Catalytic enantioselective allylation of aldehydes using β-amido functionalized allylstannanes with chiral In(OTf)3/i-Pr-pybox complexes

Article abstract of DOI:10.1016/j.tetlet.2008.05.123

The enantioselective allylation of aldehydes using a variety of β-amido functionalized allyltributylstannanes proceeded smoothly with good to high yields and enantioselectivities in the presence of 10 mol % of a chiral catalytic complex prepared from In(OTf)₃ and 2,6-bis[(S)-4-isopropyloxazolin-2-yl]pyridine {(S)-i-Pr-pybox}, providing the corresponding chiral γ-hydroxy amides.

Full text of DOI:10.1016/j.tetlet.2008.05.123

Tetrahedron Letters 49 (2008) 4701–4703
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Tetrahedron Letters
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Catalytic enantioselective allylation of aldehydes using b-amido functionalized
allylstannanes with chiral In(OTf)3/i-Pr-pybox complexes
*
Takamasa Suzuki, Tetsuya Sengoku, Masaki Takahashi, Hidemi Yoda
Department of Materials Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Naka-ku, Hamamatsu 432-8561, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective allylation of aldehydes using a variety of b-amido functionalized allyltributylstann-
anes proceeded smoothly with good to high yields and enantioselectivities in the presence of 10 mol % of
a chiral catalytic complex prepared from In(OTf)3 and 2,6-bis[(S)-4-isopropyloxazolin-2-yl]pyridine {(S)-
Received 12 May 2008
Revised 24 May 2008
Accepted 29 May 2008
Available online 2 June 2008
i-Pr-pybox}, providing the corresponding chiral
c
-hydroxy amides.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Catalytic enantioselective allylation
b-Amido allylstannane
Aldehyde
a
-Methylene-
In(OTf)3
(S)-i-Pr-pybox
c-butyrolactone
Asymmetric allylation of aldehydes using various allyl-metal
reagents such as allylsilanes and allylstannanes is one of the most
useful methods for chiral carbon–carbon bond formation.1
Although a large number of methods have been developed, there
are, to the best of our knowledge, few examples of reactions using
H
N
H
N
Lewis acid, RCHO
CH2Cl2, low temp.
∗
∗
O
O
OH
∗
SnBu3
R
1
2
allylstannanes with
a
b-amido function.2 Pioneering studies
developed by Tanaka et al.2a,b described Lewis acid mediated
stoichiometrically diastereoselective allylation between aldehydes
(RCHO) and optically active b-amido functionalized allyltributyl-
H+
∗
R
O
O
3 70~80% ee
stannanes 1, furnishing the corresponding chiral
c
-hydroxy amides
2. These can be easily converted to -methylene-
a
c-butyrolactones
Scheme 1. Diastereoselective allylation of aldehydes with b-amido allyltributyl-
3 possessing a wide range of potent biological activities (Scheme
stannanes 1 and the synthesis of
a
-methylene-
c
-butyrolactones 3.
1).3
Recently, chiral Lewis acid complexes composed of metal tri-
flates M(OTf)3 and 2,6-bis(oxazolin-2-yl)pyridine (pybox) were
shown to be effective catalysts for the enantioselective allylation
of carbonyl groups to afford the corresponding homoallylic alco-
hols in excellent enantiomeric excesses.4 Herein, we report the first
example of catalytic enantioselective allylation between b-amido
functionalized allyltributylstannanes 4 and aldehydes 5 mediated
by MX3 and 2,6-bis[(S)-4-isopropyloxazolin-2-yl]pyridine {(S)-i-
Pr-pybox} complexes (Scheme 2).
O
O
N
N
N
M
X
X
X
i-Pr
i-Pr
R1HN
O
R1HN
O
cat. MX3/(S)-iPr-pybox
OH
+
R2CHO
SnBu3
∗
R2
CH2Cl2, MS 4Å, rt
6
4
5
We attempted to determine the optimum reaction conditions
for the enantioselective allylation of benzaldehyde 5a using
2-methylene-N-phenyl-2-[(tributylstannyl)methyl]propan-amide
Scheme 2. Enantioselective allylation of aldehydes 5 with b-amido allyltributyl-
stannanes 4 catalyzed by MX3/(S)-i-Pr-pybox complexes.
4a.5 Among the various MX3/(S)-i-Pr-pybox complexes examined,
the reactions did not proceed under any conditions when InCl3,
* Corresponding author. Tel./fax: +81 53 478 1150.
