Enantioselective synthesis of α,α-disubstituted α-amino acids by Rh-catalyzed [2+2+2] cycloaddition of 1,6-diynes with protected dehydroamino acid

Article abstract of DOI:10.1016/j.tet.2008.04.107

We have determined that a cationic rhodium(I)/BINAP complex catalyzes a [2+2+2] cycloaddition of 1,6-diynes with a protected dehydroamino acid, leading to protected α-amino acids bearing a quaternary carbon center in high yield with high enantioselectivity.

Full text of DOI:10.1016/j.tet.2008.04.107

Tetrahedron 64 (2008) 6289–6293
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Tetrahedron
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Enantioselective synthesis of a,a-disubstituted a-amino acids by Rh-catalyzed
[2þ2þ2] cycloaddition of 1,6-diynes with protected dehydroamino acid
,
a
a
a
b
Ken Tanaka a , Maho Takahashi , Hidetomo Imase , Takuya Osaka , Keiichi Noguchi ,
*
Masao Hirano a
a Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
b Instrumentation Analysis Center, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have determined that a cationic rhodium(I)/BINAP complex catalyzes a [2þ2þ2] cycloaddition of
Received 24 March 2008
Received in revised form 24 April 2008
Accepted 25 April 2008
1,6-diynes with a protected dehydroamino acid, leading to protected
carbon center in high yield with high enantioselectivity.
a-amino acids bearing a quaternary
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 30 April 2008
C–H bond formation
1. Introduction
MeO2C
NH
Me
NHAc
The cationic rhodium(I)/bisphosphine complex-catalyzed
enantioselective hydrogenation of a protected dehydroamino acid
(formation of two C–H bonds) is an efficient and reliable method for
H
H
+
H2
P
P
CO2Me
Rh
*
O
A
O
Z
H
N
the synthesis of an
a-amino acid possessing a tertiary carbon
Me
center.1 Bidentate coordination through the alkene moiety and
Rh(I)+
–Rh(I)+
Z
OMe
MeO2C
HN
Me
*
O
the amide carbonyl group to rhodium furnishes intermediate A,
NHAc
CO2Me
which induces high enantioselectivity (Scheme 1).2 Although
a,a-
+
Rh
P
P
Me
disubstituted a-amino acids possessing a stereochemically stable
O
Me
Me
Me
Me
quaternary carbon center are useful compounds for controlling
secondary structures of peptides,3 they cannot be synthesized by
enantioselective hydrogenation.4 On the other hand, cationic rho-
dium(I)/modified-BINAP complexes have been used in enantiose-
lective [2þ2þ2] cycloadditions5–7 involving monoalkenes.8,9 For
example, 1,1- and 1,2-disubstituted monoalkenes bearing an
alkoxycarbonyl group reacted with 1,6-diynes to give the corre-
sponding chiral cyclohexadienes in high yields with high enantio-
meric excesses, although a large excess of monoalkenes and/or
slow addition of 1,6-diynes were necessary.8 We anticipated that
a protected dehydroamino acid would be a suitable substrate for
a rhodium-catalyzed enantioselective [2þ2þ2] cycloaddition with
1,6-diynes (formation of three C–C bonds) because of the strong
bidentate coordination through the alkene moiety and the amide
carbonyl group furnishing intermediate B, which would provide
Me
B
Z
C–C bond formation
Scheme 1. Rh-catalyzed enantioselective hydrogenation and [2þ2þ2] cycloaddition of
a protected dehydroamino acid.
2. Results and discussion
We first investigated the reaction of tosylamide linked 1,6-diyne
1a with only a slight excess (1.1 equiv) of protected dehydroamino
acid 2a at room temperature using 10 mol % of a cationic rho-
dium(I)/BINAP-type bisphosphine complex as a catalyst (Table 1).
We were pleased to find that the reaction smoothly proceeded
by using BINAP as a ligand to give the desired a-amino acid de-
a,a-disubstituted a-amino acid derivatives in high yield with high
enantioselectivity (Scheme 1).10,11
rivative 3aa in high yield with high ee without slow addition of
1,6-diyne 1a (entry 1). A comparable result was obtained by using
H8-BINAP as a ligand (entry 2), while both yield and ee were de-
creased when Segphos was used as a ligand (entry 3). The use of
sterically demanding xyl-BINAP significantly decreased the yield of
3aa (entry 4). The catalytic activity of the cationic rhodium catalyst
* Corresponding author. Tel./fax: þ81 42 388 7037.
