Enantioselective three-component synthesis of 4-arylated dehydroprolines: [3+2] annulation of allenylstannane and α-imino ester

Article abstract of DOI:10.1016/j.tetlet.2005.09.194

An enantioselective [3+2] annulation reaction of allenylstannane and α-imino ester was developed. Stille coupling of the resulting 4-stannyl dehydroproline gave optically active 4-arylated dehydroprolines in good yields.

Full text of DOI:10.1016/j.tetlet.2005.09.194

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8563–8566
Enantioselective three-component synthesis of 4-arylated
dehydroprolines: [3+2] annulation of allenylstannane
and a-imino ester
Kohei Fuchibe, Rina Hatemata and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Received 25 August 2005; accepted 30 September 2005
Available online 20 October 2005
Abstract—An enantioselective [3+2] annulation reaction of allenylstannane and a-imino ester was developed. Stille coupling of the
resulting 4-stannyl dehydroproline gave optically active 4-arylated dehydroprolines in good yields.
Ó 2005 Elsevier Ltd. All rights reserved.
1.Introduction
stannanes.4 As shown in Scheme 1, we could obtain
homopropargylamine 3 of S isomer by a reaction of
1 and 2 in the presence of [Cu(MeCN)4]ClO4 and
(R)-TolBINAP (1 mol % each)5 at ꢀ30 °C (96% yield,
86% ee). In contrast, we recently found that reaction
course changed dramatically when we attempted the
propargylation under more harsh conditions: 1 and 2
reacted in the presence of 10 mol % of the catalyst at
higher temperature to give [3+2] annulation product,
dehydroproline 4 in 66% yield, 56% ee.6,7
Proline is a ubiquitous component of proteins and pep-
tides, and at the same time, a versatile reagent in syn-
thetic organic chemistry. For instance, chiral diamines
and amino alcohols (prolinols) prepared from (S)-pro-
line are good ligands for asymmetric aldol reactions,1a
alkylation of aldehydes,1b and Michael addition reac-
tions.1c Chiral oxazaborolidines readily prepared from
the prolinols are efficient catalysts both for asymmetric
reduction of ketones1d and for asymmetric Diels–Alder
reactions.1e–h Parent proline and its substituted form
have recently attracted much attention due to their
potentiality as organocatalysts.2 Development of syn-
thetic method of proline and its derivatives is thus a sig-
nificant issue so as to supply these materials.3
In order to obtain dehydroproline 4 efficiently, we opti-
mized the reaction conditions (Table 1). When the reac-
tion was carried out in refluxing toluene, 4, and
stannyldehydroproline 58 were obtained in 78% (71%
ee) and 8% yield, respectively (entry 1).6 The ee value of
4 increased up to 91% by carrying out the reaction in
an oil bath of 80 °C (entry 5).9 Interestingly, short reac-
tion time led to improvement of the enantioselectivities
(entries 1–2 and 3–6), but 3 was formed again when the
reactions were quenched in 5 or 30 min (entries 2 and 6).
In this communication, we describe a three-component
synthesis of optically active 4-arylated dehydroprolines,
which utilizes novel [3+2] annulation of allenylstannane
and a-imino ester.
We initially surmised that this reaction proceeded by a
migratory cyclization mechanism similar to cyclopen-
tene annulation of silicon analogues (Scheme 2, left):10
nucleophilic addition of 2 to 1 gives b-carbocation inter-
mediate 6. Compound 6 undergoes 1,2-migration and
simultaneous cyclization gives the stannyl dehydropro-
line 5, which affords 4 by protonolysis. But this mecha-
nism was considerably suspicious because we obtained 3
when the reaction was carried out under mild conditions
(e.g., in Scheme 1).
2.Results and discussion
Previously, we reported copper(I)-catalyzed enantio-
selective propargylation of a-imino ester with allenyl-
Keywords: Allenylstannane; Annulation; Asymmetric synthesis;
a-Imino ester; Proline; Stille coupling.
