Preparation of aα,β-Unsaturated Lactams through intramolecular electrophilic carbamoylation of Alkenes

Article abstract of DOI:10.1055/s-0029-1217028

A general, synthetic method for the preparation of α, βunsaturated lactams startingsei from alkenylchloroformamides has been developed. The reaction was complete within five minutes at 150 °C in N-methylpyrrolidone with a catalytic amount of HBr under mic

Full text of DOI:10.1055/s-0029-1217028

PAPER
3989
Preparation of a,b-Unsaturated Lactams through Intramolecular
Electrophilic Carbamoylation of Alkenes
a
,
b
-
Unsaturated L
o
ctam
s
from
s
Carbamoy
h
lation of
A
lk
i
enes zumi Yasui,a Issei Kakinokihara,b Hiroshi Takeda,b Yoshiji Takemoto*b
WPI Advanced Institute for Materials Research, Tohoku University, Aoba, Sendai 980-8577, Japan
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
b
Received 10 June 2009; revised 24 July 2009
R2
Abstract: A general synthetic method for the preparation of a,b-
unsaturated lactams starting from alkenylchloroformamides has
been developed. The reaction was complete within five minutes at
150 °C in N-methylpyrrolidone with a catalytic amount of HBr un-
der microwave irradiation. Not only six-membered lactams, but
also five- and seven-membered lactams were obtained in high
yields.
CN
O
cat. PdLn
X = CN, R1 = H
R3
R3
R3
N
R4
B
C
R2
R2
R1
cat. PdLn
X = Cl, R1 = Me
R3
O
Key words: lactam, cyclization, electrophilic addition, acid cata-
lyst, microwave
X
N
R4
N
O
R4
A
R2
R1
O
An a,b-unsaturated lactam is a structural motif that is of-
ten found in bioactive molecules such as rebamipide,1 mi-
crocolins,2 vitexlactam A,3 and echinophyllins,4 and is
frequently used as a synthetic intermediate.5,6 In recent
years, we have focused on the formation of lactams
through transition-metal catalyzed reactions starting from
carbamoyl derivatives.7 Examples are shown in
Scheme 1. When carbamoyl cyanide A (X = CN, R1 = H),
having a 1,1-disubstituted alkene, was treated with palla-
dium catalyst, lactam B was formed through cyanoamida-
tion.8 On the other hand, chloroformamide A (X = Cl,
R1 = Me), having a 1,1,2-trisubstituted alkene, was con-
verted into vinyllactam C through a Heck-type reaction.9
During the course of those studies, we found that carbam-
oyl chloride A (X = Cl) could be converted smoothly into
a,b-unsaturated lactam D without the use of a transition-
metal catalyst.10 Details of this transformation are de-
scribed herein.
cat. H+
X = Cl
N
this work
D
R4
Scheme 1 Synthesis of functionalized lactams from alkenyl carba-
moyl derivatives
Table 1 Formation of Quinolone 2 in Various Solvents
solvent
Cl
microwave
N
O
N
150 °C, 1 h
O
Bn
Bn
1
2
Entry
Solvent
dioxane
diglyme
toluene
MeCN
NMP
Yield of 2 (%)
Recovery of 1 (%)
1
2
3
4
5
6a
7
8
21
6
76
88
93
82
3
The lactam-forming reaction was accidentally found
when carbamoyl chloride 1 was heated in dioxane under
microwave irradiation (Table 1, entry 1). After one hour
at 150 °C, quinolone 2 was isolated in 21% yield along
with 76% of unreacted starting material. The choice of
solvent was crucial for this reaction; although the reaction
in diglyme, toluene or acetonitrile gave poor conversion
(entries 2–4), when N-methylpyrrolidone (NMP) was
used, quinolone 2 was obtained in 81% yield (entry 5). A
reduction of the reaction time to five minutes led to an in-
complete reaction (entry 6). More polar solvents such as
dimethyl sulfoxide or water gave disappointing results
owing to decomposition of the starting material (entries 7
and 8).
1
16
81
40
0
NMP
53
0b
0
DMSO
H2O
25
a Reaction time was 5 min.
b N-Benzyl-2-(2-propenyl)aniline was isolated in ~60% yield.
