The mimic of type II aldolases chemistry: Asymmetric synthesis of β-Hydroxy Ketones by Direct Aldol Reaction: Research Letter

Article abstract of DOI:10.1111/j.1747-0285.2010.00998.x

An efficient direct aldol reaction has been developed for the synthesis of chiral β-hydroxy ketone using a combination of C₁-symmetric chiral prolinamides based on o-phenylenediamine and zinc triflate as catalyst. The reaction was convenient to

Full text of DOI:10.1111/j.1747-0285.2010.00998.x

ª 2010 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2010.00998.x
Chem Biol Drug Des 2010; 76: 181–186
Research Letter
The Mimic of Type II Aldolases Chemistry:
Asymmetric Synthesis of b-Hydroxy Ketones by
Direct Aldol Reaction
Zhijin Lu1, Haibo Mei1, Jianlin Han1,* and
In virtue of the importance of chiral b-hydroxy ketones, several
approaches aiming to prepare them have been reported in the last
Yi Pan1,2,
*
decade (15–27). Among all the catalytic direct aldol, the most
attractive one is the mimic of the actions of the enzymes. Although
the direct catalytic aldol systems which were assumed to proceed
through an enamine mechanism by mimic of aldolase type I have
been well explored (28–32), the direct aldol systems by using the
methods analogue to the actions of aldolase type II containing a
zinc cofactor have still remained challenging. In fact, there were
only a few reports for direct aldol reactions promoted by the zinc
complexes with N-donor ligands in the presence of water until now
(33–38). Herein, we reported a chiral ligands and zinc triflate cata-
lyzed asymmetric direct aldol reaction with water as solvent. To our
knowledge, this is the first example that mimics type II aldolase uti-
lizing C1-symmetric organic molecular based on o-phenylenediamine
as chiral ligand.
1School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China
2State Key Laboratory of Coordination Chemistry, Nanjing University,
Nanjing 210093, China
*Corresponding authors: Jianlin Han, molab@nju.edu.cn; Yi Pan,
yipan@nju.edu.cn
An efficient direct aldol reaction has been devel-
oped for the synthesis of chiral b-hydroxy ketone
using a combination of C1-symmetric chiral proli-
namides based on o-phenylenediamine and zinc
triflate as catalyst. The reaction was convenient
to carry out in aqueous media with up to 98%
chemical yields and up to 94% ee values. The cur-
rent strategy can be regarded as the analogue of
aldolase type II, which suggests a new pathway
for the designing of new organocatalysts.
Results and Discussions
According to the mechanism of type II aldolase (33–38), we
designed and prepared a series of chiral ligands (Figure 1). These
chiral ligands 1–6 were easily prepared from proline and aniline or
o-phenylenediamine in high yields. Most of these ligands have C1
symmetry, expect compound 4, which is a C2-symmetric ligand.
Then, all these compounds were used in the direct aldol reactions.
The reactions were carried out between cyclohexanone and p-nitro-
Key words: aldol reaction, chiral prolinamides, zinc triflate,
b-hydroxy ketone
Received 15 December 2009, revised 7 May 2010 and accepted for pub-
lication 7 May 2010
The development of stereoselective and enantioselective aldol reac-
tion has become an interesting and challenging topic in modern
organic and medicinal chemistry (1–3), because the resulting chiral
b-hydroxy ketones belong to an extremely important class of biolog-
ical compounds. In fact, b-hydroxy ketones can serve as versatile
building block for the asymmetric synthesis of carbohydrates, amino
acids and many other biomolecules (4–6). They also provide privi-
leged structural functionalities that exist in many important natural
products (7–12). For example, the b-hydroxy ketones functionalities
exist in macrolide classes of antibiotics such as telithromycin and
cethromycin which are targeted primarily against Gram-positive bac-
terial strains including Streptococcus pneumoniae and S. pyogenes,
fastidious Gram-negative strains including Haemophilus influenzae
and Moraxella catarrhalis, atypicals Mycoplasma pneumoniae, Chla-
mydia pneumoniae and Legionella pneumophilia (13). They were
also found in conagenin that can improve the antitumor efficacy of
adriamycin and mitomycin C against murine leukemias, which sug-
gest its potential utility for cancer chemotherapy (14).
