Asymmetric direct α-hydroxylation of β-oxo esters catalyzed by chiral quaternary ammonium salts derived from cinchona alkaloids

Article abstract of DOI:10.1021/jo3016242

Cinchona alkaloid-derived chiral quaternary ammonium organocatalysts were developed. The catalyst with a bulky 1-adamantoyl group at the C-9 position promoted the enantioselective α-hydroxylation of β-oxo esters and resulted in the corresponding products in 35-95% yields and 58-90% ee. The reaction was successfully scaled to a gram-quantity scale with a similar yield without loss of enantioselectivity.

Full text of DOI:10.1021/jo3016242

Article
pubs.acs.org/joc
Asymmetric Direct α‑Hydroxylation of β‑Oxo Esters Catalyzed by
Chiral Quaternary Ammonium Salts Derived from Cinchona Alkaloids
Hongjie Yao, Mingming Lian, Zhi Li, Yakun Wang, and Qingwei Meng*
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian
116024, China
S
* Supporting Information
ABSTRACT: Cinchona alkaloid-derived chiral quaternary
ammonium organocatalysts were developed. The catalyst
with a bulky 1-adamantoyl group at the C-9 position promoted
the enantioselective α-hydroxylation of β-oxo esters and
resulted in the corresponding products in 35−95% yields
and 58−90% ee. The reaction was successfully scaled to a
gram-quantity scale with a similar yield without loss of
enantioselectivity.
hydroxylation products with 65−74% ee. The major issue was
that the stereoselectivities of this catalyst system were
moderate; it was clear to us that our catalyst system required
further optimization. Herein, we report our recent progress on
the asymmetric α-hydroxylation of β-oxo esters via phase-
transfer catalysis. By modifying the hydroxyl and quaternary
nitrogen groups of alkaloid catalysts using bulky groups, the
enantioselectivity of the α-hydroxyaltion of β-oxo esters
reached 90%.
INTRODUCTION
■
α-Hydroxydicarbonyl compounds represent a functional and
common structural motif in a variety of natural products and
pharmaceuticals, such as vindoline, kjellmanianone, hamigeran
A, and doxycycline.1 Moreover, optically active α-hydroxydi-
carbonyl compounds are important synthetic intermediates; for
example, (S)-5-chloro-2-hydroxy-1-oxoindan-2-carboxylic acid
methyl ester is the key intermediate in the manufacture of the
insecticide indoxacarb.2
Because the cinchona alkaloids have been reported to
provide moderate stereoselectivity in the asymmetric α-
hydroxylation of dicarbonyl compounds,3 the most convenient
enantioselective synthesis of the α-hydroxydicarbonyl unit is
through the direct oxidation of β-oxo esters by metal complexes
and organocatalysts. Thus, for the past few years, efforts have
been made toward the development of highly enantioselective
catalysts. Metal complexes, such as the TASSOL−Ti complex,4
the DBFOX−Ni complex,5 and the BINAP−Pd complex,6 have
been reported to be effective catalysts for the enantioselective
α-hydroxylation of β-oxo esters using oxaziridine as the oxidant.
In the field of organocatalysis, Zhong et al. have used a chiral
phosphoric acid as a catalyst and nitroso compounds as an
oxidant to realize the highly enantioselective α-hydroxylation of
β-oxo compounds.7 However, these methodologies are limited
by the use of expensive catalysts and complicated oxidants.
Through our exploratory attempts, we found that lappaconi-
tine8 and the β-blocker inhibitor (S)-timolol derivatives9
catalyzed the asymmetric α-hydroxylation reaction in moderate
yields and enatioselectivities. Inspired by Maruoka’s asymmetric
alkylation of α-benzoyloxy β-oxo esters to produce similar
chiral compounds and other catalytic asymmetric α-oxidation
by phase-transfer catalysis,10 we also developed a phase-transfer
catalyst to achieve the asymmetric α-hydroxylation of β-oxo
esters.11 We used N-(3-trifluoromethylbenzyl)dihydro-
cinchoninium bromide as the catalyst under the phase-transfer
catalysis conditions, which resulted in the corresponding
RESULTS AND DISCUSSION
■
The combination of small molecules with macromolecules is
believed to be an effective strategy to generate a variety of new
catalysts. For example, Lectka reported that active (R)-
bromoesters catalyzed by a proline−cinchona alkaloid con-
jugated catalyst and 1,1,3,6-tetrabromonaphthalen-2-(1H)-one
as the brominating agent gave yields as high as 68% and 99%
ee.12 This strategy prompted us to investigate cinchona
catalysts through protection of the chiral secondary alcohol of
the present phase-transfer catalysts.
Initially, we attempted the α-hydroxylation of 1-indanone-
derived β-oxo ester 1a with commercially available cumyl
hydroperoxide (CHP) using Cn-1 (5 mol %) as the catalyst in
combination with K2HPO4 (50% aq), which furnished 3a in
83% yield with a moderate ee value of 52% (Table 1, entry 1).
Prompted by this result, we undertook an initial screening of
some similar catalysts with the chiral secondary alcohol
protected by Boc-amino acids (phenylalanine, β-alanine,
proline, glycine, and D-phenylglycine). All of the above catalysts
showed similar catalytic activities (Table1, entries 1−11);
among the investigated catalysts, Cn-7 gave the best perform-
ance with 85% yield and 69% ee (Table 1, entry 7). When the
configuration of the amino acids was changed from L to D, the
Received: August 3, 2012
Published: October 10, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Article
we therefore introduced Cn-12, Cn-13, Cn-14, and Qn-1, in
which the chiral secondary alcohol was protected by a bulky 1-
adamantyl group.13 Compared with amino acid groups, the 1-
adamantyl group is expected to provide greater configurational
rigidity. Both the Cn-12 and Cn-13 catalysts gave high yields
but decreased the ee values (Table 1, entries 12 and 13).
However, when the benzyl group was replaced with an
anthracene group, the ee value was improved to 88% (Table
1, entry 14). We also evaluated the quinidine-based catalyst Qn-
1 in addition to the cinchonine-based derivative Cn-14, which
resulted in the corresponding hydroxylation product 3a in 89%
yield and 84% ee (Table 1, entry 15).
