Chiral-thiourea-catalyzed direct Mannich reaction

Article abstract of DOI:10.1055/s-2007-983795

In the presence of a chiral thiourea as a bifunctional organocatalyst, Mannich reaction of N-Boc-imine with prochiral 1,3-dicarbonyl compounds proceeded with excellent enantio- and diastereoselectivities. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983795

SPECIAL TOPIC
2571
Chiral-Thiourea-Catalyzed Direct Mannich Reaction
C
hiral-Thiourea-C
o
a
talyzed Ma
u
sn
uke Yamaoka, Hideto Miyabe, Yoshizumi Yasui, Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Fax +81(75)7534569; E-mail: takemoto@pharm.kyoto-u.ac.jp
Received 1 January 2007
R
N
R
HN
Abstract: In the presence of a chiral thiourea as a bifunctional or-
ganocatalyst, Mannich reaction of N-Boc-imine with prochiral 1,3-
dicarbonyl compounds proceeded with excellent enantio- and dia-
stereoselectivities.
10 mol% catalyst 1
+
CH2(CO2Et)2
CO2Et
CH2Cl2
Ar
Ar
3
CO2Et
4a–g
2a–g
Key words: organocatalyst, thiourea, enantioselective, Mannich
reaction, imine
CF3
a: R = Ts, Ar = Ph
b: R = P(O)Ph2, Ar = Ph
c: R = Boc, Ar = Ph
S
d: R = Boc, Ar = 4-MeOC6H4
e: R = Boc, Ar = 4-CF3C6H4
f: R = Boc, Ar = 4-BrC6H4
g: R = Boc, Ar = 3-pyridyl
F3C
N
N
H
H
Chiral organocatalysts have become a field of central im-
portance for enantioselective transformations of organic
molecules.1 Recent progress in this area has resulted in the
advent and development of various organocatalysts which
do not require the strictly controlled reaction conditions
compared to many established metal-catalyzed transfor-
mations.1 Recently, our laboratory introduced the chiral
thiourea 1 as a bifunctional organocatalyst, which acceler-
ates the aza-Henry reaction and the Michael reaction of
nitroolefins or a,b-unsaturated imides as a result of dual
activation of electrophile and nucleophile (Scheme 1).2–4
N
Me
Me
catalyst 1
Scheme 1
were run in CH2Cl2 (Scheme 1). Although the electron-
deficient N-sulfonylimine 2a exhibited excellent reactivi-
ty toward nucleophilic malonate 3, no enantioselectivity
was observed (Table 1, entry 1). Good control of enantio-
selectivity was not achieved by using imine 2b either (en-
try 2). In contrast, N-Boc-imine 2c worked well to give the
product 4c with 88% ee after stirring at room temperature
for 24 hours (entry 3). The degree of selectivity was
shown to be dependent on the reaction temperature; thus,
changing the temperature from room temperature to 0 °C
led to a moderate increase in enantioselectivity to 94% ee
(entry 4). Excellent chemical yield and high enantioselec-
tivity were also obtained in the reaction of less reactive N-
Boc-imine 2d having an electron-donating methoxy
group (entry 5). The reactions of imines 2e and 2f having
In recent years, enantioselective direct Mannich reaction
has attracted much attention in approaches toward chiral
b-amino acid derivatives.5,6 Asymmetric Mannich reac-
tion with a symmetric C-nucleophile such as a dialkyl ma-
lonate has been wildly investigated. In contrast, the
reaction with an unsymmetrical nucleophile allows the
generation of two stereogenic centers in a single carbon–
carbon bond-forming process; thus, the control of both
enantio- and diastereoselectivities is a challenging task.
Cinchona alkaloids having thiourea moiety were recently
shown to be effective catalysts for direct Mannich reac-
tion independently by the research groups of Deng7a and
Dixon.7b We became interested in the possibility of the
use of simple thiourea 1 in direct Mannich reaction with
unsymmetrical prochiral nucleophiles. Herein, we report
the highly enantio- and diastereoselective Mannich reac-
tion of a wide range of cyclic 1,3-dicarbonyl compounds
catalyzed by chiral thiourea 1.
Table 1 Reaction of Malonate 3 with Imines 2a–ga
Entry Imine
Temp (°C) Time (h)
Yield (%) ee (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2c
2d
2e
2f
r.t.
r.t.
r.t.
