One-pot synthesis of chiral dehydroproline esters: [3+2]-type cycloaddition reaction of allenylstannane and α-imino ester

Article abstract of DOI:10.1016/j.tet.2006.05.018

An enantioselective [3+2]-type cycloaddition of allenylstannane and α-imino ester was developed. Synthetic utility of the 4-stannyldehydroproline ester intermediate was demonstrated: iodine oxidation and Stille coupling reaction of the intermediate afforded optically active 4-iodo- and 4-aryldehydroproline esters in good yields and in high ees, respectively.

Full text of DOI:10.1016/j.tet.2006.05.018

Tetrahedron 62 (2006) 11304–11310
One-pot synthesis of chiral dehydroproline esters: [3D2]-type
cycloaddition reaction 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 2 February 2006; revised 6 May 2006; accepted 9 May 2006
Available online 5 June 2006
Abstract—An enantioselective [3+2]-type cycloaddition of allenylstannane and a-imino ester was developed. Synthetic utility of the 4-
stannyldehydroproline ester intermediate was demonstrated: iodine oxidation and Stille coupling reaction of the intermediate afforded
optically active 4-iodo- and 4-aryldehydroproline esters in good yields and in high ees, respectively.
Ó 2006 Elsevier Ltd. All rights reserved.
NTs
Ts
Ts
N
1. Introduction
N
*
EtO2C
EtO2C
EtO2C
*
Sn
Development of the novel synthetic method of proline and
its derivatives in optically pure form is an important objec-
tive because they play key roles as chiral sources in synthetic
organic chemistry. For instance, chiral diamines and amino
alcohols (prolinols), prepared from optically active proline
are efficient ligands for asymmetric aldol reactions,1a alkyl-
ation of aldehydes,1b and Michael addition reactions.1c
Chiral oxazaborolidine, prepared from optically active pro-
linols, are useful catalysts for asymmetric borane reduction
of ketones1d and Diels–Alder reactions.1e–h Parent proline
and its substituted form have lately emerged as an efficient
chiral organocatalysts.2 Prolines have, thus, found increas-
ing synthetic utility as chiral catalysts in addition to chiral
building blocks.
Sn
Scheme 1. Our approach to optically active dehydroproline esters.
R
Based on the consideration, we studied (1) the cycloaddition
reaction of allenylstannane and a-imino ester and (2) func-
tionalization of the resulting [3+2]-type cycloadduct.7
2. Results and discussion
2.1. Cycloaddition reaction of allenylstannane and
a-imino ester
Previously, we reported [3+2]-type cycloaddition reactions
of allenylsilanes with a-imino ester, and we could obtain
4-silylated dehydroproline esters in an enantioselective
manner.3 This result encouraged us to examine the [3+2]-
type cycloaddition reactions of allenylstannane and a-imino
ester (Scheme 1): in analogy to the chemistry of the allenyl-
silanes,3,4 it is expected that allenylstannane also undergoes
[3+2]-type cycloaddition with a-imino ester.5 The resulting
4-stannylated dehydroproline ester would be a useful syn-
thetic intermediate for the preparation of optically active
4-substituted dehydroproline esters because C–Sn bond is
more reactive than the corresponding C–Si bond.6
At the outset, we studied the reaction of a-imino ester 1 and
allenyl(tributyl)stannane 2 (Scheme 2). Compounds 1 and 2
were heated in the presence of [Cu(MeCN)4]ClO4 and (R)-
TolBINAP (10 mol % each). After stirring for 5 h, we could
obtain chiral dehydroproline ester 3 in 66% yield and 56%
ee. Compound 3 is a protonolysis product of the expected
stannyldehydroproline ester 4.
This result is in clear contrast to our enantioselective propar-
gylation reaction:8,9 in the presence of 1 mol % of the
catalyst at ꢀ30 ꢁC, 1 reacted with 2 to give (S)-homopropar-
gylamine 5 in 96% yield and 86% ee. It is found that prop-
argylation product was obtained under mild conditions and
that [3+2]-type cycloaddition product was obtained under
more harsh conditions.
Keywords: Allenylstannane; Annulation; Asymmetric synthesis; a-Imino
ester; Iodine oxidation; Proline; Stille coupling.
We found that the product distribution of the cycloadduct(s)
and the propargylation product was also dependent on the
* Corresponding author. Tel.: +81 3 3986 0221; fax: +81 3 5992 1029;
e-mail: takahiko.akiyama@gakushuin.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.018

K. Fuchibe et al. / Tetrahedron 62 (2006) 11304–11310
11305
Ts
N
Ts
N
10 mol%
EtO2C
EtO2C
THF, reflux, 5 h
Sn(n–Bu)3
NTs
Cu[(MeCN)4]ClO4
4
3, 66%, 56%ee
+
Sn(n–Bu)3
(R)-TolBINAP
EtO2C
N(H)Ts
1 mol%
1
2
Et2O, –30 °C, 5 h
EtO2C
S
5, 96%, 86% ee
Scheme 2. [3+2]-Type cycloadditions of 1 and 2.
Table 1. Ligand effect
[Cu(MeCN)4] X 10 mol%
Chiral Ligand 10 mol%
Ts
N(H)Ts
N
NTs
+
EtO2C
+
Sn(n–Bu)3
EtO2C
Toluene, reflux, 1 h
EtO2C
R
3, R = H
4, R = Sn(n–Bu)3
2, 1.2 equiv
5
1
Entry
Chiral ligand
X
3+4 (%) (3/4), ee of 3 (%)a
5 (%)a,b
1
2
3
4
5
6
7
8
(R)-TolBINAP
(R)-TolBINAP
(R)-TolBINAP
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-DM–SEGPHOS
(R)-DTBM–SEGPHOS
ClO4
BF4
PF6
ClO4
BF4
PF6
86 (91/9), 71
93 (63/37), 84
78 (87/13), 85
64 (66/34), 81
9 (100/0), 70
Trace (—), —
26 (46/54), 72
Trace (—), —
—
—
—
—
55
58, 63% ee
56, 70% ee
70
ClO4
ClO4
a
The ee values of 3 and 5 were determined by chiral HPLC analysis.