Corresponding author. Tel.: +81 3 3986 0221x6489; fax: +81 3 5992
*
1029; e-mail: takahiko.akiyama@gakushuin.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.194

8564
K. Fuchibe et al. / Tetrahedron Letters 46 (2005) 8563–8566
1 mol%
Cu[(MeCN)4]ClO4
(R)-TolBINAP
N(H)Ts
3
96%, 86% ee
EtO2C
Et2O, –30 ˚C, 5 h
S
NTs
+
Sn(n–Bu)3
EtO2C
Ts
10 mol%
N
4
1
2
EtO2C
66%, 56%ee
THF, reflux, 5 h
Scheme 1. Formation of dehydroproline 4.
Table 1. Optimization of reaction temperature and time
[Cu(MeCN)4] ClO4 10 mol%
(R)-TolBINAP 10 mol%
Ts
N
N(H)Ts
NTs
EtO2C
+
+
Sn(n–Bu)3
2, 1.2 eq.
EtO2C
EtO2C
Toluene
R
1
4, R=H
5, R=Sn(n–Bu)3
3
Entry
Temperature
Reflux
Time (h)
4 (%)
ee of 4a (%)
5b (%)
3b (%)
1
2
3
4
5
6
1
78
25
57
52
36
21
71
89
77
82
91
94
8
20
30
30
29
4
—
39
—
—
—
61
5 min
5
3
1
80 °C
0.5
a ee values were determined by chiral HPLC analysis.
b ee values were not determined.
Cu(I)
Ts
N
NCu(I)Ts
1
+
2
migratory
cyclization
Cu (I)·L*
C–Sn cleavage
fast
Sn
TsN
EtO2C
+
2
1
Cu (I)·L*
EtO2C
EtO2C
Sn
Sn
[ 6 ]
[ 6 ]
Sn = Sn(n–Bu)3
[ 5 ]
Ts
N
Cu (I)·L*
EtO2C
[ 7 ]
H3O+
slow
C–Sn cleavage
Sn
4
[ 5 ]
H3O+
N(Sn)Ts
H3O+
H3O+
3
EtO2C
[ 7 ]
3
4
Migratory Cyclization Mechanism (Rejected)
Sequential Propargylation-Cyclization Mechanism (Adopted)
Scheme 2. Proposed reaction mechanisms.
We thus rejected the migratory cyclization mechanism
and adopted a sequential propargylation–cyclization
mechanism (Scheme 2, right): 6, generated from 1 and
2, undergoes rapid C–Sn bond cleavage to give homo-
propargylamide 7. Subsequent copper(I)-catalyzed cycli-
zation of 7 gives stannyl dehydroproline 5 probably via
Sn–Cu exchange and insertion to alkyne p bond.11 The
latter process is relatively slow and homopropargyl-
amine 3 is obtained by hydrolysis of 7 when the reaction
was quenched in a short period of time. Compound 7
(and/or 5) presumably racemize(s) readily under the
reaction conditions and short reaction time improved
the optical purity of 4.12
logue. Weaker C–Sn bond might be responsible for the
fast C–Sn bond cleavage of the intermediate 6.
Three-component coupling was accomplished by appli-
cation of Stille coupling reaction to 5 (Table 2). Stannyl
dehydroproline 5, generated from 1 and 2 (toluene,
reflux, 1 h), was subsequently treated with 1.2 equiv of
iodo- or bromobenzene and 10 mol % of Pd(PPh3)4 in
the same flask. After 5 h reflux, 4-phenylated dehydro-
proline 9a was obtained in good yields (entries 1 and
2) although chlorobenzene, phenyl trifluoromethane-
sulfonate, [Cu(MeCN)4]BF4, and [Cu(MeCN)4]PF6 gave
disappointing results (entries 3–6).
It is of great interest that cyclization mechanism of allen-
ylstannane is quite different from that of silicon ana-
We could synthesize optically active 4-arylated dehy-
droprolines 9 by means of the three-component coupling

K. Fuchibe et al. / Tetrahedron Letters 46 (2005) 8563–8566
8565
Table 2. Stille phenylation of 5
0.022 mmol) were added 1 (51.1 mg, 0.20 mmol in
0.8 mL toluene) and 2 (79.0 mg, 0.24 mmol in 0.7 mL
toluene) successively. The solution was stirred in an oil
bath of 80 °C for 1 h. The resulting mixture was filtered
through CeliteÒ and the filtrate was concentrated under
vacuum. The crude mixture was put on a silica gel
Cu[(MeCN)4] ClO4
10 mol%
10 mol%
Pd(PPh3)4
PhX 1.2 eq.