24
72
24
48
72
24
24
48
86
58
77
84
82
91
84
73
0b
10
88
94
93
96
98
97
0
Prior to exploring the reaction with prochiral nucleo-
philes, we first investigated the catalytic activity of thio-
urea 1 in Mannich reaction. In the presence of thiourea 1
(10 mol%), reactions of aldimines 2a–g with malonate 3
–20
–78
–78
–78
2g
a All reactions were carried out in CH2Cl2 in the presence of thiourea
1 (10 mol%).
b Racemic adduct 4a was obtained.
SYNTHESIS 2007, No. 16, pp 2571–2575
Advanced online publication: 12.07.2007
x
x.
x
x
.
2
0
0
7
DOI: 10.1055/s-2007-983795; Art ID: C03507SS
© Georg Thieme Verlag Stuttgart · New York

2572
Y. Yamaoka et al.
SPECIAL TOPIC
an electron-withdrawing group proceeded smoothly even
at –78 °C to give adducts 4e and 4f with 96% ee and 98%
ee, respectively (entries 6 and 7). The reaction of imine 2g
containing basic pyridine moiety was also successful un-
der similar reaction conditions (entry 8). These observa-
tions suggest that thiourea 1 acts as a chiral catalyst for
direct Mannich reaction with excellent catalytic activity.
Table 2 Reaction of b-Keto Ester 7 with Imine 2c
Entry Catalyst Time (h) Yield (%) dr
ee (%)
1a
2a
3a
4a
5a
6b
none
48
8
67
93
87
86
98
89
68:32
60:40
60:40
66:34
91:9
–
Et3N
–
(i-Pr)2NEt
DBU
8
–
Next, we tried the reaction of N-Boc-imine 2c with
prochiral nucleophile 5 (Scheme 2). In the presence of 1
(10 mol%), nucleophile 5 reacted with 2c at –78 °C to
give the adduct 6 in 96% yield with excellent ee. Howev-
er, valuable diastereoselectivity was not observed, proba-
bly because of epimerization.
8
–
thiourea 1
thiourea 1
9
82c
88c
72
92:8
a Reactions were carried out in CH2Cl2 in the presence of catalyst (10
mol%) at r.t.
b Reaction was carried out in CH2Cl2 in the presence of thiourea 1 (10
mol%) at –20 °C.
Boc
Boc
+
NH
O
O
N
10 mol% catalyst 1
c The ee given is for the major isomer.
EtO2C
Ph
Ph
CH2Cl2, –78 °C, 48 h
96% yield
Ph
Ph
CO2Et
2c
5
6 (96% ee)
of the 1,3-diketone 10. As expected, the reaction took
place at position 2 of 1,3-diketone 10 to give the product
15 with 87% ee accompanied by a small amount of dia-
Scheme 2
On the basis of these results, we next focused on the chiral stereomer without detection of other adducts. Only a mod-
Mannich reaction with cyclic 1,3-dicarbonyl compounds est enantioselectivity was observed in the reaction with
having a substituent at the 2-position. To test the viability six-membered b-keto ester 11, although diastereoselectiv-
of thiourea 1, the reaction with prochiral nucleophile 7 ity still remained high. The seven-membered keto ester 12
was investigated by using several catalysts (Scheme 3, also produced adduct 17 with an excellent enantioselec-
Table 2). In the presence of base such as Et3N, (i-Pr)2NEt, tivity. The diastereoselectivity was shown to be dependent
or DBU (10 mol%), the N-Boc-imine 2c reacted well with on the structure of nucleophiles. The use of five-mem-
nucleophile 7 with moderate diastereoselectivities; how-
ever, the reaction proceeded slowly in the absence of cat-
alyst (Table 2, entries 1–4). As expected, thiourea 1
Boc
O
O
O
NH
2c
worked well as an effective catalyst for the control of both
enantio- and diastereoselectivities (entry 5). These obser-
vations suggest that dual activation of electrophile and nu-
cleophile using the bifunctional thiourea 1 is crucial for
successful stereocontrol. In the presence of thiourea 1 (10
mol%), the reaction proceeded at –20 °C to give a 92:8 di-
astereomeric mixture of the desired adduct 8 in 89% yield
with 88% ee (entry 6). The absolute and relative configu-
ration of major product was determined by converting the
adduct 8 to the authentic compound 9.6c Thus, a stereose-
lective construction of quaternary carbon center was
achieved by using the simple thiourea catalyst 1.