The ee values were not determined unless otherwise indicated.
b
O
Ar=Ph for (R)-SEGPHOS
Ar=(3,5-Me2)C6H3 for (R)-DM-SEGPHOS
Ar=(3,5-t–Bu2)(4-MeO)C6H2 for (R)-DTBM-SEGPHOS
O
O
PAr2
PAr2
O
nature of the phosphine ligand employed (Table 1). When 1
and 2 (1.2 equiv) were refluxed in toluene for 1 h in the pres-
ence of (R)-TolBINAP and cuprous salt ([Cu(MeCN)4]ClO4,
–BF4, –PF6) (10 mol % each), cycloadducts (3 and survived
4) were obtained in good yields and propargylation product 5
was not obtained at all (Entries 1–3).10 However, when (R)-
SEGPHOS was used, 5 was produced by means of the BF4
and PF6 salts (Entries 5 and 6). When (R)-DM-SEGPHOS
was used as a chiral ligand, 5 was formed preferentially
even in the case of ClO4 salt (Entry 7). Use of (R)-DTBM-
SEGPHOS gave 5 as an essentially sole product (Entry 8).
It seems that electron-donating ligand gives homopropargyl-
amine 5 preferentially.
1
The structure of 4 was characterized spectroscopically. H
and 13C NMR spectra were consistent with the structure of
the expected 4-stannyldehydroproline ester. The isotope pat-
tern of observed fragment ion (M+ꢀC4H9, C22H34NO4SSn),
in particular, was in complete agreement with its computer
simulation (Fig. 1).
Figure 1. Mass spectrum of stannyldehydroproline 4.

11306
K. Fuchibe et al. / Tetrahedron 62 (2006) 11304–11310
Table 2. Temperature and reaction timea
obtain 3 and 4, instead (Table 2)—regeneration of 6 from 7 is
highly unlikely.
Entry Temp
Time (h) ee of 3 (%)b 3+4 (%) (Ratio) 5 (%)
1
2
3
4
5
6
Reflux
Reflux 5 min
80 ꢁC
80 ꢁC
80 ꢁC
80 ꢁC
1
71
89
77
82
91
94
86 (91/9)
—
39
—
—
—
61
We thus rejected the migratory cyclization mechanism and
adopted a sequential propargylation–cyclization mechanism
(right, in Scheme 3): 6, generated from 1 and 2, undergoes
rapid C–Sn bond cleavage to give 7.12 7 is a resting inter-
mediate and the subsequent copper(I)-catalyzed cyclization
gives the stannyldehydroproline ester 4 probably via cop-
per(I)-alkyne p complex.13 On the other hand, when the
reaction is carried out under mild conditions or quenched
in a short period of time, the resting 7 is hydrolyzed during
work-up to give 5.14 Use of electron-donating ligand retards
the electrophilic cyclization process and also results in the
formation of 5 (Table 1). Prolonged reaction time decreased
enantioselectivity, indicating that 7 (and/or 4) readily race-
mize(s) under the reaction conditions.15
45 (56/44)
87 (66/34)
82 (63/37)
65 (55/45)
25 (84/16)
5
3
1
0.5
a
1/2/[Cu(MeCN)4]ClO4/(R)-TolBINAP¼1/1.2/0.1/0.1, toluene.
b
The ee values were determined by chiral HPLC analysis.
We optimized the reaction conditions by means of the [Cu-
(MeCN)4]ClO4/(R)-TolBINAP system. High ee values were
achieved by carrying out the reaction at lower temperature
and that prolonging the reaction time decreased the ee values
(Table 2): the value of 71% ee (3) obtained by refluxing 1 and
2 for 1 h in toluene (Entry 1) increased up to 91% ee by car-
rying out the reaction in an oil bath of 80 ꢁC (Entry 5).11
When the reaction was allowed to proceed longer, the ee
value decreased gradually (Entries 1, 2, and 3–6).
We suppose that the absolute stereochemistry of the cyclo-
adducts 3 and 4 is S because our enantioselective propar-
gylation reaction afforded (S)-5 (Scheme 1)8 and
enantioselective [3+2]-type cyclization of 1 and allenyl-
silanes afforded silyldehydroproline esters of S isomers.3a
Re face of 1 might be shielded by pseudoequatorial tolyl
group on copper(I)/(R)-TolBINAP/1 complex (Fig. 2).
Besides, we could obtain considerable amount of 5 when the
reaction was quenched in a short period of time (Entries 2
and 6). This propargylation product disappeared by pro-
longed time, and cycloaddition products were obtained.
In analogy to the silicon analogues,4a–c we initially surmised
that this reaction proceeded by a migratory cyclization
mechanism (left, in Scheme 3): allenylstannane 2 undergoes
copper(I)-catalyzed nucleophilic addition with the a-imino
ester 1, giving a b-carbocation intermediate 6. 6 undergoes
C–Sn bond cleavage under mild conditions (e.g., in Scheme
2)togivestannylamideintermediate7, whichisreadilyhydro-
lyzed to furnish homopropargylamine 5. On the other hand,
stannyl moiety of 6 undergoes 1,2-migration under more
harsh conditions and simultaneous cyclization gives the
stannyldehydroproline ester 4 and its protonolysis product 3.