Ts
(R)-TolBINAP
1
+
2
N
10 mol%
EtO2C
[ 5 ]
Toluene
reflux, 1 h
reflux, 5 h
(2 cm 30 cm) and a mixed eluent (hexane/AcOEt =
Ph
*
1.2 eq.
9a
10/1, 150 mL) was passed through the SiO2 column to
remove non-polar stannane residue and then fractions
containing 4 (21.4 mg, 36% yield, 91% ee) and 5
(33.8 mg, 29% yield) were collected (hexane/AcOEt =
8/1). The ee value of 4 was determined by chiral HPLC
analysis (Daicel Chiralpak, AD-H, hexane/EtOH = 5/
1). (S)-1-Tosyl-4,5-dehydroproline ethyl ester (4): 1H
NMR (400 MHz): d = 1.31 (3H, t, J = 7.2 Hz), 2.44
(3H, s), 2.65 (1H, ddt, J = 16.4, 7.2, 2.4 Hz), 2.78 (1H,
ddt, J = 16.4, 11.2, 2.4 Hz), 4.23 (1H, dd, J = 11.2,
7.2 Hz), 4.25 (2H, q, J = 7.2 Hz), 5.07 (1H, dt, J = 4.4,
2.4 Hz), 6.37 (1H, dt, J = 4.4, 2.4 Hz), 7.33 (2H, d,
J = 8.2 Hz), 7.70 (2H, d, J = 8.2 Hz); 13C NMR
(75 MHz): d = 14.04, 21.56, 35.23, 60.20, 61.71, 109.55,
127.70, 129.74, 130.35, 133.38, 144.15, 170.94; IR
Entry
PhX
9a (%), ee (%)
4 (%), ee (%)
1
2
3
4
5a
6b
PhI
76, 78
81, 81
—
—
4, —
6, —
20, 78
15, 85
76, 75
80, 75
22, 72
41, 75
PhBr
PhCl
PhOTf
PhI
PhI
a Cu[(MeCN)4]BF4 was employed.
b Cu[(MeCN)4]PF6 was employed.
Table 3. Three-component synthesis of 4-arylated dehydroprolinesa
Entry
1
Ar
Ph
9 (%), ee (%)b
m = 1016, 1169, 1362, 1734, 1749, 3022 cmꢀ1; EA Calcd
~
62, 90 (9a)
for C14H17NO4S: C, 56.93; H, 5.80; N, 4.74; S, 10.86.
Found: C, 56.78; H, 5.87; N, 4.71; S, 10.98;
2
3
4
46, 93 (9b)
80, 84 (9c)
66, 90 (9d)
Cl
27
½aꢁD ꢀ443.10 (c 1.00, CHCl3, 91% ee). (S)-1-Tosyl-4-
tributylstannyl-4,5-dehydroproline ethyl ester (5): 1H
NMR (400 MHz): d = 0.85–0.91 (15H, m), 1.23–1.32
(9H, m), 1.38–1.44 (6H, m), 2.43 (3H, s), 2.68 (1H,
ddd, J = 16.2, 7.4, 2.0 Hz), 2.81 (1H, ddd, J = 16.2,
10.8, 2.0 Hz), 4.11 (1H, dd, J = 10.8, 7.4 Hz), 4.24
(2H, q, J = 7.2 Hz), 6.18 (1H, t, J = 2.0 Hz), 7.31
(2H, d, J = 8.2 Hz), 7.68 (2H, d, J = 8.2 Hz); 13C
NMR (75 MHz): d = 9.53, 13.59, 14.06, 21.52, 27.12,
28.92, 41.88, 60.54, 61.53, 119.42, 127.68, 129.58,
133.45, 134.78, 143.88, 171.54; IR ~m = 1167, 1205,
1225, 1356, 1734, 1749, 3017, 3022 cmꢀ1; MS m/z =
528 (M+ꢀC4H9, C22H34NO4SSn).