10 mol% catalyst 1
Me
Ph
MeOC
15 (87% ee)
CH2Cl2, –40 °C, 96 h
89% yield, dr 90:10
10
Boc
O
NH
O
2c
10 mol% catalyst 1
MeO2C
Ph
CH2Cl2, –20 °C, 72 h
81% yield, dr 91:9
MeO2C
16 (56% ee)
11
Boc
NH
O
O
2c
MeO2C
10 mol% catalyst 1
Ph
MeO2C
17 (92% ee)
CH2Cl2, –40 °C, 96 h
98% yield, dr 80:20
The scope of enantio- and diastereoselective reaction cat-
alyzed by thiourea 1 was investigated under the optimized
conditions (Scheme 4). At first, we tested the reaction site
12
Boc
O
NH
O
2c
MeO2C
10 mol% catalyst 1
Boc
Ph
O
Boc
+
O
NH
(S)
MeO2C
18 (90% ee)
CH2Cl2, –20 °C, 48 h
81% yield, dr 54:46
N
10 mol% catalyst
CH2Cl2
(R)
Ph
MeO2C
MeO2C
13
Ph
Boc
7
2c
O
NH
O
Ac
8
2c
OAc
NMe
MeO2C
10 mol% catalyst 1
1) LiAlH4, THF, reflux, 24 h
2) Ac2O, py, r.t., 12 h
Ph
8
Ph
MeO2C
19 (83% ee)
CH2Cl2, –20 °C, 72 h
89% yield, dr 99:1
(88% ee)
AcO
14
9
Scheme 4
Scheme 3
Synthesis 2007, No. 16, 2571–2575 © Thieme Stuttgart · New York

SPECIAL TOPIC
Chiral-Thiourea-Catalyzed Mannich Reaction
2573
13C NMR (125 MHz, CDCl3): d = 167.9, 166.8, 155.0, 143.8, 129.9
(q, J = 32 Hz), 126.8, 125.5, 124.4 (q, J = 272 Hz), 80.0, 62.1, 61.7,
56.5, 53.1, 28.1, 13.8, 13.7.
MS (FAB+): m/z (%) = 434 (12, [M + H]+), 174 (100).
HRMS (FAB+): m/z calcd for C20H27F3NO6 [M + H]+: 434.1791;
bered b-keto ester 13, bearing an aromatic ring, as a
prochiral nucleophile led to decreased diastereoselectivi-
ty. In contrast, a high degree of diastereocontrol was
achieved in the reaction of six-membered b-keto ester 14.
In summary, we have developed the thiourea-catalyzed
direct Mannich reaction of N-Boc-imine with a wide
range of unsymmetrical cyclic 1,3-dicarbonyl com-
pounds. The reaction using simple thiourea 1 as bifunc-
tional catalyst proceeded smoothly to afford the
corresponding adducts with good enantio- and diastereo-
selectivities.
found: 434.1799.
Diethyl (S)-[1-(4-Bromophenyl)-1-(tert-butoxycarbonyl-
amino)methyl]malonate (4f)
Colorless crystals; mp 61–63 °C (EtOAc–hexane). HPLC (DA-
ICEL Chiralcel OD-H, hexane–propan-2-ol, 97:3, 0.5 mL/min, 210
nm): tR (minor) = 14.6 min, tR (major) = 17.4 min. A sample of 98%
ee by HPLC analysis gave [a]D27 +6.6 (c 1.5, CHCl3).
IR (CHCl3): 3428, 2984, 1728, 1494 cm–1.
