Silyloxy Amino Alcohol Organocatalyst for Enantioselective 1,3-Dipolar Cycloaddition of Nitrones to α,β-Unsaturated Aldehydes

Article abstract of DOI:10.1002/ejoc.201500926

The catalytic activity of a simple amino alcohol that contains a bulky super silyl group [i.e., tris(trimethylsilyl)silyl (TTMSS)] bonded to the oxygen atom at the γ-position along with a primary amine moiety was examined in the enantioselective 1,3-dipolar cycloaddition of nitrones to α,β-unsaturated aldehydes. The organocatalyst successfully provided optically active isoxazolidines in good chemical yields (up to 86 %) with excellent diastereoselectivities (endo/exo, up to 96:4) and enantioselectivities (up to 97 % ee). Furthermore, the obtained isoxazolidines were easily converted into γ-amino diols that contain three contiguous stereogenic centers.

Full text of DOI:10.1002/ejoc.201500926

FULL PAPER
DOI: 10.1002/ejoc.201500926
Silyloxy Amino Alcohol Organocatalyst for Enantioselective 1,3-Dipolar
Cycloaddition of Nitrones to α,β-Unsaturated Aldehydes
Teppei Otsuki,[a] Jun Kumagai,[a] Yoshihito Kohari,[a] Yuko Okuyama,[b] Eunsang Kwon,*[c]
Chigusa Seki,[a] Koji Uwai,[a] Yasuteru Mawatari,[a] Nagao Kobayashi,[d] Tatsuo Iwasa,[e]
Michio Tokiwa,[f] Mitsuhiro Takeshita,[f] Atushi Maeda,[g] Akihiko Hashimoto,[h]
Kana Turuga,[h] and Hiroto Nakano*[a]
Keywords: Organocatalysis / Cycloaddition / Enantioselectivity / Diastereoselectivity / Nitrogen heterocycles / Amino
alcohols
The catalytic activity of a simple amino alcohol that contains
bulky super silyl group [i.e., tris(trimethylsilyl)silyl
(TTMSS)] bonded to the oxygen atom at the γ-position along
optically active isoxazolidines in good chemical yields (up to
86%) with excellent diastereoselectivities (endo/exo, up to
96:4) and enantioselectivities (up to 97%ee). Furthermore,
a
with a primary amine moiety was examined in the enantiose- the obtained isoxazolidines were easily converted into γ-
lective 1,3-dipolar cycloaddition of nitrones to α,β-unsatu- amino diols that contain three contiguous stereogenic cen-
rated aldehydes. The organocatalyst successfully provided ters.
to prepare and having the desirable structural characteris-
Introduction
tics. It is easily derived from the corresponding amino acid
ester and contains both an amino covalent site and a hy-
droxy noncovalent binding site in a single molecule
(Scheme 1).
The development of new optically active organocatalysts
for use in asymmetric synthesis has attracted considerable
interest in the scientific community over the past 10 years.[1]
Excellent covalent and noncovalent organocatalysts have
been developed for use in a wide range of reactions. Re-
cently, we reported that an amino alcohol that contains a
primary amino group can act as an efficient organocatalyst
in the enantioselective Diels–Alder reaction of 1,2-dihy-
dropyridines with dienophiles.[2] Amino alcohol A is stable
when exposed to air and has the advantages of being easy
The enantioselective 1,3-dipolar cycloaddition (1,3-DC)
of nitrones to α,β-unsaturated aldehydes is an efficient reac-
tion for the construction of optically active isoxazolid-
ines.[3,4] Isoxazolidines are valuable chiral building blocks
that are readily converted into γ-amino alcohols, β-amino
acids, and β-lactams, which can be used in the synthesis of
various biological compounds.[5] Although several groups
have reported enantioselective organocatalytic versions of
this cycloaddition, few examples have employed a primary
amine[4f] in a 1,3-DC, and the catalytic effectiveness of an
amino alcohol as an organocatalyst in a 1,3-DC has not yet
been revealed.
[a] Department of Bioengineering, Graduate School of
Engineering, Muroran Institute of Technology,
27-1 Mizumoto, Muroran 050-8585, Japan
E-mail: catanaka@mmm.muroran-it.ac.jp
http://www3.muroran-it.ac.jp/hnakano/
[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
http://www.kiki.chem.tohoku.ac.jp/index.html
[d] Department of Chemistry, Graduate School of Science, Tohoku
University,
To further expand the usefulness of an amino alcohol
with a primary amino group as an organocatalyst in asym-
metric reactions, we focused on investigating simple amino
alcohol A, which contains a primary amine moiety and a
bulky substituent (Scheme 1). In the pathway for the 1,3-
DC reaction, an iminium ion intermediate is first formed
from the condensation of amino alcohol A with an α,β-
unsaturated aldehyde in the presence of a proton from an
acid additive. The steric influence between the α-, β-, or γ-
substituents in this intermediate and the counter anion of
the acid might control the approach of the nitrone sub-
strate.
6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
[e] Division of Engineering for Composite Functions, Graduate
School of Engineering, Muroran Institute of Technology,
27-1 Mizumoto, Muroran 050-8585, Japan
[f] Tokiwakai Group,
62 Numajiri Tsuduri-chou Uchigo Iwaki 973-8053, Japan
[g] Shin-Nihon Kogyo Co., Ltd.,
6-5-8 Higashi 8-jyo, Asahikawa 070-0028, Japan
[h] Technos Hokkaido Co., Ltd.,
7-4-10 Chuwa 4-jo, Asahikawa 070-8044, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500926.
Thus, we report herein that TTMSS-amino alcohol 1
[TTMSS = tris(trimethylsilyl)silyl], which contains a pri-
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Organocatalyst for Enantioselective 1,3-Dipolar Cycloaddition
butyldimethylsilyl), TPS (triphenylsilyl), and OTf = tri-
fluoromethanesulfonate]. In addition, the bulkiest β-amino
alcohol catalyst 1, which contained a super silyl group[6] on
the oxygen atom at the γ-position was also easily obtained
in 53% yield by the reaction between 4 and TTMSSOTf.[2a]
Catalyst 6, which has a trimethylsilyl-protected (TMS = tri-
methylsilyl) hydroxy group was obtained in moderate yield
from the reaction of 1 with TMSOTf.