NO2
CF3
CF3
5
43, 84 (9e)
CF3
F
6
7
68, 87 (9f)
F
F
Me
3.2. Preparation of 9a (Table 3, entry 1)
34, 74 (9g)c
To a toluene solution (0.5 mL) containing [Cu-(MeCN)4]-
ClO4 (6.5 mg, 0.020 mmol) and (R)-TolBINAP (14.9 mg,
0.022 mmol) were added 1 (51.9 mg, 0.20 mmol in
0.8 mL toluene) and 2 (79.0 mg, 0.24 mmol in 0.7 mL
toluene) successively. The solution was stirred in an oil
bath of 80 °C for 1 h. To the resulting mixture were
added Pd(PPh3)4 (23.3 mg, 0.020 mmol) and bromo-
benzene (37.7 mg, 0.24 mmol in 1 mL of toluene) at
room temperature and the solution was refluxed for
5 h. The resulting mixture was filtered through CeliteÒ
and the filtrate was concentrated under vacuum. The
a 1:2:[Cu(MeCN)4ClO4]–(R):TolBINAP = 1:1.2:0.1:0.1, toluene, 80 °C,
1 h; then ArBr (1.2 equiv), Pd(PPh3)4 (10 mol %), reflux, 5 h.
b ee values were determined by chiral HPLC analysis.
c 24% yield of 4 was obtained (92% ee).
reaction (Table 3). Aryl bromides bearing electron-with-
drawing group particularly gave good results.
In summary, we could develop a three-component syn-
thesis of 4-arylated dehydroprolines, utilizing enantio-
selective [3+2] annulation reaction of allenylstannane
with a-imino ester.
crude mixture was put on a silica gel (2 cm 30 cm)
*
and a mixed eluent (hexane/AcOEt = 10/1, 150 mL)
was passed through the SiO2 column to remove non-
polar stannane residue. Fractions containing prod-
ucts were collected (hexane/AcOEt = 5/1, 200 mL) and
purification by preparative TLC (SiO2, toluene/
MeCN = 5/1) gave 9a (45.8 mg, 62% yield, 90% ee)
and 4 (11.7 mg, 20%, 91% ee). The ee values of 9a and
4 were determined by chiral HPLC analysis (Daicel
Chiralcel, OD-H, hexane/i-PrOH = 5/1 for 9a). (S)-
4-Phenyl-1-tosyl-4,5-dehydroproline ethyl ester (9a):
3.Experimental
3.1. Preparation of 4 and 5 (Table 1, entry 5)
To a toluene solution (0.5 mL) containing [Cu-(MeCN)4]-
ClO4 (6.5 mg, 0.020 mmol) and (R)-TolBINAP (14.9 mg,

8566
K. Fuchibe et al. / Tetrahedron Letters 46 (2005) 8563–8566
1H NMR (400 MHz): d = 1.32 (3H, t, J = 7.2 Hz),
2.42 (3H, s), 2.98 (1H, ddd, J = 15.6, 7.2, 1.8 Hz),
3.15 (1H, ddd, J = 15.6, 11.6, 1.8 Hz), 4.28 (2H,
q, J = 7.2 Hz), 4.37 (1H, dd, J = 11.6, 7.2 Hz), 6.85
(1H, dd, J = 1.8, 1.8 Hz), 7.21 (1H, dd, J = 6.4,
6.4 Hz), 7.23 (2H, d, J = 7.8 Hz), 7.26–7.35 (4H,
m), 7.74 (2H, d, J = 7.8 Hz); 13C NMR (75 MHz):
d = 14.08, 21.57, 35.82, 60.60, 61.90, 122.68,
124.67, 124.83, 127.34, 127.63, 128.62, 129.91, 132.92,
3. (a) Casas, J.; Grigg, R.; Najera, C.; Sansano, J. M. Eur. J.
Org. Chem. 2001, 10, 1971; (b) Davis, F. A.; Zhang, H.;
Lee, S. H. Org. Lett. 2001, 3, 759.
4. Kagoshima, H.; Uzawa, T.; Akiyama, T. Chem. Lett.
2002, 31, 298.
5. (a) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J.