Melting points were taken on a Yanagimoto micromelting point ap-
paratus and are uncorrected. 1H and 13C NMR spectra were recorded
in CDCl3 at 500 MHz, and 125 MHz, respectively; TMS was used
as an internal standard. IR spectra were recorded on a Jasco FT/IR-
410 Fourier-transfer IR spectrometer. Optical rotations were re-
corded on a Jasco DIP-360 polarimeter. Enantiomeric excess was
determined by high-performance liquid chromatography (HPLC)
analysis. Compound 4c is a known compound.4b
1H NMR (500 MHz, CDCl3): d = 7.45 (2 H, d, J = 8.3 Hz), 7.20 (2
H, d, J = 8.3 Hz), 6.20 (1 H, br m), 5.43 (1 H, br m), 4.27–4.04 (4
H, m), 3.84 (1 H, br m), 1.44 (9 H, s), 1.27 (3 H, t, J = 7.2 Hz), 1.16
(3 H, t, J = 7.2 Hz).
13C NMR (125 MHz, CDCl3): d = 167.9, 166.9, 155.0, 138.8, 131.6,
128.1, 121.5, 79.8, 62.0, 61.7, 56.6, 52.9, 28.2, 13.9, 13.8.
MS (FAB+): m/z (%) = 444 (16, [M + H]+), 446 (15, [M + H]+), 161
(100).
Chiral-Thiourea-Catalyzed Direct Mannich Reaction; General
Procedure
HRMS (FAB+): m/z calcd for C19H2779BrNO6 [M + H]+: 444.1022;
To a solution of N-Boc-imine 2c–g (0.30 mmol) and thiourea cata-
lyst 1 (12.4 mg 0.03 mmol) in anhyd CH2Cl2 (0.6 mL), was added
the appropriate 1,3-dicarbonyl compound (0.60 mmol) under argon
at the temperature indicated in the text. After stirring at the same
temperature, the mixture was concentrated under reduced pressure.
Purification of the residue by flash chromatography [hexane–
EtOAc (3:1) in the cases of 4c–g and 15–19 or hexane–Et2O (2:1)
in the case of 8] afforded adducts 4c–g, 8 and 15–19.
found: 444.1007.
Anal. Calcd for C19H26BrNO6: C, 51.36; H, 5.90; N, 3.15; Br, 17.98.
Found: C, 51.33; H, 5.82; N, 2.91; Br, 17.95.
Diethyl (S)-[1-(tert-Butoxycarbonylamino)-1-(3-pyridyl)meth-
yl]malonate (4g)
Colorless oil. HPLC (DAICEL Chiralcel OD-H, hexane–propan-2-
ol, 95:5, 0.5 mL/min, 210 nm): tR (major) = 24.0 min, tR
(minor) = 27.6 min. A sample of 97% ee by HPLC analysis gave
[a]D22 +8.9 (c 0.9, CHCl3).
Diethyl (S)-[1-(tert-Butoxycarbonylamino)-1-(4-methoxyphe-
nyl)methyl]malonate (4d)
Colorless crystals; mp 89–93 °C (EtOAc–hexane). HPLC (DA-
ICEL Chiralcel OD-H, hexane–propan-2-ol, 97:3, 0.5 mL/min, 210
nm): tR (minor) = 21.0 min, tR (major) = 23.2 min. A sample of 93%
ee by HPLC analysis gave [a]D25 +3.0 (c 1.3, CHCl3).
IR (CHCl3): 3428, 2984, 1714, 1497 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.52 (1 H, s), 8.44 (1 H, br m),
7.60 (1 H, br d, J = 7.9 Hz), 7.20 (1 H, br m), 6.18 (1 H, br m), 5.45
(1 H, br m), 4.22–3.97 (4 H, br m), 3.82 (1 H, br m), 1.34 (9 H, s),
1.20 (3 H, t, J = 7.0 Hz), 1.09 (3 H, t, J = 7.2 Hz).
IR (CHCl3): 3430, 2983, 1726, 1498 cm–1.
13C NMR (125 MHz, CDCl3): d = 167.8, 166.8, 155.0, 149.0, 148.2,
1H NMR (500 MHz, CDCl3): d = 7.22 (2 H, d, J = 8.6 Hz), 6.84 (2
H, d, J = 8.6 Hz), 6.13 (1 H, br m), 5.43 (1 H, br m), 4.26–4.05 (4
H, m), 3.85 (1 H, br m), 3.78 (3 H, s), 1.41 (9 H, s), 1.26 (3 H, t,
J = 7.0 Hz), 1.16 (3 H, t, J = 7.2 Hz).