E-mail address: tanaka-k@cc.tuat.ac.jp (K. Tanaka).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.107

6290
K. Tanaka et al. / Tetrahedron 64 (2008) 6289–6293
Table 1
Table 2
Screening of ligands for Rh-catalyzed enantioselective [2þ2þ2] cycloaddition of 1a
Rh(I)þ/(R)-BINAP-catalyzed enantioselective [2þ2þ2] cycloaddition of 1a–g
with 2aa
with 2aa
2.5–10 mol %
[Rh(cod) ]BF /
Me
*
Entry
Diyne 1
Time
(h)
Product 3/4, % yieldb
O
NHAc
CO2Me
H
N
2
4
(% ee)
Me
Me
Me
Ligand
OMe
+
TsN
O
TsN
Me
CH2Cl2, rt
NHAc
O
Me
Me
1a
2a (1.1 equiv)
Me
3aa
CO2Me
TsN
TsN
1
1
3
1a
Me
O
O
PPh2
PPh2
PAr2
PAr2
(S)-(+)-3aa, 95 (96)
PPh2
PPh2
Me
NHAc
Me
Me
BnO2C
BnO2C
BnO2C
BnO2C
CO2Me
*
O
2
3
(R)-BINAP (Ar = Ph)
(R)-H8-BINAP
(R)-Segphos
(R)-xyl-BINAP (Ar = 3,5-Me2C6H3)
1b
Me
(+)-3ba, 90 (93)
Me
Entry
Ligand
Catalyst
(mol %)
Time
(h)
Yieldb
(%)
ee
(%)
NHAc
Me
Me
Ac
Ac
Ac
Ac
CO2Me
*
1
2
3
4
5
6
(R)-BINAP
10
10
10
10
5
1
1
1
3
1
1
96
97
91
68
95
91
97 (S)
98 (S)
91 (S)
97 (R)
96 (S)
97 (S)
16
(R)-H8-BINAP
(R)-Segphos
(S)-xyl-BINAP
(R)-BINAP
1c
Me
(+)-3ca, 91 (98)
Me
NHAc
(R)-BINAP
2.5
Me
a
CO2Me
[Rh(cod)2]BF4 (0.0038–0.015 mmol, 2.5–10 mol %), ligand (0.0038–0.015 mmol,
2.5–10 mol %), 1a (0.15 mmol), 2a (0.165 mmol, 1.1 equiv), and CH2Cl2 (1.5 mL) were
*
O
O
O
4
5
1
Me
used.
1d
Me
b
Isolated yield.
(+)-3da, 68 (99)
Ph
NHAc
Ph
Ph
with BINAP ligand is very high so that the reaction could be carried
out with 5 mol % (entry 5) and 2.5 mol % (entry 6) of the catalyst
without appreciable erosion of both yield and ee.
CO2Me
*
O
16
1e
Ph
Thus, we explored the scope of this process with respect to 1,6-
diynes as shown in Table 2. Not only tosylamide (1a, entry 1) but
also malonate (1b, entry 2), acetyl acetone (1c, entry 3), and oxygen
(1d, entry 4) linked 1,6-diynes could be employed for this reaction.
With respect to the substituents at the alkyne terminus, not only
methyl (1a–d, entries 1–4) but also phenyl (1e and 1f, entries 5 and
6) and methoxycarbonyl (1g, entry 7) substituted 1,6-diynes could
participate in this reaction. In the case of unsymmetrical 1,6-diynes,
perfect regioselectivity was observed in the reaction of 1,6-diyne 1g
with 2a furnishing the corresponding protected acidic amino acid
(ꢀ)-3ga in good yield with excellent ee (entry 7), while moderate
regioselectivity was observed in the reaction of 1,6-diyne 1f with 2a
(entry 6). The absolute configuration of (ꢀ)-3aa, which was pre-
pared by using (S)-xyl-BINAP as a ligand (Table 1, entry 4), was
determined to be R configuration by the anomalous dispersion
method (Fig. 1).
(+)-3ea, 84 (99)
Me
*
Ph
*
NHAc
CO2Me
NHAc
CO2Me
Ph
O
O
O
6
1
3
Me
1f
Ph
Me
(+)-3fa, 53 (99)
(+)-4fa, 20 (99)
MeO2C
NHAc
CO2Me
CO2Me
Me
*
O
O
7
1g
Me
(–)-3ga, 67 (99)
a
Reactions were conducted using [Rh(cod)2]BF4/(R)-BINAP (0.0075 mmol,
5 mol %), 1a–g (0.15 mmol), 2a (0.165 mmol, 1.1 equiv), and CH2Cl2 (1.5 mL) at room
temperature.