Scheme 2. Synthesis of amino alcohol organocatalysts.
We first examined the 1,3-DC of common N-benzyl-
idenebenzylamine N-oxide (7) with (E)-crotonaldehyde (8,[4]
Table 1). The reaction of 7 and 8 was carried out in toluene
Scheme 1. Function of amino alcohol organocatalyst.
mary amine and a super silyl group (i.e., TTMSS) is an at room temperature in the presence of 10 mol-% of cata-
efficient organocatalyst in the enantioselective 1,3-DC of lysts 3a–3d and HOTf (10 mol-%) as an acid additive to
nitrones with α,β-unsaturated aldehydes to afford optically afford optically active DC adducts 9 [i.e., endo-(3R,4S,5R)-
active isoxazolidines in good chemical yields (up to 86%) 9 and exo-(3S,4S,5R)-9]. The enantiomeric excess value of
and with excellent enantioselectivities (up to 97%ee). We the major endo adduct was determined by converting the
also report the convenient transformation of the obtained mixture into the corresponding alcohols 10.[4n] The relative
optically active isoxazolidines into γ-amino alcohols that and absolute configurations of the obtained DC adducts
contain three contiguous stereogenic centers.
and the endo/exo stereochemistry were determined by ana-
lyzing the relationship of the 1H NMR signals for the
phenyl group at the 3-position and the aldehyde at the 4-
position of the corresponding DC adduct and by compar-
Results and Discussion
Amino alcohol catalysts 1, 3a–3d, and 5a–5d that contain ing the experimental and literature data.[4n] The results are
several substituents at the β- or γ-position were prepared as summarized in Table 1. In the absence of the amine catalyst
shown in Scheme 2. Amino alcohols 3a–3d, which have an or an acid additive, the reaction barely occurred. When cat-
aliphatic or aromatic substituent at the β-position, were eas- alyzed by β-Ph-substituted 3a, the reaction afforded endo-
ily obtained by using a Grignard reaction to obtain the cor- DC adduct 9 in a moderate chemical yield (57%) with good
responding α-amino acid esters, and the bulkier β-amino diastereoselectivity (endo/exo, 78:22) but low enantio-
alcohols 5a–5d, which have several different silyl groups selectivity (46%ee; Table 1, Entry 1). Similarly, the use of
bonded to the oxygen atom at the γ-position, were also eas- β-Bn-substituted catalyst 3b produced almost the same
ily prepared[2d] by treating amino diol 4 with RЈOTf [RЈ = enantioselectivity (42%ee), although the chemical yield and
TES (triethylsilyl), TIPS (triisopropylsilyl), TBDMS (tert- the diastereoselectivity increased (71% yield, endo/exo,
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E. Kwon, H. Nakano et al.
FULL PAPER
87:13; Table 1, Entry 2). Catalyst 3c with a β-tert-butyl sub- enantioselectivity (73%ee; Table 1, Entry 4). Taking these
stituent resulted in a greatly increased enantioselectivity of results into consideration, we concluded that the substitu-
76%ee with a moderate chemical yield (53%) and very ent at the β-position of the amino alcohol may have a sig-
good diastereoselectivity (endo/exo, 92:8; Table 1, Entry 3). nificant role in the strategy to increase the enantio-
The β-iPr-substituted catalyst 3d also had sufficient cata- selectivity.
lytic activity and provided endo-DC adduct 9 in good chem-
Next, we examined the same reaction by using β-amino
ical yield (72%), diastereoselectivity (endo/exo = 89:11), and alcohol organocatalysts 5a–5d, which have the bulkier silyl
groups (i.e., TES, TIPS, TBDMS, and TPS) on the oxygen
atom at the γ-position (Table 1, Entries 5–9). All of the re-
Table 1. 1,3-DC of 7 and 8 by using amino alcohol catalysts.
actions afforded the desired endo-DC adduct 9 in moderate
to good chemical yields (58–86%) with good diastereoselec-
tivities (endo/exo, 81:19–87:13) and moderate to good
enantioselectivities (65–75%ee). These results show that a
β-amino alcohol with the bulkier substituent at the γ-posi-
tion may more effectively provide the desired DC adduct
9 in satisfactory chemical yield and enantioselectivity. The
reaction with β-amino alcohol catalyst 1, which may effec-
tively provide DC adduct 9 in satisfactory chemical yield
and enantioselectivity, was then examined under the same
reaction conditions as those used for catalysts 5a–5d
(Table 1, Entry 9). Catalyst 1 afforded the best results with
high catalytic activity to give a good chemical yield (83%)
along with good diastereoselectivity (endo/exo, 94:6) and
enantioselectivity (91%ee). However, when the same reac-
tion was catalyzed by γ-TTMSSO-α-TMSO-amino silyl
Entry
Catalyst Yield [%][a] endo/exo[b]
% ee of endo[c]
ether 6, in which the α-hydroxy group was protected by a
trimethylsilyl group, the enantioselectivity (43%ee) was sig-
nificantly less that that afforded by TTMSS-amino alcohol
1 with a free hydroxy group (91%ee; Table 1, Entry 10).
The difference in the data may result from weaker electric
interactions with the counter anions or from the steric in-
fluence of the bulkier trimethylsilyl group, although the
reasons are not clear. Nevertheless, this result indicates that
the presence of the free hydroxy group at the α-position in
the catalyst may be necessary to realize satisfactory results.
To optimize the reaction conditions by using the superior
TTMSS-amino alcohol 1, we next examined the effect of
reducing the molar ratio of catalyst 1 in the reaction system
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
5a
5b
5c
5d
1
57
71
53
72
58
76
86
79
83
64
78:22
87:13
92:8
89:11
87:13
86:14
81:19
83:17
94:6
46
42
76
73
73
66
65
75
91
43
6
80:20
[a] Isolated combined yield of endo and exo products. [b] Deter-
mined by H NMR spectroscopic analysis of 1,3-DC adducts 9.[4]
1
[c] Determined by HPLC analysis of the endo isomer using a chiral
column.