E-mail address: tchyoda@ipc.shizuoka.ac.jp (H. Yoda).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.123

4702
T. Suzuki et al. / Tetrahedron Letters 49 (2008) 4701–4703
La(OTf)3, Sm(OTf)3, and Yb(OTf)3 were used even in the presence of
stoichiometric amounts of metal salts. Treatment of this reaction
with Sc(OTf)3, however, gave the desired c-hydroxy amide 6a but
effect was found, providing the corresponding c-hydroxy amides
6d–f in satisfactory ees as well as good yields, respectively (entries
7–9). In particular, we were delighted to find that the reaction
using N-(4-tert-butylphenyl) allyltributylstannane 4f gave 6f with
the highest enantioselectivity (entry 9).
Encouraged by this success, we extended the scope of this
methodology employing different aldehydes 5a–h and the results
from our survey are summarized in Table 2. The characteristic fea-
tures of these reactions are as follows: (i) use of aliphatic alde-
hydes decreased the stereoselectivity as well as the reactivity
(entries 1 and 2); (ii) little effect of the substituents on the aro-
matic aldehyde was observed (entries 3–5); (iii) the reaction with
the large alkyl-substituent connected to the aromatic ring gave the
highest enantioselectivity (79% ee, entry 8).
in low yield and enantiomeric excess (ee). In contrast to these find-
ings, use of In(OTf)3 had a significant effect on the rate and stereo-
selectivity, and an expected enhancement was observed in the use
of only 30 mol % of this reagent, leading to 6a in high yield with
moderate enantioselectivity as shown in Table 1 (81%, 37% ee; en-
try 1). We next examined the catalytic amounts in order to study
the reactivity of the In(OTf)3/(S)-i-Pr-pybox complex (entries 1–
3). Improved yield and ee were finally obtained in reaction
employing 10 mol % of catalyst (96%, 63% ee, entry 3), although
the use of 5 mol % of catalyst as well as the case of the addition
of TMSCl (1.2 equiv)4a reversely decreased the enantiomeric ex-
cesses, respectively (entries 4 and 5). With these results in hand,
further experiments have been performed on the catalytic allyl-
ation using several N-substituted b-amido allyltributylstannanes
4b–f under the same reaction conditions. In the cases that N-aro-
matic reagents 4d–f were employed, the beneficial stereoselective
Although the obvious reason for these results is not clarified at
present and the mechanistic research of the related reactions has
not been appeared to date,4 it should be considered that the steric
hindrance between the alkyl-substituent on aromatic aldehydes
employed and the isopropyl group of In(OTf)3/(S)-i-Pr-pybox
Table 1
Enantioselective allylation of 5a with allyltributylstannanes 4a–f catalyzed by In(OTf)3/(S)-i-Pr-pybox complexa,b
O
R1HN
O
R1HN
O
cat. In(OTf )3/(S)-i-Pr-pybox
OH
+
H
SnBu3
CH2Cl2, MS 4Å, rt
4a-f
5a
6a-f
Entry
R1
In(OTf)3 (mol %)
TMSCl (equiv)
Time (h)
Yieldc (%)
eed (%)
Configuration
1
2
3
4
5
6
7
8
9
Phenyl (4a)
Phenyl (4a)
Phenyl (4a)
Phenyl (4a)
Phenyl (4a)
C2H5 (4b)
c-C6H11 (4c)
biphenyl-3-yl (4d)
(3,5-Di-tert-butyl)phenyl (4e)
(4-tert-Butyl)phenyl (4f)
30
20
10
10
5
10
10
10
10
10
—
—
—
1.2
—
—
—
—
—
—
16
4
16
21
4
24
72
16
16
24
81 (6a)
72 (6a)
96 (6a)
85 (6a)
41 (6a)
78 (6b)
78 (6c)
74 (6d)
81 (6e)
78 (6f)
37
51
63
32
53
31
39
63
70
77
Se
Se
Se
Se
Se
Sf
Sf
Sf
Sf
Sf
10
a
All reactions employed 4 (1.0 equiv) and 5a (1.2 equiv) in the presence of activated MS 4 Å (120 mg) in CH2Cl2 (0.2 M).
b
c
d
e
f
See experimental procedure in Ref. 6.
Isolated yield.
Determined by chiral HPLC analysis using a Daicel Chiralpak IB column.
See Ref. 7.