Next, we made efforts to find an effective additive that
could induce the completion of the reaction in a shorter
period (Table 2). The reaction was carried out in NMP for
five minutes at 150 °C under microwave irradiation in the
SYNTHESIS 2009, No. 23, pp 3989–3993
Advanced online publication: 12.10.2009
DOI: 10.1055/s-0029-1217028; Art ID: F11809SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9

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Y. Yasui et al.
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presence of 30 mol% of various additives. After several enylamines, gave the corresponding six-membered unsat-
attempts, we found that the halide ion plays an interesting urated lactams in high yields (entries 3–5). It is worth not-
role in this reaction. When tetrabutylammonium halide ing that the substituents on the alkene have little effect in
(TBAX; X = F, Cl, Br, I) was tested, TBABr and TBAI this reaction. Propenylamine derivative 13 did not cyclize,
promoted the reaction dramatically (entries 1–4). Other presumably because of the difficulty of 5-endo-trig cy-
bromide salts such as KBr were less active, but HBr had clization (entry 6). On the other hand, seven-membered
an effect similar to that of TBABr (entries 5 and 6). Nei- lactam 16 was cleanly formed through 7-endo-trig cy-
ther changing the heating method to an oil bath nor reduc- clization from styrene derived chloroformamide 15 (entry
ing the amount of acid improved the yield (entries 7 and 7). An interesting observation was that when chloroform-
8). Among the acids investigated, HCl was inactive but amide 17, which contains a 4-methylpent-4-enyl group,
trifluoromethanesulfonic acid (TfOH) showed a similar was subjected to the reaction (entry 8), instead of forma-
effect to HBr (entries 9 and 10). On the basis of these re- tion of the seven-membered lactam, the five-membered
sults, we propose the effect of the halogen to be as de- lactam 18 with an exo-alkene was isolated. Styrene deriv-
scribed below. When chloroformamides are converted to ative 19 also afforded a mixture of five-membered lac-
lactams, an equal amount of HCl appears. When bromide tams 20a and 20b. We suppose these reactions proceed
or iodide ions are present in the reaction mixture, a stron- through electrophilic attack of the carbamoyl chloride on
ger acid such as HBr or HI should be obtained from the the olefin with elimination of HCl. For all entries in
equilibrium. We assume that these strong acids somehow Table 3, the electrophilic attack seems to proceed in a
promote the reaction, which seems consistent with the manner that generates the more stable cation intermediate.
case of TfOH.
Even the reactions of compounds 17 and 19, which gave
five-membered lactams with an exo-alkene, proceeded in
this manner. In these reactions, the difficulty in forming
the seven-membered ring likely resulted in alkene isomer-
ization to generate the trisubstituted olefins, which then
underwent cyclization through tertiary cation intermedi-
ates. In contrast, compound 15, having a double bond, was
prevented from isomerization and gave the seven-
membered ring via a benzylic cation intermediate.
Table 2 Effect of Additives on the Formation of Quinolone 2
additive
(30 mol%)
Cl
NMP
microwave
150 °C, 5 min
N
O
N
O
Bn
Bn
1
2
Entry
Additive
Yield of 2 (%) Recovery of 1 (%)
In addition, it was found that quinolone 2 can be formed,
through a one-pot procedure, from aniline 21 (Scheme 2).
Thus, aniline 21 was treated with triphosgene (0.4 equiv)
in dioxane and, after five minutes, HBr (30 mol%) and
NMP were added. Microwave irradiation for ten minutes
afforded quinolone 2 in 68% yield.
1
2
TBAF
TBACl
TBABr
TBAI
KBr
13
43
86
82
53
89
54
80
44
80
16
40
6
3
4
2
5
42
0
triphosgene
(0.4 equiv)
HBr
(30 mol%)
6
HBra
dioxane
r.t., 5 min
NMP
N
O
microwave
NH
Bn
7b
8
HBra
30
11
31
0
150 °C, 10 min
21
2
Bn
68%
HBra,c
HCld
Scheme 2 ne-pot synthesis of quinolone 4
9
In conclusion, we have developed a new method for con-
structing a,b-unsaturated lactams from alkenylchloro-
formamides. The combination of suitable solvent and
catalyst allowed the completion of the reaction in five
minutes with high yield. Because of the simple reaction
conditions, this reaction should be useful for the synthesis
of a variety of a,b-unsaturated lactams.