Table 1. Screening of Phase-Transfer Catalysts for the
Organocatalytic α-Hydroxylation of β-Oxo Ester 1a
a
After a suitable catalyst was identified, further reaction
optimization was undertaken. Table 2 summarizes the effect of
several parameters on this reaction. We found that changing
cumyl hydroperoxide (CHP) to tert-butyl hydroperoxide
(TBHP) led to a slightly lower yield and ee value (Table 2,
entry 2). Performing the reaction at either lower or higher
temperature reduced the enantioselectivity of the product
(Table 2, entries 3 and 4). Variation of either the oxidant used
(Table 2, entry 5) or the catalyst loading (Table 2, entries 6 and
7) failed to improve the enantioselectivity. Dilution of the
reaction also did not give positive results (Table 2, entries 8 and
9). We also tested other bases (Table 2, entries 10−14); for
example, the base was changed from 50% K2HPO4 to 30%
K2CO3, and although this change led to complete conversion, it
also led to lower ee (Table 2, entry 10). The use of an organic
base or a solid resulted in an obvious decrease in the product ee
value (Table 2, entries 11−14). These results collectively
revealed that the original reaction conditions were the best
ones. Under the optimized conditions, the hydroxylation
process was considerably more enantioselective in the phase-
transfer catalysis method (where a relatively stable and
commercially available cumyl hydroperoxide and a cincho-
nine-based ammonium salt at lower loading were used) at −5
°C.
The scope of the method was next probed using various β-
oxo esters (Table 3). First, substituted 1-Ad esters were
investigated. The reactivity of 1b and 1c bearing an electron-
donating group afforded the corresponding products 3b and 3c
in high yields and high enantioselectivities (Table 3, entries 2
and 3). Slightly modified conditions were needed for the 5,6-
dimethoxy β-oxo ester because of its lower reactivity; however,
it still gave excellent results (Table 3, entry 4). Halogen
substitutions were uniformly tolerated (Table 3, entries 5−7)
and afforded the oxidation products in satisfactory yields and
enantioselectivities. Interestingly, although not significant, the
yields and enantioselectivities of the current asymmetric
oxidation using Cn-14 were influenced by the substituent on
the benzene ring of the indanone derivatives (Table 3, entries
1−7). For example, a bromine substituent at the C-6 position
decreased the ee value to 58% (Table3, entry 5), and a bromine
substituent at the C-4 position decreased the enantioselectivity
from 88 to 76% (Table 3, entry 6), whereas a methoxy
substituent was less influential (Table 3, entries 2−4). These
results indicate that electron-withdrawing substituents on the
indanone derivatives deteriorate the observed enantioselectiv-
ities. When the 1-Ad of R2 was changed to 2-Ad, complete
conversion and a good yield were achieved, although the
observed ee value decreased (Table 3, entry 8). tert-Butyl esters
and 3-ethyl amyl esters were investigated. The α-hydroxylation
of these substrates gave moderate to good yields and 78−85%
ee values (Table 3, entries 9−14). Despite having results similar
b
c
entry
catalyst
yield (%)
ee (%)
d
1
2
Cn-1
Cn-2
Cn-3
Cn-4
Cn-5
Cn-6
Cn-7
Cn-8
Cn-9
Cn-10
Cn-11
Cn-12
Cn-13
Cn-14
Qn-1
83
82
79
82
76
81
85
83
78
75
65
88
89
90
89
52(s)
60
54
56
41
62
69
69
55
61
30
42
44
88
84
3
4
5
6
7
8
9
10
11
12
13
14
15
a
The reaction was performed with 0.2 mmol of 1a, 1.5 equiv of cumyl
hydroperoxide (CHP), and 50% aq K2HPO4 (1 mL) in the presence
of 5 mol % of catalyst in toluene (2 mL) under −5 °C for 60 h.
Isolated yield (3a). The enantiomeric excess was determined by
HPLC analysis of product 3a using a chiral column (DAICEL
Chiralcel AD-H) with hexane/2-propanol (80:20) as the eluent. The
b
c
d
absolute configuration was determined by comparison with the optical
rotation and the HPLC retention time of an authentic sample.14
absolute stereochemistry of the products was not reversed, and
the reaction was not improved (Table 1, entries 9 and 10 vs 1−
8). In contrast, the Cn-11 with a urea substitution decreased
the catalytic activity significantly (Table 1, entry 11).
Although we did not obtain the desired effect with these
catalysts, the results indicated that the esterification of the C-9
hydroxy group would affect the catalytic activity of the catalysts;
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Table 2. Optimization of the Reaction Conditions
a
b
entry
sub (mmol)
solvent (2 mL)
oxidant (equiv)
Cn-14 (mol %)
T (°C)
base
yield (%)
ee (%)
1
2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.05
0.2
0.2
0.2
0.2
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
CH2Cl2
PhMe
PhMe
CHP (1.5)
TBHP (1.5)
CHP (1.5)
CHP (1.5)
CHP (1.2)
CHP (1.5)
CHP (1.5)
CHP (1.5)
CHP (1.5)
CHP (1.5)
CHP (1.5)
CHP (1.5)
CHP (1.5)
CHP (1.5)
5
5
−5
−5
0
50% K2HPO4
50% K2HPO4
50% K2HPO4
50% K2HPO4
50% K2HPO4
50% K2HPO4
50% K2HPO4
50% K2HPO4
50% K2HPO4
30% K2CO3
90
82
92
78
83
76
92
85
80
97
nd
nd
84
95
88
82
83
80
88
80
85
87
80
23
19
21
40
0
3
5
4
5
−15
−5
−5
−5
−5
−5
−5
−5
−5
−5
−5
5
5
6
2.5
10
5
7
8
9
5
10
11
12
13
14
5
5
iPr2EtN (0.3 equiv)
iPr2EtN (0.3 equiv)
K2HPO4(0.5 g)
K2CO3(0.3 g)
5
5
0.2
b
5
a
Isolated yields. The enantiomeric excess was determined by HPLC analysis of the product 3a using a chiral column (DAICEL Chiralcel AD-H)
with hexane/2-propanol (80:20) as the eluent.
to those of the 1-Ad esters, the yields and enantioselectivities
were slightly lower with the tert-butyl esters and 3-ethyl amyl
esters. These results suggest that the 1-Ad moiety was better
suited to provide a good yield and selectivity than were other
bulky ester groups.
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of Phase-Transfer
Catalysts. The phase-transfer catalysts Cn-1 to Cn-10 were
synthesized following known procedures.12 To a flame-dried flask
equipped with a magnetic stirring bar and a reflux condenser were
added cinchoninium bromide, dried CH2Cl2 (10 mL), and the desired
Boc-amino acids, dimethylaminopyridine (0.1 equiv); the solution was
subsequently cooled to 0 °C. Dicyclohexylcarbodiimide (2.5 equiv)
dissolved in 10 mL of CH2Cl2 was then added, and the reaction was
allowed to warm to room temperature overnight. The reaction mixture
was filtered, and the filtrate was concentrated. The residue was
separated by CC (CH2Cl2/MeOH = 50:3) to give a solid.