Although Rh(I)þ/BINAP-catalyzed [2þ2þ2] cycloadditions of
b
Isolated yield.
1,6-diyne 1a with protected 1,2-disubstituted dehydro-
acids 2b–d were also investigated, the desired protected
acids 3ab–3ad were not obtained at all (Scheme 2).
b
b
-amino
-amino
a complex mixture of dienes. Accordingly, the methoxycarbonyl
group of 2a is not necessary to induce high enantioselectivity,
but it stabilizes the cyclohexadiene structure and avoids the
aromatization.
Scheme 3 depicts a possible mechanism for the highly selective
formation of (S)-(þ)-3aa by using the cationic rhodium(I)/(R)-
BINAP complex as a catalyst. The reaction of 1,6-diyne 1a with
rhodium followed by coordination of 2a to rhodium through the
alkene moiety and the amide carbonyl furnishes intermediate C
due to the steric repulsion between the methoxycarbonyl group of
2a and the axial phenyl group of (R)-BINAP. Insertion and reductive
elimination of rhodium furnishes (S)-3aa.
Me
CO2Me
The reactions of various enamides with 1,6-diyne 1a were also
examined as shown in Scheme 4. Enamide 2e bearing a methyl
group instead of a methoxycarbonyl group reacted with 1a to fur-
nish the corresponding cyclohexadiene (þ)-3ae with high ee along
with aromatized product 5. The reaction of 1a with enamide 2f
bearing a hydrogen instead of a methoxycarbonyl group furnished
NHAc
TsN
Me
Figure 1. X-ray crystal structure of (R)-(ꢀ)-3aa, prepared by using (S)-xyl-BINAP as
a ligand.

K. Tanaka et al. / Tetrahedron 64 (2008) 6289–6293
6291
10 mol %
[Rh(cod)2]BF4/
(R)-BINAP
4. Experimental
4.1. General
Me
O
CO2Me
Me
Me
OMe
+
TsN
TsN
R1
N
R1
CH2Cl2, rt
16 h
N
Me R2
1H NMR spectra were recorded at 300 MHz using JEOL AL 300
spectrometer. 13C NMR spectra were obtained with complete pro-
ton decoupling at 75 MHz using JEOL AL 300 spectrometer. HRMS
data were obtained on JEOL JMS-700. Infrared spectra were
obtained on a Jasco FT/IR-4100. Optical rotation was measured with
Jasco DIP-1000 polarimeter. Anhydrous CH2Cl2 (No. 27,099-7) was
obtained from Aldrich and used as received. H8-BINAP, Segphos,
and xyl-BINAP were obtained from Takasago International Corpo-
ration. 1,6-Diynes 1a,12 1b,8a 1c,13 1d,12 1e,14 1f,12 and 1g,15 and
enamides 2b16 and 2c17 were reported in the literatures. Enamides
2a, 2d, and 2f were commercially available. All other reagents were
obtained from commercial sources and used as received. All re-
actions were carried out under an atmosphere of argon or nitrogen
in oven-dried glassware with magnetic stirring.
R2
1a
(1.1 equiv)
3ab–3ad
2b (R1 = H, R2= Ac)
2c (R1 = H, R2 = Bn)
2d (R1R2N = 1-pyrrolidinyl)
Scheme 2. Rh-catalyzed reactions of 1,6-diyne 1a with protected dehydroamino acids
2b–d.
MeO2C
Ph
Me
Me
HN
Rh(I)+/
(R)-BINAP
NHAc
CO2Me
Ph
+
Rh
1a
P
P
Me
Ph
O
+
2a
TsN
Me
Me
–Rh(I)+
Ph
4.2. Representative procedure for Rh-catalyzed [2D2D2]
cycloadditions of 1,6-diynes 1 with protected dehydroamino
acid 2a (Table 2, entry 1)
N
C
(S)-3aa
Ts
Scheme 3. Possible mechanism for the selective formation of (S)-(þ)-3aa by using
a Rh(I)þ/(R)-BINAP complex as a catalyst.
(R)-BINAP (4.7 mg, 0.0075 mmol) and [Rh(cod)2]BF4 (3.1 mg,
0.0075 mmol) were dissolved in CH2Cl2 (1.0 mL) and the mixture
was stirred at room temperature for 5 min. H2 was introduced to the
resulting solution in a Schlenk tube. After stirring at room temper-
ature for 0.5 h, the resulting solution was concentrated to dryness
and dissolved in CH2Cl2 (0.3 mL). To this solution was added a solu-
tion of 1a (41.3 mg, 0.15 mmol) and 2a (23.6 mg, 0.165 mmol) in
CH2Cl2 (1.2 mL). The mixture was stirred at room temperature
for 1 h. The resulting solution was concentrated and purified by
preparative TLC (hexane/EtOAc/Et3N¼1:4:1), which furnished (S)-
(þ)-3aa (59.8 mg, 0.143 mmol, 95% yield, 96% ee) as a colorless solid.