Ts
Tol
N
Re
Si
Tol
P
P
Cu
Tol
O
OEt
Tol
2
Figure 2. Working hypothesis of Si-face selective attack.
2.2. Functionalization of 4—iodine oxidation
However, this mechanism is apparently inconsistent with the
fact that we could obtain considerable amount of 5 in a short
period of time, and after prolonging reaction time, we could
The stannyldehydroproline ester 4 appeared to be an elec-
tron-rich, and thus reactive alkenylstannane. We expected
NCu(I)Ts
Cu(I)
Cu (I)·L*
C–Sn cleavage
fast
Ts
N
migratory
1
+
2
Sn
+
1
2
TsN
EtO2C
Cu (I)·L*
cyclization
EtO2C
EtO2C
[ 6 ]
Sn
Sn
[ 6 ], Sn = Sn(n–Bu)3
[ 4 ]
Ts
N
N(Sn)Ts
Cu (I)·L*
slow
EtO2C
EtO2C
H3O+
C–Sn cleavage
Sn
[ 7 ]
H3O+
[ 4 ]
H3O+
N(H)Ts
Ts
N
H3O+
N(Sn)Ts
EtO2C
+
Ts
EtO2C
N(H)Ts
EtO2C
N
5
+
3
EtO2C
EtO2C
[ 7 ]
Migratory Cyclization Mechanism (Rejected)
Scheme 3. Reaction mechanisms.
5
3
Sequential Propargylation-Cyclization Mechanism

K. Fuchibe et al. / Tetrahedron 62 (2006) 11304–11310
11307
that 4 was a useful intermediate for synthesis of chiral dehy-
droproline ester derivatives: after 1 and 2 (1.2 equiv) were
stirred for 1 h at 80 ꢁC in the presence of [Cu(MeCN)4]ClO4
and (R)-TolBINAP (10 mol %, each), the resulting mixture
containing 4 was treated with iodine (I2, 1.5 equiv) at
room temperature in the same flask. The iodine was con-
sumed quite rapidly and reductive work-up with aqueous
Na2S2O3 gave 4-iododehydroproline ester 8 in 62% yield
and 91% ee (Scheme 4). It should be noted that one recrys-
bromobenzene and 10 mol % of Pd(PPh3)4 in the same flask.
After refluxing for 5 h, 4-phenylated dehydroproline ester 9a
was obtained in good yields (Entries 1 and 2). Chlorobenz-
ene, phenyl trifluoromethanesulfonate, [Cu(MeCN)4]BF4,
and [Cu(MeCN)4]PF6 gave disappointing results (Entries
3–6).
We could synthesize various 4-arylated dehydroproline es-
ters in good yields and in high ees by the three-component
Cu[(MeCN)4]ClO4,10 mol%
Ts
N
Ts
N
I2 1.5 eq.
rt, 5 min.
EtO2C
(R)-TolBINAP, 10 mol%
EtO2C
1
+
2
Toluene, 80 °C, 1 h
Sn
[ 4 ], Sn = Sn(n–Bu)3
I
1.2 eq.
8, 62%, 91% ee
Scheme 4. Synthesis of chiral 4-iododehydroproline 8.
tallization of 8 (90% ee) from toluene dramatically im-
proved the ee value (Scheme 5). The minor enantiomer
was not detected by chiral HPLC analysis and it is estimated
that optical purity is >99% ee.
coupling reaction, using aryl bromides particularly bearing
electron-withdrawing group on their aromatic rings
(Table 4).
Ts
N
Ts
N
Table 4. Three-component synthesis of 9a
recrystallization
Toluene, 53%
EtO2C
EtO2C
Entry
1
Ar
Ph
9 (%), ee (%)b
62, 90 (9a)
3 (%), ee (%)b
I
I
20, 91
8, 90% ee
Scheme 5. Recrystallization of 8.
8, >99% ee
2
3
4
46, 93 (9b)
80, 84 (9c)
66, 90 (9d)
20, 93
13, 87
18, 92
Cl
NO2
2.3. Functionalization of 4—Stille coupling reaction
Three-component coupling was also accomplished by appli-
cation of the Stille coupling reaction to 4 (Table 3). Stannyl-
dehydroproline 4, generated from 1 and 2 (toluene, reflux,
1 h), was subsequently treated with 1.2 equiv of iodo- or
CF3
CF3
5
6
43, 84 (9e)
20, 91
Table 3. Stille-type phenylation of 4
CF3
F
10 mol%
Cu[(MeCN)4] ClO4
Ts
N
(R)-TolBINAP
EtO2C
1
+
2
F
68, 87 (9f)
34, 74 (9g)
18, 72
24, 92
Toluene
reflux, 1 h
Sn
1.2 equiv
F
[ 4 ], Sn = Sn(n–Bu)3
CH3
Pd(PPh3)410 mol%
PhX 1.2 equiv
Ts
7
N
EtO2C
+
3
reflux, 5 h
a
1/2/[Cu(MeCN)4]ClO4/(R)-TolBINAP¼1/1.2/0.1/0.1, toluene, 80 ꢁC, 1 h;
then ArBr (1.2 equiv), Pd(PPh3)4 (10 mol %), reflux, 5 h.
The ee values were determined by chiral HPLC analysis.
Ph
9a
b
Entry
PhX
9a (%), ee (%)a
3 (%), ee (%)a
1
2
3
PhI
76, 78
81, 81
—
20, 78
15, 85
76, 75
80, 75
22, 72
41, 75
PhBr
PhCl
PhOTf
PhI
3. Conclusion
4
—
5b
6c
4d
We have developed a novel enantioselective [3+2]-type
cycloaddition reactions of allenylstannane and a-imino
ester. The reaction could be rationalized by a sequential pro-
pargylation–cyclization mechanism. Synthetic utility of the
stannyldehydroproline ester intermediate was demonstrated;
iodine oxidation and Stille coupling reaction afforded
PhI
6d
a
The ee values were determined by chiral HPLC analysis.
