2885, 1428, 1255; 1H NMR (CDCl3)
d: 7.55–7.12 (m, 20H), 4.00–3.97 (m, 1H), 3.68–3.66 (m, 1H), 0.57
(s, 3H); 13C NMR (CDCl3) d: 146.4, 146.3, 146.2, 144.5, 135.3,
135.2, 134.3, 130.1, 129.9, 128.5, 128.2, 128.0, 126.8, 126.6,
125.6, 125.1, 78.5, 64.7, 60.5, 57.6, 55.7, ꢀ3.3; EI-MS m/z: 440 (M
+H)+; HRMS (EI) calcd for C28H30NO2Si (M+H)+: 440.2046, found:
440.2054.
propane-2-amine 3
Colorless oil; [
a
]
D
19 = ꢀ43.8 (c 1.05, CHCl3); IR (neat) cmꢀ1: 2953,
2876, 1248; 1H NMR (CDCl3) d: 7.43–7.42 (m, 2H), 7.35–7.34 (m,
2H), 7.30–7.21 (m, 6H), 3.88–3.85 (m, 1H), 3.73–3.71 (m, 1H),
3.00–2.96 (t, J = 9.5 Hz, 9H), 0.54–0.49 (m, 6H), ꢀ0.11 (s, 9H); 13C
NMR (CDCl3) d: 144.7, 144.2, 128.1, 128.0, 127.8, 127.5, 127.2,
127.0, 82.6, 64.8, 59.2, 6.8, 4.4, 2.1; EI-MS m/z: 430 (M+H)+; HRMS
(EI) calcd for C24H40NO2Si2 (M+H)+: 430.2598, found: 430.2612.
4.2.4. (S)-2-Amino-1,1-diphenyl-3-(triphenylsilyloxy)propanol
2d
4.4. Preparation of amino alcohol catalyst 4
White solid (Et2O/pentane); mp 91–92 °C; [
a]
22 = ꢀ55.8 (c 0.52,
D
CHCl3); IR (neat) cmꢀ1: 2951, 2882, 1468, 1307; 1H NMR (CDCl3) d:
7.53–7.50 (m, 8H), 7.46–7.43 (m, 3H), 7.37–7.35 (m, 6H), 7.30–7.27
(m, 4H), 7.18–7.14 (m, 3H), 7.11–7.08 (m, 1H), 4.68 (s, 1H), 4.02–
3.98 (dd, J = 6.5 Hz, J = 3.5 Hz, 1H), 3.80–3.75 (m, 2H); 13C NMR
(CDCl3) d: 146.3, 144.1, 135.3, 133.5, 130.2, 128.4, 128.1, 128.0,
126.7, 126.5, 125.5, 125.0, 78.2, 65.0, 57.7; EI-MS m/z: 501 (M+);
HRMS (EI) calcd for C33H31NO2Si (M+): 501.2124, found: 501.2123.
Amino alcohol 2e (358 mg, 1 mmol), K2CO3 (276 mg, 2 mmol),
and iodomethane (120 lL, 2 mmol) were stirred in EtOH (4 mL)
at room temperature for 24 h. The reaction mixture was filtered
with ethyl acetate. The combined organic layer was washed with
water, brine, dried over anhydrous Na2SO4, and filtered. The filtrate
was concentrated under reduced pressure to give the residue. The
residue was purified by column chromatography on silica gel
(n-hexane/ethyl acetate = 4:1) to afford 4 (152 mg, 41%).
4.2.5. (S)-2-Amino-1,1-diphenyl-3-(triethylsilyloxy)propanol 2e
Colorless oil; [
a
]
24 = ꢀ63.4 (c 0.55, EtOH); IR (neat) cmꢀ1: 2911,
4.4.1. N-Dimethyl-(S)-2-amino-1,1-diphenyl-3-(triethylsilyloxy)
D
2876, 1449, 1269; 1H NMR (CDCl3) d: 7.60–7.58 (m, 2H), 7.50–7.49
(m, 2H), 7.34–7.15 (m, 6H), 3.94–3.93 (t, J = 4.3 Hz, 1H), 3.60–3.59
(m, 2H), 0.91–0.88 (t, J = 8.0 Hz, 9H), 0.56–0.51 (q, J = 8.0 Hz, 6H);
13C NMR (CDCl3) d: 146.1, 145.0, 128.5, 128.2, 126.7, 126.5,
propanol 4
Colorless oil; [
a
]
D
23 = ꢀ29.7 (c 0.74, CHCl3); IR (neat) cmꢀ1: 2953,
2875, 1447, 1234; 1H NMR (CDCl3) d: 7.46–7.44 (m, 2H), 7.36–7.34
(m, 2H), 7.31–7.18 (m, 6H), 4.03–4.01 (m, 1H), 3.68–3.64 (m, 1H),
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J. Kumagai et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
3.57–3.55 (m, 1H), 2.37 (s, 6H), 0.94–0.91 (t, J = 8.0 Hz, 9H), 0.58–
0.53 (m, 6H); 13C NMR (CDCl3) d: 146.2, 145.5, 128.0, 127.6,
127.1, 127.0, 77.6, 70.7, 61.1, 44.0, 6.8, 4.3; EI-MS m/z: 386 (M
+H)+; HRMS (EI) calcd for C23H36NO2Si (M+H)+: 386.2515, found:
386.2507.