R2
N
10 mol % [Rh(cod)2]BF4/
R1
Me
Me
Me
(R)-BINAP
+
TsN
CH2Cl2, rt, 1h
O
(1.1 equiv)
1a
Me
Me
Me
NR2Ac
2e (R1 = Me, R2 = Bn)
R1
2f (R1= H, R2 = Me)
R1
*
+
TsN
TsN
3
Me
5
R1 = Me, R2 = Bn: 63%, 99% ee [(+)-3ae]; 24% (5)
R1 = H, R2 = Me: 55% (complex mixture of dienes); 0% (5)
4.2.1. (S)-(þ)-5-Acetylamino-4,7-dimethyl-2-(toluene-4-sulfonyl)-
Scheme 4. Rh-catalyzed reactions of 1,6-diyne 1a with enamides 2e and 2f.
2,3,5,6-tetrahydro-1H-isoindole-5-carboxylic acid methyl ester
[(S)-(þ)-3aa]
As electron-deficient enamide 2a showed high reactivity
and selectivity toward the reaction with 1,6-diyne 1a, N,N-di-
methylmethacrylamide (2g) possessing an electron-deficient and
coordinating carbamoyl group would show higher reactivity and
selectivity toward the reaction with 1,6-diyne 1a than do meth-
acrylates.8a Indeed, the reaction of 1a with 2g proceeded in high
yield with perfect ee without employment of excess 2g and slow
addition of 1a (Scheme 5).
25
Mp 178.0–178.8 ꢁC; [
a
]
D
þ176.3 (c 1.23, CHCl3, 96% ee); IR (neat)
3366, 2951, 1735, 1654, 1163 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
d 7.72
(d, J¼8.1 Hz, 2H), 7.35 (d, J¼8.1 Hz, 2H), 6.24 (s, 1H), 4.03–3.89 (m,
4H), 3.72 (s, 3H), 2.87 (d, J¼18.6 Hz, 1H), 2.78 (d, J¼18.6 Hz, 1H),
2.44 (s, 3H), 1.95 (s, 3H), 1.66 (s, 3H), 1.61 (s, 3H); 13C NMR (CDCl3,
75 MHz) d 172.3, 169.5, 143.8, 133.4, 132.6, 129.8, 127.7, 125.0, 124.9,
118.0, 62.7, 53.0, 51.0, 50.3, 38.3, 23.5, 21.5, 19.1, 14.4; HRMS (ESI)
calcd for C21H26N2O5SNa [MþNa]þ 441.1460, found 441.1450;
CHIRALPAK AD–H, hexane/2-PrOH¼90:10, 1.0 mL/min, retention
times: 31.1 min (minor isomer) and 41.2 min (major isomer).
5 mol %
[Rh(cod)2]BF4/
(R)-BINAP
CH2Cl2, rt
1 h
Me
*
O
CONMe2
Me
Me
Me
Me
4.2.2. (þ)-5-Acetylamino-4,7-dimethyl-1,3,5,6-tetrahydro-indene-
Me2N
TsN
+
TsN
2,2,5-tricarboxylic acid dibenzyl ester methyl ester [(þ)-3ba]
25
Colorless oil; [
a
]
þ85.7 (c 2.16, CHCl3, 93% ee); IR (neat) 2951,
D
1a
2g (1.1 equiv)
Me
2371, 1734, 1653, 1239 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
d 7.32–7.24
(+)-3ag 84%, >99% ee
(m,10H), 5.65 (s,1H), 5.13 (s, 4H), 3.70 (s, 3H), 3.05 (d, J¼16.5 Hz, 2H),
Scheme 5. Rh-catalyzed reaction of 1,6-diyne 1a with N,N-dimethylmethacryl-
amide (2g).