Cu[(MeCN)4]BF4 was employed.
Cu[(MeCN)4]PF6 was employed.
b
c
d
The ee values were not determined.

11308
K. Fuchibe et al. / Tetrahedron 62 (2006) 11304–11310
optically active 4-iodo- and 4-aryldehydroproline esters in
good yields and in high ees, respectively.
the resulting mixture were added iodine (I2, 57.1 mg,
0.23 mmol in 1.0 mL toluene) at room temperature, and after
5 min, saturated aqueous sodium thiosulfate was added.
Products were extracted with ethyl acetate and combined
organic layers were dried over anhydrous sodium sulfate.
Purification by column chromatography (SiO2, Hexane/
AcOEt¼8/1) gave 8 (101.9 mg, 62% yield, 91% ee). The
ee value of 8 was determined by chiral HPLC analysis
(Daicel Chiralpak, AS-H, Hexane/i-PrOH¼5/1).
4. Experimental
4.1. General
NMR spectra were recorded on an Unity Inova-400 instru-
1
ment (Varian Japan Ltd, 400 MHz for H, 100 MHz for
13C) and JNM-Al300 instrument (JEOL, 300 MHz for
1H, 75 MHz for 13C) using CDCl3 as a solvent. Chemical
shifts (d) for 1H were referenced to tetramethylsilane
(d¼0.00 ppm) as an internal standard. Chemical shifts (d)
for 13C were referenced to a solvent signal (CDCl3, d¼
77.00 ppm). IR spectra were recorded on FTIR-8600PC
instrument (Shimadzu Co.) using CHCl3 as a solvent. Ele-
mental analysis (EA) was carried out on EA1110 instrument
(Amco Inc.). Mass spectra (MS) were recorded on JMS-
AX505HA instrument (JEOL). Specific rotation was
recorded on SEPA-300 instrument (HORIBA, Ltd).
4.1.4. Synthesis of 9a (Entry 1, Table 4). To a toluene solu-
tion (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 bromobenzene (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 crude mixture was put on a silica gel (2 cmꢂ30 cm)
and a mixed eluent (Hexane/AcOEt¼10/1, 150 mL) was
passed through the SiO2 column to remove non-polar
stannane residue. Fractions containing the products were
collected (Hexane/AcOEt¼5/1, 200 mL) and purification
by preparative TLC (SiO2, toluene/MeCN¼5/1) gave 9a
(45.8 mg, 62% yield, 90% ee) and 3 (11.7 mg, 20%, 91%
ee). The ee values of 9a and 3 were determined by chiral
HPLC analysis (Daicel Chiralcel, OD-H, Hexane/
i-PrOH¼5/1 for 9a).
4.1.1. Preparation of the starting materials. a-Imino
ester
1
was prepared according to the literature16
[Cu(MeCN)4]PF6 was prepared according to the literature,17
and its ClO4 and BF4 analogues were prepared by its modi-
fication. Allenyl(tributyl)stannane 2 was prepared by the
following procedure: to a flask containing magnesium
(0.44 g, 18 mmol), lead dibromide (0.33 g, 0.90 mmol),
tetrahydrofuran (30 mL), and chloro(tributyl)stannane was
added propargyl bromide (2.14 g, 18 mmol) over 5 min
and the mixture was heated carefully. The mixture was
stirred for 1 h at ambient temperature, quenched with satu-
rated aqueous ammonium chloride, filtered through a pad
of CeliteÒ, and the residue was washed with ethyl acetate.
Products were extracted with ethyl acetate and the combined
organic layers were dried over anhydrous sodium sulfate.
Solvents were evaporated under vacuum and purification
by column chromatography (SiO2, Hexane) gave allenyl-
(tributyl)stannane 2 (4.35 g, 88%).
4.1.5. Compound data.
4.1.5.1. (S)-1-Tosyl-4,5-dehydroproline ethyl ester (3).
1H NMR d¼1.31 (3H, t, J¼7.2 Hz), 2.44 (3H, s), 2.65 (1H,
ddt, J¼16.4, 7.2, 2.4 Hz), 2.78 (1H, ddt, J¼16.4, 11.2,
2.4 Hz), 4.23 (1H, dd, J¼11.2, 7.2 Hz), 4.25 (2H, q, J¼
7.2 Hz), 5.07 (1H, dt, J¼4.4, 2.4 Hz), 6.37 (1H, dt, J¼4.4,
2.4 Hz), 7.33 (2H, d, J¼8.2 Hz), 7.70 (2H, d, J¼8.2 Hz);
13C NMR d¼14.0, 21.6, 35.2, 60.2, 61.7, 109.6, 127.7,
129.7, 130.4, 133.4, 144.2, 170.9; IR n¼1016, 1169, 1362,
1734, 1749, 3022 cmꢀ1; EA Calcd 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%; [a]D27 ꢀ443.10 (c 1.00, CHCl3, 91% ee,
Daicel Chiralpak AD-H, Hexane/EtOH¼5/1, Flow rate
0.7 mL/min, UV¼228 nm, tR¼16.91 min, tS¼21.43 min).
4.1.2. Synthesis of 3 and 4 (Entry 5, Table 2). 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 (51.1 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 (2 cmꢂ30 cm) and a mixed eluent (Hexane/
AcOEt¼10/1, 150 mL) was passed through the SiO2 column
to remove non-polar stannane residue and then fractions
containing 3 (21.4 mg, 36% yield, 91% ee) and 4 (33.8 mg,
29% yield) were collected (Hexane/AcOEt¼8/1). The ee
value of 3 was determined by chiral HPLC analysis (Daicel
Chiralpak, AD-H, Hexane/EtOH¼5/1).