10
TfOH
a HBr was generated in situ from AcBr (30 mol%) and MeOH (30
mol%).
b Reaction was performed in an oil bath.
c HBr (5 mol%) was used.
d HCl was generated in situ from AcCl (30 mol%) and MeOH (30
mol%).
1H NMR spectra were recorded at 500 MHz, and chemical shifts (d)
are reported relative to TMS (d = 0.00 ppm). 13C NMR spectra were
recorded at 125 MHz, and chemical shifts are reported relative to
CDCl3 (d = 77.0 ppm). Infrared spectra were recorded from KBr
pellets or thin films on NaCl plates. Only charged molecular ion
data are reported for low-resolution mass spectra (LRMS). All mi-
crowave irradiation experiments were carried out in a CEM Discov-
er microwave apparatus.
A variety of a,b-unsaturated lactams were obtained under
the optimized conditions (NMP, 150 °C, 5 min with 30
mol% HBr) determined above (Table 3). Quinolones 4
and 6, with different substituents, were obtained in high
yields (entries 1 and 2). Furthermore, the reaction was ex-
panded to aliphatic chloroformamides. Chloroform-
amides 7, 9 and 11, which were derived from but-3-
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a,b-Unsaturated Lactams from Carbamoylation of Alkenes
3991
Table 3 Synthesis of a,b-Unsaturated Lactams through Intramolecular Electrophilic Carbamoylation of Alkenesa
Entry Substrate
Product(s)
Yield (%)b
Cl
O
1
93
N
O
N
Me
Me
4
6
3
5
Cl
O
2
76
N
O
N
Me
Me
R
R
R
3
4
5
7 (R = H)
9 (R = Me)
11 (R = Ph)
8a (R = H)
10a (R = Me)
12a (R = Ph)
8b (R = H)
10b (R = Me)
12b (R = Ph)
70 (70:30)
76 (86:14)
64 (84:16)
Cl
O
N
O
O
N
O
N
Bn
Bn
Bn
N
Cl
c
6
7
–
N
Bn
Bn
O
14
13
79
Cl
N
N
O
Bn
Bn
O
16
18
15
8
9
91
Cl
O
N
N
Bn
O
Bn
17
Ph
Ph
Ph
87 (75:25)
Cl
O
O
N
N
N
Bn
Bn
O
Bn
20b
19
20a
a Reaction conditions: HBr (30 mol%), MW (150 °C), 5 min, NMP.
b Ratios (a/b) of isomers are shown in parentheses.
c 13 was recovered in 63% yield.
1-Benzyl-4-methylquinolin-2(1H)-one (2);11 Typical Procedure
A mixture of chloroformamide 1 (141 mg, 0.493 mmol), AcBr (11
mL, 0.15 mmol), NMP (0.17 mL) and MeOH (6 mL, 0.15 mmol) was
placed in a reaction vessel and stirred under Ar for 5 min at r.t. The
vessel was then placed in a microwave reactor and heated at 150 °C
for 5 min by microwave irradiation (48 W). After cooling to 0 °C,
the reaction mixture was diluted with EtOAc (10 mL) and brine (10
mL). The mixture was basified to pH 9 with sat. aq NaHCO3 and ex-
tracted with EtOAc (10 × 5 mL). The combined organic layers were
washed with brine (20 mL) and dried over Na2SO4. Removal of the
solvent under reduced pressure afforded the crude product, which
was purified by silica gel column chromatography (hexane–EtOAc,
10:0→5:5) to give quinolone 2.
Yield: 110 mg (89%); white solid; mp 112–113 °C (Lit.11 110.5–
111.5 °C).
IR (KBr): 1651, 1594 cm–1.