13C NMR (125 MHz, CDCl3): d = 168.2, 167.2, 159.0, 155.0, 131.8,
127.5, 113.9, 79.5, 61.8, 61.5, 57.0, 55.2, 52.9, 28.2, 13.9, 13.8.
135.3, 134.2, 123.3, 80.0, 62.1, 61.8, 56.4, 51.5, 28.2, 13.9, 13.7.
MS (FAB+): m/z (%) = 367 (100, [M + H]+).
HRMS (FAB+): m/z calcd for C18H27N2O6 [M + H]+: 367.1869;
found: 367.1871.
MS (FAB+): m/z (%) = 396 (10, [M + H]+), 180 (100).
HRMS (FAB+): m/z calcd for C20H30NO7 [M + H]+: 396.2022;
Ethyl (S)-2-Benzoyl-3-(tert-butoxycarbonylamino)-3-phenyl-
propionate (6)
Colorless oil; inseparable 5:3 diastereomeric mixture. HPLC (DA-
ICEL Chiralcel AD-H, hexane–propan-2-ol, 95:5, 0.5 mL/min, 210
nm): tR (major) = 49.9 and 62.7 min, tR (minor) = 73.9 and 115.7
min. A sample of 96% ee (5:3 diastereomeric mixture) by HPLC
analysis gave [a]D28 +31.9 (c 1.1, CHCl3).
found: 396.2016.
Anal. Calcd for C20H29NO7: C, 60.74; H, 7.39; N, 3.54. Found: C,
60.71; H, 7.27; N, 3.47.
Diethyl (S)-[1-(tert-Butoxycarbonylamino)-1-(4-trifluorometh-
ylphenyl)methyl]malonate (4e)
Colorless oil. HPLC (DAICEL Chiralcel OD-H, hexane–propan-2-
ol, 90:10, 1.0 mL/min, 210 nm): tR (minor) = 12.4 min, tR
(major) = 27.1 min. A sample of 96% ee by HPLC analysis gave
[a]D28 +15.3 (c 1.1, CHCl3).
IR (CHCl3): 3435, 2983, 1732, 1710, 1497 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.95 (6/8 H, br d, J = 7.3 Hz), 7.80
(10/8 H, br d, J = 7.3 Hz), 7.62–7.14 (8 H, br m), 6.38 (5/8 H, br m),
6.08 (3/8 H, br m), 5.61 (5/8 H, br m), 5.52 (3/8 H, br m), 4.95 (5/8
H, br m), 4.92 (3/8 H, br m), 4.19–4.05 (2 H, br m), 1.40 (45/8 H,
s), 1.36 (27/8 H, br s), 1.20–1.06 (3 H, br m).
13C NMR (125 MHz, CDCl3): d = 195.1, 193.2, 168.5, 167.7, 155.3,
155.0, 140.3, 140.1, 136.8, 135.7, 133.8, 133.7, 128.9, 128.7, 128.6,
128.5, 128.4, 128.3, 127.6, 127.4, 126.5, 79.5, 61.9, 61.6, 59.2,
IR (CHCl3): 3428, 2983, 1728, 1497 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.51 (2 H, d, J = 8.2 Hz), 7.37 (2
H, d, J = 8.2 Hz), 6.20 (1 H, br m), 5.46 (1 H, br m), 4.22–3.93 (4
H, m), 3.82 (1 H, br m), 1.34 (9 H, s), 1.19 (3 H, t, J = 7.2 Hz), 1.06
(3 H, t, J = 7.2 Hz).
Synthesis 2007, No. 16, 2571–2575 © Thieme Stuttgart · New York

2574
Y. Yamaoka et al.
SPECIAL TOPIC
57.2, 54.3, 53.6, 28.2, 13.8. Two carbon peaks were missing due to
overlapping.
H, br m), 2.45 (1 H, br m), 2.06 (1 H, m), 1.95–1.60 (3 H, br m),
1.70 (1 H, br m), 1.60–1.35 (3 H, m), 1.38 (9 H, s).
MS (FAB–): m/z (%) = 396 (45, [M – H]+), 153 (100).
HRMS (FAB–): m/z calcd for C23H26NO5 [M – H]+: 396.1811;
13C NMR (125 MHz, CDCl3): d = 208.9, 172.0, 155.1, 138.2, 128.3,
128.2, 127.8, 79.7, 68.6, 59.7, 52.1, 40.5, 33.5, 30.3, 28.2, 26.6,
25.5.
found: 396.1814.