The scope of the reaction was further probed using six-
membered cyclic and acyclic substrates. The six-membered
cyclic substrates 1-tetralone-derived β-oxo esters were not
active and only gave 35% yields and moderate ee values (Table
3, entries 15 and 16). Notably, the asymmetric oxidations of
such substrates, even in low yields, are typically very
challenging.15 The simple β-oxo ester 1q could not be oxidized
when THP was used as the oxygen source under the
investigated reaction conditions (Table 3, entry 17), and
acyclic substrate 1r was inert under our asymmetric oxidation
conditions, even when aqueous NaOH solution was used as the
base (Table 3, entry 18). To test the generality of our
asymmetric oxidation, 1a was treated with CHP (1.5 equiv) on
a gram-quantity scale. After only 30 h at −5 °C, the
hydroxylation product was obtained in 85% yield without any
loss of enantioselectivity (87% ee). The shorter reaction time
was ascribed to the intensive mixing conditions under high-
speed mechanical agitation (800 rpm).
O(9)-Boc-Phenylalanineyl-N-benzylcinchoninium Bromide (Cn-
1): White powder (1.33 g, yield 86.8%); [α]D 71.0 (c 0.10,
20
MeOH); mp 168−170 °C; 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J
= 4.3 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.64
(s, 2H), 7.59 (t, J = 9.0 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1H), 7.48 (t, J =
7.2 Hz, 4H), 7.40 (d, J = 4.4 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.15 (t,
J = 7.4 Hz, 2H), 6.67 (d, J = 7.1 Hz, 2H), 6.38 (d, J = 12.0 Hz, 1H),
6.11−5.90 (m, 1H), 5.47 (t, J = 11.1 Hz, 1H), 5.35 (d, J = 10.2 Hz,
1H), 5.18 (d, J = 16.9 Hz, 1H), 5.10 (dd, J = 14.4, 10.0 Hz, 1H), 4.38
(t, J = 9.8 Hz, 1H), 4.09 (d, J = 12.1 Hz, 1H), 3.45−3.33 (m, 1H), 3.14
(dd, J = 14.0, 5.3 Hz, 1H), 2.78 (dd, J = 20.9, 9.8 Hz, 1H), 2.41−2.25
(m, 2H), 1.89 (s, 1H), 1.77 (d, J = 9.9 Hz, 1H), 1.68 (s, 1H), 1.63 (s,
9H), 1.04 (s, 1H), 0.88 (t, J = 6.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 171.0, 155.8, 149.1, 147.0, 138.8, 136.7, 135.2, 134.6, 130.7,
129.7, 129.5, 129.1, 129.0, 128.8, 127.3, 126.8, 123.6, 122.7, 119.1,
118.3, 80.2, 68.5, 65.1, 62.5, 55.9, 55.0, 54.0, 38.3, 37.2, 28.6, 27.2,
23.4, 22.2; HRMS(ES+) calcd for [C40H46N3O4Br − Br]+ 632.3488,
found 632.3499.
CONCLUSION
■
In conclusion, although the application value of traditional
organocatalysts was restricted, we found that the cinchona
alkaloid catalysts with a bulky 1-adamantyl group at C-9 are
capable of promoting the desired enantioselective α-hydrox-
ylation of 1-indanone-derived β-oxo esters under mild
conditions. High selectivity was obtained for a range of
substituted indanone derivatives (58−90% ee). Another
significant improvement over the literature benchmark is that
the enantioselective α-hydroxylation of 1-tetralone-derived β-
oxo ester (1o and 1p) was also achieved. Moreover, this
improved α-oxidation method for β-oxo esters was successfully
scaled up to a gram-quantity in 85% yield without loss of
enantioselectivity (87% ee).
O(9)-Fmoc-Phenylalanineyl-N-(3-trifluoromethylbenzyl)-
cinchoninium Bromide (Cn-2): Yellowish powder (1.1 g, yield
25
65.4%); [α]D 31.0 (c 0.2, MeOH); mp 150−152 °C (dec.); 1H
NMR (400 MHz, CDCl3) δ 8.68 (d, J = 3.5 Hz, 2H), 8.62 (s, 1H),
8.06 (s, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H), 7.75 (t, J = 6.7 Hz,
3H), 7.59 (m, J = 8.7 Hz, 6H), 7.41 (dd, J = 14.2, 7.0 Hz, 2H), 7.31
(m, J = 12.6, 5.5 Hz, 6H), 7.07 (s, 2H), 6.42 (d, J = 11.8 Hz, 1H),
6.02−5.85 (m, 1H), 5.53 (s, 1H), 5.19 (dd, J = 27.4, 13.7 Hz, 1H),
4.84 (s, 1H), 4.68 (s, 1H), 4.54−4.42 (m, 1H), 4.38−4.30 (m, 1H),
4.26 (d, J = 11.7 Hz, 1H), 4.18 (t, J = 7.1 Hz, 1H), 3.41−3.18 (m,3H),
2.75−2.59 (m, 1H), 2.43 (d, J = 8.7 Hz, 1H), 2.37−2.26 (m, 1H),
2.02−1.79 (m, 3H), 1.73 (s, 1H), 1.19 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 170.5, 156.7, 149.0, 147.4, 143.5, 143.3, 141.2, 139.1, 138.5,
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Article
a
126.6, 124.5, 124.0, 118.5, 118.1, 79.7, 69.1, 65.2, 62.4, 56.4, 54.7, 37.5,
35.5, 28.4, 26.9, 23.4, 22.6; HRMS (ES+) calcd for [C34H42N3O4Br −
Br]+ 556.3175, found 556.3188.
Table 3. Substrate Scope Evaluation
O(9)-Boc-β-Alanineyl-N-(3-trifluoromethylbenzyl)cinchoninium
Bromide (Cn-4): Yellowish powder (0.5 g, yield 63.4%); [α]D25 75.0 (c
1
0.10, MeOH); mp 147−149 °C (dec.); H NMR (400 MHz, CDCl3)
δ 8.86 (d, J = 4.2 Hz, 1H), 8.65 (t, J = 11.6 Hz, 1H), 8.58 (d, J = 6.9
Hz, 1H), 8.27 (s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.87 (t, J = 7.2 Hz,
1H), 7.72 (t, J = 7.7 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 4.1
Hz, 1H), 7.32 (d, J = 3.7 Hz, 1H), 6.17 (d, J = 11.5 Hz, 1H), 5.99
(ddd, J = 17.1, 10.2, 6.8 Hz, 1H), 5.50 (s, 1H), 5.44−5.25 (m, 3H),
4.80 (dd, J = 21.8, 11.0 Hz, 2H), 4.15−3.92 (m, 1H), 3.81−3.54 (m,
2H), 3.48 (d, J = 5.1 Hz, 1H), 2.97 (s, 1H), 2.89- 2.67 (m, 2H), 2.60
(d, J = 7.5 Hz, 1H), 2.54−2.36 (m, 1H), 2.04 (s, 1H), 1.84 (dd, J =
25.6, 10.2 Hz, 2H), 1.36 (s, 9H), 1.26 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 169.7, 156.3, 149.2, 148.2, 139.9, 138.5, 135.2, 131.5, 131.2,
130.5, 130.0, 129.9, 129.2, 127.9, 127.6, 124.9, 124.5, 124.1, 122.2,
118.8, 118.0, 79.9, 69.3, 65.6, 61.3, 56.4, 55.1, 37.6, 36.5, 35.9, 28.3,
26.9, 23.4, 22.7; HRMS (ES+) calcd for [C35H41N3O4F3Br − Br]+
624.3049, found 624.3030.
