Enantioselective α-hydroxylation of β-keto esters catalyzed by chiral S-timolol derivatives

Article abstract of DOI:10.1016/j.tet.2012.07.003

A screen of aryloxy aminopropanol organocatalysts derived from the β-blocker inhibitor S-timolol determined the most active catalyst of asymmetric α-hydroxylation of β-keto esters. (R)-1-(tert-butylamino)- 3-(3,4,5-trimethoxyphenoxy) propan-2-ol (3k) was the most effective derivative, enantioselectively catalyzing α-hydroxylation of β-keto esters using tert-butyl hydroperoxide as the oxidant in hexane to afford the corresponding products in excellent yield and with good enantioselectivity (up to 96% yield, 88% ee).

Full text of DOI:10.1016/j.tet.2012.07.003

Tetrahedron 68 (2012) 7973e7977
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective
derivatives
a-hydroxylation of b-keto esters catalyzed by chiral S-timolol
*
Yuanchun Cai, Mingming Lian, Zhi Li, Qingwei Meng
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, Liaoning Province, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A screen of aryloxy aminopropanol organocatalysts derived from the
determined the most active catalyst of asymmetric a-hydroxylation of b
b
-blocker inhibitor S-timolol
-keto esters. (R)-1-(tert-butyla-
mino)-3-(3,4,5-trimethoxyphenoxy) propan-2-ol (3k) was the most effective derivative, enantiose-
lectively catalyzing -hydroxylation of -keto esters using tert-butyl hydroperoxide as the oxidant in
Received 30 March 2012
Received in revised form 7 June 2012
Accepted 3 July 2012
a
b
Available online 20 July 2012
hexane to afford the corresponding products in excellent yield and with good enantioselectivity (up to
96% yield, 88% ee).
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Chiral drug
Aryloxy aminopropanol organocatalyst
b
-Keto ester
Asymmetric
a
-hydroxylation
1. Introduction
The -hydroxydicarbonyl moiety is an important structural
motif in a variety of natural products, pharmaceutical products and
key intermediates, such as kjellmanianone, hamigeran A, and vin-
doline.1 (S)-5-Chloro-2-hydroxy-1-oxo-indan-2-carboxylic acid
methyl ester is an especially important intermediate in the syn-
thesis of the insecticide Indoxacarb (Fig. 1A) by the Dupont com-
pany.2 The most convenient enantioselective synthesis of the
from chiral phosphoric acid as a catalyst and nitroso compounds as
oxidant to realize highly enantioselective
a-hydroxylation of b-
a
dicarbonyl compounds. However, these methodologies are limited
by the use of expensive catalysts and complicated oxidants. Chiral
Brønsted bases can also be used as effective catalysts. The Dupont
company and Jørgensen groups, as well as our group, have applied
alkaloids and their derivatives, such as cinchonine, dihydroquinine,
lappaconitine, and cinchonine-based ammonium salts (phase-
transfer catalysts) as catalysts and tert-butyl hydroperoxide (TBHP)
or cumyl hydroperoxide (CHP) as oxidants to obtain moderate to
good enantioselective oxidation products.6 Notably, the Dupont
company manufactures hundreds of tons of Indoxacarb annually
using cinchonine as catalyst. This type of organocatalyst is stable in
air and water and is relatively nontoxic. Despite these contribu-
tions, few chiral Brønsted base catalysts are known, and there is
great need for new chiral Brønsted bases, which are easily pre-
pared, nontoxic, economical, and efficient.
A
B
Our group has screened chiral drugs including vindoline,
erythromycin, tadalafil, azithromycin, S-timolol and R-propranolol
Fig. 1. The structures of Indoxacarb and S-timolol.
for
intermediate in the synthesis of the insecticide Indoxacarb.7 The
conversion of this -hydroxylation reaction, catalyzed by S-timolol
a-hydroxylation of methyl 5-chloro-1-indone carboxylate, a key
a
-hydroxydicarbonyl unit is through direct oxidation of b-keto
esters by metal complexes and organocatalysts. Metal complexes,
a
such as the TASSOL-Ti complex3 and the DBFOX-Ni complex4 have
(Fig. 1B), was 92%, with 32% ee (R).
been reported to be effective catalysts for enantioselective a-hy-
The thiadiazole group of S-timolol was unstable and could de-
compose during the reaction process; in addition, S-timolol affor-
ded an R-enantiomeric excess, which was the opposite of the
desired configuration. Here, we use S-timolol as a lead compound
droxylation of b-keto esters using oxaziridine as the oxidant. In the
field of organocatalysis, Zhong5 used a chiral Brønsted acid derived
to synthesize more stable and R-configured catalysts for the
droxylation of -keto esters.
a-hy-
* Corresponding author. Tel.: þ86 411 84986201; e-mail address: mengqw@
dlut.edu.cn (Q. Meng).
b
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.003

7974
Y. Cai et al. / Tetrahedron 68 (2012) 7973e7977
Table 1
2. Results and discussion
Screening of reaction conditions for asymmetric
a
-hydroxylation of
b
-ketoestera
Initially, we synthesized various aryloxy aminopropanol orga-
nocatalysts using commercial raw materials, including different
phenols, S-epichlorohydrin and tert-butylamine (Scheme 1).