2.97 (d, J¼16.5 Hz, 2H), 2.88 (s, 2H), 1.90 (s, 3H), 1.69 (s, 3H), 1.66 (s,
3H); 13C NMR (CDCl3, 75 MHz)
d 172.4, 171.2, 170.8, 169.6, 137.0,
135.39,135.36,128.51,128.49,128.3,128.2,127.81,127.76,125.3,118.4,
67.18, 67.15, 63.0, 58.7, 52.6, 38.0, 37.8, 36.7, 23.5, 19.2, 14.6; HRMS
(ESI) calcd for C31H33NO7Na [MþNa]þ 554.2155, found 554.2149;
CHIRALCEL OD–H, hexane/2-PrOH¼90:10, 1.0 mL/min, retention
times: 26.9 min (major isomer) and 35.9 min (minor isomer).
3. Conclusion
In conclusion, we have determined that a cationic rhodium(I)/
BINAP complex catalyzes a [2þ2þ2] cycloaddition of 1,6-diynes
with a protected dehydroamino acid leading to protected
a,a-
disubstituted
lectivity. Future studies will focus on the utilization of new
-disubstituted -amino acids as chiral reagents or building
blocks in organic synthesis.
a
-amino acids in high yield with high enantiose-
4.2.3. (þ)-2,2-Diacetyl-5-acetylamino-4,7-dimethyl-2,3,5,6-
tetrahydro-1H-indene-5-carboxylic acid methyl ester [(þ)-3ca]
25
a
,a
a
Pale yellow oil; [
a
]
þ100.4 (c 0.95 CHCl3, 98% ee); IR (neat)
D
3384, 2952, 1698, 1658, 735 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
d 5.96

6292
K. Tanaka et al. / Tetrahedron 64 (2008) 6289–6293
(s, 1H), 3.73 (s, 3H), 2.94 (d, J¼16.2 Hz, 2H), 2.88 (d, J¼18.0 Hz, 1H),
2.86 (d, J¼16.2 Hz, 2H), 2.80 (d, J¼18.0 Hz, 1H), 2.16 (s, 3H), 2.13 (s,
3H), 1.97 (s, 3H), 1.74 (s, 3H), 1.69 (s, 3H); 13C NMR (CDCl3, 75 MHz)
13.0 min (major isomer) and 17.8 min (minor isomer). The
regioisomer structure was determined by NOE experiment.
NOE
d
205.6, 205.5, 172.7, 169.4, 136.7, 127.8, 125.2, 118.6, 72.3, 63.0, 52.8,
38.5, 35.6, 34.5, 26.7, 26.6, 23.6, 19.1, 14.5; HRMS (ESI) calcd for
C
Ph
NHAc
19H25NO5Na [MþNa]þ 370.1630, found 370.1618; CHIRALCEL OD–
CO2Me
O
H, hexane/2-PrOH¼90:10, 1.0 mL/min, retention times: 20.7 min
(major isomer) and 27.6 min (minor isomer).
NOE
Me
4.2.4. (þ)-5-Acetylamino-4,7-dimethyl-1,3,5,6-tetrahydro-
4.2.8. (ꢀ)-5-Acetylamino-7-methyl-1,3,5,6-tetrahydro-iso-
isobenzofuran-5-carboxylic acid methyl ester [(þ)-3da]
25
benzofuran-4,5-dicarboxylic acid dimethyl ester [(ꢀ)-3ga]
Colorless oil; [
a
]
D
þ198.8 (c 1.20, CHCl3, 99% ee); IR (neat) 3410,
25
2952, 1734, 1653, 1235 cmꢀ1
1H), 4.55–4.44 (m, 4H), 3.77 (s, 3H), 2.93 (s, 2H), 1.99 (s, 3H), 1.70 (s,
3H), 1.64 (s, 3H); 13C NMR (CDCl3, 75 MHz)
172.5, 169.5, 136.9,
;
1H NMR (CDCl3, 300 MHz)
d 6.05 (s,
Colorless oil; [
a]
ꢀ87.6 (c 1.03, CHCl3, 99% ee); IR (neat) 3364,
D
2952, 1746, 1710, 1685, 1281 cmꢀ1 1H NMR (CDCl3, 300 MHz)
;
d
7.06 (s, 1H), 4.97 (d, J¼16.8 Hz, 1H), 4.87 (d, J¼16.8 Hz, 1H), 4.65
d
(d, J¼12.9 Hz, 1H), 4.60 (d, J¼12.9 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H),
2.84 (d, J¼18.9 Hz, 1H), 2.73 (d, J¼18.9 Hz, 1H), 1.97 (s, 3H), 1.82
128.0, 122.6, 115.3, 70.5, 70.2, 63.1, 52.9, 38.6, 23.5, 19.2, 14.6; HRMS
(ESI) calcd for C14H19NO4Na [MþNa]þ 288.1212, found 288.1194;
CHIRALPAK AD–H, hexane/2-PrOH¼97:3, 1.0 mL/min, retention
times: 36.7 min (minor isomer) and 38.2 min (major isomer).