Predicted absolute configuration on the basis of reaction mechanism and the sign of the specific rotations of 6.
Table 2
Enantioselective allylation of aldehydes 5a–h with 4f
H
H
N
N
O
O
cat. In(OTf )3/(S)-i-Pr-pybox
OH
R2
R2CHO
+
SnBu3
t-Bu
t-Bu
CH2Cl2, MS 4Å, rt
4f
5a-h
6f-m
Entry
R2CHO
Time (h)
Yielda (%)
eeb (%)
Configuration
1
2
3
4
5
6
7
8
Isovaleraldehyde (5b)
Pivaldehyde (5c)
20
20
20
20
20
14
16
20
45 (6g)
45 (6h)
91 (6i)
92 (6j)
90 (6k)
89 (6l)
78 (6f)
94 (6m)
48
58
58
59
61
74
77
79
Rc
Rd
Sd
Sd
Sd
Sd
Se
Sd
4-Nitrobenzaldehyde (5d)
4-Anisaldehyde (5e)
3-Chloroaldehyde (5f)
1-Naphthaldehyde (5g)
Benzaldehyde (5a)
4-Isopropylbenzaldehyde (5h)
a
Isolated yield.
b
c
Determined by chiral HPLC analysis using a Daicel Chiralpak IA, IB, or IC column.
See Ref. 8.
Predicted absolute configuration on the basis of reaction mechanism and the sign of the specific rotations of 6.
d
e
See Ref. 7.

T. Suzuki et al. / Tetrahedron Letters 49 (2008) 4701–4703
4703
E.-L.; Loh, T.-P. Tetrahedron Lett. 2005, 46, 6209; (o) Kwiatkowski, P.; Chaladaj,
W.; Jurczak, J. Synlett 2005, 2301; (p) Kwiatkowski, P.; Jurczak, J. Synlett 2005,
227; (q) Malkov, A. V.; Bell, M.; Castelluzzo, F.; Kocovsky, P. Org. Lett. 2005, 7,
3219; (r) Xia, G.; Shibatomi, K.; Yamamoto, H. Synlett 2004, 2437; (s) Kina, A.;
Shimada, T.; Hayashi, T. Adv. Synth. Catal. 2004, 346, 1169; (t) Yanagisawa, A.;
Nakamura, Y.; Arai, T. Tetrahedron: Asymmetry 2004, 15, 1909; (u) Nakajima, M.;
Kotani, S.; Ishizuka, T.; Hashimoto, S. Tetrahedron Lett. 2004, 46, 157. and
references cited therein.
O
O
O
O
N
N
OTf
OTf
N
TfO
O
N
N
TfO
O
N
In
In
O
O
R2
H
2. (a) Tanaka, K.; Yoda, H.; Isobe, Y.; Kaji, A. Tetrahedron Lett. 1985, 26, 1337; (b)
Tanaka, K.; Yoda, H.; Isobe, Y.; Kaji, A. J. Org. Chem. 1986, 51, 1856. Recently
diastereoselective allylation was reported; (c) Nishigaichi, Y.; Tamura, K.; Ueda,
N.; Iwamoto, H.; Takuwa, A. Tetrahedron Lett. 2008, 49, 2124.
R1
R1
H
R2
N
H
N
H
SnBu3
SnBu3
3. For reviews on
a-methylene-c-lactones, see: (a) Bandichhor, R.; Nosse, B.;
Model A
Figure 1. Plausible transition structure model.
Model B
Reiser, O. Top. Curr. Chem. 2005, 243, 43; (b) Janecki, T.; Blaszczyk, E.; Studzian,
K.; Janecka, A.; Krajewska, U.; Rosalski, M. J. Med. Chem. 2005, 48, 3516; (c)
Hoffmann, H. M.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94; For recent
examples, see: (d) Isabelle, C.; Françoise, Z.; Jacques, L.; Jean, V. Tetrahedron
2008, 64, 2441; (e) Ramachandran, P. V.; Pratihar, D. Org. Lett. 2007, 9, 2087; (f)
Le Lamer, A.-C.; Gouault, N.; David, M.; Boustie, J.; Uriac, P. J. Comb. Chem. 2006,
8, 643; (g) Szumny, A.; Wawrzenczyk, C. Synlett 2006, 1523; (h) Consorti, C. S.;
Ebeling, G.; Dupont, J. Tetrahedron Lett. 2002, 43, 753; (i) Yamauchi, S.;
Yamamoto, N.; Kinoshita, Y. Biosci. Biotechnol. Biochem. 2000, 64, 2209; (j)
Adam, W.; Groer, P.; Saha-Moller, C. R. Tetrahedron: Asymmetry 2000, 11, 2239
and references cited therein.