Moreover, this route was easy to implement. The a-hydroxylation
of methyl 5-chloro-1-indone carboxylate (6a) was then used as
a template to screen these organocatalysts. Based on previous re-
search,7 we carried out the reaction of 6a (0.180 mmol, 1.0 equiv)
and commercially available TBHP (0.540 mmol, 3.0 equiv) in 3 mL
of hexane in the presence of catalyst (0.054 mmol, 30 mol %). After
stirring at 15 ꢀC for 40 h, the reaction provided the desired product
7a with an 83% yield and 20% ee using catalyst 3a without sub-
stituents on the phenyl ring (Table 1, entry 1). Both yields and ee
values decreased when the o- or p-hydrogen atoms of the phenolic
hydroxyl group were substituted with chlorine (Table 1, entries 2
and 3). When the o- or p-hydrogen atoms of the phenolic hydroxyl
group were substituted with a methyl group, the reaction pro-
ceeded to completion, with nearly constant yields and ee values
(Table 1, entries 4 and 5). Unfortunately, enantioselectivity de-
creased significantly when the o-hydrogen atom was substituted by
a phenyl group (Table 1, entry 6). However, changing the position of
the phenyl group to para-gave a higher ee value (Table 1, entry 7).
We believe that a large, sterically hindered group is not propitious
for this reaction. Encouragingly, for catalysts with methoxy at the
ortho- or para-position of the phenyl ring, the reaction gave higher
yields, with 28% ee and 32% ee, respectively (Table 1, entries 8 and
9). Apparently, electron-donating substituents on the phenyl ring
improve reaction enantioselectivity and yield. Catalytic efficiency is
greater for the same substituent at the para-position of the phenyl
ring than at the ortho-position. In view of the above rules, we
synthesized catalyst 3j, which has two electron-donating sub-
stituents at the para- and meta-positions. Enantioselectivity and
yield were enhanced to 36% ee and 90%, respectively (Table 1, entry
10). We further increased the number of electron-donating sub-
stituents to synthesize 3k. As expected, the reaction occurred
smoothly, with a 38% ee and 93% yield, in agreement with our
previous hypothesis (Table 1, entry 11). Catalyst loading could be
lowered to 20 mol % while still giving similar enantioselectivity and
yield (Table 1, entry 12), However, 10 mol % catalyst led to lower ee
values and yield (Table 1, entry 13).
,
Entry
Cat. (mol %)
Solvent
Concn (M)
Yieldb (%)
eec h (%)
1
2
3
4
5
6
7
8
3a(30)
3b(30)
3c(30)
3d(30)
3e(30)
3f(30)
3g(30)
3h(30)
3i(30)
3j(30)
3k(30)
3k(20)
3k(10)
3k(20)
3k(20)
3k(20)
3k(20)
3k(20)
3k(20)
3k(20)
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
CH2Cl2
CHCl3
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.060
0.040
0.020
83
72
75
81
82
74
83
85
86
90
93
92
75
90
75
79
23
20
93
78
20
13
16
20
22
13
27
28
32
36
38
38
30
34
30
27
9
9
10
11
12d
13e
14
15
16
17
18
19f
20g
Toluene
AcOEt
EtOH
Hexane
Hexane
5
41
40
a
Reaction conditions: 0.180 mmol of
b-keto ester, 0.540 mmol of tert-butyl
hydroperoxide, 15 ꢀC, 40 h.
b
Isolated yield after flash chromatography.
c
The enantiomeric excess was determined by chiral HPLC using a chiral column
(Daicel OD-H) with hexane/2-propanol (90:10) as the eluent.
d
Compound 3k (0.036 mmol).
Compound 3k (0.018 mmol).
b
b
e
f
-keto ester (0.12 mmol).
-keto ester (0.06 mmol).
The absolute configuration was assigned to S based on the literature.4,6,7
g
h
a range of b-keto esters were further investigated as outlined in
Table 2. The reaction could be completed smoothly within 40 h
with high yield (87e96%), except in two cases (Table 2, entries 11
and 12). Compound 6b without aromatic substituents afforded 7b
with moderate enantioselectivity (51% ee, Table 2, entry 2). Un-
fortunately, 6-bromo-1-oxo-indan-2-carboxylic acid methyl ester
gave low enantioselectivity of 16% ee (Table 2, entry 3). b-Keto es-
ters with methoxy groups on the aromatic ring afforded moderate
to good enantioselectivity (55e88% ee, Table 2, entries 4e10).
When the aromatic rings were substituted with the same group, ee
values dropped with increasing steric hindrance of the ester func-
tionality (Table 2, entries 4e7, 8e10). Notably, the aromatic ring
with an electron-donating methoxy group at position 4 afforded
the corresponding oxidation product with the highest enantiose-
lectivity and excellent yield (88% ee, 96%, Table 2, entry 4). Even
under the optimized reaction conditions, tetralone
(6k and 6l) did not give the oxidation product, nor did the simple
five-member -keto ester 6m and the acyclic -keto ester 6n. A
plausible explanation is that these -keto esters (6ke6n) are less
rigid compared to indanone -keto esters. In addition, the activity
of -hydrogen atom is weak and catalyst 3k is not basic enough to
active the -hydrogen atom.
b-keto esters
Scheme 1. Synthetic routes of catalysts 3aek. 3aek: R¼H, 2-Cl, 4-Cl, 2-CH3, 4-CH3,
2-Ph, 4-Ph, 2-OMe, 4-OMe, 3,4-OCH2Oe, 3,4,5-OMe.