1H NMR (CDCl3): d = 7.71 (dd, J1 = 1.4 Hz, J2 = 8.0 Hz, 1 H), 7.41
(ddd, J1 = 1.7 Hz, J2 = 7.8 Hz, J3 = 7.9 Hz, 1 H), 7.29–7.25 (m,
3 H), 7.23–7.19 (m, 4 H), 6.70 (d, J = 1.2 Hz, 1 H), 5.56 (s, 2 H),
2.51 (d, J = 1.2 Hz, 3 H).
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3992
Y. Yasui et al.
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13C NMR (CDCl3): d = 162.1, 146.9, 139.0, 136.5, 130.3, 128.6,
LRMS (EI): m/z = 201 [M+].
127.0, 126.4, 125.1, 121.9, 121.5, 120.8, 115.2, 45.5, 19.0.
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C,
77.67; H, 7.65; N, 6.89.
LRMS (EI): m/z = 249 [M+].
Anal. Calcd for C17H15NO: C, 81.90; H, 6.06; N, 5.62. Found: C,
82.03; H, 6.23; N, 5.67.
1-Benzyl-5,6-dihydro-4-phenylpyridin-2(1H)-one (12a) and
1-Benzyl-1,6-dihydro-4-phenylpyridin-2(3H)-one (12b)
Mixture of 12a/12b (84:16); white solid; mp 97–98 °C.
IR (KBr): 1649, 1603 cm–1.
1,4-Dimethylquinolin-2(1H)-one (4)11
White solid; mp 131.5–132.5 °C (Lit.11 129.5–130.5 °C).
IR (KBr): 1654, 1592 cm–1.
1H NMR (CDCl3): d (* peaks of minor isomer) = 7.51–7.26 (m,
10 H), 6.38 (s, 1 H), 6.07* (br s), 4.74* (s), 4.69 (s, 2 H), 4.01* (dd,
J1 = 4.1 Hz, J2 = 8.1 Hz), 3.46 (t, J = 6.9 Hz, 2 H), 2.75 (t, J = 6.9
Hz, 2 H).
13C NMR (CDCl3): d (* peaks of minor isomer) = 167.2*, 165.3,
149.3, 138.1*, 137.5, 137.4, 136.6*, 132.7*, 129.5, 128.7, 128.7*,
128.6, 128.2*, 128.04, 127.98*, 127.6*, 127.4, 125.7, 124.8*,
119.8, 116.3*, 49.6, 49.5*, 48.5*, 44.6, 34.1*, 26.6.
1H NMR (CDCl3): d = 7.71 (dd, J1 = 1.2 Hz, J2 = 8.1 Hz, 1 H), 7.57
(ddd, J1 = 1.2 Hz, J2 = J3 = 8.1 Hz, 1 H), 7.38 (d, J = 8.1 Hz, 1 H),
7.26 (ddd, J1 = 1.2 Hz, J2 = J3 = 8.1 Hz, 1 H), 6.60 (s, 1 H), 3.71 (s,
3 H), 2.47 (d, J = 1.2 Hz, 3 H).
13C NMR (CDCl3): d = 161.8, 146.1, 139.6, 130.2, 125.0, 121.7,
121.2, 120.9, 114.2, 29.0, 18.7.
LRMS (EI): m/z = 173 [M+].
LRMS (EI): m/z = 263 [M+].
Anal. Calcd for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C,
76.04; H, 6.36; N, 8.07.
Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32. Found: C,
81.97; H, 6.53; N, 5.26.
1,3,4-Trimethylquinolin-2(1H)-one (6)12
2-Benzyl-1,2-dihydro-5-methylbenzo[c]azepin-3-one (16)
White solid; mp 109–110 °C.
IR (KBr): 1633, 1594 cm–1.
1H NMR (CDCl3, 50 °C): d = 7.44 (d, J = 8.0 Hz, 1 H), 7.32 (dd,
J1 = J2 = 8.0 Hz, 1 H), 7.28–7.18 (m, 6 H), 6.90 (d, J = 8.0 Hz, 1 H),
6.42 (s, 1 H), 4.65 (br s, 2 H), 4.11 (br s, 2 H), 2.30 (s, 3 H).
13C NMR (CDCl3, 50 °C): d = 166.5, 143.3, 137.6, 137.3, 136.6,
128.6, 128.4, 128.2, 128.0, 127.34, 127.32, 126.7, 125.1, 50.4, 49.8,
23.8.