b
yield
(%)
c
entry sub
n
R1
R2
ee %
88
1
2
1a
1b
1c
1d
1e
1f
1
1
1
1
1
1
1
1
1
1
1
H
1Ad
1Ad
1Ad
1Ad
1Ad
1Ad
1Ad
2Ad
tBu
tBu
90
6-MeO
4-MeO
85
83
61
45
73
88
95
79
75
70
86
90
90
58
76
82
75
78
84
83
3
d
4
5,6-diMeO
6-Br
4-Br
5-Cl
H
5
6
7
1g
1h
1i
O(9)-Boc-Prolineyl-N-(3-trifluoromethylbenzyl)cinchoninium Bro-
20
8
e
mide (Cn-5): Yellowish powder (1.1 g, yield 80.3%); [α]D 57.0 (c
1
9
H
0.10, MeOH); mp 144−146 °C (dec.); H NMR (400 MHz, CDCl3)
δ 9.03 (d, J = 8.4 Hz, 1H), 8.93 (d, J = 4.5 Hz, 1H), 8.83 (d, J = 7.5
Hz, 1H), 8.23−8.11 (m, 2H), 8.05 (t, J = 7.5 Hz, 1H), 7.93−7.82 (m,
1H), 7.78 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.60 (s, 1H),
7.43 (d, J = 4.3 Hz, 1H), 6.54 (d, J = 11.6 Hz, 1H), 6.06−5.81 (m,
2H), 5.38 (d, J = 10.4 Hz, 1H), 5.30 (t, J = 8.6 Hz, 1H), 5.08 (t, J = 9.6
Hz, 1H), 4.60 (dd, J = 9.0, 4.8 Hz, 1H), 4.30 (d, J = 11.6 Hz, 1H),
3.88−3.77 (m, 1H), 3.71−3.58 (m, 2H), 3.53−3.37 (m, 1H), 2.88−
2.73 (m, 1H), 2.64−2.50 (m, 1H), 2.38 (dd, J = 23.0, 11.2 Hz, 2H),
2.24 −2.10 (m, 3H), 2.04(s, 4H), 1.84(s, 1H), 1.72 (s, 2H), 1.48 (s,
9H), 1.34 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 170.7, 155.7,
149.0, 148.3, 139.6, 138.4, 135.6, 131.6, 131.3, 130.7, 129.9, 129.8,
129.4, 127.9, 127.6, 125.0, 124.1, 122.3, 119.1, 117.8, 81.4, 69.3, 64.9,
61.0, 60.0, 56.0, 55.2, 53.5, 47.7, 37.9, 30.3, 28.5, 28.4, 27.5, 25.2, 23.3,
22.8; HRMS (ES+) calcd for [C37H43N3O4F3Br − Br]+ 650.3206,
found 650.3220.
10
11
1j
4-MeO
H
f
1k
3-ethyl
amyl
12
13
14
1l
1
1
1
4-MeO
5,6-diMeO
5-Cl
3-ethyl
amyl
78
82
69
82
85
79
d
f
1m
1n
3-ethyl
amyl
3-ethyl
amyl
g
15
16
17
1o
1p
1q
2
2
1
H
H
methyl
1Ad
35(98)
35
63(44)
71
i
j
without benzene
ring
Bn
trace
nd
j
18
1r
1Ad
trace
nd
a
Unless otherwise specified, the reaction was performed with 1 (0.2
mmol) and 5 mol % of catalyst Cn-14 in a mixture of toluene (2 mL)
and 50% aqueous K2HPO4 solution at −5 °C. Isolated yields. The
enantiomeric excess was determined by HPLC analysis of the product
using a chiral column (DAICEL Chiralcel AD-H) with hexane/2-
propanol as the eluent. Oxidant loading: 2.0 equiv. Reaction time: 80
h. The enantiomeric excess was determined by HPLC analysis of the
product using a chiral column (DAICEL Chiralcel OD-H) with
hexane/2-propanol as the eluent. The enantiomeric excess was
determined by HPLC analysis of the product using a chiral column
(DAICEL Chiralcel AS-H) with hexane/2-propanol as the eluent. For
cases where 30% K2CO3 was used as the base, the ee value and yield
are given in parentheses. By using 30% K2CO3 as base. Monitored by
O(9)-Boc-Glycineyl-N-benzylcinchoninium Bromide (Cn-6): White
b
c
powder (0.37 g, yield 74.0%); [α]D25 121.0 (c 0.10, MeOH); mp 158−
1
160 °C (dec.); H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 8.9 Hz,
1H), 8.19 (d, J = 6.7 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.00 (t, J = 7.6
Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 7.63 (s, 1H), 7.48−7.37 (m, 2H),
7.22 (d, J = 3.5 Hz, 1H), 6.24 (s, 1H), 6.16 (d, J = 11.7 Hz, 1H), 5.92
(ddd, J = 16.9, 10.5, 6.1 Hz, 1H), 5.43−5.20 (m, 1H), 4.66 (s, 1H),
4.54 (d, J = 11.7 Hz, 1H), 4.12 (qd, J = 16.8, 6.0 Hz, 1H), 4.00−3.90
(m, 1H), 3.66 (t, J = 11.9 Hz, 1H), 2.81 (m, 1H), 2.47 (d, J = 7.8 Hz,
1H), 2.31−2.17 (m, 1H), 1.97 (s, 1H), 1.93−1.81 (m, 1H), 1.76 (d, J
= 10.7 Hz, 1H), 1.33 (s, 9H), 1.13 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 169.5, 156.9, 149.3, 147.7, 139.2, 135.7, 134.5, 130.4, 130.0,
128.9, 126.9, 124.6, 123.4, 118.4, 118.1, 80.0, 68.5, 65.5, 62.4, 56.5,
54.4, 43.7, 37.4, 28.1, 27.0, 23.4, 22.5; HRMS(ES+) calcd for
[C33H40N3O4Br − Br]+ 542.3019, found 542.3024.