b
b
b
We next investigated the solvent effect using 20 mol % 3k; the
results are listed in Table 1, entries 14e18. Reactions in ethyl acetate
and EtOH led to very low enantioselectivities and yields (Table 1,
entries 17 and 18). Better reactivities and selectivities were ob-
served in less polar solvents, including dichloromethane, chloro-
form, and toluene (Table 1, entries 14e16). However, the reaction
proceeded best in hexane, our first choice of solvent (Table 1, entry
12). Reducing the concentration of 6a to 0.040 mol/L, afforded the
desired products with higher enantioselectivity (41% ee) and 93%
yield (Table 1, entry 19). Regrettably, diluting the concentration of
6a to 0.020 mol/L lowered the yield significantly (Table 1, entry 20).
b
a
a
3. Conclusion
In conclusion, we have synthesized eleven aryloxy amino-
propanol organocatalysts using the -blocker inhibitor S-timolol as
lead compound. Using (R)-1-(tert-butylamino)-3-(3,4,5-
trimethoxyphenoxy) propan-2-ol (3k) as the organocatalyst and
TBHP as the oxidant in hexane, -hydroxylation of -keto esters
was performed in excellent yield with good enantioselectivity (up
b
a
Under the optimized reaction conditions (1 equiv of
b-keto
a
b
ester, 3 equiv of TBHP and 20 mol % of 3k in hexane at 15 ꢀC),

Y. Cai et al. / Tetrahedron 68 (2012) 7973e7977
7975
Table 2
for 9 h (TLC-monitoring). When the reaction was complete, the
solvent was removed under reduced pressure. The residue was
extracted with EtOAc (3ꢁ30 mL). The combined organic layers
were washed with brine (20 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The obtained crude product
was purified by column chromatography (hexane/EtOAc, 2:1) to
give pure 2a as colorless liquid; yield: 6.61 g (88%).
Scope of the asymmetric a-hydroxylation of b
-keto ester catalyzed by 3ka
Epoxide 2a (2.25 g, 0.015 mol), water (10 mL) and EtOH (5 mL)
were placed in a flask with a magnetic stirrer. Then, tert-butylamine
(5.48 g, 0.075 mol) was added in one portion, and the mixture was
vigorously stirred at room temperature for 10 h (TLC-monitoring).
Then, the solvent was removed under reduced pressure. The resi-
due was extracted with CH2Cl2 (3ꢁ20 mL). The combined organic
layers were washed with brine (20 mL), dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The obtained
crude product was purified by column chromatography (CH2Cl2/
MeOH/Et3N, 10:1:0.1) to give pure 3a as a white powder; yield:
Entry
Sub.
n
R1
R2
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
1
1
1
1
1
1
1
1
1
1
2
2
1
d
5-Cl
H
6-Br
Me
Me
Me
Me
Et
i-Pr
Bn
Me
Et
i-Pr
Me
Me
Bn
93
89
87
96
93
90
91
94
92
90
Trace
Trace
Trace
Trace
41
51
16
88
78
69
55
73
65
56
d
4-OMe
4-OMe
4-OMe
4-OMe
6-OMe
6-OMe
6-OMe
7-Br
3.05 g (91%). White solid; mp: 53e55 ꢀC; ½a D18
þ1.5 (c 0.50, CHCl3);
ꢂ
IR (KBr)
n 3419, 3062, 2967, 2919, 2868, 2919, 2868, 1600, 1587,
1497, 1459, 1389, 1365, 1245, 1044, 754, 691 cmꢃ1
(400 MHz, CDCl3)
;
1H NMR
9
d
7.27 (d, J¼8.3 Hz, 2H), 6.94 (d, J¼8.2 Hz, 2H),
10
11d
12d
13d
14d
6.91 (s, 1H), 4.11e3.85 (m, 3H), 2.94e2.80 (m, 1H), 2.69 (dd, J¼9.9,
5.2 Hz, 1H), 2.59 (br, 2H), 1.13 (s, 9H) ppm; 13C NMR (101 MHz,
H
d
Without benzene ring
d
d
CDCl3)
d 154.29, 148.23, 141.79, 107.91, 105.70, 101.15, 71.58, 68.72,
d
d
50.33, 44.68, 29.14 ppm; HRMS (ESþ) calcd for C13H21NO2
a
[MþNa]þ: 246.1470, found: 246.1473.
Reaction conditions: 0.120 mmol of b-keto ester, 0.360 mmol of tert-butyl hy-
droperoxide, 3 mL of hexane, 0.024 mmol of catalyst 3k, 15 ꢀC, 40 h.
b
Isolated yield after flash chromatography.
The enantiomeric excess was determined by chiral HPLC analysis.
Monitored by TLC.
c
4.2.2. (R)-1-(tert-Butylamino)-3-(2-chlorophenoxy) propan-2-ol
(3b). White solid (yield 81%); mp: 85e87 ꢀC; ½a D25
þ1.4 (c 0.33,
ꢂ
d
CHCl3); IR (KBr)
n 3313, 3067, 2966, 2871, 1590, 1486, 1446, 1389,
1365, 1278, 1250, 1121, 1063, 1039, 747, 693 cmꢃ1
;
1H NMR
to 88% ee). In addition, under the optimized reaction conditions, 3k
catalyzed methyl 5-chloro-1-indone carboxylate (6a) to afford (S)-
5-chloro-2-hydroxy-1-oxo-indan-2-carboxylic acid methyl ester
(7a, the important intermediate of Indoxacarb) in 93% yield with
moderate S-enantioselectivity (41% ee).