Table 2. Opimization of 1,3-DC of 7 and 8 by using catalyst 1.
Entry
Catalyst 1
[mol-%]
Temp.
[°C]
HX
Solvent
Yield
[%][a]
endo/
% ee of
exo[b]
endo[c]
1
2
3
4
5
6
7
8
20
5
r.t.
r.t.
r.t.
0
–25
–50
0
0
0
0
0
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
HCl
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
MeCN
CHCl3
CH2Cl2
Et2O
82
73
63
79
30
trace
trace
9
6
4
71
63
65
54
73
94:6
94:6
91:9
94:6
95:5
–
92
90
71
92
92
–
2.5
10
10
10
10
10
10
10
10
10
10
10
10
–
–
TFA[d]
TBA[d]
PFA[d]
TfOH
TfOH
TfOH
TfOH
TfOH
84:16
85:15
93:7
93:7
95:5
93:7
91:9
96:4
76
76
76
91
92
92
89
95
9
10
11
12
13
14
15
0
0
0
0
[a] Isolated combined yield of endo and exo products. [b] Determined by 1H NMR spectroscopic analysis of 1,3-DC adducts 9.[4] [c] Deter-
mined by HPLC analysis of the endo isomer using a chiral column. [d] TFA = trifluoroacetic acid, TBA = tribromoacetic acid, PFA =
CF3(CF2)5CO2H.
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Organocatalyst for Enantioselective 1,3-Dipolar Cycloaddition
(Table 2, Entries 1–3). The use of 20 mol-% of 1 provided
We also examined the effects of solvent on the reaction.
DC adduct 9 in good chemical yield (82%), excellent dia- Commonly used solvents (i.e., benzene, MeCN, CHCl3,
stereoselectivity (endo/exo, 94:6), and fairly good enantio- CH2Cl2, and Et2O) were screened in the 1,3-DC (Table 2,
selectivity (92%ee), which is very similar to that of the ear- Entries 11–15) and showed good results in each case with
lier reaction that employed 10 mol-% of 1 (Table 2, En- regard to chemical yield, diastereoselectivity, and enantio-
try 1). When 5 mol-% of 1 was employed, the reaction also selectivity. The best enantioselectivity (95%ee) was ob-
gave the DC adduct 9 with good enantioselectivity (90%ee) tained by using Et2O as the solvent. In diethyl ether, a good
but with a lower chemical yield (73%; Table 2, Entry 2). chemical yield (73%) and excellent diastereoselectivity also
Employing a catalytic loading of 2.5 mol-% also resulted in resulted (endo/exo, 96:4; Table 2, Entry 15).
a
lower chemical yield (63%) and enantioselectivity
Under the optimized conditions, a wide range of 1,3-DC
(71%ee; Table 2, Entry 3).
reactions were investigated. Nitrones 7 and 11a–11k with
To further optimize the reaction conditions for TTMSS- α,β-unsaturated aldehydes 8 and 12 were submitted to the
amino alcohol 1, the reactions were carried out at lower reaction with catalyst 1 and TfOH in Et2O at 0 °C, and
temperatures, that is, from 0 to –50 °C (Table 2, Entries 4– the enantioselectivities were determined by converting the
6). At 0 °C, a good chemical yield (79%), diastereoselectiv- resulting DC endo adduct into the corresponding alcohols
ity (endo/exo, 94:6), and enantioselectivity (92%ee) were 14a–14l.[4,7] The absolute configuration of the DC adduct
obtained at similar levels to those achieved at room tem- and the endo/exo stereochemistry were determined by ana-
1
perature (Table 2, Entry 4). At –25 °C, the reaction resulted lyzing the relationship of the H NMR signals for the aro-
in a significantly decreased chemical yield (30%), although matic hydrocarbon at the 3-position and the aldehyde at the
the enantioselectivity remained high at 92%ee (Table 2, En- 4-position of the corresponding DC adduct and by compar-
try 5). The reaction virtually ceased when carried out at ing this data with that in the literature.[4c,4f,4i,4n] The results
–50 °C (Table 2, Entry 6).
are summarized in Table 3. The reaction of 4-MeC6H4-sub-
The effect of acid additives (10 mol-%) such as HCl, stituted nitrone 11a, 4-iPrC6H4-substituted 11b, and 4-
CF3CO2H, CBr3CO2H, and CF3(CF2)5CO2H in the reac- OMeC6H4-substituted 11c, which have electron-donating
tion were also investigated (Table 2, Entries 7–10). Unfortu- groups on the benzene ring afforded the desired endo-DC
nately, these additives did not perform more effectively than adducts 13a–13c in excellent enantioselectivities (90–
TfOH, and the chemical yields were significantly lower un- 94%ee) with good chemical yields and diastereoselectivities
der these reaction conditions.
(67–76% yield, endo/exo, 95:5–96:4; Table 3, Entries 1–3).
Table 3. 1,3-DC of 7 and 11a–11k with 8 and 12 using β-amino alcohol catalyst 1.
Entry
Nitrone
R1
R2
Aldehyde
DC adduct 13 Yield [%][a]
endo/exo[b]
% ee of endo[c]
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
7
4-MeC6H4
4-iPrC6H4
4-OMeC6H4
4-ClC6H4
4-BrC6H4
2-ClC6H4
4-CF3C6H4
1-naphthyl
2-naphthyl
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Bn
8
8
13a
13b
13c
13d
13e
13f
13g
13h
13i
67
75
76
59
44
49
58
59
63
65
37
79
95:5
96:4
96:4
89:11
90:10
93:7
92:8
92:8
92:8
96:4
94
90
92
89
90
93
62
71
92
97
96
70
8
8
8
8
8
8
9
8
10
11
12
8
13j
4-ClC6H4
Ph
8
13k
13l
90:10
61:39
12
[a] Isolated combined yield of endo and exo products. [b] Determined by 1H NMR spectroscopic analysis of 1,3-DC adducts 13.[4] [c] De-
termined by HPLC analysis of endo isomer using a chiral column.