O(9)-Boc-Glycineyl-N-(3-trifluoromethylbenzyl)cinchoninium
Bromide (Cn-7): Yellowish powder (0.37g, yield 71.4%); [α]D20 102.0
(c 0.10, MeOH); mp 168−170 °C (dec.); 1H NMR (400 MHz,
CDCl3) δ 8.94 (1 H, d, J 8.4), 8.89 (1 H, d, J 7.6), 8.85 (1 H, d, J =
4.6), 8.21 (1 H, s), 8.13 (1 H, d, J = 8.4), 8.04 (1 H, t, J = 7.7), 7.83 (1
H, t, J = 7.3), 7.76 (1 H, d, J = 7.7), 7.65 (1 H, t, J = 7.8), 7.56 (1 H, s),
7.40 (1 H, d, J = 4.4), 6.42 (1 H, d, J = 11.6), 5.98 (1 H, ddd, J = 17.1,
10.4, 6.6), 5.63 (1 H, d, J = 9.0), 5.58 (1 H, t, J = 6.1), 5.40 (1 H, d, J =
10.4), 5.32 (1 H, d, J = 17.9), 4.97 (1 H, t, J = 8.9), 4.53 (1 H, d, J =
11.7), 4.16 (1 H, dd, J = 16.8, 6.1), 4.07−3.99 (1 H, m), 3.94 (1 H, dd,
J = 16.9, 5.5), 3.63 (1 H, t, J = 12.0), 2.70 (1 H, dd, J = 20.9, 9.9), 2.57
(1 H, d, J = 8.0), 2.43−2.30 (1 H, m), 2.06 (1 H, s), 2.02−1.94 (1 H,
m), 1.81 (2 H, s), 1.38 (9 H, s), 1.32 (1 H, s); 13C NMR (100 MHz,
CDCl3) δ 169.1, 156.9, 149.3, 147.9, 139.3, 138.6, 135.4, 130.6, 130.2,
129.9, 129.7, 129.1, 128.1, 127.4, 124.9, 124.8, 123.8, 122.2, 118.8,
118.4, 80.4, 68.8, 65.7, 61.1, 56.5, 55.1, 43.8, 37.5, 28.1, 27.1, 23.4,
d
e
f
g
i
j
TLC.
136.5, 134.9, 131.6, 131.3, 130.1, 129.8, 129.7, 129.0, 128.4, 127.9,
127.8, 127.3, 127.3, 127.2, 125.4, 125.3, 124.2, 123.2, 122.2, 119.9,
119.2, 118.4, 69.3, 67.3, 65.7, 61.2, 56.3, 56.1, 54.6, 47.0, 38.0, 36.7,
30.6, 26.9, 23.3, 22.6; HRMS(ES+) calcd for [C51H47N3O4F3Br − Br]+
822.3519, found 822.3533.
O(9)-Boc-β-Alanineyl-N-benzylcinchoninium Bromide (Cn-3):
White powder (1.4 g, yield 67.6%); [α]D 89.0 (c 0.10, MeOH);
mp 153−156 °C (dec.); H NMR (400 MHz, CDCl3) δ 8.89 (d, J =
4.2 Hz, 1H), 8.80 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.99
(d, J = 5.3 Hz, 3H), 7.82 (t, J = 7.2 Hz, 1H), 7.48 (s, 3H), 7.43 (s,
2H), 6.30 (d, J = 11.6 Hz, 1H), 6.04−5.89 (m, 1H), 5.55 (s, 1H), 5.32
(dd, J = 45.4, 13.8 Hz, 4H), 5.15 (s, 1H), 4.88 (s, 1H), 4.44 (d, J =
11.7 Hz, 1H), 3.79 (t, J = 10.5 Hz, 1H), 3.69 (t, J = 11.5 Hz, 1H), 3.55
(s, 1H), 3.46 (s, 2H), 2.91 (dd, J = 11.1, 5.6 Hz, 3H), 2.56 (d, J = 8.4
Hz, 1H), 2.45−2.29 (m, 1H), 2.04 (s, 1H), 1.99 (s, 2H), 1.82 (s, 1H),
1.43 (s, 9H), 1.33 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 170.0,
156.2, 149.3, 148.1, 140.0, 135.4, 134.3, 130.7, 130.4, 129.9, 129.2,
25
1
9604
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Article
22.7; HRMS (ES+) calcd for [C34H39N3O4F3Br − Br]+ 610.2893,
found 610.2891.
7.75 (2 H, d, J = 7.5), 7.71 (1 H, d, J = 4.7), 7.56 (1 H, d, J = 7.2), 7.51
(2 H, t, J = 7.2), 7.45 (1 H, s), 7.34 (2 H, d, J = 7.8), 7.19 (2 H, t, J =
7.9), 6.96 (1 H, t, J = 7.4), 6.37 (1 H, s), 6.21 (1 H, ddd, J = 17.3, 10.4,
7.0), 5.39 (2 H, dd, J = 41.7, 30.4), 4.94 (2 H, d, J = 5.2), 4.14 (1 H, t,
J = 9.2), 4.03−3.92 (1 H, m), 3.87−3.73 (2 H, m), 3.63 (2 H, m),
3.16−3.00 (2 H, m), 2.99−2.89 (1 H, m), 2.72 (2 H, d, J = 9.4), 2.07
(1 H, s), 1.89 (2 H, d, J = 10.0), 1.48 (1 H, s); 13C NMR (101 MHz,
CDCl3) δ 170.5, 156.6, 149.2, 147.5, 140.2, 139.5, 135.0, 134.0, 130.9,
130.0, 129.9, 129.4, 128.7, 127.9, 126.5, 123.0, 122.5, 121.7, 118.9,
118.4, 117.6, 68.9, 66.4, 63.8, 56.9, 54.7, 37.4, 36.0, 35.2, 29.7, 26.7,
23.6, 22.4; HRMS (ES+) calcd for [C36H39N4O3Br − Br]+ 575.3022,
found 575.3022.