(400 MHz, CDCl3)
d
7.39 (d, J¼3.9 Hz, 1H), 7.27e7.23 (m, 1H),
7.06e6.95 (m, 2H), 4.05e3.90 (m, 3H), 2.92 (dd, J¼10.8, 6.0 Hz, 1H),
2.84 (dd, J¼13.9, 5.3 Hz,1H), 2.69 (br, 2H),1.12 (s, 9H) ppm; 13C NMR
(101 MHz, CDCl3)
d 154.25, 130.19, 127.78, 122.89, 121.67, 113.64,
72.08, 68.22, 50.50, 44.78, 28.90; HRMS (ESþ) calcd for C13H20ClNO2
[MþNa]þ: 280.1080, found 280.1073.
4. Experimental
4.1. General
4.2.3. (R)-1-(tert-Butylamino)-3-(4-chlorophenoxy) propan-2-ol
(3c). White solid (yield 87%); mp: 71e73 ꢀC; ½a D20
þ10.6 (c 0.50,
ꢂ
All commercial reagents and solvents were used without further
purification, except that the oxidant tert-butyl hydroperoxide
(TBHP) was purified by distillation from 65% TBHP under vacuum
(42 ꢀC/2.5 kPa). Analytical TLC was visualized with UV light at
254 nm. Thin layer chromatography was carried out on TLC alu-
minum sheets with silica gel 60 F254. Purification of reaction
products was carried out with chromatography on silica gel 60
(200e400 mesh). Melting points were determined on an SWG X-4
melting point apparatus. Optical rotation was measured on JASCO
P-1010 polarimeter. The 1H NMR and 13C NMR spectra were
recorded on a Bruker AV 400 MHz spectrometer (400 MHz for 1H,
101 MHz for 13C). Chemical shifts are reported in parts per million
CHCl3); IR (KBr)
n 3293, 3148, 2973, 2925, 2869, 1597, 1579, 1493,
1453, 1433, 1369, 1357, 1247, 1220, 1077, 819 cmꢃ1
(400 MHz, CDCl3)
7.22 (d, J¼9.0 Hz, 2H), 6.84 (d, J¼9.0 Hz, 2H),
4.03e3.84 (m, 3H), 2.82 (dd, J¼11.8, 3.3 Hz, 1H), 2.65 (dd, J¼12.0,
7.2 Hz, 1H), 1.12 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3)
157.38,
;
1H NMR
d
d
129.36, 125.78, 115.83, 70.92, 68.59, 50.32, 44.67, 29.07 ppm; HRMS
(ESþ) calcd for C13H20ClNO2 [MþNa]þ: 280.1080, found 280.1078.
4.2.4. (R)-1-(tert-Butylamino)-3-(o-tolyloxy) propan-2-ol
(3d). Yellow oil (yield 84%); ½a D20
ꢂ
þ10.3 (c 0.26, CHCl3); IR (KBr)
n
3298, 3064, 3025, 2966, 2916, 2869, 1602, 1591, 1495, 1462, 1389,
1364, 1307, 1288, 1246, 1195, 1122, 1051, 1038, 750 cmꢃ1
(400 MHz, CDCl3) 7.14 (t, 2H), 6.90e6.78 (m, 2H), 4.08e3.90 (m,
3H), 2.88 (dd, J¼11.8, 3.7 Hz, 1H), 2.81e2.42 (m, 3H), 2.23 (s, 3H),
1.12 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3)
156.84, 130.70,
;
1H NMR
referenced to TMS (
d
¼0). High-resolution mass spectra were
d
recorded on a Q-TOF mass spectrometer (Micromass, England) with
a Z-spray ionization source. The enantiomeric excess (ee) of the
products was determined with HPLC with a Daicel Chiralcel OD-H
or AD-H column (wavelength¼254 nm) and a hexane/i-PrOH sol-
vent system.
d
126.87, 126.69, 120.66, 111.14, 70.72, 68.75, 50.40, 45.06, 29.03,
16.32 ppm; HRMS (ESþ) calcd for C14H23NO2 [MþNa]þ: 260.1626,
found 260.1632.
4.2. General procedure I: synthesis of catalysts
4.2.5. (R)-1-(tert-Butylamino)-3-(p-tolyloxy) propan-2-ol (3e). White
solid (yield 86%); mp: 58e60 ꢀC; ½a D18
ꢂ
þ12.0 (c 0.50, CHCl3); IR (KBr)
4.2.1. (R)-1-(tert-Butylamino)-3-phenoxypropan-2-ol (3a). To a stir-
red solution of phenol (4.7 g, 0.05 mol) in 30 mL ethanol, was added
NaOH (2.4 g, 0.06 mol). After stirring for 20 min at room temper-
ature, S-epichlorohydrin (13.88 g, 0.15 mol) was added dropwise
for 30 min. The resulting mixture was stirred at room temperature
n
3416, 3292, 2968, 2920, 2868, 1614, 1585, 1512, 1454, 1369, 1357,
1288, 1245, 1221, 843 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
7.06 (d,
J¼8.4 Hz, 2H), 6.80 (d, J¼8.6 Hz, 2H), 4.09e3.80 (m, 3H), 2.81 (dd,
J¼11.8, 3.5 Hz, 1H), 2.66 (dd, J¼11.8, 7.5 Hz, 1H), 2.27 (s, 3H), 1.11 (s,
9H) ppm; 13C NMR (101 MHz, CDCl3)
d 156.66, 130.12, 129.91, 114.41,

7976
Y. Cai et al. / Tetrahedron 68 (2012) 7973e7977
70.75, 68.74, 50.40, 44.88, 29.06, 20.50 ppm; HRMS (ESþ) calcd for
121.38, 112.90, 71.32, 68.67, 50.31, 45.05, 28.92 ppm; HRMS (ESþ)
C14H23NO2 [MþNa]þ: 260.1626, found 260.1630.
calcd for C16H27NO5 [MþNa]þ: 336.1787, found 336.1783.