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FULL PAPER
The use of ClC6H4- and BrC6H4-substituted nitrones 11d–
The reaction of nitrone 7 (R1 = Ph, R2 = Bn) with simple
11f, which contain electron-withdrawing groups on the acrolein (12) as the α,β-unsaturated aldehyde provided
benzene ring, provided endo-DC adducts 13d–13f in fairly endo-DC adduct 13l in good chemical yield (79%) and good
good to excellent enantioselectivities (89–93%ee) and dia- enantioselectivity (70%ee) but with a significantly lower
stereoselectivities (endo/exo, 89:11–93:7), but the chemical diastereoselectivity (61:39; Table 3, Entry 12).
yields were poor to moderate (44–59%; Table 3, Entries 4–
On the basis of the high enantiopurity (95%ee) of op-
6). The reaction with CF3C6H4-substituted nitrone 7g led tically active endo-DC adduct 9, which was obtained from
to a substantial decrease in the enantioselectivity to 62%ee the reaction of nitrone 7 with α,β-unsaturated aldehyde 8,
(Table 3, Entry 7). These results indicate that substrates that and studies of the mechanism of amino organocatalyzed
have an electron-withdrawing group on the benzene ring cycloadditions by Ishihara, Seebach, Melchiorre, and our
lead to a sharp decrease in chemical yield, whereas bulkier group,[2a,8] a plausible model for the mechanism of this
substituents may induce more satisfactory enantioselectivit- enantioselective reaction is proposed (Scheme 3). The com-
ies. The 1,3-DC reactions that employed bulkier 1-naphthyl bination of catalyst 1, α,β-unsaturated aldehyde 8, and
nitrone 11h or 2-naphthyl nitrone 11i were also examined TfOH is thought to form intermediate I-1, in which there
under the same reaction conditions as used for of 11a–11g is less steric interaction between the TTMSS substituent on
(Table 3, Entries 8 and 9). Substrate 11h provided endo-DC the oxygen atom at the γ-position of the catalyst and the
adduct 13h in good chemical yield (59%), diastereoselectiv- olefin portion of the dienophile.[9] The reaction then pro-
ity (endo/exo, 92:8), and enantioselectivity (71%ee; ceeds through transition state Ts-1, in which there is less
(Table 3, Entry 8). The reaction of 11i also proceeded with steric interaction between the intermediate I-1 and nitrone
fairly good enantioselectivity (92%ee), diastereoselectivity 7 moieties than found in Ts-2 or Ts-3, in which there is
(endo/exo, 92:8), and chemical yield (63%) to provide the greater repulsive interactions between these units. Thus, the
endo-DC adduct 13i (Table 3, Entry 9). In addition, the re- steric effects from the bulky TTMSS, diphenyl, and TfO–
action of nitrone 11j (R1 = Ph, R2 = Me) with aldehyde 8 units in I-1 prevent nitrone 7 from approaching the steri-
was examined under the same reaction conditions, and the cally hindered re face of iminium ion intermediate I-1 in
highest enantioselectivity (97%ee) and a good chemical Ts-2. Thus, 7 attacks the sterically less-hindered si face as
yield (65%) were obtained along with excellent diastereo- shown in Ts-1. In Ts-1 and Ts-3, the endo/exo diastereo-
selectivity (endo/exo, 96:4; Table 3, Entry 10). On the other selectivity (endo-9/endo-9Ј, 96:4) of the reaction could de-
hand, the use of nitrone 11k (R1 = 4-ClC6H4, R2 = Me) led pend on the steric interactions of the diphenyl and TfO–
to a significant decrease in the chemical yield (37%), but moieties of I-1 with nitrone 7. Hence, the reaction may oc-
the enantioselectivity was almost the same as that for cur through Ts-1, which has less steric interactions between
nitrone 11j (Table 3, Entry 11).
I-1 and 7, rather than through Ts-3, which has greater steric
Scheme 3. Plausible reaction mechanism for 1,3-DC reaction of 7 with 8 using 1.
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Organocatalyst for Enantioselective 1,3-Dipolar Cycloaddition
interactions between I-1 and 7. Our calculations show a (Scheme 4). The conversions of 10 and 14j were smoothly
conformational predominancy of iminium ion intermediate carried out, and optically active γ-amino diols 15 and 17
I-1 .[9]
were obtained in good chemical yields (66 and 71%, respec-
Theoretical calculations were performed to elucidate the tively) and excellent enantioselectivities (95 and 97%ee,
diastereoselectivity of Ts-1.[9] As shown in Figure 1, the or- respectively). Similarly, isoxazolidine 14i was also converted
bital interactions between the LUMO of the iminium ion into γ-amino diol 16 in moderate chemical yield (50%) with
and the HOMO of nitrone in Ts-1 are phase matched, and 92%ee. Subsequently, γ-amino diols 15 and 16 were puri-
the cycloaddition reaction was allowed. However, a phase fied by recrystallization to Ͼ99%ee.
mismatch between the molecular orbitals was determined
for Ts-3. Because the steric hindrance of the super silyl
Conclusions
group of the iminium ion does not allow easy access to the
dienophile moiety of the nitrone, only a small amount of
the endo-9Ј product was obtained through transition state
Ts-2.[9] Similar 1,3-DC of other nitrones with α,β-unsatu-
rated aldehydes may also proceed according to this plaus-
ible reaction mechanism.
In summary, new catalytically active amino alcohol or-
ganocatalysts 1 and 5a–5d, which contain a primary amine,
were easily prepared in two steps, and their use in the asym-
metric 1,3-dipolar cycloaddition of nitrones 7 and 11a–11k
with α,β-unsaturated aldehydes 8 and 12 was investigated.
These amino alcohols worked effectively as organocatalysts,
and, in particular, TTMSS-β-amino alcohol 1, which has a
TTMSS group on the oxygen atom at the γ-position, exhib-
ited dramatic catalytic activity. When 10 mol-% of catalyst
1 and TfOH as a acid additive were used, the corresponding
optically active endo-DC adducts 9 and 13a–13l were af-
forded in good to excellent chemical yields (up to 86%
yield), diastereoselectivities (endo/exo, up to 96:4), and
enantioselectivities (up to 97%ee). The advantages of this
catalyst are that it is very stable when exposed to air and is
easily prepared in two steps. The obtained optically pure
nitrones 10, 14i, and 14j were easily converted into optically
active γ-amino diols 15–17, which contain three contiguous
stereogenic centers. These compounds may be useful syn-
thetic intermediates for the preparation of new biologically
active compounds with potential applications in pharma-
ceutical chemistry. Studies aimed at examining the scope
and limitations of this β-amino alcohol organocatalyst in
asymmetric 1,3-DC reactions of other nitrones with other
α,β-unsaturated aldehydes are now in progress.