The phase-transfer catalysts Cn-12 to Cn-14 and Qn-1 were
synthesized by an analogous procedure as reported by Jorgensen.13 To
a flame-dried flask equipped with a magnetic stirring bar and a reflux
condenser was added cinchoninium bromide or quinidium bromide (1
mmol), CH2Cl2 (10 mL), and adamantane carbonyl chloride (0.6 g,
3.2 mmol) was added to a suspension of the above salt; 30% w/w
NaOH solution (1.4 mL) was added, and the suspension was stirred
vigorously at room temperature for 30 min, during which time the
solid fully dissolved. Water (10 mL) was added, and the two layers
were separated. The aqueous layer was extracted with CH2Cl2 (3 × 5
mL). The combined organic fractions were dried by Na2SO4, filtered,
and concentrated to ∼1 mL and then poured onto Et2O (30 mL). The
precipitate was filtered and washed thoroughly with Et2O to give the
products as a solid. The product was purified by a neutral alumina
column (CH2Cl2/MeOH = 20:1) to give a bright powder.
O(9)-Boc-Glycineyl-N-(3,5-tert-butyllbenzyl)cinchoninium Bro-
25
mide (Cn-8): Yellowish powder (0.1 g, yield 15.6%); [α]D 95.0 (c
1
0.10, MeOH); mp 159−161 °C (dec.); H NMR (400 MHz, CDCl3)
δ 8.87 (d, J = 4.5 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 9.2
Hz, 1H), 7.85 (s, 2H), 7.76−7.64 (m, 2H), 7.58 (d, J = 8.2 Hz, 2H),
7.47 (s, 1H), 6.09 (t, J = 5.9 Hz, 1H), 6.01 (ddd, J = 17.2, 10.4, 6.9 Hz,
1H), 5.77 (d, J = 12.0 Hz, 1H), 5.29 (dd, J = 24.8, 13.8 Hz, 2H), 5.17
(s, 1H), 4.58 (d, J = 11.6 Hz, 2H), 4.21 (t, J = 5.3 Hz, 2H), 4.03−3.90
(m, 1H), 3.84 (t, J = 11.5 Hz, 1H), 3.14 (dd, J = 20.2, 9.6 Hz, 1H),
2.62 (dd, J = 16.6, 8.5 Hz, 1H), 2.46−2.29 (m, 1H), 1.99 (s, 1H), 1.84
(d, J = 7.6 Hz, 2H), 1.41 (s, 9H), 1.35 (s, 18H), 1.25 (d, J = 5.1 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 169.0, 156.5, 152.3, 149.6,
148.2, 139.7, 135.8, 130.2, 130.1, 128.9, 128.5, 126.1, 124.6, 124.0,
124.0, 118.7, 118.5, 80.3, 69.4, 64.9, 64.3, 56.9, 56.3, 43.6, 37.8, 35.1,
31.5, 28.3, 27.2, 23.7, 22.7; HRMS (ES+) calcd for [C41H56N3O4Br −
Br]+ 654.4271, found 654.4272.
O(9)-Boc-D-Phenylglycineyl-N-benzylcinchoninium Bromide (Cn-
25
9): White powder (0.6 g, yield 92.7%); [α]D 56.0 (c 0.10, MeOH);
1
mp 148−150 °C (dec.); H NMR (400 MHz, CDCl3) δ 8.94 (d, J =
8.2 Hz, 1H), 8.38 (d, J = 4.6 Hz, 1H), 8.33−8.26 (m, 2H), 8.11−7.98
(m, 2H), 7.80 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 3.4 Hz, 2H), 7.48 (ddd,
J = 17.5, 10.9, 4.9 Hz, 6H), 7.41−7.36 (m, 2H), 6.54 (d, J = 4.6 Hz,
1H), 6.38 (d, J = 11.4 Hz, 1H), 6.02 (ddd, J = 17.0, 10.5, 6.3 Hz, 1H),
5.75 (t, J = 11.0 Hz, 1H), 5.48 (d, J = 10.5 Hz, 1H), 5.40 (d, J = 17.6
Hz, 1H), 5.29 (td, J = 5.4, 2.4 Hz, 2H), 5.00 (t, J = 9.2 Hz, 1H), 4.56
(d, J = 11.4 Hz, 1H), 4.20−4.00 (m, 1H), 3.82−3.69 (m, 1H), 3.54 (d,
J = 4.8 Hz, 1H), 3.54 (d, J = 4.8 Hz, 1H), 2.88 (dd, J = 20.7, 10.0 Hz,
1H), 2.58 (dd, J = 16.3, 8.2 Hz, 1H), 2.31−2.15 (m, 1H), 2.02 (d, J =
20.6 Hz, 1H), 1.82 (s, 2H), 1.47 (s, J = 4.2 Hz, 9H), 1.33−1.17 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 169.1, 155.9, 148.7, 148.0,
139.1, 136.2, 134.6, 132.1, 130.5, 130.5, 130.2, 129.7, 129.5, 129.5,
128.9, 128.2, 127.0, 125.1, 124.0, 118.1, 117.5, 81.3, 69.1, 65.1, 64.9,
62.0, 59.8, 56.3, 54.5, 41.9, 37.3, 30.1, 29.1, 28.2, 26.9, 23.4, 23.3, 23.0,
22.7; HRMS(ES+) calcd for [C39H44N3O4Br − Br]+ 618.3332, found
618.3346.
O-1-Adamantoyl-N-benzylcinchoninium Bromide (Cn-12): White
20
powder (0.6 g, yield 98.3%); [α]D 65.0 (c 0.10, MeOH); mp 147−
1
149 °C (dec.); H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 8.4 Hz,
1H), 8.92 (d, J = 4.6 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 8.02 (t, J = 7.6
Hz, 1H), 7.89−7.83 (m, 3H), 7.55−7.51 (m, 3H), 7.49 (d, J = 2.3 Hz,
1H), 7.40 (d, J = 4.5 Hz, 1H), 6.48 (d, J = 11.8 Hz, 1H), 6.01 (ddd, J =
17.3, 10.4, 7.0 Hz, 1H), 5.77 (t, J = 11.0 Hz, 1H), 5.43−5.20 (m, 3H),
4.99 (t, J = 9.5 Hz, 1H), 4.17 (d, J = 11.7 Hz, 1H), 3.78 (dt, J = 22.5,
11.0 Hz, 2H), 2.95 (dd, J = 21.2, 10.0 Hz, 1H), 2.58 (dd, J = 16.9, 9.0
Hz, 1H), 2.45−2.34 (m, 1H), 2.19 (s, 4H), 2.10 (s, 9H), 1.83 (dd, J =
32.4, 12.0 Hz, 8H), 1.44−1.28 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 174.7, 149.0, 148.2, 140.5, 135.1, 134.0, 130.8, 130.6, 129.6, 129.4,
129.2, 126.6, 125.0, 124.2, 118.9, 117.6, 68.6, 64.9, 62.3, 56.0, 54.7,
41.1, 39.2, 39.1, 37.8, 36.2, 27.6, 26.8, 23.4, 23.0; HRMS(ES+) calcd
for [C37H43N2O2Br − Br]+ 547.3325, found 547.3329.