4.2.6. (R)-1-(tert-Butylamino)-3-(2-phenylphenoxy) propan-2-ol
4.3. General procedure II: 3k-catalyzed asymmetric
droxylation of -keto esters
a-hy-
(3f). Yellow oil (yield 85%); ½a D21
ꢂ
þ2.3 (c 0.50, CHCl3); IR (KBr)
n
b
3298, 3062, 2966, 2870, 1597, 1584, 1504, 1482, 1434, 1388, 1364,
1263, 1231, 1123, 752, 734, 699 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
A mixture of b-keto ester 6 (0.120 mmol), catalyst 3
d
7.51 (d, J¼7.5 Hz, 2H), 7.37 (dd, J¼8.1, 6.8 Hz, 2H), 7.34e7.25 (m,
(0.024 mmol) and tert-butyl hydroperoxide (0.360 mmol) in 3 mL
of hexane was stirred for 40 h at 15 ꢀC. The reaction was monitored
by TLC, and the solvent was removed under reduced pressure at the
completion of the reaction. The residue was extracted with EtOAc
(2ꢁ50 mL). The combined organic layers were washed with brine
(20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography (n-hex-
ane/EtOAc¼3/1) to give the product. The ee value was determined
by chiral HPLC on a Chiralcel OD-H or AD-H column (hexane/i-
PrOH¼90:10, flow rate 1.0 mL/min, 254 nm, unless noted). The
absolute stereochemistry of 7aej was assigned as (S), based on the
literature.4,6,7
3H), 7.05e6.97 (m, 2H), 4.15e3.60 (m, 3H), 2.68 (dd, J¼11.8, 4.0 Hz,
1H), 2.55 (dd, J¼17.9, 7.3 Hz, 1H), 2.47 (br, 2H), 1.02 (s, 9H) ppm; 13C
NMR (101 MHz, CDCl3) d 153.06, 137.13, 133.81, 104.42, 73.18, 69.02,
60.61, 55.89, 50.36, 45.06, 28.60 ppm; HRMS (ESþ) calcd for
C19H25NO2 [MþNa]þ: 322.1783, found 322.1779.
4.2.7. (R)-1-(tert-Butylamino)-3-(4-phenylphenoxy) propan-2-ol
(3g). White solid (yield 75%); mp: 81e83 ꢀC; ½a D26
þ13.6 (c 0.50,
ꢂ
CHCl3); IR (KBr)
n 3423, 3287, 3063, 2960, 2924, 2869, 1610, 1584,
1489, 1453, 1391, 1247, 1127, 1036, 760 cmꢃ1
CDCl3)
;
1H NMR (400 MHz,
d
7.52e7.46 (m, 4H), 7.39 (t, J¼8.0 Hz, 2H), 7.29 (t, J¼7.9 Hz
1H), 7.03e6.97 (m, 2H), 4.04e3.94 (m, 3H), 2.89 (dd, J¼11.8, 6.1 Hz,
1H), 2.70 (dd, J¼12.9, 3.9 Hz, 1H), 2.59 (br, 2H), 1.14 (s, 9H) ppm; 13C
4.3.1. (S)-5-Chloro-2-hydroxy-1-oxo-indan-2-carboxylic acid methyl
a 25
ꢀ
NMR (101 MHz, CDCl3)
d
158.34, 140.76, 134.09, 128.73, 128.17,
ester (7a). White solid; mp: 135e137 C; ½ ꢂD þ40.86 (c 1.04,
126.74, 114.89, 70.69, 68.68, 50.51, 44.76, 29.13 ppm; HRMS (ESþ)
CHCl3, 41% ee); 1H NMR (400 MHz, CDCl3)
d
7.74 (d, J¼8.2 Hz, 1H),
calcd for C19H25NO2 [MþNa]þ: 322.1783, found 322.1788.
7.50 (s,1H), 7.42 (dd, J¼8.2, 0.6 Hz,1H), 4.16 (s,1H), 3.75 (s, 3H), 3.71
(d, J¼17.5 Hz, 1H), 3.24 (d, J¼17.5 Hz, 1H) ppm; 13C NMR (101 MHz,
4.2.8. (R)-1-(tert-Butylamino)-3-(2-methoxyphenoxy) propan-2-ol
CDCl3) d 199.42, 171.54, 153.55, 142.86, 131.99, 129.07, 126.77,
(3h). Colorless oil (yield 87%); ½a D24
ꢂ
þ5.9 (c 0.25, CHCl3); IR (KBr)
126.40, 80.44, 53.61, 38.98 ppm; HRMS (ESþ) calcd for C11H9ClO4
Mþ: 240.0189, found 240.0184; HPLC (Chiralcel OD-H, hexane/i-
PrOH¼90:10): tR(major)¼13.0 min, tR(minor)¼16.2 min.
n
3303, 3065, 2964, 2871, 2836, 1593, 1506, 1455, 1363, 1330, 1253,
1225, 1124, 1028, 742 cmꢃ1; 1H NMR (400 MHz, CDCl3)
(m, 4H), 4.14e3.93 (m, 3H), 3.85 (s, 3H), 3.26e2.13 (m, 4H), 1.11 (s,
9H) ppm; 13C NMR (101 MHz, CDCl3)
149.70, 148.40, 121.60,
d 7.01e6.81
d
4.3.2. (S)-2-Hydroxy-1-oxo-indan-2-carboxylic acid methyl ester
120.96, 114.33, 111.94, 72.83, 68.58, 55.75, 53.48, 50.15, 44.94,
29.02 ppm; HRMS (ESþ) calcd for C14H23NO3 [MþNa]þ: 276.1576,
found 276.1571.