4.7. General procedure for the asymmetric Diels–Alder reaction
of anthrones 6,9a,b, with maleimides 7,10a–f
Anthrones 6,9a,b (0.10 mmol), maleimides 7,10a–f (0.12 mmol)
and amino alcohol catalysts 2e (0.02 mmol) were stirred in CH2Cl2
(1 mL) at room temperature for 48 h. The reaction mixture was
directly purified by preparative TLC on silica gel (CHCl3) to afford
Diels–Alder adducts 11a–h. The enantiomeric excess (ee) was
determined by HPLC (DAICEL CHIRALPAK AD-H, 1.0 mL/min, n-
hexane/2-propanol = 80:20). Compounds 11a–h were known com-
pounds and were identified by spectroscopic data, which were in
good agreement with those reported.2–9
4.5. Preparation of amino alcohol catalyst 5
Amino alcohol 2e (358 mg, 1 mmol), K2CO3 (332 mg, 2.4 mmol)
and benzyl bromide (140 lL, 1.2 mmol) were stirred in CHCl3
(10 mL) at room temperature for 72 h. The reaction mixture was
then filtered with ethyl acetate. The combined organic layer was
washed with water, brine, dried over anhydrous Na2SO4, and fil-
tered. The filtrate was concentrated under reduced pressure to give
the residue. The residue was purified by column chromatography
on silica gel (n-hexane/ethyl acetate = 4:1) to afford 5 (206 mg,
46%).
References
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propanol 5
Colorless oil; [
a]
24 = ꢀ24.8 (c 1.05, CHCl3); IR (neat) cmꢀ1: 2954,
D
2875, 1449, 1238; 1H NMR (CDCl3) d: 7.62–7.57 (m, 2H), 7.53–7.49
(m, 2H), 7.34–7.13 (m, 11H), 3.75–3.60 (m, 3H), 3.50–3.46 (m, 2H),
0.89–0.86 (t, J = 8.0 Hz, 9H), 0.54–0.49 (m, 6H); 13C NMR (CDCl3) d:
146.6, 145.6, 128.4, 128.3, 128.1, 127.0, 126.5, 125.9, 125.5, 79.0,
63.2, 62.1, 52.4, 6.7, 4.2; EI-MS m/z: 447 (M+); HRMS (EI) calcd
for C28H37NO2Si (M+): 447.2594, found: 447.2589.
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4.6. General procedure for the asymmetric Diels–Alder reaction
of anthrones 6 with maleimides 7
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Anthrone 6 (0.10 mmol), N-phenylmaleimide 7 (0.12 mmol)
and amino alcohol catalysts 1a–f, 2a–h, 3, 4 and 5 (0.01 mmol)
were stirred in CH2Cl2 (1 mL) at room temperature for 24 h. The
reaction mixture was directly purified by preparative TLC on silica
gel (CHCl3) to afford Diels–Alder adducts 8. The enantiomeric
excess (ee) was determined by HPLC (DAICEL CHIRALPAK AD-H,
1.0 mL/min, n-hexane/2-propanol = 80:20). Compounds 8 were
known compounds and were identified by spectroscopic data
which were in good agreement with those reported.2–9
11. (a) Suttibut, C.; Kohari, Y.; Igarashi, K.; Nakano, H.; Hirama, M.; Seki, C.;
Matsuyama, H.; Uwai, K.; Takano, N.; Okuyama, Y.; Osone, K.; Takeshita, M.;
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Matsuyama, H.; Takano, N.; Tokiwa, M.; Takeshita, M.; Nakano, H. Heterocycles
2012, 86, 1379–1388; (c) Kohari, Y.; Okuyama, Y.; Kwon, E.; Furuyama, T.;
Kobayashi, N.; Otuki, T.; Kumagai, J.; Seki, C.; Uwai, K.; Dai, G.; Iwasa, T.;
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Please cite this article in press as: Kumagai, J.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.022