complex plays an important role in this selectivity. Thus, we
postulate that the observed high degree of stereoselectivity in
these reactions may be attributed to the stronger chelating ability
of indium ion which coordinates with the amide moiety of the
organotin reagent and the oxygen atom of the aldehyde to organize
cyclic transition states A and B (Fig. 1). Model A would be preferred
over B in which the steric interaction between the stannyl group
and the aryl group (R2) of the aldehyde is minimized to occupy
the remotest positions each other. In addition, the allyltributyl-
stannane approaches the carbonyl si-face because the re-face is
shielded by the isopropyl substituent on the oxazoline ring of the
pybox ligand,9 leading to the (S)-adduct predominantly.
4. For recent examples, see: (a) Lu, J.; Ji, S.-J.; Teo, Y.-C.; Loh, T.-P. Org. Lett. 2005, 7,
159; (b) Lu, J.; Hong, M.-L.; Ji, S.-J.; Loh, T.-P. Chem. Commun. 2005, 1010; (c) Lu,
J.; Ji, S.-J.; Loh, T.-P. Chem. Commun. 2005, 2345; (d) Lu, J.; Hong, M.-L.; Ji, S.-J.;
Teo, Y.-C.; Loh, T.-P. Chem. Commun. 2005, 4217; (e) Teo, Y.-C.; Goh, E.-L.; Loh, T.-
P. Tetrahedron Lett. 2005, 46, 4573; (f) Lu, J.; Ji, S.-J.; Teo, Y.-C.; Loh, T.-P.
Tetrahedron Lett. 2005, 46, 7435 and references cited therein.
5. A general method for preparation of b-amido allylstannanes was reported in Ref.
2b.
6. Representative procedure for the synthesis of 6a (Table 1, entry 3): Under argon
atmosphere, to the suspension of In(OTf)3 (14.3 mg, 0.0254 mmol) {predried at
120 °C for 1 h under reduced pressure (ca, 1.0 Torr)} and MS 4 Å (120 mg) {also
predried at 180 °C for 3 h under reduced pressure (ca, 1.0 Torr)} in CH2Cl2
(0.8 mL) was added i-Pr-pybox (15.3 mg, 0.0508 mmol) at room temperature.
After stirring for 0.5 h, a solution of benzaldehyde 5a (32.0 mg, 0.305 mmol) in
CH2Cl2 (0.2 mL) was added and stirred for 1 h. Then, 2-methylene-N-phenyl-2-
[(tributylstannyl)methyl]propanamide 4a (114 mg, 0.254 mmol) in CH2Cl2
(0.3 mL) was slowly added dropwise at the same temperature. After stirring
for 16 h, the reaction was quenched with aq Na2CO3 (5 mL), then CH2Cl2 was
removed in vacuo. The mixture was filtered with Celite and extracted with ethyl
acetate. The combined organic layers were washed with brine, dried over
Na2SO4, and evaporated under reduced pressure. The residue was purified by
column chromatography (3:1 to 2:1 hexane/ethyl acetate) to give the allylated
product 6a (65.0 mg, 0.243 mmol, 96%, 63% ee) as a white solid: mp 99–100 °C;
Furthermore, allylated products thus obtained were easily
converted to potentially useful
a-methylene-c-butyrolactones,
respectively.3
In summary, we have demonstrated the first example of
catalytic enantioselective allylation of various aldehydes using
b-amido functionalized allyltributylstannanes with 10 mol % of
In(OTf)3/(S)-i-Pr-pybox complex, and found that the reactions
between N-aryl allyltributylstannanes and aromatic aldehydes
were effective to give high enantioselectivity.