(7b). White solid; mp: 133e135 ꢀC; ½a D25
þ34.43 (c 1.09, CHCl3, 51%
ꢂ
ee); 1H NMR (400 MHz, CDCl3)
d
7.80 (d, J¼7.7 Hz, 1H), 7.68 (t,
J¼7.5 Hz, 1H), 7.50 (d, J¼7.7 Hz, 1H), 7.44 (t, J¼7.5 Hz, 1H), 4.08 (s,
1H), 3.75 (s, 3H), 3.79e3.68 (m, 4H), 3.26 (d, J¼17.3 Hz, 1H) ppm;
4.2.9. (R)-1-(tert-Butylamino)-3-(4-methoxyphenoxy) propan-2-ol
13C NMR (101 MHz, CDCl3)
d 200.82, 171.93, 152.21, 136.21, 133.54,
(3i). White solid (yield 83%); mp: 81e83 ꢀC; ½a D25
ꢂ
þ13.6 (c 0.50,
128.19, 126.49, 125.36, 80.39, 53.50, 39.27 ppm; HRMS (ESþ) calcd
for C11H10O4 Mþ: 206.0579, found 206.0582; HPLC (Chiralcel OD-H,
hexane/i-PrOH¼93:7): tR(major)¼13.6 min, tR(minor)¼17.2 min.
CHCl3); IR (KBr)
n 3423, 3290, 2969, 2920, 2867, 1590, 1509, 1454,
1392, 1368, 1236, 1222, 1126, 1106, 1041, 829 cmꢃ1
(400 MHz, CDCl3) 6.96e6.72 (m, 4H), 4.01e3.86 (m, 3H), 3.77 (s,
3H), 2.90e2.81 (m, 1H), 2.74e2.30 (m, 3H), 1.13 (s, 9H) ppm; 13C
;
1H NMR
d
4.3.3. (S)-6-Bromo-2-hydroxy-1-oxo-indan-2-carboxylic acid methyl
NMR (101 MHz, CDCl3)
d
154.01, 152.94, 115.55, 114.65, 71.31, 68.74,
ester (7c). Yellow solid; mp: 130e132 ꢀC; ½a D25
þ9.71 (c 0.24, CHCl3,
ꢂ
55.72, 50.48, 44.77, 29.08 ppm; HRMS (ESþ) calcd for C14H23NO3
16% ee); 1H NMR (400 MHz, CDCl3)
d
7.93 (s, 1H), 7.78 (d, J¼8.1 Hz,
[MþNa]þ: 276.1576, found 276.1569.
1H), 7.39 (d, J¼8.1 Hz, 1H), 3.99 (s, 1H), 3.75 (s, 3H), 3.67 (d,
J¼17.4 Hz, 1H), 3.20 (d, J¼17.4 Hz, 1H) ppm; 13C NMR (101 MHz,
4.2.10. (R)-1-(tert-Butylamino)-3-[(1,3-dihydroisobenzofuran-5-yl)
CDCl3) d 199.50, 171.48, 150.66, 138.92, 135.36, 128.12, 128.01,
oxy]propan-2-ol (3j). White solid (yield 85%); mp: 69e71 ꢀC; ½a D21
ꢂ
122.29, 80.61, 53.64, 38.92 ppm; HRMS (ESþ) calcd for C11H9BrO4
Mþ: 283.9684, found 283.9687; HPLC (Chiralcel AD-H, hexane/i-
PrOH¼90:10): tR(major)¼21.4 min, tR(minor)¼28.6 min.
þ10.7 (c 0.50, CHCl3); IR (KBr)
n 3427, 3276, 3083, 2974, 2931, 2899,
2875, 1634, 1608, 1491, 1367, 1287, 1194, 1040, 888, 799 cmꢃ1
NMR (400 MHz, CDCl3)
;
1H
d
6.70 (d, J¼8.5 Hz, 1H), 6.52 (d, J¼2.5 Hz,
1H), 6.34 (dd, J¼8.5, 2.5 Hz, 1H), 5.91 (s, 2H), 4.02e3.81 (m, 3H),
4.3.4. (S)-4-Methoxy-2-hydroxy-1-oxo-indan-2-carboxylicacid
2.83 (dd, J¼11.0, 2.6 Hz, 1H), 2.66 (dd, J¼11.7, 7.1 Hz, 1H), 2.44 (br,
methyl ester (7d). Pink white solid; mp: 141e143 ꢀC; ½a D25
þ59.27 (c
ꢂ
2H), 1.12 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3)
d
158.73, 129.48,
1.39, CHCl3, 88% ee); 1H NMR (400 MHz, CDCl3)
d 7.45e7.37 (m, 2H),
120.96, 114.56, 70.52, 68.67, 50.49, 44.85, 29.06 ppm; HRMS (ESþ)
7.11 (dd, J¼6.9, 1.9 Hz, 1H), 3.92 (s, 3H), 3.74 (s, 3H), 3.66 (d,
calcd for C14H21NO4 [MþNa]þ: 290.1368, found 290.1366.