MS (FAB+): m/z (%) = 376 (3, [M + H]+), 106 (100).
Methyl (1S)-1-[(R)-1-(tert-Butoxycarbonylamino)-1-phenyl-
HRMS (FAB+): m/z calcd for C21H30NO5 [M + H]+: 376.2124;
found: 376.2127.
methyl]-2-oxocyclopentanecarboxylate (8)
1
Colorless oil; inseparable 92:8 diastereomeric mixture. H NMR
and HPLC data of major diastereoisomer are given. HPLC (DA-
ICEL Chiralcel AD-H, hexane–propan-2-ol, 97:3, 0.6 mL/min, 210
nm): tR (major) = 30.6 min, tR (minor) = 82.8 min.
IR (CHCl3): 3441, 3027, 2981, 1751, 1725, 1497 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.30–7.12 (5 H, m), 5.89 (1 H, br
m), 5.14 (1 H, d, J = 9.5 Hz), 3.61 (3 H, s), 2.45 (1 H, br m), 2.26 (2
H, br m), 1.98–1.75 (3 H, m), 1.32 (9 H, s).
Methyl (2S)-2-[(R)-1-(tert-Butoxycarbonylamino)-1-phenyl-
methyl]-1-oxo-2-indancarboxylate (18)
Colorless oil; inseparable 54:46 diastereomeric mixture. IR, 1H
NMR, MS, and HPLC data of diastereomeric mixture are given.
HPLC (DAICEL Chiralcel OD-H, hexane–propan-2-ol, 99:1, 1.0
mL/min, 210 nm): tR (major) = 37.1 and 43.8 min, tR (minor) = 53.4
and 63.7 min.
IR (CHCl3): 3438, 3030, 1710, 1497 cm–1.
MS (FAB+): m/z (%) = 348 (2, [M + H]+), 106 (100).
HRMS (FAB+): m/z calcd for C19H26NO5 [M + H]+: 348.1811;
1H NMR (500 MHz, CDCl3): d = 7.73–7.10 (9 H, m), 6.73 (46/100
H, br m), 6.00 (54/100 H, br m), 5.43 (54/100 H, br m), 5.33 (46/
100 H, br m), 3.79 (46/100 H, d, J = 17.7 Hz), 3.73 (3 H, br s), 3.48
(54/100 H, d, J = 17.7 Hz), 3.25 (46/100 H, d, J = 17.7 Hz), 3.23
(54/100 H, d, J = 17.7 Hz), 1.38 (9 H, br s).
MS (FAB+): m/z (%) = 396 (1, [M + H]+), 106 (100).
HRMS (FAB+): m/z calcd for C23H26NO5 [M + H]+: 396.1811;
found: 348.1818.
(2R)-2-Acetyl-2-[(R)-1-(tert-butoxycarbonylamino)-1-phenyl-
methyl]cyclopentanone (15)
Major diastereoisomer was isolated as a colorless oil. HPLC (DA-
ICEL Chiralcel AD-H, hexane–propan-2-ol, 85:15, 0.5 mL/min,
210 nm): tR (minor) = 13.3 min, tR (major) = 36.7 min. A sample of
87% ee by HPLC analysis gave [a]D26 –74.1 (c 1.1, CHCl3).
found: 396.1816.
IR (CHCl3): 3439, 3029, 2980, 1708, 1496 cm–1.
Methyl (2S)-2-[(R)-1-(tert-Butoxycarbonylamino)-1-phenyl-
methyl]-1-tetralone-2-carboxylate (19)
Major diastereoisomer was isolated as a colorless oil. HPLC (DA-
ICEL Chiralcel AD-H, hexane–propan-2-ol, 90:10, 1.0 mL/min,
210 nm): tR (minor) = 12.8 min, tR (major) = 21.7 min. A sample of
83% ee by HPLC analysis gave [a]D25 –32.1 (c 1.5, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.34–7.17 (5 H, m), 5.72 (1 H, br
d, J = 9.5 Hz), 4.97 (1 H, br m) 2.63 (1 H, br m), 2.37 (3 H, s), 2.15
(1 H, br m), 1.78–1.25 (4 H, m), 1.39 (9 H, s).