This method possesses desirable advantages of being not only
catalytic and enantioselective in the allylation, but able to give
½
a 1D7
ꢀ
ꢁ 46:7 (c 1.00, CHCl3); IR (KBr) 3279 (O–H), 2868 (N–H), 1614 cmꢁ1 (C@O);
1H NMR (300 MHz. CDCl3):
d 8.51 (br, 1H, NH), 7.55–7.51 (m, 2H, ArH),
optically active
a-methylene-c-butyrolactones directly without
7.37–7.22 (m, 7H, ArH), 7.15–7.09 (m, 1H, ArH), 5.84 (s, 1H, C@CH), 5.33 (s, 1H,
C@CH), 4.90 (dt, J = 3.3, 8.1 Hz, 1H, PhCH), 4.28 (d, J = 2.9 Hz, 1H, OH), 2.78 (ddd,
J = 0.84, 7.0, 14 Hz, 1H, CH2), 2.67 (dd, J = 8.3, 14 Hz, 1H, CH2); 13C NMR (75 MHz.
CDCl3): d 172.4 (C@O), 144.5 (C@CH2), 144.3 (C@CH2), 140.1 (CH), 129.4 (CH),
128.2 (CH), 127.2 (CH), 127.1 (CH), 126.6 (CH), 125.7 (CH), 122.7 (CH), 74.1
(CH2), 44.8 (CH); HRMS (ESI+) m/z calcd for C17H17NO2+Na: 290.1157, found
290.1128.
employing chiral allylstannanes prepared through tedious elabora-
tion.2a,b Further work on a more detailed mechanism and effort to
expand the scope of synthetic applications are currently in pro-
gress and will be discussed elsewhere.
7. The absolute configuration of the stereogenic center of 6a was easily determined
Acknowledgments
to be S after derivation to the corresponding a-methylene-c-butyrolactone 7a as
shown below, see: Csuk, R.; Schröder, C.; Hutter, S.; Mohr, K. Tetrahedron:
Asymmetry 1997, 8, 1411.
This work was supported in part by a Grant-in-Aid for Scientific
Research from Japan Society for the Promotion of Science. We
acknowledge Nanotechnology Network Project (Kyushu-area
Nanotechnology Network)of the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
H
N
O
OH
H+
O
O
References and notes
7a (91%)
6a
[α]D31 +12.9 (c 1.00,CHCl3)
1. For a general review, see: (a) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763.
and references cited therein.; For recent examples on the asymmetric allylation
of aldehydes, see: (b) Malkov, A. V.; Ramirez-Lopez, P.; Biedermannova, L.;
Rulisek, L.; Dufkova, L.; Kotora, M.; Zhu, F.; Kocovsky, P. J. Am. Chem. Soc. 2008,
130, 5341; (c) Sharma, R. K.; Samuelson, A. G. Tetrahedron: Asymmetry 2007, 18,
2387; (d) Liu, L.-y.; Sun, J.; Liu, N.; Chang, W.-x.; Li, J. Tetrahedron: Asymmetry
2007, 18, 710; (e) Chelucci, G.; Belmonte, N.; Benaglia, M.; Pignataro, L.
Tetrahedron Lett. 2007, 48, 4037; (f) Kotani, S.; Hashimoto, S.; Nakajima, M.
Tetrahedron 2007, 63, 3122; (g) Takeuchi, K.; Takeda, T.; Fujimoto, T.;
Yamamoto, I. Tetrahedron 2007, 63, 5319; (h) Denmark, S. E.; Fu, J.; Lawler, M.
J. J. Org. Chem. 2006, 71, 1523; (i) Chen, M.; Zheng, Y.; Fan, S.; Gao, G.; Yang, L.;
Tian, L.; Du, Y.; Tang, F.; Hua, W. Synth. Commun. 2006, 36, 1063; (j) Chai, Q.;
Song, C.; Sun, Z.; Ma, Y.; Ma, C.; Dai, Y.; Andrus, M. B. Tetrahedron Lett. 2006, 47,
8611; (k) Kwiatkowski, P.; Chaladaj, W.; Jurczak, J. Tetrahedron 2006, 62, 5116;
(l) Li, G.-L.; Zhao, G. J. Org. Chem. 2005, 70, 4272; (m) Chen, M.; Guo, S.; Zheng, Y.;
Chen, L.; Tang, F.; Hua, W. Heterocycl. Commun. 2005, 11, 285; (n) Teo, Y.-C.; Goh,
8. The absolute configuration of the stereogenic center of 6g was determined to be
R2a after cyclization again to the corresponding lactone 7b as shown below.
H
N
O
OH
H+
i-Bu
O
t-Bu
i-Bu
O
6g
7b (99%)
[α]D21 +26.1 (c 0.956, EtOH)
9. Motoyama, Y.; Narusawa, H.; Nishiyama, H. Chem. Commun. 1999, 131.