J¼17.7 Hz, 1H), 3.11 (d, J¼17.7 Hz, 1H) ppm; 13C NMR (101 MHz,
CDCl3) d 200.98, 172.05,156.74,141.21,134.88,129.69,116.67,116.30,
4.2.11. (R)-1-(tert-Butylamino)-3-(3,4,5-trimethoxyphenoxy)
propan-2-ol (3k). Compound 1k was prepared according to the
literature.8
80.24, 55.58, 53.46, 36.15 ppm; HRMS (ESþ) calcd for C12H12O5 Mþ:
236.0685, found 236.0681; HPLC (Chiralcel OD-H, hexane/i-
PrOH¼90:10): tR(minor)¼16.3 min, tR(major)¼18.4 min.
White solid (yield 88%); mp: 101e102 ꢀC; ½a D20
þ1.2 (c 0.50,
ꢂ
CHCl3); IR (KBr)
n
3431, 3284, 3017, 2959, 2875, 2822, 1603, 1509,
4.3.5. (S)-4-Methoxy-2-hydroxy-1-oxo-indan-2-carboxylic acid ethyl
1463, 1367, 1345, 1232, 1197, 1127, 1049, 876 cmꢃ1
;
1H NMR
ester (7e). Yellow solid; mp: 41e43 ꢀC; ½a D25
þ23.36 (c 1.27, CHCl3,
ꢂ
(400 MHz, CDCl3) 6.18 (s, 2H), 4.00e3.89 (m, 3H), 3.84 (s, 6H), 3.79
d
78% ee); 1H NMR (400 MHz, CDCl3)
d 7.43e7.30 (m, 2H), 7.08 (dd,
(s, 3H), 2.94e2.79 (dd, J¼10.9, 5.6 Hz, 1H), 2.67 (dd, J¼11.8, 6.6 Hz,
J¼6.6, 2.2 Hz, 1H), 4.19 (q, 2H), 3.89 (s, 3H), 3.62 (d, J¼17.7 Hz, 1H),
1H), 2.43 (br, 2H), 1.13 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3)
3.08 (d, J¼17.7 Hz, 1H), 1.16 (t, 3H) ppm; 13C NMR (101 MHz, CDCl3)
d
155.58, 138.53, 131.17, 130.92, 129.59, 128.73, 128.01, 126.95,
d 201.14, 171.62, 156.72, 141.30, 134.93, 129.63, 116.63, 116.25, 80.13,

Y. Cai et al. / Tetrahedron 68 (2012) 7973e7977
7977
62.77, 55.58, 36.19, 14.00 ppm; HRMS (ESþ) calcd for C13H14O5 Mþ:
250.0841, found 250.0843; HPLC (Chiralcel OD-H, hexane/i-
PrOH¼90:10): tR(minor)¼9.6 min, tR(major)¼10.8 min.
found 250.0845; HPLC (Chiralcel OD-H, hexane/i-PrOH¼90:10):
tR(major)¼10.5 min, tR(minor)¼12.3 min.
4.3.10. (S)-6-Methoxy-2-hydroxy-1-oxo-indan-2-carboxylic
acid
4.3.6. (S)-4-Methoxy-2-hydroxy-1-oxo-indan-2-carboxylic acid iso-
isopropyl ester (7j). White solid; mp: 75e77 ꢀC; ½a D25
ꢂ
þ16.80 (c 1.28,
propyl ester (7f). White solid; mp: 79e81 ꢀC; ½a D25
ꢂ
þ19.53 (c 0.95,
CHCl3, 56% ee); 1H NMR (400 MHz, CDCl3)
d
7.38 (d, J¼8.4 Hz, 1H),
CHCl3, 69% ee); 1H NMR (400 MHz, CDCl3)
d
7.44e7.35 (m, 2H), 7.11
7.26 (dd, J¼8.5, 2.4 Hz, 1H), 7.21 (d, J¼2.5 Hz, 1H), 5.07 (dt, J¼12.5,
6.3 Hz, 1H), 4.02 (s, 1H), 3.85 (s, 3H), 3.61 (d, J¼16.9 Hz, 1H), 3.16 (d,
J¼16.9 Hz,1H), 1.20 (d, J¼6.3 Hz, 3H), 1.14 (d, J¼6.3 Hz, 3H) ppm; 13C
(dd, J¼6.6, 2.2 Hz,1H), 5.08 (dt, J¼12.5, 6.3 Hz, 1H), 3.92 (s, 3H), 3.61
(d, J¼17.7 Hz, 1H), 3.10 (d, J¼17.7 Hz, 1H), 1.21 (d, J¼6.3 Hz, 3H), 1.14
(d, J¼6.3 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3):
d
201.22, 171.18,
NMR (101 MHz, CDCl3) d 201.01, 171.14, 159.80, 145.33, 134.79,
156.70, 141.35, 134.95, 129.56, 116.54, 116.20, 80.05, 70.82, 55.57,
36.19, 21.53, 21.34 ppm; HRMS (ESþ) calcd for C14H16O5 Mþ:
264.0998, found 264.0996; HPLC (Chiralcel OD-H, hexane/i-
PrOH¼90:10): tR(minor)¼8.2 min, tR(major)¼9.3 min.
127.12, 125.48, 106.22, 80.99, 70.87, 55.62, 38.71, 21.52, 21.35 ppm;
HRMS (ESþ) calcd for C14H16O5 Mþ: 264.0998, found 264.0999;
HPLC (Chiralcel OD-H, hexane/i-PrOH¼90:10): tR(major)¼9.3 min,
tR(minor)¼11.1 min.