4.1.5.2. (S)-1-Tosyl-4-tributylstannyl-4,5-dehydropro-
line ethyl ester (4). 1H NMR d¼0.85–0.91 (15H, m),
1.23–1.32 (9H, m), 1.38–1.44 (6H, m), 2.43 (3H, s), 2.68
(1H, ddd, J¼16.2, 7.4, 2.0 Hz), 2.81 (1H, ddd, J¼16.2,
10.8, 2.0 Hz), 4.11 (1H, dd, J¼10.8, 7.4 Hz), 4.24 (2H, q,
J¼7.2 Hz), 6.18 (1H, t, J¼2.0 Hz), 7.31 (2H, d,
J¼8.2 Hz), 7.68 (2H, d, J¼8.2 Hz); 13C NMR d¼9.5, 13.6,
14.1, 21.5, 27.1, 28.9, 41.9, 60.5, 61.5, 119.4, 127.7,
129.6, 133.5, 134.8, 143.9, 171.5; IR n¼1167, 1205, 1225,
1356, 1734, 1749, 3017, 3022 cmꢀ1; MS (DI) Isotope pat-
tern of fragment ion (M+ꢀC4H9, C22H34NO4SSn) was in
complete agreement with its computer simulation (see text).
4.1.3. Synthesis of 8 (Scheme 4). To a toluene solution
(0.5 mL) containing [Cu(MeCN)4]ClO4 (4.7 mg, 0.014
mmol) and (R)-TolBINAP (11.2 mg, 0.016 mmol) were
added 1 (38.3 mg, 0.15 mmol in 0.5 mL toluene) and 2
(59.2 mg, 0.18 mmol in 0.5 mL toluene) successively. The
solution was stirred in an oil bath of 80 ꢁC for 1 h. To
4.1.5.3. Ethyl (S)-2-tosylamino-4-pentynoate (5). 1H
NMR d¼1.17 (3H, t, J¼7.2 Hz), 2.03 (1H, t, J¼2.6 Hz),
2.42 (3H, s), 2.65 (1H, ddd, J¼16.8, 5.2, 2.6 Hz), 2.72

K. Fuchibe et al. / Tetrahedron 62 (2006) 11304–11310
11309
(1H, ddd, J¼16.8, 4.4, 2.6 Hz), 4.02–4.11 (3H, m), 5.43 (1H,
d, J¼8.4 Hz), 7.30 (2H, d, J¼8.0 Hz), 7.75 (2H, d,
J¼8.0 Hz); 13C NMR d¼13.9, 21.5, 24.1, 54.0, 62.2, 72.2,
127.2, 129.7, 136.9, 143.8, 169.5; IR n¼1018, 1094, 1163,
1229, 1371, 1740, 3013 cmꢀ1; EA Calcd for C14H17NO4S:
C 56.93, H 5.80, N 4.74, S 10.86%; Found: C 57.10,
H 5.82, N 4.53, S 10.64%; [a]2D6 +15.20 (c 1.00,
CHCl3, 67% ee, Daicel Chiralpak AD-H, Hexane/EtOH¼
5/1, Flow rate 0.5 mL/min, UV¼228 nm, tR¼42.46 min,
tS¼36.14 min).
21.6, 35.6, 60.7, 62.1, 119.8, 124.1, 124.8, 127.6, 129.1,
130.1, 133.6, 139.7, 144.8, 146.2, 170.2; IR n¼1169,
1205, 1225, 1344, 1518, 1734, 3024 cmꢀ1; EA Calcd for
C20H20N2O6S: C 57.68, H 4.84, N 6.73, S 7.70%; Found:
C 57.72, H 4.93, N 6.79, S 7.60%; [a]2D5 +42.35 (c 1.00,
CHCl3, 84% ee, Daicel Chiralcel OD-H, Hexane/EtOH¼
5/1, Flow rate 0.5 mL/min, UV¼350 nm, tR¼63.20 min,
tS¼53.82 min).
4.1.5.8. (S)-1-Tosyl-4-(4-trifluoromethylphenyl)-4,5-
1
dehydroproline ethyl ester (9d). H NMR d¼1.32 (3H, t,
4.1.5.4. (S)-4-Iodo-1-tosyl-4,5-dehydroproline ethyl
ester (8). 1H NMR d¼1.30 (3H, t, J¼7.2 Hz), 2.45 (3H, s),
2.82 (1H, ddd, J¼16.2, 7.2, 2.0 Hz), 2.97 (1H, ddd,
J¼16.2, 11.2, 2.0 Hz), 4.25 (2H, q, J¼7.2 Hz), 4.27 (1H,
dd, J¼11.2, 7.2 Hz), 6.53 (1H, t, J¼2.0 Hz), 7.36 (2H, d,
J¼8.2 Hz), 7.70 (2H, d, J¼8.2 Hz); 13C NMR d¼14.1,
21.8, 44.4, 61.1, 62.1, 67.9, 127.6, 129.8, 132.9, 135.3,
144.5, 169.7; IR n¼1099, 1169, 1296, 1364, 1734,
3032 cmꢀ1; EA Calcd for C14H16INO4S: C 39.92, H 3.83,
N 3.33, S 7.61%; Found: C 39.98, H 3.74, N 3.31, S
7.58%; [a]2D7 ꢀ175.80 (c 1.00, CHCl3, >99% ee, Daicel
Chiralpak AS-H, Hexane/i-PrOH¼5/1, Flow rate 0.7 mL/
min, UV¼228 nm, tS¼36.73 min).