Figure 1. Depiction of the frontier orbitals of the iminium ion and
nitrone calculated at the B3LYP/6-311++g(d,2p) level of theory.
We then examined the conversion of optically active isox-
azolidines 10, 14i, and 14j into γ-amino diols 15–17
(Scheme 4). Optically active amino alcohols, including
amino diols, are useful chiral building blocks[10] for intro-
ducing one or more asymmetric centers of many biolo-
gically active compounds. Moreover, they can be employed
not only as a chiral building block for the synthesis of bio-
logically active compounds but also as a chiral ligand,[11]
catalyst,[12] and auxiliary[13] for asymmetric synthesis.
Therefore, the exploration of an efficient synthetic method
for the preparation of optically active amino alcohols that
have a set of one or more asymmetric centers is quite im-
portant to the field of synthetic organic chemistry. For this
purpose, the conversion of the obtained optically active
isoxazolidines 10, 14i, 14j into γ-amino diols 15–17 by cata-
lytic hydrogenation [H2, Pd(OH)2][10a] was examined
Experimental Section
General Methods: All commercial reagents were purchased and
used without further purification. All reactions were carried out
under argon in flame-dried glassware with magnetic stirring. Thin
layer chromatography was performed on silica gel 60 F254, and the
analytes were detected by using UV light (254 nm) and iodine
vapor. Column chromatography was carried out on silica gel 60N
(40–100 μm), and preparative TLC was carried out on silica gel
60 F254. Melting points were measured with a micromelting point
apparatus. Infrared spectra were measured with an FTIR spectro-
photometer. The 1H and 13C NMR spectroscopic data were re-
corded with a 500 and 125 MHz spectrometer, respectively. The
1
samples were dissolved in CDCl3, (CD3)2SO, or CD3OD. The H
NMR data are reported as follows: chemical shifts in ppm from
tetramethylsilane (δ = 0.0 ppm) or the residual protio solvent [for
(CD3)(CD2H)SO, δ = 2.50 ppm; for CD2HOD, δ = 3.31 ppm] as an
internal standard, integration, multiplicity [s (singlet), d (doublet), t
(triplet), q (quartet), dd (double of doublets), m (multiplet). and
br. (broad)], coupling constants in Hz, number of protons, and as-
signment. The 13C NMR spectra were measured with complete pro-
ton decoupling. Chemical shifts were reported in ppm from the
Scheme 4. Conversion of isoxazolidines to γ-amino alcohols.
Eur. J. Org. Chem. 2015, 7292–7300
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7297

E. Kwon, H. Nakano et al.
FULL PAPER
residual solvent as the internal standard (for CDCl3,
δ
=
10 H, C6H5), 3.83 (dd, J = 6.0, 2.9 Hz, 1 H, NCH), 3.52 (dd, J =
9.7, 6.0 Hz, 1 H, CCH2), 3.32 (dd, J = 9.5, 2.9 Hz, 1 H, CCH2),
0.11 [s, 27 H, Si(TMS)3] ppm. 13C NMR (125 MHz, CDCl3): δ =
146.0, 145.4, 128.6, 128.3, 126.8, 126.6, 125.8, 125.2, 79.5, 69.5,
77.16 ppm; for CD3OD, δ = 49.0 ppm). High performance liquid
chromatography was performed with AD-H, AS-H, and OD-H
(4.6 mmϫ 25 cm) chiral columns. Optical rotations were measured
with a digital polarimeter. HRMS spectra were performed by EI 57.2, 0.26 ppm. MS (EI): m/z = 489 [M]+. HRMS (EI): calcd. for
using sector instruments.
C24H43NO2Si4 [M]+ 489.2371; found 489.2367.
General Procedure for the 1,3-DC of Nitrones 7 and 11a–11k with
α,β-Unsaturated Aldehydes 8 and 12: The catalyst (0.01 mmol) and
TfOH (0.01 mmol) were dissolved in diethyl ether (1.00 mL) at
0 °C, and the resulting solution was stirred for 5 min. To the solu-
tion was added the corresponding nitrone (0.10 mmol) followed by
the corresponding α,β-unsaturated aldehyde (0.40 mmol). The reac-
tion mixture was stirred at room temperature (or as indicated in
Table 2) for 24 h and then passed through a silica gel column
(EtOAc). The filtrate was concentrated under reduced pressure. The
crude mixture was subjected to 1H NMR analysis to determine the
diastereoselectivity. The residue was purified by flash chromatog-
raphy on silica gel (EtOAc/hexane, 1:2) to afford DC adducts 9
(20.6 mg, 73%) or DC adducts 13a–13l (13a: 19.7 mg, 67%; 13b:
24.2 mg, 75%; 13c: 23.6 mg, 76%; 13d: 18.7 mg, 59%; 13e: 15.9 mg,
44%; 13f: 15.4 mg, 49%; 13g: 20.3 mg, 58%; 13h: 19.5 mg, 59%;
13i: 21.0 mg, 63%; 13j: 13.4 mg, 65%; 13k: 8.9 mg, 37%; 13l:
21.1 mg, 79%) as a colorless oil. To a solution of DC adduct 9 or
13a–13l in EtOH (2.00 mL) was added NaBH4 (0.10 mmol) at 0 °C,
and the mixture was stirred at room temperature for 1 h and then
quenched with H2O. EtOH was removed under reduced pressure,
and the residue was extracted with EtOAc (3ϫ 10 mL). The com-
bined organic layers were washed with brine and dried with
Na2SO4. The solvent was evaporated under reduced pressure to
give a residue, which was purified by flash chromatography (SiO2;
EtOAc/hexane, 1:2) to give the corresponding alcohol 10 or 14a–
14l. The ee values were determined by HPLC [DAICEL chiral OD-
H column; hexane/2-propanol, 98:2; flow rate: 0.70 mLmin–1]: 10:
tR = 46.9 (major) and 44.1 min (minor, 95%ee); 14a: tR = 57.6
(major) and 36.3 min (minor, 94%ee); 14c: tR = 108.5 (major) and
69.3 min (minor, 92%ee); 14d: tR = 58.9 (major) and 47.3 min
(minor, 89%ee); 14e: tR = 75.5 (major) and 54.2 min (minor,
90%ee); 14f: tR = 31.9 (major) and 30.4 min (minor, 93%ee); 14h:
tR = 91.4 (major) and 85.6 min (minor, 71%ee); 14j: tR = 46.7
(major) and 39.0 min (minor, 97%ee); 14k: tR = 32.0 (major) and
26.7 min (minor, 96%ee); 14l: tR = 22.9 (major) and 18.6 min
(minor, 70%ee). HPLC [DAICEL chiral AD-H column; hexane/
EtOH, 97:3; flow rate: 1.0 mLmin–1]: 14i: tR = 238.3 (major) and
77.3 min (minor, 92%ee). HPLC [DAICEL chiral AS-H column;
hexane/2-propanol, 98:2; flow rate: 0.70 mLmin–1]: 14b: tR = 28.3
(major) and 18.9 min (minor, 90%ee); 14g: tR = 26.5 (major) and
31.9 min (minor, 62%ee).