Figure 1: Structure of the catalysts 1–6.
181

Lu et al.
benzaldehyde in aqueous media (Table 1). As shown by Table 1, all
the designed chiral prolinamide derivatives worked well in the
direct aldol reactions and gave the desired b-hydroxy ketone in
good yields and good enantioselectivities. Addition of zinc trifluo-
romethanesulfonate could obviously improve the diastereoselectivi-
ties and enantioselectivities (entry 10 versus entry 9). Good result
was obtained when the combined catalyst of zinc triflate and the
C2-symmetric prolinamide ligand 4 containing two amino acid mo-
ities was used (Table 1, entry 8). However, the best result with
respect to yield and enantioselectivity was observed with C1-sym-
metric prolinamide ligand 5 and Zn(OTf)2 as additive (96% yield and
93% ee, Table 1, entry 10). The loading amount of Zn(OTf)2 in the
reaction was also investigated. The use of 5 mmol% of Zn(OTf)2
seemed best for the reaction (Table 1, entry 10). Although lower
loading of Zn(OTf)2 slightly decreased both yields and selectivities
(Table 1, entries 15 and 16), no improvement was detected when
more than 10 mmol% catalyst was used (Table 1, entries 13 and
14).
form product and control the stereoselectivity of the reaction. Reac-
tion temperature was also found to have some effect on the cur-
rent catalytic system. When the temperature was increased to
50 ꢀC, both the diastereoselectivity and the enantioselectivity
decreased (Table 2, entry 8). Decreasing the temperature to 3 ꢀC
still did not show any improvement on diastereoselectivity (Table 2,
entry 10). From the results above, we found that these new chiral
ligands together with zinc triflate could act as catalysts for direct
aldol in aqueous media. Both zinc triflate and chiral prolineamides
were essential for the catalytic system. In this respect, the com-
bined catalysts could be regarded as mimic of type II aldolase, and
an enamine was presumed to be formed in the active site (33–38).
After the optimized reaction conditions was obtained, several aldol
reactions under the above-mentioned conditions were carried out to
check their catalytic activities, and the results are summarized in
Table 3. Several aromatic aldehydes were suitable substrates for
the reaction and gave corresponding b-hydroxy ketone with good to
excellent yields. Especially for aldehydes with strong electron-with-
drawing group (NO2) on the aromatic ring, the reaction gave excel-
lent yields, high enantioselectivities (Table 3, entries 1–3). However,
for the aldehyde substituted with a CF3 group, only moderate dia-
stereoselectivity was found (anti:syn = 59:41, Table 3, entry 7). In
the cases of the aldehydes with electron-donating group (OMe) on
the aromatic ring, such as 4-methoxybenzaldehyde and 4-methyl-
benzaldehyde, only a trace amout of desired products were
observed even after the reaction time had been extended to 72 h.
From Table 1, it was also found that the prolinamides and zinc tri-
flate combined catalyst can work very well in aqueous media. Then,
the solvents used for this reaction were examined (Table 2). The
chemical yields were increased by the use of water as co-solvent
(Table 2, entries 3–5). The best result was observed when the ratio
of cyclohexanone to water was 5:1, and 96% chemical yield and
93% ee value were obtained (Table 2, entry 5). Almost no desired
product was detected when DMSO was used as solvent (Table 2,
entry 7), and only medium yield and enantioselectivity were found
with neat cyclohexanone (Table 2, entry 6) or tetrahydrofuran
(Table 2, entry 2) as solvent. It is obvious that water is helpful to
Acetone was also used as substrate in the direct aldol reaction
with p-nitrobenzaldehyde under the same reaction condition
Table 1: Screening of catalysts in the reaction between cyclohexanone and p-nitrobenzaldehydea
Entry
Ligand
Zn(OTf)2 (mol%)
Yield (%)b
Anti ⁄ sync
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1
1
2
2
3
3
4
4
5
5
6
6
5
5
5
5
0
5
0
5
0
5
0
5
0
88
85
90
88
92
95
90
88
95
96
94
95
30
92
88
90
85:15
90:10
87:13
88:12
78:22
78:22
72:28
83:17
73:27
83:17
69:31
75:25
61:39
60:40
62:38
60:40
80
87
80
85
71
78
77
86
78
93
77
92
89
82
88
73
5
0
5
20
10
2.5
1.25
aReaction conditions: aldehyde (75.5 mg, 0.5 mmol), cyclohexanone (1 mL), ligand (5 mol%), water (0.2 mL), room temperature.