O(9)-Boc-D-Phenylglycineyl-N-(3-trifluoromethylbenzyl)-
cinchoninium Bromide (Cn-10): Yellowish powder (0.23 g, yield
25
1
53.5%); [α]D 53.0 (c 0.10, MeOH); mp 140−143 °C (dec.); H
NMR (400 MHz, CDCl3) δ 9.03 (1 H, d, J = 7.8), 8.97 (1 H, d, J =
6.4), 8.39 (1 H, d, J = 4.6), 8.24 (1 H, s), 8.12 (1 H, d, J = 8.4), 8.02 (1
H, t, J = 7.3), 7.81 (2 H, m), 7.70 (1 H, t, J = 7.6), 7.52−7.55 (3 H,
m), 7.47 (2 H, t, J = 7.4), 7.40 (1 H, s), 7.38 (1 H, s), 6.59 (1 H, s),
6.59 (1 H, s), 6.55 (1 H, m) 6.03 (1 H, ddd, J = 17.1, 10.5, 6.5), 5.84
(1 H, d, J = 9.0), 5.51 (1 H, d, J = 10.5), 5.41 (1 H, d, J = 17.3), 5.26
(2 H, d, J = 2.3), 5.09 (1 H, d, J = 9.4), 4.60 (1 H, d, J = 11.5), 4.19 (1
H, dd, J = 17.9, 7.1), 3.74−3.64 (1 H, m), 3.55 (2 H, d, J = 4.8), 2.81−
2.68 (1 H, m), 2.63 (1 H, d, J = 7.4), 2.31- 2.18 (1 H, m), 2.04 (3 H, d,
J = 13.6), 1.84 (3 H, s), 1.42 (9 H, s), 1.32−1.23 (1 H, m); 13C NMR
(100 MHz, CDCl3) δ 169.0, 156.0, 148.7, 148.1, 139.0, 138.9, 135.8,
132.0, 130.6, 130.2, 129.9, 129.8, 129.6, 129.5, 128.3, 128.2, 125.2,
124.0, 118.4, 117.5, 81.5, 69.3, 65.2, 65.1, 60.9, 59.7, 56.4, 55.0, 42.0,
37.4, 30.1, 29.7, 29.1, 28.2, 28.1, 27.0, 23.4, 23.3, 23.1, 22.8; HRMS(ES
+) calcd for [C40H43N3O4F3Br − Br]+ 686.3206, found 686.3177.
Cn-11: The catalyst was synthesized following known procedures.
To a flame-dried flask equipped with a magnetic stirring bar were
added Cn-3 (0.3 g) and dried CH2Cl2 (10 mL), and the solution was
cooled to 0 °C, then TFA (1 mL) was added slowly and the reaction
kept at this temperature for 4 h. The mixture was concentrated to ∼1
mL and poured onto Et2O (100 mL). The precipitate was filtered and
was washed thoroughly with Et2O to give the primary amine product
as a white solid. Phenylcarbimide solution (75 mg, 0.629 mmol in 5
mL of dried THF) was added to a suspension of the above primary
amine (270 mg) in dried THF (7.5 mL). The reaction was stirred at
room temperature for 8 h, then was concentrated, and the product was
purified by CC (CH2Cl2/MeOH = 50:3) to give a bright powder (0.16
O-1-Adamantoyl-N-(3-trifluoromethylbenzyl)cinchoninium Bro-
20
mide (Cn-13): Yellowish powder (0.71 g, yield 98%); [α]D 64.0 (c
1
0.10, MeOH); mp 142−144 °C (dec.); H NMR (400 MHz, CDCl3)
δ 8.98 (d, J = 8.4 Hz, 1H), 8.93 (d, J = 4.5 Hz, 1H), 8.56 (d, J = 7.5
Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.02 (t, J = 7.7 Hz, 1H), 7.90−7.76
(m, 2H), 7.75−7.68 (m, 2H), 7.49 (s, 1H), 7.41 (d, J = 4.5 Hz, 1H),
6.76 (d, J = 11.9 Hz, 1H), 6.02 (ddd, J = 17.2, 10.4, 7.1 Hz, 1H), 5.91
(t, J = 11.0 Hz, 1H), 5.48−5.18 (m, 2H), 5.06 (t, J = 9.6 Hz, 1H), 4.20
(d, J = 11.8 Hz, 1H), 3.86 (t, J = 9.6 Hz, 1H), 3.61 (t, J = 11.1 Hz,
1H), 2.87 (dd, J = 20.9, 9.9 Hz, 1H), 2.68−2.50 (m, 1H), 2.42 (t, J =
12.4 Hz, 1H), 2.17 (d, J = 20.9 Hz, 3H), 2.08 (d, J = 18.9 Hz, 9H),
1.84 (dd, J = 34.3, 12.3 Hz, 9H), 1.40 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 174.7, 148.8, 148.1, 140.4, 138.3, 134.8, 130.9, 130.5, 129.7,
129.6, 129.4, 127.9, 127.7, 124.9, 124.3, 119.2, 117.6, 68.6, 65.2, 61.3,
56.1, 55.0, 41.2, 39.2, 39.1, 37.9, 36.2, 27.7, 26.9, 23.4, 23.0; HRMS
(ES+) calcd for [C38H42F3N2O2Br − Br]+ 615.3198, found 615.3193.