(s, 3H); 13C NMR (CDCl3, 75 MHz)
d 174.7, 168.7, 166.5, 152.7,
131.6, 128.6, 111.0, 73.4, 69.7, 59.3, 53.4, 51.6, 42.0, 24.0, 19.4;
HRMS (ESI) calcd for C15H19NO6Na [MþNa]þ 332.1110, found
332.1075; CHIRALPAK AD–H, hexane/2-PrOH¼90:10, 1.0 mL/min,
retention times: 13.6 min (major isomer) and 20.2 min (minor
isomer). The regioisomer structure was determined by NOE
experiment.
4.2.5. (þ)-5-Acetylamino-4,7-diphenyl-1,3,5,6-tetrahydro-
isobenzofuran-5-carboxylic acid methyl ester [(þ)-3ea]
25
Colorless solid; mp 94.1–95.0 ꢁC; [
a]
þ161.2 (c 0.57, CHCl3, 99%
D
ee); IR (neat) 3420, 2366, 1734, 1652, 699 cmꢀ1
;
1H NMR (CDCl3,
300 MHz)
d
7.40–7.26 (m, 8H), 7.16 (d, J¼7.8 Hz, 2H), 6.23 (s, 1H),
MeO2C
NHAc
4.78 (s, 2H), 4.47 (d, J¼13.5 Hz, 1H), 4.38 (d, J¼13.5 Hz, 1H), 3.82 (d,
J¼17.7 Hz, 1H), 3.61 (s, 3H), 3.42 (d, J¼17.7 Hz, 1H), 1.89 (s, 3H); 13
C
CO2Me
O
NMR (CDCl3, 75 MHz) d 172.5, 169.4, 140.4, 139.2, 136.5, 131.2, 128.5,
NOE
Me
128.3, 128.2, 127.9, 127.6, 127.4, 126.7, 124.1, 71.1, 70.7, 63.6, 52.9,
37.6, 23.7; HRMS (ESI) calcd for C24H23NO4Na [MþNa]þ 412.1525,
found 412.1515; CHIRALPAK AD–H, hexane/2-PrOH¼90:10,
1.0 mL/min, retention times: 18.1 min (major isomer) and 33.8 min
(minor isomer).
4.2.9. (þ)-N-Benzyl-N-[4,5,7-trimethyl-2-(toluene-4-sulfonyl)-
2,3,5,6-tetrahydro-1H-isoindol-5-yl]-acetamide [(þ)-3ae]
25
Yellow oil; [
a
]
þ25.5 (c 0.68, CHCl3, 99% ee); IR (neat) 3063,
D
1645, 1342, 1163, 668 cmꢀ1 1H NMR (CDCl3, 300 MHz)
; d 7.71 (d,
4.2.6. (þ)-5-Acetylamino-4-methyl-7-phenyl-1,3,5,6-tetrahydro-
J¼8.1 Hz, 2H), 7.37–7.24 (m, 5H), 7.19 (d, J¼8.1 Hz, 2H), 4.89–4.45
(m, 2H), 4.13–3.90 (m, 2H), 3.90–3.61 (m, 2H), 3.35–3.00 (m, 1H),
2.43 (s, 3H), 2.12 (s, 3H), 1.84–1.68 (m, 1H), 1.55 (s, 6H), 1.15 (s, 3H);
isobenzofuran-5-carboxylic acid methyl ester [(þ)-3fa]
25
Colorless oil; [
a]
þ165.3 (c 0.61, CHCl3, 99% ee); IR (neat) 3289,
D
3018, 1732, 1653, 1518, 758 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
d
7.33–
13C NMR (CDCl3, 75 MHz)
d 171.6, 143.6, 138.7, 132.8, 129.7, 128.81,
7.26 (m, 3H), 7.09–7.06 (m, 2H), 6.26 (s, 1H), 4.62–4.53 (m, 2H), 4.41
128.78, 128.7, 127.7, 127.2, 125.8, 123.5, 63.4, 50.8, 50.5, 49.7, 42.8,
24.1, 23.7, 21.5, 19.3, 14.0; HRMS (ESI) calcd for C27H32N2O3SNa
[MþNa]þ 487.2031, found 487.2025; CHIRALPAK AD–H, hexane/2-
PrOH¼80:20, 1.0 mL/min, retention times: 15.9 min (minor isomer)
and 19.2 min (major isomer).