bIsolated yield.
cDetermined by chiral HPLC (Chiralpak AD-H). This system seems to be selective for the formation of the R configuration.
182
Chem Biol Drug Des 2010; 76: 181–186

Mimic of Type II Aldolases
Table 2: The optimization of the current aldol reaction conditionsa
Entry
Solvent
T (ꢀC)
Yield (%)b
Anti ⁄ sync
ee (%)c
1
2
3
4
5
6
7
8
9
Water
25
25
25
25
25
25
25
50
30
3
95
50
98
97
96
60
<10%
98
98
90
74:26
83:17
68:32
72:28
83:17
58:42
–
64:36
88:12
73:27
79
89
88
87
93
69
–
79
94
96
THF ⁄ H2O = 9:1
cyclo ⁄ H2O = 9:1
Cyclo ⁄ H2O = 1:1
Cyclo ⁄ H2O =5:1
Cyclohexanone
DMSO
Cyclo ⁄ H2O = 5:1
Cyclo ⁄ H2O = 5:1
Cyclo ⁄ H2O = 5:1
10
aReaction conditions: aldehyde (75.5 mg, 0.5 mmol), cyclohexanone (260 lL, 2.5 mmol), 5 mmol% 5 and 5 mmol% Zn(OTf)2 in 1 mL solvent.
bIsolated yield.
cDetermined by chiral HPLC (Chiralpak AD-H). This system seems to be selective for the formation of the R configuration.
Table 3: Catalytic aldol reaction between cyclohexanone and aryl aldehydesa
Entry
R
Product
Yield (%)b
Anti ⁄ sync
ee (%)c
1
2
3
5
6
7
4-NO2
3-NO2
2-NO2
7a
7b
7c
7d
7e
7f
98
92
90
34
83
92
88:12
60:40
90:10
82:18
46:54
59:41
94
87
95
84
74
85
2-naphthyl
4-CN
4-CF3
aReaction conditions: aldehyde (0.5 mmol), cyclohexanone (1 mL), water (0.2 mL), room temperature.
bIsolated yield.
cDetermined by chiral HPLC (Chiralpak AD-H, OD-H and AS-H). This system seems to be selective for the formation of the R configuration.
(Scheme 1). The corresponding product 8 was formed with excellent
chemical yield (90% yield). However, It was obvious that acetone
gave a little bit lower enantioselectivity compared to the cyclohexa-
none substrates, and only 60% ee value was obtained.
lases. The Zn2+ ion may co-ordinate to ketone and can promote the
formation of ketone-enolate. Although the asymmetric ligand pro-
vides a chiral environment, resulting in the enantioselectivity of the
current system.
The mechanism of this catalytic system is believed to be similar to
that of previous reported zinc-proline complex catalyzed aldol reac-
tions (39,40), which can be assumed as the mimic of Type II aldo-
In summary, a series of C1-symmetric chiral prolinamides based on
o-phenylenediamine were designed and were successfully used as
chiral ligands in metal-assisted asymmetric direct aldol reactions in
aqueous media for the first time. This catalytic direct aldol provides
an easy access to the chiral b-hydroxy ketones with good diastere-
oselectivities (dr up to 88:12) and high enantioselectivities (up to
96% ee). This catalytic results were really good in the area of mim-
icking the type II aldolase. These new C1-symmetric chiral
prolinamides based on o-phenylenediamine explore an interesting
area of direct aldol reaction catalyzed by zinc salt and organocata-
lysts in aqueous media.