(S)-2-Amino-1,1-diphenyl-3-(triethylsilyloxy)propanol (5a): To a
solution of 4 (122 mg, 0.50 mmol) in dry CHCl3 (10.0 mL) were
added triethylsilyl triflate (135.6 μL, 0.60 mmol) and Et3N
(83.6 μL, 0.60 mmol) at –30 °C over 10 min under argon. The solu-
tion was stirred at room temperature for 16 h and then quenched
with H2O. The resulting mixture was extracted with CHCl3 (3ϫ
30mL), and the combined organic layers were washed with brine
and dried with Na2SO4. The solvent was removed under reduced
pressure to give a residue, which was purified by flash chromatog-
raphy (SiO2; EtOAc/hexane, 1:4) to give 5a (128.6 mg, 72%) as a
yellow oil. [α]2D4 = –63.38 (c = 0.55, EtOH). IR (neat): ν = 2911,
˜
2876, 1449, 1269 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.60–7.58
(m, 2 H, C6H5), 7.50–7.49 (m, 2 H, C6H5), 7.34–7.15 (m, 6 H,
C6H5), 3.94–3.93 (t, J = 4.3 Hz, 1 H, NCH), 3.60–3.59 (m, 2 H,
CCH2), 1.81 (br. signal, 2 H, NH2), 0.91–0.88 (t, J = 8.0 Hz, 9 H,
CCH3), 0.56–0.51 (q, J = 8.0 Hz, 6 H, SiCH2) ppm. 13C NMR
(125 MHz, CDCl3): δ = 146.1, 145.0, 128.5, 128.2, 126.7, 126.5,
125.5, 125.1, 79.1, 64.1, 57.2, 6.64, 4.12 ppm. MS (EI): m/z = 358
[M + H]+. HRMS (EI): calcd. for C21H32NO2Si [M + H]+
358.2202; found 358.2202.
(S)-2-Amino-1,1-diphenyl-3-(triisopropylsilyloxy)propanol (5b): To a
solution of 4 (122 mg, 0.50 mmol) in dry CHCl3 (10.0 mL) were
added triisopropylsilyl triflate (161 μL, 0.60 mmol) and Et3N
(83.6 μL, 0.60 mmol) at –30 °C over 10 min under argon. The solu-
tion was stirred at room temperature for 16 h and then quenched
with H2O. The resulting mixture was extracted with CHCl3 (3ϫ
30mL). The combined organic layers were washed with brine and
dried with Na2SO4. The solvent was removed under reduced pres-
sure to give a residue, which was purified by flash chromatography
(SiO2; EtOAc/hexane, 1:4) to give 5b (118.9 mg, 60%) as a yellow
oil. [α]2D4 = –57.14 (c = 0.63, EtOH). IR (neat): ν = 2942, 2889,
˜
1
1449, 1248 cm–1. H NMR (500 MHz, CDCl3): δ = 7.60–7.59 (m,
2 H, C6H5), 7.51–7.47 (m, 2 H, C6H5), 7.34–7.14 (m, 6 H, C6H5),
3.95–3.93 (dd, J = 5.8 Hz, J = 3.8 Hz, 1 H, NCH), 3.71–3.65 (m,
2 H, CCH2), 1.67 (br. signal, 2 H, NH2), 1.00–0.98 {m, 21 H,
Si[CH(CH3)2]3} ppm. 13C NMR (125 MHz, CDCl3): δ = 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 ppm. MS (EI): m/z = 399 [M]+. HRMS (EI): calcd. for
C24H37NO2Si [M]+ 399.2594; found 399.2589.
(S)-2-Amino-3-(tert-butyldimethylsilyloxy)-1,1-diphenylpropanol
(5c): To a solution of 4 (73.0 mg, 0.30 mmol) in dry CHCl3
(S)-2-Amino-1,1-diphenyl-3-[tris(trimethylsilyl)silyloxy]propan-1-ol
(1): Triflic acid (177.8 μL, 2.0 mmol) was added to dry CH2Cl2 (6.00 mL) were added tert-butyldimethylsilyl chloride (54.3 mg,
(3.0 mL), and the solution was cooled to 0 °C. Tris(trimethylsilyl)-
0.36 mmol), and Et3N (65.2 μL, 0.36 mmol) at 0 °C over 10 min
silane (617.8 μL) was added slowly, and the resulting solution was
under argon. The solution was stirred at room temperature for 16 h
stirred at room temperature for 1 h. To a solution of 4 (122 mg, and then quenched with H2O. The resulting mixture was extracted
0.50 mmol) in dry CH2Cl2 (7.0 mL) were added the solution of with CHCl3 (3ϫ 30mL), and the combined organic layers were
tris(trimethylsilyl)silyl triflate and Et3N (278.8 μL, 2.00 mmol) at washed with brine and dried with Na2SO4. The solvent was re-
–30 °C over 10 min under argon. The reaction mixture was stirred
at room temperature for 24 h and then quenched with H2O. The
resulting mixture was extracted with CH2Cl2 (3ϫ 30 mL), and the
combined organic layers were washed with brine and dried with
Na2SO4. The solvent was removed under reduced pressure to give
the crude residue, which was purified by flash chromatography
(SiO2; EtOAc/hexane, 1:6) to give 1 (130.3 mg, 53%) as a yellow
moved under reduced pressure to give a residue, which was purified
by flash chromatography (SiO2; EtOAc/hexane, 1:4) to give 5c
(69.7 mg, 65 %) as a white solid; m.p. 49–51 °C (Et2O/hexane).