White solid; mp 109–110 °C (Lit.12 106.5–107.5 °C).
IR (KBr): 1633, 1593 cm–1.
1H NMR (CDCl3): d = 7.75 (dd, J1 = 1.1 Hz, J2 = 8.0 Hz, 1 H), 7.51
(ddd, J1 = 1.1 Hz, J2 = J3 = 8.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H),
7.25 (dd, J1 = J2 = 8.0 Hz, 1 H), 3.75 (s, 3 H), 2.46 (s, 3 H), 2.30 (s,
3 H).
13C NMR (CDCl3): d = 162.2, 140.7, 138.1, 129.0, 127.0, 124.6,
121.6, 121.4, 113.9, 29.7, 15.2, 13.8.
LRMS (EI): m/z = 187 [M+].
LRMS (EI): m/z = 263 [M+].
Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C,
76.78; H, 6.96; N, 7.22.
Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32. Found: C,
82.29; H, 6.63; N, 5.32.
1-Benzyl-5,6-dihydropyridin-2(1H)-one (8a)13 and 1-Benzyl-
1,6-dihydropyridin-2(3H)-one (8b)
Mixture of 8a/8b (70:30); yellow oil.
1-Benzyl-3-(propan-2-ylidene)pyrrolidin-2-one (18)15
White solid; mp 81.5–82.5 °C (Lit.15 77–79 °C).
IR (KBr): 1682, 1656 cm–1.
IR (thin film): 1663, 1607 cm–1.
1H NMR (CDCl3): d = 7.33–7.25 (m, 5 H), 4.50 (s, 2 H), 3.21 (t,
J = 6.9 Hz, 2H), 2.63–2.60 (m, 2 H), 2.32–2.31 (m, 3 H), 1.78 (s,
3 H).
13C NMR (CDCl3): d = 168.9, 141.7, 136.9, 128.5, 128.2, 127.3,
123.8, 46.8, 42.9, 23.9, 23.5, 18.8.
1H NMR (CDCl3): d (* peaks of minor isomer) = 7.34–7.25 (m,
5 H), 6.55 (dt, J1 = 4.6 Hz, J2 = 9.8 Hz, 1 H), 6.00 (dt, J1 = 1.7 Hz,
J2 = 9.8 Hz, 1 H), 5.78–5.75* (m), 5.69–5.66* (m), 4.67* (s), 4.63
(s, 2 H), 3.83–3.80* (m), 3.32 (t, J = 6.9 Hz, 2 H), 3.06–3.03* (m),
2.34–2.30 (m, 2 H).
13C NMR (CDCl3): d (* peaks of minor isomer) = 167.1*, 164.5,
139.3, 137.4, 136.7*, 128.6*, 128.5, 128.1*, 127.9, 127.4*, 127.3,
125.3, 122.5*, 120.8*, 49.6, 48.2*, 44.5, 32.1*, 24.1.
LRMS (EI): m/z = 215 [M+].
Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found: C,
78.32; H, 8.10; N, 6.49.
LRMS (EI): m/z = 187 [M+].
(E)-1-Benzyl-3-(1-phenylethylidene)pyrrolidin-2-one (20a)
Yellow oil.
IR (thin film): 1674 cm–1.
1H NMR (CDCl3): d = 7.37–7.32 (m, 4 H), 7.29–7.25 (m, 4 H),
7.22–7.20 (m, 2 H), 4.54 (s, 2 H), 3.15 (t, J = 6.3 Hz, 2 H), 2.62 (t,
J = 1.7 Hz, 3 H), 2.59–2.55 (m, 2 H).
13C NMR (CDCl3): d = 169.2, 144.3, 143.8, 136.7, 128.6, 128.3,
128.2, 127.5, 127.3, 126.8, 126.3, 47.0, 43.3, 25.7, 18.9.
Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C,
76.69; H, 7.08; N, 7.43.
1-Benzyl-5,6-dihydro-4-methylpyridin-2(1H)-one (10a)14 and 1-
Benzyl-1,6-dihydro-4-methylpyridin-2(3H)-one (10b)
Mixture of 10a/10b (86:14); yellow oil.