O
OH
O
CHO
10 mol% 5 and Zn(OTf)2
+
wate, r.t., 24 h
O2N
8 (R)
90% yield, 60% ee
NO2
Scheme 1: Aldol reaction with acetone.
Chem Biol Drug Des 2010; 76: 181–186
183

Lu et al.
Boc-protected proline (0.65 g, 3 mmol) and TEA (0.31 g, 3 mmol)
were dissolved in THF (20 mL). To the solution was added dropwise
ethylchloroformate (0.38 g, 3.5 mmol) at 0 ꢀC. After the solution
was stirred for 15 min, the intermedia obtained above (0. 96 g,
3 mmol) was added. The resulting solution was stirred at 0 ꢀC for
1 h, at room temperature for 16 h, detected by TLC. The reaction
mixture was filtered and washed with THF, and the filtrate
was evaporated to dryness. The residue was purified through
chromatography on a silica gel column eluted with methanol and
dichloromethane to give colorless oil ((R)-tert-butyl 2-((2-((2S,4R)-4-
hydroxypyrrolidine-2-carboxamido)phenyl)carbamoyl)pyrrolidine-1-car-
boxylate) with 65% yield. Then, the Boc-protect 3 was dissolved in
CH2Cl2 (12 mL) and CF3COOH (3 mL) and stirred for 2 h; the reaction
was treated by ammonia solution (10 mL) for 0.5 h; the aqueous
layer was extracted with CH2Cl2 (20 mL · 3). The combined organic
phase was washed with brine, dried over anhydrous Na2SO4 and
removal of the solvent gave brown oil 3 (0.61 g, 38% yield overall
Experimental Section
General remarks
Cyclohexanone was distilled and p-nitrobenzaldehyde was subli-
mated before use. All reagents not listed were used as received from
common commercial sources. NMR spectra were obtained on Bruker
300 or 500 MHz spectrometer in DMSO-d6 or CDCl3, and chemical
shifts are reported in ppm using tetramethylsilane as internal stan-
dard. IR and ESI-MS spectra were measured on Bruker Vector 22 as
KBr pellets and Finnigan Mat TSQ 7000 instruments (Finnigan, San
Jose, CA, USA), respectively. Microanalyses were obtained on Per-
kin-Elmer 240 instruments (PerkinElmer, CT, USA), and melting points
(mp) were determined with a digital electrothermal apparatus with-
out further correction. Optical rotation measurements were deter-
mined at RT using HPLC-grade solvents. Analytical HPLC
measurements were carried out on the Perkin-Elmer machine.
Compound 1 was prepared according to the reported method (41).
20
1
steps). ½aꢀD = )30.1 (c = 1.0, CH3OH). H NMR (300 MHz, DMSO-
d6): 1H d 9.87 (s, 1H), 7.67-7.61 (m, 2H), 7.15-7.12 (m, 2H), 4.22-
4.21 (m, 2H), 3.92-3.87 (m, 2H), 3.74-3.69 (m, 2H), 2.95-2.78 (m, 4H),
2.10-1.98 (m, 2H), 1.88-1.78 (m, 2H), 1.71-1.59 (m, 2H).13C NMR
(75 MHz, DMSO-d6): d 174.4, 174.4, 131.0, 130.7, 125.4, 125.3,
124.4,.124.1, 71.9, 61.1, 60.3, 55.5, 47.2, 40.25, 30.9, 26.4. IR (KBr
disc): 3422, 3332, 3234 cm)1. ESI-MS: m ⁄ z = 319.33 [M + H+].
Anal. Calcd (%) for C16H22N4O3 C, 60.36; H, 6.97; N, 17.60; Found:
C, 60.29; H, 7.01; N, 17.55.