13C NMR (125 MHz, CDCl3): d = 213.2, 202.5, 154.7, 138.3, 128.5,
127.8, 127.4, 80.2, 73.6, 56.8, 39.1, 28.1, 25.4, 19.2. One carbon
peak was missing due to overlapping.
MS (FAB+): m/z (%) = 332 (4, [M + H]+), 106 (100).
HRMS (FAB+): m/z calcd for C19H26NO4 [M + H]+: 332.1862;
IR (CHCl3): 3444, 2980, 1730, 1707, 1494 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.01 (1 H, d, J = 7.7 Hz), 7.60–
7.42 (3 H, m), 7.34–7.17 (5 H, br m), 5.99 (1 H, br m), 5.34 (1 H, d,
J = 10.4 Hz), 3.48 (3 H, s), 3.08 (2 H, br m), 2.72 (1 H, br m), 2.29
(1 H, br m), 1.36 (9 H, s).
found: 332.1869.
13C NMR (125 MHz, CDCl3): d = 194.7, 170.4, 155.2, 142.4, 138.8,
133.7, 132.4, 128.7, 128.2, 128.1, 127.6, 126.8, 79.6, 63.2, 57.8,
52.4, 30.4, 28.1, 25.8. One carbon peak was missing due to overlap-
ping.
MS (FAB+): m/z (%) = 432 (4, [M + Na]+), 150 (100).
HRMS (FAB+): m/z calcd for C24H27NO5 + Na [M + Na]+:
Methyl (1S)-1-[(R)-1-(tert-Butoxycarbonylamino)-1-phenyl-
methyl]-2-oxocyclohexanecarboxylate (16)
Colorless oil; inseparable 91:9 diastereomeric mixture. H NMR
1
and HPLC data of major diastereoisomer are given. HPLC
(DAICEL Chiralcel OJ-H, hexane–propan-2-ol, 98:2, 0.4 mL/min,
210 nm): tR (major) = 33.7 min, tR (minor) = 51.2 min.
IR (CHCl3): 3445, 3030, 2951, 1708, 1494 cm–1.
432.1787; found: 432.1783.
1H NMR (500 MHz, CDCl3): d = 7.36–7.21 (5 H, m), 6.27 (1 H, br
d, J = 9.5 Hz), 5.25 (1 H, br d, J = 9.5 Hz), 3.54 (3 H, s), 2.65 (1 H,
br m), 2.48 (1 H, br m), 2.41 (1 H, br m), 2.05–1.85 (4 H, br m), 1.70
(1 H, br m), 1.38 (9 H, s).
MS (FAB+): m/z (%) = 362 (2, [M + H]+), 106 (100).
HRMS (FAB+): m/z calcd for C20H28NO5 [M + H]+: 362.1968;
Conversion of Adduct 8 into Compound 9
To a solution of the diastereomeric mixture of Mannich product 8
(51 mg, 0.15 mmol, dr 92:8) in THF (2 mL), was slowly added
LiAlH4 (168 mg, 4.5 mmol) at r.t. After heating at reflux under ar-
gon for 24 h, the mixture was diluted with CH2Cl2 (5 mL) at r.t. H2O
(0.16 mL), followed by aq 1 M NaOH (0.16 mL), and again H2O
(0.5 mL) were successively added to this solution at –78 °C. The re-
sulting mixture was gradually warmed to r.t. The mixture was fil-
tered through a Celite pad, washed with CH2Cl2 (5 × 10 mL), and
the combined CH2Cl2 washings were concentrated under reduced
pressure to afford the crude product. To a solution of the crude prod-
uct in pyridine (2.5 mL), was added Ac2O (1.25 mL) under argon at
r.t. After stirring at room temperature for 12 h, the mixture was con-
centrated under reduced pressure. Purification of the residue by
flash chromatography (hexane–EtOAc, 1:1) afforded the desired
product 9 (19.6 mg, 37%) as a colorless oil.6c Diastereoisomers
could not be separated. 1H and 13C NMR data of major diastereoiso-
found: 362.1963.