[α]2D2 = –51.11 (c = 0.45, EtOH). IR (neat): ν = 2951, 2882, 1468,
˜
1307 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.59–7.57 (m, 2 H,
C6H5), 7.50–7.48 (m, 2 H, C6H5), 7.34–7.15 (m, 6 H, C6H5), 3.92–
3.90 (t, J = 4.6 Hz, 1 H, NCH), 3.59–3.58 (d, J = 4.6 Hz, 2 H,
CCH2), 0.86 [s, 9 H, C(CH3)3], –0.02 (s, 3 H, SiCH3), –0.05 (s, 3
H, SiCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 146.0, 145.1,
oil. [α]2D5 = –41.33 (c = 0.75, EtOH). IR (neat): ν = 2948, 2892,
˜
1
1448, 1244 cm–1. H NMR (500 MHz, CDCl3): δ = 7.58–7.13 (m,
7298
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7292–7300

Organocatalyst for Enantioselective 1,3-Dipolar Cycloaddition
128.5, 128.2, 126.7, 126.6, 125.5, 125.3, 125.1, 79.3, 64.6, 57.1, 25.8,
CD3OD): δ = 136.6, 130.1, 130.0, 129.2, 67.8, 60.5, 58.3, 51.1,
18.1, –5.60, –5.71 ppm. MS (EI): m/z = 358 [M + H]+. HRMS (EI): 22.8 ppm. MS (EI): m/z = 195 [M]+. HRMS (EI): calcd. for
calcd. for C21H31NO2Si [M + H]+ 358.2202; found 358.2202.
C11H17NO2 [M]+ 195.1259; found 195.1262.
(1R,2R,3R)-1-(Amino)-2-(hydroxymethyl)-1-(2-naphthyl)butan-3-ol
(16): Isoxazolidine 14i (66.3 mg, 0.20 mmol) was dissolved in
MeOH (5.00 mL), and 20 wt.-% Pd(OH)2/C (69.2 mg, 0.13 mmol)
was added to the solution at room temperature. The resulting mix-
ture was stirred at room temperature for 16 h under H2 (1 atm) and
then passed through Celite (MeOH). The filtrate was concentrated
under reduced pressure to give a residue, which was purified by
flash chromatography (SiO2; MeOH/CHCl3 = 1:4) to give 16
(24.4 mg, 50 %) as a white solid. After crystallization (MeOH/
ether), the desired compound was obtained in Ͼ99%ee. The ee
value was determined by HPLC [DAICEL chiral AS-H column;
hexane/2-propanol, 80:20; flow rate: 0.50 mL min–1]: tR = 66.7
(S)-2-Amino-1,1-diphenyl-3-(triphenylsilyloxy)propanol (5d): To a
solution of 4 (48.7 mg, 0.20 mmol) in dry CHCl3 (4.00 mL) were
added triphenylsilyl chloride (70.8 mg, 0.24 mmol) and Et3N
(27.9 μL, 0.24 mmol) at 0 °C for 10 min under argon. The solution
was stirred at room temperature for 16 h and then quenched with
H2O. The resulting mixture was extracted with CHCl3 (3ϫ 30mL),
and the combined organic layers were washed with brine and dried
with Na2SO4. The solvent was removed under reduced pressure to
give a residue, which was purified by flash chromatography (SiO2;
EtOAc/hexane, 1:4) to give 5d (86.4 mg, 86%) as a white solid; m.p.
91–92 °C (Et2O/pentane). [α]2D2 = –55.76 (c = 0.52, CHCl3). IR
(neat): ν = 2951, 2882, 1468, 1307 cm–1 1H NMR (500 MHz,
.
˜
(major) and 125.8 min (minor). [α]2D0 = 9.47 (c = 0.95, EtOH). IR
CDCl3): δ = 7.53–7.50 (m, 8 H, C6H5), 7.46–7.43 (m, 3 H, C6H5),
7.37–7.35 (m, 6 H, C6H5), 7.30–7.27 (m, 4 H, C6H5), 7.18–7.14 (m,
3 H, C6H5), 7.11–7.08 (m, 1 H, C6H5), 4.68 (s, 1 H, OH), 4.02–
3.98 (dd, J = 6.5 Hz, J = 3.5 Hz, 1 H, NCH), 3.80–3.75 (m, 2 H,
CCH2) ppm. 13C NMR (125 MHz, CDCl3): δ = 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 ppm. MS (EI): m/z = 501 [M]+. HRMS (EI): calcd. for
C33H31NO2Si [M]+ 501.2124; found 501.2123.
1
(neat): ν = 3282, 2967, 2926, 1495, 846 cm–1, m.p. 225–227 °C. H
˜
NMR [500 MHz, (CD3)2SO]: δ = 8.02–7.90 (m, 4 H, C10H7), 7.67–
7.54 (m, 3 H, C10H7), 4.74–4.73 (d, J = 6.5 Hz, 1 H, NCH), 3.69–
3.63 (m, 1 H, CCH), 3.27–3.16 (m, 2 H, CCH2), 2.09–2.06 (m, 1
H, CCH), 1.16–1.15 (d, J = 6.0 Hz, 3 H, CCH3) ppm. 13C NMR
(125 MHz, CD3OD): δ = 134.9, 134.6, 133.9, 129.9, 129.2, 129.0,
128.8, 128.0, 127.8, 126.1, 68.0, 60.6, 58.5, 51.2, 22.9 ppm. MS (EI):
m/z = 245 [M]+. HRMS (EI): calcd. for C15H19NO2 [M]+ 245.1416;
found 245.1418.