(d, J¼13.5 Hz, 1H), 4.31 (d, J¼13.5 Hz, 1H), 3.63 (s, 3H), 3.22 (d,
J¼18.3 Hz, 1H), 2.94 (d, J¼18.3 Hz, 1H), 1.88 (s, 3H), 1.77 (s, 3H); 13
C
NMR (CDCl3, 75 MHz) d 172.9, 169.1, 139.3, 136.7, 128.7, 128.3, 128.2,
127.6, 124.5, 121.2, 71.1, 70.0, 63.1, 52.9, 39.8, 23.8, 19.3; HRMS (ESI)
calcd for C19H21NO4Na [MþNa]þ 350.1368, found 350.1345; CHIR-
ALPAK AD–H, hexane/2-PrOH¼90:10, 1.0 mL/min, retention times:
8.7 min (major isomer) and 14.6 min (minor isomer). The regio-
isomer structure was determined by NOE experiment.
4.2.10. 4,5,7-Trimethyl-2-(toluene-4-sulfonyl)-2,3-dihydro-1H-
isoindole (5)
Colorless solid; mp 179.4–180.3 ꢁC; IR (KBr) 3089, 2918, 2853,
2734, 1937, 1596, 1463, 1302, 1096, 822 cmꢀ1 1H NMR (CDCl3,
;
300 MHz)
4.57 (s, 2H), 4.55 (s, 2H), 2.40 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H), 2.05 (s,
3H); 13C NMR (CDCl3, 75 MHz)
143.5, 136.1, 135.0, 133.8, 132.2,
d
7.78 (d, J¼8.1 Hz, 2H), 7.31 (d, J¼8.1 Hz, 2H), 6.83 (s, 1H),
NOE
Me
NHAc
d
130.3,129.7,129.2,128.0,127.5, 53.7, 53.4, 21.4,19.1,18.1,15.3; HRMS
(EI) calcd for C18H21NO2S [M]þ 315.1293, found 315.1280.
CO2Me
O
Ph
4.2.11. (þ)-4,5,7-Trimethyl-2-(toluene-4-sulfonyl)-2,3,5,6-tetra-
4.2.7. (þ)-5-Acetylamino-7-methyl-4-phenyl-1,3,5,6-tetrahydro-
hydro-1H-isoindole-5-carboxylic acid dimethylamide [(þ)-3ag]
25
isobenzofuran-5-carboxylic acid methyl ester [(þ)-4fa]
Pale yellow oil; [
a]
þ30.3 (c 2.44, CHCl3, >99% ee); IR (neat)
D
25
Pale yellow oil; [
a
]
þ253.6 (c 1.29, CHCl3, 99% ee); IR (neat)
2925, 1634, 1344, 1162, 753 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
d 7.74
D
3293, 3014, 1736, 1653, 1521, 1230, 761 cmꢀ1
300 MHz)
;
1H NMR (CDCl3,
(d, J¼8.1 Hz, 2H), 7.35 (d, J¼8.1 Hz, 2H), 4.10–3.82 (m, 4H), 2.94 (s,
d
7.36–7.18 (m, 5H), 6.06 (s, 1H), 4.75 (d, J¼14.7 Hz, 1H),
6H), 2.58 (d, J¼18.3 Hz, 1H), 2.44 (s, 3H), 1.95 (d, J¼18.3 Hz, 1H), 1.65
4.70 (d, J¼14.7 Hz, 1H), 4.60–4.49 (m, 2H), 3.79 (s, 3H), 3.52 (d,
(s, 3H), 1.55 (s, 3H), 1.13 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 175.4,
J¼17.4 Hz, 1H), 3.36 (d, J¼17.4 Hz, 1H), 1.98 (s, 3H), 1.74 (s, 3H); 13C
143.6, 132.9, 129.7, 127.7, 126.2, 125.7, 125.5, 121.4, 50.6, 50.5, 47.6,
40.3, 38.1, 36.7, 24.3, 21.5, 19.2, 14.7; HRMS (ESI) calcd for
NMR (CDCl3, 75 MHz) d 172.2, 169.7, 139.4, 138.0, 130.7, 128.4, 127.3,
126.4, 125.5, 118.7, 71.3, 70.0, 63.4, 53.0, 36.4, 23.5, 15.0; HRMS (ESI)
calcd for C19H21NO4Na [MþNa]þ 350.1368, found 350.1365; CHIR-
ALPAK AD–H, hexane/2-PrOH¼90:10, 1.0 mL/min, retention times:
C
21H28N2O3SNa [MþNa]þ 411.1718, found 411.1683; CHIRALPAK
AD–H, hexane/2-PrOH¼90:10, 1.0 mL/min, retention times:
25.0 min (minor isomer) and 32.9 min (major isomer).