General procedure for the synthesis of 2–6
(Data S2)
2: (2S,4R)-4- hydroxypyrrolidine-2-carboxylic acid (1.15 g, 5 mmol)
and TEA (0.61 g, 6 mmol) were dissolved in THF (20 mL). To the
solution was added dropwise ethylchloroformate (0.65 g, 6 mmol)
at 0 ꢀC. After the solution was stirred for 15 min, aniline (0.46 g,
5 mmol) was added. The resulting solution was stirred at 0 ꢀC for
1 h, at room temperature for 16 h, detected by TLC. The reaction
mixture was filtered and washed with THF, and the filtrate was
evaporated to dryness. The residue was purified through chromatog-
raphy on a silica gel column eluted with methanol and dichlorome-
thane to give colorless oil. The colorless product were dissolved in
CH2Cl2 (12 mL) and F3CCOOH (3 mL) and stirred for 2 h; the reaction
was treated by ammonia solution (10 mL) for 0.5 h; the aqueous
layer was extracted with CH2Cl2 (20 mL · 3). The combined organic
phase was washed with brine, dried over anhydrous Na2SO4 and
removal of the solvent gave a white solid 2 with 90% yield
4: (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (2.32 g, 10 mmol)
and TEA (1.22 g, 6 mmol) were dissolved in THF (30 mL). To the
solution was added dropwise ethylchloroformate (1.31 g, 12 mmol)
at 0 ꢀC. After the solution was stirred for 15 min, o-phenylenedi-
amine (0.54 g, 5 mmol) was added. The resulting solution was stir-
red at 0 ꢀC for 1 h, at room temperature for 16 h, detected by TLC.
The reaction mixture was filtered and washed with THF, and the fil-
trate was evaporated to dryness. The residue was purified through
chromatography on a silica gel column eluted with methanol and
dichloromethane to give colorless oil (Bco-protect 4) with 62%
yield. Then, colorless Bco-protected 4 were dissolved in CH2Cl2
(12 mL) and CF3COOH (3 mL) and stirred for 2 h. The reaction was
treated by ammonia solution (10 mL) for 0.5 h; the aqueous layer
was extracted with CH2Cl2 (20 mL · 3). The combined organic
phase was washed with brine, dried over anhydrous Na2SO4 and
removal of the solvent gave brown oil 4 (0.71 g, 42% yield overall
20
1
½aꢀD = )29.3 (c = 1.0, CH3OH). H NMR (300 MHz, CDCl3): d 9.79
(s, 1H), 7.61-7.58 (m, 2H), 7.36-7.31 (m, 2H), 7.14-7.09 (m, 1H), 4.49-
4.47 (t, J = 3.2 Hz 1H), 4.18-4.13 (t, J = 8.6 Hz 1H), 3.14-3.09 (dd,
J = 1.5, 12.2 Hz 1H), 2.92-2.87 (dd, J = 3.0, 12.6 Hz, 1H), 2.42-2.34
(m, 1H), 2.09-2.00 (m, 1H).13C NMR (75 MHz, CDCl3): d 173.2,
137.6, 129.0, 124.2, 119.5, 73.2, 60.2, 55.3, 39.8. IR (KBr disc):
3450 cm)1.ESI-MS: m ⁄ z = 207.24[M + H+]. Anal. Calcd (%) for
C11H14N2O2: C, 64.06; H, 6.84; N, 13.58; Found: C, 64.03; H, 6.85;
N, 13.55.
20
steps).½aꢀD = )45.7 (c = 1.0, CH3OH). 1H NMR (300 MHz, DMSO-
d6): d 9.88 (s, 1H), 7.65-7.62 (m, 2H), 7.15-7.11 (m, 2H), 4.22-4.20
(m, 2H), 3.92-3.87 (m, 2H), 2.83-2.82 (d, 2H), 2.07-2.00 (m, 2H), 1.88-
1.80 (m, 2H). 13C NMR (75 MHz, DMSO-d6): d 174.4, 130.9, 125.4,
3: (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (1.15 g, 5 mmol)
and TEA (0.61 g, 6 mmol) were dissolved in THF (20 mL). To the
solution was added dropwise ethylchloroformate (0.65 g, 6 mmol)
at 0 ꢀC. After the solution was stirred for 15 min, o-phenylenedi-
amine (0.54 g, 5 mmol) was added. The resulting solution was stir-
red at 0 ꢀC for 1 h, at room temperature for 16 h, detected by TLC.