J¼7.0 Hz), 2.43 (3H, s), 3.00 (1H, ddd, J¼15.6, 7.2,
1.8 Hz), 3.20 (1H, ddd, J¼15.6, 11.4, 2.0 Hz), 4.27 (2H, q,
J¼7.0 Hz), 4.43 (1H, dd, J¼11.4, 7.2 Hz), 6.97 (1H, s),
7.30 (2H, d, J¼8.6 Hz), 7.34 (2H, d, J¼8.0 Hz), 7.53 (2H,
d, J¼8.6 Hz), 7.75 (2H, d, J¼8.0 Hz); 13C NMR d¼14.0,
3
21.6, 35.7, 60.6, 62.0, 120.9, 124.7, 125.6 (q, JC–F
3.8 Hz), 127.1, 127.6, 127.9 (q, JC–F¼285 Hz), 129.0 (q,
2JC–F¼33 Hz), 123.0, 133.5, 136.5, 144.6, 170.5; IR
¼
1
n¼1130, 1169, 1209, 1325, 1616, 1749, 2359, 3018 cmꢀ1
;
EA Calcd for C21H20NO4S: C 57.40, H 4.59, N 3.19, S
7.30%; Found: C 57.47, H 4.37, N 3.28, S 7.12%; [a]D24
ꢀ26.90 (c 1.00, CHCl3, 90% ee, Daicel Chiralpak AD-H,
Hexane/EtOH¼5/1, Flow rate 0.5 mL/min, UV¼228 nm,
tR¼65.07 min, tS¼56.22 min).
4.1.5.5. (S)-4-Phenyl-1-tosyl-4,5-dehydroproline ethyl
1
ester (9a). H NMR d¼1.32 (3H, t, J¼7.2 Hz), 2.42 (3H,
4.1.5.9. (S)-4-[3,5-Bis(trifluoromethyl)phenyl]-1-tosyl-
4,5-dehydroproline ethyl ester (9e). 1H NMR d¼1.33 (3H,
t, J¼7.2 Hz), 2.44 (3H, s), 3.03 (1H, ddd, J¼15.6, 7.2,
1.8 Hz), 3.27 (1H, ddd, J¼15.6, 11.6, 1.8 Hz), 4.27 (2H, q,
J¼7.2 Hz), 4.49 (1H, dd, J¼11.6, 7.2 Hz), 7.06 (1H, s),
7.36 (2H, d, J¼8.6 Hz), 7.59 (2H, s), 7.68 (1H, s), 7.77
(2H, d, J¼8.6 Hz); 13C NMR d¼14.0, 21.6, 35.6, 60.5,
62.2, 119.2, 120.1–120.5 (m), 124.2, 127.6, 128.3, 130.1,
s), 2.98 (1H, ddd, J¼15.6, 7.2, 1.8 Hz), 3.15 (1H, ddd,
J¼15.6, 11.6, 1.8 Hz), 4.28 (2H, q, J¼7.2 Hz), 4.37 (1H,
dd, J¼11.6, 7.2 Hz), 6.85 (1H, t, J¼1.8 Hz), 7.21 (1H, t,
J¼6.4 Hz), 7.23 (2H, d, J¼7.8 Hz), 7.26–7.35 (4H, m),
7.74 (2H, d, J¼7.8 Hz); 13C NMR d¼14.1, 21.6, 35.8,
60.6, 61.9, 122.7, 124.7, 124.8, 127.3, 127.6, 128.6, 129.9,
132.9, 133.4, 144.3, 170.8; IR n¼1167, 1205, 1227, 1362,
1734, 1749, 3024 cmꢀ1; EA Calcd for C20H21NO4S: C
64.67, H 5.70, N 3.77, S 8.63%; Found: C 64.80, H 5.62,
N 3.59, S 8.46%; [a]D26 ꢀ41.30 (c 1.00, CHCl3, 90% ee,
Daicel Chiralcel OD-H, Hexane/i-PrOH¼5/1, Flow rate
0.5 mL/min, UV¼228 nm, tR¼21.96 min, tS¼34.47 min).
2
132.0 (q, JC–F¼33 Hz), 133.6, 135.3, 144.8, 170.2; IR
n¼1142, 1169, 1184, 1281, 1369, 1634, 1749, 3032 cmꢀ1
;
EA Calcd for C22H19F6NO4S: C 52.07, H 3.77, N 2.76, S
6.32%; Found: C 52.30, H 3.76, N 2.50, S 6.57%; [a]D24
ꢀ42.90 (c 1.00, CHCl3, 84% ee, Daicel Chiralpak AD-H,
Hexane/EtOH¼50/1, Flow rate 0.5 mL/min, UV¼228 nm,
tR¼30.72 min, tS¼23.26 min).
4.1.5.6. (S)-4-(4-Chlorophenyl)-1-tosyl-4,5-dehydro-
proline ethyl ester (9b). 1H NMR d¼1.32 (3H, t, J¼
7.2 Hz), 2.43 (3H, s), 2.95 (1H, ddd, J¼15.6, 7.2, 1.8 Hz),
3.14 (1H, ddd, J¼15.6, 11.4, 1.8 Hz), 4.27 (2H, q,
J¼7.2 Hz), 4.39 (1H, dd, J¼11.4, 7.2 Hz), 6.84 (1H, t,
J¼1.8 Hz), 7.14 (2H, d, J¼8.4 Hz), 7.26 (2H, d, J¼8.4 Hz),
7.33 (2H, d, J¼8.4 Hz), 7.73 (2H, d, J¼8.4 Hz); 13C NMR
d¼14.1, 21.6, 35.8, 60.6, 62.0, 121.4, 125.4, 125.8, 127.6,
128.8, 130.0, 131.5, 132.9, 133.4, 144.5, 170.6; IR n¼1096,
1167, 1211, 1362, 1495, 1636, 1734, 2359, 3017 cmꢀ1; EA
Calcd for C20H20ClNO4S: C 59.18, H 4.97, N 3.45, S
7.90%; Found: C 58.99, H 4.83, N 3.20, S 7.70%; [a]D25
ꢀ17.37 (c 0.95, CHCl3, 93% ee, Daicel Chiralpak AD-H,
Hexane/i-PrOH¼5/1, Flow rate 0.5 mL/min, UV¼228 nm,
tR¼51.82 min, tS¼56.96 min).