Methyl (1S)-1-[(R)-1-(tert-Butoxycarbonylamino)-1-phenyl-
methyl]-2-oxocycloheptanecarboxylate (17)
Major diastereoisomer was isolated as a colorless oil. HPLC (DA-
ICEL Chiralcel OD-H, hexane–propan-2-ol, 95:5, 0.5 mL/min, 210
nm): tR (minor) = 16.5 min, tR (major) = 19.3 min. A sample of 92%
ee by HPLC analysis gave [a]D25 +45.7 (c 1.2, CHCl3).
IR (CHCl3): 3440, 3030, 2937, 1705, 1493 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.33–7.22 (5 H, m), 6.45 (1 H, br
d, J = 10.1 Hz), 5.21 (1 H, br d, J = 10.1 Hz), 3.67 (3 H, s), 2.89 (1
Synthesis 2007, No. 16, 2571–2575 © Thieme Stuttgart · New York

SPECIAL TOPIC
Chiral-Thiourea-Catalyzed Mannich Reaction
2575
26
mer are given. A sample of 92:8 diastereomeric mixture gave [a]D
–45.8 (c 0.9, CHCl3).
(3) For examples of urea-catalyzed reactions, see: (a)Sohtome,
Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Chem.
Pharm. Bull. 2004, 52, 477. (b) Maher, D. J.; Connon, S. J.
Tetrahedron Lett. 2004, 45, 1301. (c) Sohtome, Y.;
Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron
Lett. 2004, 45, 5589. (d) Yoon, T. P.; Jacobsen, E. N.
Angew. Chem. Int. Ed. 2005, 44, 466. (e) Taylor, M. S.;
Tokunaga, N.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2005,
44, 6700. (f) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem.
Soc. 2005, 127, 8964. (g) Raheem, I. T.; Jacobsen, E. N.
Adv. Synth. Catal. 2005, 347, 1701. (h) Berkessel, A.;
Cleemann, F.; Mukherjee, S.; Müller, T. N. Angew. Chem.
Int. Ed. 2005, 44, 807. (i) Berkessel, A.; Mukherjee, S.;
Cleemann, F.; Müller, T. N. Chem. Commun. 2005, 1898.
(j) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu,
Y. Synlett 2005, 603. (k) Vakulya, B.; Varga, A.; Csampai,
A.; Soos, T. Org. Lett. 2005, 7, 1967. (l) McCooey, S. H.;
Connon, S. J. Angew. Chem. Int. Ed. 2005, 44, 6367.
(m) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A.
Angew. Chem. Int. Ed. 2005, 44, 6576. (n) Wang, J.; Li, H.;
Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293.
(o) Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett.
2005, 7, 4713. (p) Berkessel, A.; Cleemann, F.; Mukherjee,
S. Angew. Chem. Int. Ed. 2005, 44, 7466. (q) Ye, J.; Dixon,
D. J.; Hynes, P. S. Chem. Commun. 2005, 4481.
1H NMR (500 MHz, CDCl3 at 50 °C): d = 7.42–7.17 (5 H, m), 6.27
(1 H, s), 5.29 (1 H, m), 4.19 (1 H, d, J = 11.9 Hz), 3.89 (1 H, d,
J = 11.9 Hz), 2.97 (3 H, s), 2.07 (3 H, s), 2.03 (3 H, s), 1.88 (3 H, s),
2.25–1.60 (6 H, m).
13C NMR (125 MHz, CDCl3 at 50 °C): d = 171.3, 171.0, 170.5,
139.3, 129.6, 128.3, 127.2, 79.2, 65.8, 57.5, 53.0, 34.1, 31.8, 30.9,
22.4, 21.2, 21.1, 20.9.
MS (FAB+): m/z (%) = 362 (70, [M + H]+), 302 (100).
HRMS (FAB+): m/z calcd for C20H28NO5 [M + H]+: 362.1968;
found: 362.1971.
Acknowledgment
This work was supported in part by Grant-in-Aid for Scientific
Research (B) (Y.T.) and Scientific Research on Priority Areas:
Advanced Molecular Transformations of Carbon Resources (Y.T.
and H.M.) from the Ministry of Education, Culture, Sports, Science
and Technology of Japan, 21st Century COE Program ‘Knowledge
Information Infrastructure for Genome Science’.
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Synthesis 2007, No. 16, 2571–2575 © Thieme Stuttgart · New York