The reaction mixture was filtered and washed with THF, and the fil-
trate was evaporated to dryness. The residue was purified through
chromatography on a silica gel column eluted with methanol and
dichloromethane to give colorless oil ((2S,4R)-N-(2-aminophenyl)-4-
hydroxypyrrolidine-2-carboxamide) with 72% yield.
124.3, 71.9, 60.3, 55.5, 40.2. IR (KBr disc): 3434, 3340, 3201 cm)1
.
ESI-MS: m ⁄ z = 335.33 [M + H+]. Anal. Calcd (%) for C16H22N4O4 C,
57.47; H, 6.63; N, 16.76; Found: C, 57.55; H, 6.59; N, 16.72.
5: The o-phenylenediamine (1.08 g, 10 mmoL) and pyridine
(0.96 g,12 mmol) were dissolved in the THF (20 mL). To the solution
was added dropwise 1-naphthoyl chloride in THF (20 mL) in 30 min;
the resulting solution was stirred at room temperature for 4 h,
detected by TLC. Then, the mixture was filtered to get the solution
of N-(2-aminophenyl)-1-naphthamide.
184
Chem Biol Drug Des 2010; 76: 181–186

Mimic of Type II Aldolases
Boc-protected proline (1.61 g, 8 mmol) and TEA (0.82 g, 8 mmol)
were dissolved in THF (20 mL). To the solution was added dropwise
ethylchloroformate (1.08 g, 10 mmol) at 0 ꢀC. After the solution
was stirred for 15 min, the prepared solvent mentioned above was
added. The resulting solution was stirred at 0 ꢀC for 1 h at room
temperature for 16 h and detected by TLC. The reaction mixture
was filtered and washed with THF, and the filtrate was evaporated
to dryness. The residue was purified through chromatography on a
silica gel column eluted with methanol and dichloromethane to give
colorless oil as Boc-protect 5. Then, the colorless Boc-protect 5
was dissolved in CH2Cl2 (12 mL) and CF3COOH (3 mL), and stirred
for 2 h; the reaction was treated by ammonia solution (10 mL) for
0.5 h; the aqueous layer was extracted with CH2Cl2 (20 mL · 3).
The combined organic phase was washed with brine, dried over
anhydrous Na2SO4 and removal of the solvent gave brown oil 5
m ⁄ z = 376.25 [M + H+] Anal. Calcd (%) for C22H21N3O3 C, 70.38; H,
5.64; N, 11.19; Found: C, 70.30; H, 5.60; N, 11.25.
Typical procedure for the direct aldol reaction
Catalyst 5 (5 mol%, 0.025 mmol, 8.99 mg) and Zn(OTf)2 (5 mol%,
0.025 mmol, 9.08 mg) were stirred in the solvent (1.2 mL, cyclohexa-
none:H2O = 5:1) for 10 min. The 4-nitrobenzaldehyde (0.5 mmoL,
75.5 mg) was then added and the resulted mixture was stirred for the
given time and temperature. The aqueous layer was decanted from the
precipitated products and extracted with ether. The desired products 7
and 8 were obtained by flash chromatography and have been charac-
terized to be identical to those of known samples (42) (Data S1).
20
1
(2.34 g, 65% yield overall steps). ½aꢀD = 3.03 (c = 1.0, CH3OH). H
NMR (300 MHz, DMSO-d6): d 10.38 (s, 1H), 10.33 (s, 1H), 8.46-8.44
(d, 1H), 8.19-8.16 (d, 1H), 8.14-8.11 (d, 1H), 8.06-8.03 (m, 1H), 7.98-
7.96 (d, 1H), 7.68-7.61 (m, 3H), 7.46-7.44 (m,1H), 7.36-7.30 (m, 1H),
7.22-7.17 (m, 1H), 3.80-3.76 (m, 1H), 2.92-2.84 (m, 1H), 2.75-2.68
(m, 1H), 2.12-2.00 (m, 1H), 1.89-1.78 (m, 1H), 1.68-1.56 (m, 2H). 13C
NMR (75 MHz, DMSO-d6): d 174.1, 168.5, 134.3, 134.2, 133.7,
131.0, 128.8, 128.4, 127.7, 126.4, 126.0, 125.4, 124.3, 122.0, 61.4,
Acknowledgments
We gratefully acknowledge National Natural Science Foundation of
China (Grant No. 20772056) and Jiangsu 333 program (for Pan) for
the generous financial support. The research funds for Pan from the
Qing-Lan program of Jiangsu Province and the Kua-Shi-Ji program
of the Education Ministry of China are also acknowledged.