IR (thin film): 1669, 1619 cm–1.
1H NMR (CDCl3): d (* peaks of minor isomer) = 7.33–7.24 (m,
5 H), 5.80–5.79 (m, 1 H), 5.38–5.35* (m), 4.66* (s), 4.61 (s, 2 H),
3.78–3.75* (m), 3.29 (t, J = 7.5 Hz, 2 H), 2.94* (t, J = 4.0 Hz), 2.25
(t, J = 7.5 Hz, 2 H), 1.90 (s, 3 H), 1.72* (s).
13C NMR (CDCl3): d (* peaks of minor isomer) = 167.4*, 165.1,
150.6, 137.6, 136.8*, 130.4*, 128.5*, 128.5, 128.0*, 127.9, 127.4*,
127.2, 120.5, 114.8*, 49.4*, 49.3, 48.1*, 44.4, 36.7*, 29.3, 22.7,
21.8*.
LRMS (EI): m/z = 277 [M+].
Anal. Calcd for C19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C,
82.43; H, 6.99; N, 5.26.
(Z)-1-Benzyl-3-(1-phenylethylidene)pyrrolidin-2-one (20b)
White solid; mp 112.5–113.5 °C.
Synthesis 2009, No. 23, 3989–3993 © Thieme Stuttgart · New York

PAPER
a,b-Unsaturated Lactams from Carbamoylation of Alkenes
3993
IR (KBr): 1686, 1660 cm–1.
Niida, A.; Tsuji, T.; Shigenaga, A.; Fujii, N.; Otaka, A.
J. Org. Chem. 2006, 71, 4969. (d) García, E.; Lete, E.;
Sotomayor, N. J. Org. Chem. 2006, 71, 6776. (e) Albrecht,
Ł.; Richter, B.; Krawczyk, H.; Jørgensen, K. A. J. Org.
Chem. 2008, 73, 8337.
1H NMR (CDCl3): d = 7.36–7.33 (m, 2 H), 7.31–7.28 (m, 3 H),
7.28–7.22 (m, 5 H), 4.44 (s, 2 H), 3.28 (t, J = 6.9 Hz, 2 H), 2.80–
2.77 (m, 2 H), 2.08 (t, J = 1.8 Hz, 3 H).
13C NMR (CDCl3): d = 166.8, 142.8, 141.3, 136.8, 128.5, 128.3,
127.7, 127.5, 127.4, 127.0, 125.9, 46.9, 42.7, 24.5, 24.1.
(6) For examples of synthetic methods for a,b-unsaturated
lactams, see: (a) Crisp, G. T.; Meyer, A. G. Tetrahedron
1995, 51, 5585. (b) Andrus, M. B.; Li, W.; Keyes, R. F.
J. Org. Chem. 1997, 62, 5542. (c) Kobayashi, K.; Kitamura,
T.; Yoneda, K.; Morikawa, O.; Konishi, H. Chem. Lett.
2000, 798. (d) Grison, C.; Genève, S.; Coutrot, P.
Tetrahedron Lett. 2001, 42, 3831. (e) Niida, A.; Oishi, S.;
Sasaki, Y.; Mizumoto, M.; Tamamura, H.; Fujii, N.; Otaka,
A. Tetrahedron Lett. 2005, 46, 4183. (f) Collison, C. G.;
Chen, J.; Walvoord, R. Synthesis 2006, 2319. (g) Spiess, S.;
Berthold, C.; Weihofen, R.; Helmchen, G. Org. Biomol.
Chem. 2007, 5, 2357.
LRMS (EI): m/z = 277 [M+].
Anal. Calcd for C19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C,
82.21; H, 6.98; N, 5.02.
Acknowledgment
This work was supported in part by Grants-in-Aid for Scientific Re-
search B (No. 193990005) (Y.T.) and for Young Scientists B (No.
20790008) (Y.Y.), ‘Targeted Proteins Research Program’ from the
Ministry of Education, Culture, Sports, Science and Technology of
Japan, and the 21st Century COE Program ‘Knowledge Information
Infrastructure for Genome Science’.
(7) For a review, see: Yasui, Y.; Takemoto, Y. Chem. Rec. 2008,
8, 386.
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