(S)-1,1-Diphenyl-1-(trimethylsilyloxy)-3-[tris(trimethylsilyl)silyl-
oxy]propane-2-amine (6): To a solution of 1 (147 mg, 0.30 mmol)
in dry CHCl3 (10.0 mL) were added trimethylsilyl triflate (109 μL,
0.60 mmol), and Et3N (50.2 μL, 0.36 mmol) at –30 °C for 10 min
under argon. The solution was stirred at room temperature for 24 h
and then quenched with H2O. The resulting mixture was extracted
with CHCl3 (3ϫ 30mL), and the combined organic layers were
washed with brine and dried with Na2SO4. The solvent was re-
moved under reduced pressure to give a residue, which was purified
by flash chromatography (SiO2; EtOAc/hexane, 1:20) to give 6
(99.5 mg, 59%) as a yellow oil. [α]2D2 = –47.23 (c = 0.55, EtOH). IR
(1R,2R,3R)-2-(Hydroxymethyl)-1-(methylamino)-1-phenylbutan-3-ol
(17): Isoxazolidine 14j (41.5 mg, 0.20 mmol) was dissolved in
MeOH (5.00 mL), and 20 wt.-% Pd(OH)2/C (69.2 mg, 0.13 mmol)
was added to the solution at room temperature. The reaction mix-
ture was stirred at room temperature for 16 h under H2 (1 atm) and
then passed through Celite (MeOH). The filtrate was concentrated
under reduced pressure to give a residue, which was purified by
flash chromatography (SiO2; MeOH/CHCl3, 1:4) to give 17
(29.8 mg, 71%) as a yellow oil. The ee value were determined by
HPLC [DAICEL chiral AD-H column; hexane/2-propanol, 80:20;
flow rate: 0.50 mLmin–1]: tR = 32.3 (major) and 30.5 min (minor,
(neat): ν = 2950, 2893, 1492, 1311 cm–1 1H NMR (500 MHz,
.
˜
CDCl3): δ = 7.45–7.21 (m, 10 H, C6H5), 3.83–3.81 (dd, J = 9.8 Hz,
J = 3.1 Hz, 1 H, CCH2), 3.47–3.44 (dd, J = 9.2 Hz, J = 3.2 Hz, 1
H, CCH2), 2.84–2.80 (t, J = 9.5 Hz, 1 H, NCH), 1.64 (br. signal, 2
H, NH2), 0.09 [s, 27 H, Si(TMS)3], –0.13 [s, 9 H, Si(CH3)3] ppm.
13C NMR (125 MHz, CDCl3): δ = 144.6, 143.9, 128.2, 128.0, 127.8,
127.4, 127.2, 126.9, 82.4, 69.8, 58.9, 2.07, 0.18 ppm. MS (EI): m/z
= 562 [M + H]+. HRMS (EI): calcd. for C27H51NO2Si5 [M + H]+
562.2844; found 562.2858.
97%ee). [α]2D2 = –19.69 (c = 0.66, EtOH). IR (neat): ν = 3316, 2964,
˜
1305, 1202, 865 cm–1. 1H NMR (500 MHz, CD3OD): δ = 7.38–7.26
(m, 5 H, C6H5), 4.04–4.00 (m, 1 H, CCH), 3.83–3.81 (d, J = 9.0 Hz,
1 H, NCH), 3.46–3.44 (dd, J = 4.0 Hz, J = 11.0 Hz, 1 H, CCH2),
3.16–3.14 (dd, J = 3.5 Hz, J = 11.0 Hz, 1 H, CCH2), 2.18 (s, 3 H,
NCH3), 1.76–1.70 (m, 1 H, CCH), 1.26–1.25 (d, J = 6.0 Hz, 3 H,
CCH3) ppm. 13C NMR (125 MHz, CD3OD): δ = 142.0, 129.5,
129.3, 129.1, 128.4, 70.3, 68.0, 61.1, 52.4, 33.8, 22.2 ppm. MS (EI):
m/z = 209 [M]+. HRMS (EI): calcd. for C12H19NO2 [M]+ 209.1416;
found 209.1425.
(1R,2R,3R)-1-(Amino)-2-(hydroxymethyl)-1-phenylbutan-3-ol (15):
Isoxazolidine 10 (57.9 mg, 0.20 mmol) was dissolved in MeOH
(5.00 mL), and 20 wt.-% Pd(OH)2/C (69.2 mg, 0.13 mmol) was
added to the solution at room temperature. The resulting mixture
was stirred at room temperature for 16 h under H2 (1 atm) and
then passed through Celite (MeOH). The filtrate was concentrated
under a reduced pressure to give a residue, which was purified by
flash chromatography (SiO2; MeOH/CHCl3, 1:4) to give 15
(25.8 mg, 66 %) as a white solid. After crystallization (MeOH/
ether), the desired compound was obtained in Ͼ99%ee. The ee
value was determined by HPLC [DAICEL chiral OD-H column;
hexane/2-propanol, 80:20; flow rate: 0.50 mL min–1]: tR = 37.3
(major) and = 23.7 min (minor). [α]2D0 = 12.69 (c = 0.63, EtOH).
Acknowledgments
This research was partially supported by Japan Science and Tech-
nology Agency (JST) (Adaptable & Seamless Technology Transfer
Program through Target-driven R&D, grant numbers
AS231Z01382G and AS221Z01186D).
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1H NMR (500 MHz, CD3OD): δ = 7.53–7.41 (m, 5 H, C6H5), 4.73–
4.71 (d, J = 7.0 Hz, 1 H, NCH), 3.79–3.75 (m, 1 H, CCH), 3.44–
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3.7 Hz, J = 10.9 Hz, 1 H, CCH2), 2.06–2.02 (m, 1 H, CCH), 1.27–
1.26 (d, J = 6.2 Hz, 3 H, CCH3) ppm. 13C NMR (125 MHz,
Eur. J. Org. Chem. 2015, 7292–7300
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7299

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Received: July 10, 2015
Published Online: October 16, 2015
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