47.2, 30.9, 26.4. IR (KBr disc): 3464, 3249 cm)1
. ESI-MS:
m ⁄ z = 360.25 [M + H+].Anal. Calcd (%) for C22H21N3O2 C, 73.52; H,
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6: The o-phenylenediamine (1.08 g, 10 mmol) and pyridine
(0.96 g,12 mmol) were dissolved in the THF (20 mL). To the solution
was added dropwise 1-naphthoyl chloride in THF (20 mL) in 30 min,
the resulting solution was stirred at room temperature for 4 h and
detected by TLC. Then, the mixture was filtered to get the solution
of N-(2-aminophenyl)-1-naphthamide.
(2S,4R)-4-Hydroxypyrrolidine-2-carboxylic acid (1.95 g, 8 mmol) and
TEA (0.82 g, 8 mmol) were dissolved in THF (30 mL). To the solution
was added dropwise ethylchloroformate (1.08 g, 10 mmol) at 0 ꢀC.
After the solution was stirred for 15 min, the solution obtained
above (0.54 g, 5 mmol) was added. The resulting solution was stir-
red at 0 ꢀC for 1 h, at room temperature for 16 h and detected by
TLC. The reaction mixture was filtered and washed with THF, and
the filtrate was evaporated to dryness. The residue was purified
through chromatography on a silica gel column eluted with methanol
and dichloromethane to give colorless oil as Boc-protected 6. Then,
the colorless Boc-protected 6 was dissolved in CH2Cl2 (12 mL) and
CF3COOH (3 mL) and stirred for 2 h; the reaction was treated by
ammonia solution (10 mL) for 0.5 h; the aqueous layer was extracted
with CH2Cl2 (20 mL · 3). The combined organic phase was washed
with brine, dried over anhydrous Na2SO4 and removal of the solvent
20
gave brown oil 6 (1.73 g, 46% yield overall steps). ½aꢀD = )30.4
(c = 1.0, CH3OH). 1H NMR (300 MHz, DMSO-d6): d 10.34 (s, 1H),
10.29 (s, 1H), 8.42-8.39 (m, 1H), 8.15-8.10 (m, 2H), 8.05-8.02 (m, 1H),
7.96-7.93 (m, 1H), 7.67-7.59 (m, 3H), 7.45-7.42 (m,1H), 7.34-7.29 (m,
1H), 7.21-7.12 (m, 2H), 3.98-3.87 (m, 1H), 2.82-2.68 (m, 3H), 2.10-2.03
(m, 1H), 1.84-1.76 (m, 1H). 13C NMR (75 MHz, DMSO-d6): d 174.0,
168.5, 134.3,134.1, 133.7, 131.0, 130.3, 129.1, 128.8, 128.4, 127.6,
127.4, 127.2, 126.9, 126.4, 126.2, 125.9, 125.5, 124.4, 122.1. 71.9,
60.6, 55.4, 40.2, 28.6. IR (KBr disc): 3422, 3338 cm)1; ESI-MS:
Chem Biol Drug Des 2010; 76: 181–186
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1
Data S2. H and 13C NMR spectrums compounds 2–6.
Please note: Wiley-Blackwell is not responsible for the content or
functionality of any supporting materials supplied by the authors.
Any queries (other than missing material) should be directed to the
corresponding author for the article.
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asymmetric aldol reactions. J Am Chem Soc;122:2395–2396.
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