Am. Chem. Soc. 1998, 120, 4548; (b) Drury, W. J., III;
Ferraris, D.; Cox, C.; Young, B.; Lectka, T. J. Am. Chem.
Soc. 1998, 120, 11006.
6. We suppose that absolute stereochemistry of 4 and 5 to be
S. See Refs. 4 and 7c.
7. Annulation of stannane compounds: (a) Maruyama, K.;
Matano, Y. Bull. Chem. Soc. Jpn. 1989, 62, 3877; (b)
Herndon, J. W.; Wu, C.; Harp, J. J.; Kreutzer, K. A. Synlett
1991, 1; [3+2] annulation of allenylsilanes and a-imino
esters: (c) Daidouji, K.; Fuchibe, K.; Akiyama, T. Org. Lett.
2005, 7, 1051; See also: (d) Danheiser, R. L.; Kwasigroch, C.
A.; Tsai, Y.-M. J. Am. Chem. Soc. 1985, 107, 7233.
8. Compound 4 was not detected just after concentration of
the reaction mixture (1H NMR analysis). Partial proton-
olysis of 5 took place on silica gel during purification.
9. Ee value was not improved further by carrying out the
reaction in an oil bath of 60 °C (93% ee) and the yield of 4
decreased to 13%.
10. (a) Danheiser, R. L.; Carini, D. J.; Fink, D. M.; Basak, A.
Tetrahedron 1983, 39, 935; (b) Masse, C. E.; Panek, J. S.
Chem. Rev. 1995, 95, 1293; See also: (c) Kno¨lker, H.-J.
J. Prakt. Chem. 1997, 339, 304; (d) Panek, J. S. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, p 579.
11. Compound 3 (69% ee) underwent cyclization in the
presence of the copper(I) catalyst (10 mol %, toluene,
80 °C, 5 h) to give 18% yield of 4 (83% ee) and 82%
recovery of 3 (62% ee). See also: Wolf, L. B.; Tjen, K. C.
M. F.; ten Brink, H. T.; Blaauw, R. H.; Hiemstra, H.;
Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal.
2002, 344, 70.
~
133.43, 144.31, 170.76; IR m = 1167, 1205, 1227,
1362, 1734, 1749, 3024 cmꢀ1; EA Calcd for C20H21-
NO4S: C, 64.67; H, 5.70; N, 3.77; S, 8.63. Found: C,
26
64.80; H, 5.62; N, 3.59; S, 8.46; ½aꢁD ꢀ41.30 (c 1.00,
CHCl3, 90% ee).
References and notes
1. (a) Carreira, E. M. In Comprehensive Asymmetric Cataly-
sis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 3, p 997; (b) Mukaiyama, T.;
Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. J. Am.
Chem. Soc. 1979, 101, 1455; (c) Dieter, R. K.; Tokles,
M. J. Am. Chem. Soc. 1987, 109, 2040; (d) Corey, E. J.;
Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986; (e)
Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125,
6388; (f) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am.
Chem. Soc. 2002, 124, 9992; See also (g) Kobayashi, S.;
Murakami, M.; Harada, T.; Mukaiyama, T. Chem.
Lett. 1991, 1341; (h) Aggarwal, V. K.; Anderson, E.;
Giles, R.; Zaparucha, A. Tetrahedron: Asymmetry 1995, 6,
1301.
2. For reviews, see: (a) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138; (b) Special Issue on
Asymmetric Organocatalysis; Houk, K. N., List, B. Eds.;
Acc. Chem. Res. 2004, 37, 487; (c) Organo Catalysis Issue;
List, B., Bolm, C. Eds.; Adv. Synth. Catal. 2004, 346, 1021;
(d) Asymmetric Organocatalysis; Berkessel, A., Gro¨ber,
H., Eds.; Wiley-VCH: Weinheim, 2005; (e) Seayad, J.;
List, B. Org. Biomol. Chem. 2005, 13, 719.
12. It was confirmed that dehydroproline 4 did not racemize
under the reaction conditions (10 mol % of [Cu(MeCN)4]-
ClO4, 10 mol % of (R)-TolBINAP, toluene, 80 °C). Com-
pound 4 of 83% ee afforded 91% recovery of 4 with 83% ee
even after 5 h stirring.