K. Tanaka et al. / Tetrahedron 64 (2008) 6289–6293
6293
Lavielle, S. Biopolymers 1996, 39, 67–74; (e) Benedetti, E.; Gavuzzo, E.; Santini,
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349–359.
4.3. N-Benzyl-N-isopropenylacetamide (2e)
A mixture of benzylamine (1.1 g, 10.0 mmol) and acetone
(2.0 mL) in a sealed tube was stirred at 120 ꢁC for 1 h using mi-
crowave reactor. The resulting mixture was dried over MgSO4 and
concentrated under reduced pressure. The residue was dissolved in
CH2Cl2 (15 mL). After cooling to 0 ꢁC, Et3N (2.1 mL, 15 mmol) and
acetyl chloride (0.79 g, 10 mmol) were added in this order. After
stirring at room temperature for 0.5 h, the reaction was quenched
with water and extracted with CH2Cl2. The organic layer was dried
over MgSO4 and concentrated under reduced pressure. The residue
was purified by a silica gel column chromatography (eluent: hex-
ane/EtOAc) to give 2e (0.48 g, 0.25 mmol, 25% yield) as a yellow oil.
4. For reviews of asymmetric synthesis of a,a-disubstituted a-amino acids, see:
(a) Vogt, H.; Braese, S. Org. Biomol. Chem. 2007, 5, 406–430; (b) Ohfune, Y.;
Shinada, T. Eur. J. Org. Chem. 2005, 5127–5143; (c) Park, K. H.; Kurth, M. J.
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342–351.
6. For recent reviews of transition metal-catalyzed [2þ2þ2] cycloadditions, see:
(a) Agenet, N.; Buisine, O.; Slowinski, F.; Gandon, V.; Aubert, C.; Malacria, M.
Organic Reactions; Overman, L. E., Ed.; John Wiley & Sons: Hoboken, NJ, 2007;
Vol. 68, pp 1–302; (b) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348,
2307–2327; (c) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006,
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4741–4767; (e) Yamamoto, Y. Curr. Org. Chem. 2005, 9, 503–509; (f) Fujiwara,
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IR (neat) 3330, 2979, 2936, 1645, 1391 cmꢀ1
300 MHz) 7.31–7.18 (m, 5H), 4.97 (s, 1H), 4.66 (s, 1H), 4.63 (s, 2H),
2.11 (s, 3H), 1.82 (s, 3H); 13C NMR (CDCl3, 75 MHz)
169.4, 144.3,
;
1H NMR (CDCl3,
d
d
137.8, 128.5, 128.3, 127.2, 115.8, 48.8, 21.7, 20.9; HRMS (ESI) calcd for
C
12H15NONa [MþNa]þ 212.1051, found 212.1051.
7. For our first discovery of a cationic rhodium(I)/modified-BINAP complex as
a catalyst for [2þ2þ2] cycloadditions, see: (a) Tanaka, K.; Shirasaka, K. Org. Lett.
2003, 5, 4697–4699; (b) Tanaka, K.; Toyoda, K.; Wada, A.; Shirasaka, K.; Hirano,
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Jpn. 2007, 65, 862–873.
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13687; (b) Tanaka, K.; Nishida, G.; Sagae, H.; Hirano, M. Synlett 2007, 1426–
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Acknowledgements
This work was supported partly by a Grant-in-Aid for Scientific
Research (No. 19350046) from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. We thank Takasago Inter-
national Corporation for the gift of modified-BINAP ligands, and
Mr. T. Shibata and Mr. D. Hojo for their experimental assistances.
9. For a Ni-catalyzed enantioselective [2þ2þ2] cycloaddition of monoalkynes
with monoalkenes, see: Ikeda, S.; Kondo, H.; Arii, T.; Odashima, K. Chem.
Commun. 2002, 2422–2423.
Supplementary data
10. Co-mediated [2þ2þ2] cycloadditions of alkynes with double bonds in nitrogen
heterocycles, see: (a) Aubert, C.; Betschmann, P.; Eichberg, M. J.; Gandon, V.;
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5496–5498; (g) Grotjahn, D. B.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1986, 108,
2091–2093.
1H NMR spectra of all new compounds (PDF) and X-ray crys-
tallographic files for (R)-(ꢀ)-3aa (CIF) are provided. This material is
available free of charge via the internet. Supplementary data as-
sociated with this article can be found in the online version, at
doi:10.1016/j.tet.2008.04.107.
References and notes
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