4.1.5.10. (S)-1-Tosyl-4-(3,4,5-trifluorophenyl)-4,5-de-
1
hydroproline ethyl ester (9f). H NMR d¼1.32 (3H, t,
J¼7.0 Hz), 2.44 (3H, s), 2.91 (1H, ddd, J¼15.6, 7.2,
1.6 Hz), 3.11 (1H, ddd, J¼15.6, 11.6, 1.6 Hz), 4.26 (2H, q,
J¼7.0 Hz), 4.42 (1H, dd, J¼11.6, 7.2 Hz), 6.80 (2H, dd,
J¼6.4, 8.4 Hz), 6.82 (1H, s), 7.35 (2H, d, J¼8.4 Hz), 7.74
(2H, d, J¼8.4 Hz); 13C NMR d¼14.1, 21.6, 35.7, 60.5,
62.1, 108.6 (dd, 2JC–F¼15 Hz, 3JC–F¼6.8 Hz), 119.4–119.6
1
(m), 127.0, 127.6, 129.7, 130.0, 133.5, 138.8 (d, JC–F
¼
1
252 Hz), 144.7, 151.3 (d, JC–F¼236 Hz), 170.3; IR
n¼1016, 1169, 1205, 1227, 1533, 1734, 1749, 3017,
3024 cmꢀ1; EA Calcd for C20H18F3NO4S: C 56.46, H
4.26, N 3.29, S 7.54%; Found: C 56.28, H 4.29, N 3.30, S
7.54%; [a]2D6 ꢀ64.05 (c 1.00, CHCl3, 87% ee, Daicel Chiral-
pak AD-H, Hexane/EtOH¼5/1, Flow rate 0.7 mL/min,
UV¼228 nm, tR¼25.56 min, tS¼18.11 min).
4.1.5.7. (S)-4-(4-Nitrophenyl)-1-tosyl-4,5-dehydropro-
1
line ethyl ester (9c). H NMR d¼1.32 (3H, t, J¼7.2 Hz),
2.44 (3H, s), 3.04 (1H, ddd, J¼15.6, 7.2, 1.8 Hz), 3.26
(1H, ddd, J¼15.6, 11.6, 1.8 Hz), 4.27 (2H, q, J¼7.2 Hz),
4.49 (1H, dd, J¼11.6, 7.2 Hz), 7.09 (1H, t, J¼1.8 Hz),
7.33 (2H, d, J¼8.6 Hz), 7.36 (2H, d, J¼8.6 Hz), 7.76 (2H,
d, J¼8.6 Hz), 8.15 (2H, d, J¼8.6 Hz); 13C NMR d¼14.0,
4.1.5.11.
(S)-4-(3-Tolyl)-1-tosyl-4,5-dehydroproline
1
ethyl ester (9g). H NMR d¼1.32 (3H, t, J¼7.0 Hz), 2.32
(3H, s), 2.42 (3H, s), 2.96 (1H, ddd, J¼15.8, 7.1, 1.8 Hz),
3.14 (1H, ddd, J¼15.8, 11.5, 1.8 Hz), 4.27 (2H, q,

11310
K. Fuchibe et al. / Tetrahedron 62 (2006) 11304–11310
J. Org. Chem. 1992, 57, 6094; (m) Danheiser, R. L.;
´
Takahashi, T.; Bertok, B.; Dixon, B. R. Tetrahedron Lett.
1993, 34, 3845; (n) Monti, H.; Audran, G.; Monti, J.-P.;
J¼7.0 Hz), 4.35 (1H, dd, J¼11.5, 7.1 Hz), 6.84 (1H, t,
J¼1.8 Hz), 7.01–7.05 (2H, m), 7.16–7.24 (2H, m), 7.32
(2H, d, J¼8.1 Hz), 7.73 (2H, d, J¼8.1 Hz); 13C NMR
d¼14.1, 21.4, 21.6, 35.9, 60.6, 61.9, 121.8, 122.8, 124.7,
125.4, 127.6, 128.2, 128.5, 129.9, 132.8, 133.4, 138.2,
´
Leandri, G. Synlett 1994, 403; (o) Evans, D. A.; Sweeney,
Z. K.; Rovis, T.; Tendrow, J. S. J. Am. Chem. Soc. 2001, 123,
12095; see also; (p) Fuchibe, K.; Aoki, Y.; Akiyama, T.
Chem. Lett. 2005, 34, 538; (q) Yadav, V. K.; Kumar, N. V.
J. Am. Chem. Soc. 2004, 126, 8652; (r) Yadav, V. K.;
Sriramurthy, V. Angew. Chem., Int. Ed. 2004, 43, 2669; (s)
Yadav, V. K.; Sriramurthy, V. Org. Lett. 2004, 6, 4495.
5. It is known that allylstannanes undergo cycloaddition reactions
with electron-deficient olefins; (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.