4.3.7. (S)-4-Methoxy-2-hydroxy-1-oxo-indan-2-carboxylic
acid
Acknowledgements
benzyl ester (7g). White solid; mp: 97e99 ꢀC; ½a D25
ꢂ
þ13.68 (c 1.20,
CHCl3, 55% ee); 1H NMR (400 MHz, CDCl3)
d 7.38e7.29 (m, 5H),
We are grateful for grants from the National Natural Science
Foundation of China (No. 21176041) and support from the State Key
Laboratory of Fine Chemicals.
7.18e7.09 (m, 3H), 5.18 (dd, J¼29.8, 12.4 Hz, 2H), 4.70 (s,1H), 3.90 (s,
3H), 3.66 (d, J¼17.7 Hz, 1H), 3.11 (d, J¼17.6 Hz, 1H) ppm; 13C NMR
(101 MHz, CDCl3)
d 200.93, 171.42, 156.74, 141.21, 134.90, 134.83,
129.69, 128.57, 128.43, 127.76, 116.67, 116.34, 80.44, 67.98, 55.58,
36.13 ppm; HRMS (ESþ) calcd for C18H16O5 [MþNa]þ: 335.0895,
found 335.0901; HPLC (Chiralcel OD-H, hexane/i-PrOH¼90:10):
tR(minor)¼13.0 min, tR(major)¼16.7 min.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.07.003.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.3.8. (S)-6-Methoxy-2-hydroxy-1-oxo-indan-2-carboxylic
acid
methyl ester (7h). White solid; mp: 119e121 ꢀC; ½a D25
ꢂ
þ38.83 (c
1.26, CHCl3, 73% ee); 1H NMR (400 MHz, CDCl3)
d
7.38 (d, J¼8.4 Hz,
References and notes
1H), 7.28 (d, J¼8.4 Hz, 1H), 7.22 (d, J¼2.5 Hz, 1H), 3.85 (s, 3H), 3.75
(s, 3H), 3.65 (d, J¼17.0 Hz, 1H), 3.18 (d, J¼17.0 Hz, 1H) ppm; 13C NMR
1. Christoffers, J.; Baro, A.; Werner, T. Adv. Synth. Catal. 2004, 346, 143e151.
2. McCann, S. F.; Annis, G. D.; Shapiro, R.; Piotrowski, D. W.; Lahm, G. P.; Long, J. K.;
Lee, K. C.; Hughes, M. M.; Myers, B. J.; Griswold, S. M.; Reeves, B. M.; March, R.
W.; Sharpe, P. L.; Lowder, P.; Barnette, W. E.; Wing, K. D. Pest Manag. Sci. 2001, 57,
153e164.
(101 MHz, CDCl3):
d 200.78, 172.01, 159.87, 145.18, 134.69, 127.20,
125.68, 106.26, 81.06, 55.67, 53.47, 38.68 ppm; HRMS (ESþ) calcd for
C12H12O5 Mþ: 236.0685, found 236.0687; HPLC (Chiralcel OD-H,
hexane/i-PrOH¼90:10): tR(major)¼15.3 min, tR(minor)¼18.0 min.
3. Toullec, P. Y.; Bonaccorsi, C.; Mezzetti, A.; Togni, A. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5810e5814.
4. Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am.
Chem. Soc. 2006, 128, 16488e16489.
5. Lu, M.; Zhu, D.; Lu, Y. P.; Zeng, X. F.; Tan, B.; Xu, Z. J.; Zhong, G. F. J. Am. Chem. Soc.
2009, 131, 4562e4563.
6. (a) Taylor, E. G.; Wilmington, D. D. WO 03/040083, 2003,; (b) Acocella, M. R.;
Mancheno, O. G.; Bella, M.; Jørgensen, K. A. J. Org. Chem. 2004, 69, 8165e8167;
(c) Gong, B.; Meng, Q. W.; Su, T.; Lian, M. M.; Wang, Q.; Gao, Z. X. Synlett 2009,
2659e2662; (d) Lian, M. M.; Li, Z.; Du, J.; Meng, Q. W.; Gao, Z. X. Eur. J. Org. Chem.
2010, 6525e6530.
4.3.9. (S)-6-Methoxy-2-hydroxy-1-oxo-indan-2-carboxylic acid ethyl
ester (7i). White solid; mp: 55e57 ꢀC; ½a D25
þ17.63 (c 1.03, CHCl3,
ꢂ
65% ee); 1H NMR (400 MHz, CDCl3)
d
7.39 (d, J¼8.4 Hz,1H), 7.27 (dd,
J¼8.1, 2.9 Hz, 1H), 7.22 (d, J¼2.5 Hz, 1H), 4.22 (m, 2H), 4.03 (s, 1H),
3.85 (s, 3H), 3.64 (d, J¼16.9 Hz, 1H), 3.17 (d, J¼16.9 Hz, 1H), 1.19 (t,
J¼7.1 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3)
d 200.93, 171.54,
159.80, 145.26, 134.75, 127.16, 125.53, 106.23, 80.98, 62.73, 55.63,
7. Gong, B.; Meng, Q. W.; Su, T.; Gao, Z. X. Chin. J. Org. Chem. 2010, 30, 401e408.
8. Venkat Narsaiah, A.; Nagaiah, B. Synthesis 2010, 16, 2705e2707.
38.73, 13.97 ppm; HRMS (ESþ) calcd for C13H14O5 Mþ: 250.0841,