144.3, 170.8; IR n¼1092, 1167, 1362, 1734, 3018 cmꢀ1
;
EA Calcd for C21H23NO4S: C 65.43, H 6.01, N 3.63, S
8.32%; Found: C 65.24, H 5.95, N 3.61, S 8.17%; [a]D27
ꢀ19.04 (c 0.99, CHCl3, 74% ee, Daicel Chiralpak AS-H,
Hexane/EtOH¼5/1, Flow rate 0.5 mL/min, UV¼228 nm,
tR¼23.22 min, tS¼18.28 min).
Acknowledgements
6. Other recent studies on synthesis of proline derivatives; (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.
We appreciate Takasago International Corp. (Tokyo, Japan)
for providing (R)-SEGPHOS, (R)-DM-SEGPHOS, and (R)-
DTBM-SEGPHOS as chiral ligands.
7. Our preliminary report: Fuchibe, K.; Hatemata, R.; Akiyama,
T. Tetrahedron Lett. 2005, 46, 8563.
References and notes
8. Kagoshima, H.; Uzawa, T.; Akiyama, T. Chem. Lett. 2002, 298.
9. For enantioselective copper(I)-catalyzed nucleophilic addition
to a-imino ester, see: (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; (c) Yao, S.; Fang, X.; Jørgensen,
K. A. Chem. Commun. 1998, 2547; (d) Yao, S.; Saaby, S.;
Hazell, R. Z.; Jørgensen, K. A. Chem. Eur. J. 2000, 6, 2435;
(e) Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Ryzhkov,
L.; Taggi, A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67;
(f) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res.
2003, 36, 10. See Refs. 3a and 4d, also.
10. Compound 3 was not observed just after concentration of the
reaction mixture (1H NMR analysis). Partial protonolysis of
the cycloadduct 4 took place on silica gel during purification.
Compounds 3 and 4 were isolated and total yields are indicated
in Table 1 for clarity.
1. (a) Carreira, E. M. Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, 1999; Vol. 3, p 997; (b) Noyori, R.; Kitamura, M.
Angew. Chem., Int. Ed. Engl. 1991, 30, 49; (c) Dieter, R. K.;
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Aggarwal, V. K.; Anderson, E.; Giles, R.; Zaparucha, A.
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Ed. 2004, 43, 5138; (b) Special issue on asymmetric organo-
catalysis; Houk, K. N., List, B., Eds.; Acc. Chem. Res. 2004,
37, 487; (c) Organocatalysis issue; List, B., Bolm, C., Eds.;
Adv. Synth. Catal. 2004, 346, 1021; (d) Asymmetric
11. The ee value was not improved further by carrying out the
reaction in an oil bath of 60 ꢁC (93% ee) and the yield of 3
miserably decreased to 13%.
Organocatalysis; Berkessel, A., Grober, H., Eds.; Wiley-
¨
12. We suppose that weaker C–Sn bond is responsible for this fast
process.
VCH: Weinheim, 2005; (e) Seayad, J.; List, B. Org. Biomol.
Chem. 2005, 3, 719.
13. In the presence of the copper(I) catalyst, 5 (69% ee) underwent
cyclization to give 18% yield of 3 (83% ee) and 82% recovery
of 5 (62% ee) (10 mol % of [Cu(MeCN)4]ClO4, 10 mol % (R)-
TolBINAP, toluene, 80 ꢁC, 5 h). For Pd(0)-catalyzed cycliza-
tion of methyl ester corresponding to 5 see: Wolf, L. B.;
Tjen, K. C. M. F.; Rutjes, F. P. J. T.; Hiemstra, H.; Schoemaker,
H. E. Tetrahedron Lett. 1998, 39, 5081; We also treated 5 with
n-BuLi/n-Bu3SnCl in THF at –78 ꢁC and then attempted Cu(I)-
catalyzed cyclization. Indeed, 3 was obtained, but in 3% yield.
14. When the catalyst loading was lowered to 1 mol %, the cycliza-
tion did not take place to give homopropargylamine 5 exclu-
sively in 75% yield, 64% ee (toluene, reflux, 1 h).
15. It was confirmed that dehydroproline ester 3 did not racemize
under the reaction conditions. Compound 3 of 83% ee afforded
91% recovery of 3 with 83% ee even after 5 h stirring
(10 mol % of [Cu(MeCN)4]ClO4, 10 mol % (R)-TolBINAP,
toluene, and 80 ꢁC).
3. (a) Daidouji, K.; Fuchibe, K.; Akiyama, T. Org. Lett. 2005, 7,
1051. For non-asymmetric [3+2]-type cycloaddition reaction
of allenylsilanes and imines, see: (b) Danheiser, R. L.; Kwasi-
groch, C. A.; Tsai, Y.-M. J. Am. Chem. Soc. 1985, 107, 7233.
4. For reviews of cycloaddition reactions of group 14 compounds,
see: (a) Panek, J. S. Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1,
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¨
Representative reports; (d) Akiyama, T.; Daidouji, K.;
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3889; (f) Panek, J. S.; Jain, N. F. J. Org. Chem. 1994, 59,
2674; (g) Akiyama, T.; Ishikawa, K.; Ozaki, S. Chem. Lett.
1994, 627; (h) Akiyama, T.; Yasusa, T.; Ishikawa, K.; Ozaki,
S. Tetrahedron Lett. 1994, 35, 8401; (i) Akiyama, T.; Hoshi,
E.; Fujiyoshi, S. J. Chem. Soc., Perkin Trans. 1 1998, 2121;
(j) Akiyama, T.; Yamanaka, M. Tetrahedron Lett. 1998, 39,
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2345; (l) Danheiser, R. L.; Dixon, B. R.; Gleason, R. W.
16. Hamley, P.; Holmes, A. B.; Kee, A.; Ladduwahetty, T.; Smith,
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17. Kubas, G. J. Inorg. Synth. 1979, 19, 90.