O-1-Adamantoyl-N-(9-anthracenylmethyl)cinchonium Bromide
20
(Cn-14): Yellow powder (0.71 g, yield 97.5%); [α]D 136.0 (c 0.10,
MeOH); mp 101−103 °C (dec.); 1H NMR (400 MHz, CDCl3) δ 9.80
(d, J = 8.9 Hz, 1H, CH Ar), 9.03 (d, J = 4.2 Hz, 1H, CH Ar), 8.94 (d, J
= 8.4 Hz, 1H, CH Ar), 8.69 (s, 1H, CH Ar), 8.26 (d, J = 8.3 Hz, 1H,
CH Ar), 8.19- 8.11 (m, 1H, CH Ar), 8.06 (d, J = 8.4 Hz, 2H, 2 × CH
Ar), 7.98 (t, J = 7.7 Hz, 1H, CH Ar), 7.89 (m, 3H, 3 × CH Ar), 7.81
(d, J = 4.1 Hz, 1H, CH Ar), 7.66−7.52 (m, 3H, 3 × CH Ar), 6.44 (d, J
= 13.3 Hz, 1H, CHO), 6.01 (t, J = 8.9 Hz, 1H, CHN
methylanthracene), 5.93 (ddd, J = 17.1, 10.3, 6.7 Hz, 1H, CH
vinyl), 5.83 (t, J = 10.7 Hz, 1H, CHN methylanthracene), 5.27 (d, J =
10.3 Hz, 1H, CHH′ vinyl), 5.06(d, J = 17.1 Hz, 1H, CHH′ vinyl), 3.81
25
g, yield 78.7%): [α]D 44 (c 0.10, MeOH); mp 165−168 °C (dec.);
1H NMR (400 MHz, CDCl3) δ 8.82 (1 H, d, J = 4.6), 8.28 (1 H, d, J =
8.4), 8.14 (1 H, d, J = 8.4), 7.90 (1 H, t, J = 7.7), 7.83 (1 H, t, J = 7.6),
9605
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(t, J = 10.1 Hz, 1H, CHN), 3.81 (t, J = 10.1 Hz, 1H, CHN), 3.18 (t, J
= 11.4 Hz, 1H, CHN), 3.18 (t, J = 11.4 Hz, 1H, CHN), 2.57 (m, 3H),
2.22 (s, 6H), 2.18 (s, 6H), 2.02 (d, J = 16.4 Hz, 2H), 1.89 (dd, J =
25.3, 12.8 Hz, 8H), 1.73 (d, J = 11.9 Hz, 1H), 1.61 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 175.6, 149.1, 148.5, 148.5, 140.7, 135.4, 134.1,
134.0, 132.7, 131.5, 130.6, 130.6, 130.3, 129.8, 129.4, 128.8, 127.6,
126.9, 126.4, 125.1, 124.9, 123.6, 122.5, 118.9, 118.5, 69.0, 65.7, 56.9,
55.3, 54.9, 41.5, 39.5, 38.8, 36.3, 27.8, 27.2, 25.9, 23.9, 23.3; HRMS
(ES+) calcd for [C45H47N2O2Br − Br]+ 647.3638, found 647.3646.
O-1-Adamantoyl-N-(9-anthracenylmethyl)quinidium Bromide
107.25, 104.78, 89.97, 56.24, 56.04, 54.78, 30.30, 26.77, 7.55, minor
peaks due to enol observed at 150.36, 149.39, 129.88, 107.50, 104.17,
74.57, 36.48, 25.53; HRMS (ES+) calcd for [C19H26O5 + Na]+
357.1678, found 357.1685.
3-Ethyl Amyl 5-Chloro-1-indanone-2-carboxylate (1n): Colorless
1
crystal (0.78 g, 56.9% yield); mp 91−93 °C; H NMR (400 MHz,
CDCl3) δ 3.65 (dd, J = 8.2, 3.9 Hz, 1H), 3.47 (dd, J = 17.4, 3.8 Hz,
1H), 3.32 (dd, J = 17.4, 8.2 Hz, 1H), 1.89−1.78 (m, 6H), 0.83 (t, J =
7.5 Hz, 9H), minor peaks due to enol observed at 7.53 (d, J = 8.1 Hz,
1H), 7.42 (d, J = 1.1 Hz, 1H), 3.47 (s, 2H), 1.94 (q, J = 7.5 Hz, 6H),
0.88 (t, J = 7.5 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 194.8, 163.7,
151.4, 138.0, 130.3, 124.8, 123.0, 121.9, 86.8, 50.9, 26.6, 23.1, 3.9,
minor peaks due to enol observed at 194.8, 140.8, 123.5, 121.3, 117.7,
29.0, 23.6; HRMS (ES+) calcd for [C17H21ClO3 + Na]+ 331.1077,
found 331.1069.
25
(Qn-1): Yellow powder (0.75 g, yield 98.0%); [α]D 160.0 (c 0.10,
MeOH); mp 108−110 °C (dec.); 1H NMR (400 MHz, CDCl3) δ 9.70
(d, J = 8.8 Hz, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 8.16 (d, J = 8.7 Hz,
2H), 8.08 (d, J = 8.2 Hz, 3H), 8.01−7.89 (m, 3H), 7.83 (d, J = 7.9 Hz,
2H), 7.76 (d, J = 4.3 Hz, 1H), 7.65−7.53 (m, 4H), 7.49 (d, J = 9.3 Hz,
1H), 6.35 (s, 1H), 6.25 (s, 1H), 5.96 (m, 2H), 5.70 (d, J = 13.4 Hz,
1H), 5.28 (d, J = 10.3 Hz, 1H), 5.08 (d, J = 17.4 Hz, 1H), 4.35 (s, 3H),
3.23 (t, J = 11.4 Hz, 1H), 2.75−2.60 (m, 1H), 2.53−2.46 (m, 1H),
2.23−1.51 (m, 24H); 13C NMR(100 MHz, CDCl3) δ 175.9, 158.5,
147.1, 146.6, 144.8, 140.6, 138.8, 136.3, 133.7, 133.0, 132.8, 131.7,
131.6, 131.3, 131.0, 130.7, 129.9, 129.6, 129.4, 129.2, 128.8, 127.8,
127.7, 126.9, 126.2, 126.1, 125.9, 125.2, 125.0, 124.8, 123.5, 123.0,
122.3, 119.8, 119.0, 118.7, 116.6, 102.5, 68.5, 66.1, 59.5, 56.8, 56.2,
55.7, 55.0, 49.6, 49.0, 41.6, 40.9, 40.7, 39.2, 39.1, 38.8, 38.6, 38.2, 36.6,
36.2, 36.1, 27.8, 27.6, 27.2, 26.7, 24.0, 23.3, 11.2; HRMS (ES+) calcd
for [C46H49N2O3Br − Br]+ 677.3743, found 677.3774.
General Procedure for the Synthesis of β-Oxo Esters. β-Oxo
esters 1a−1h,11 1i−1j,16 and 1o−1r11 were prepared according to the
literature procedure, and 1k, 1l, 1m, and 1n were synthesized in
accordance with a modified literature procedure as described here: To
a flask equipped with a Dean−Stark trap and reflux condenser were
added β-oxo methyl ester (1.0 g), corresponding alcohol (1.2 equiv),
the transesterification catalyst ZnO17 (20 mol %), and toluene. The
mixture was heated to reflux, distilling the methanol formed during the
reaction. The mixture was refluxed until complete conversion was
observed by TLC, then concentrated under reduced pressure, and the
crude residue was purified by column chromatography (silica gel,
petroleum ether/ethyl acetate = 3/1), then recrystallization in n-
hexane to give a crystal.
General Procedure for the Catalytic Enantioselective
Hydroxylation Reaction. β-Oxo ester 1 (0.2 mmol) and catalyst
Cn-14 (7.2 mg, 0.01 mmol, 5 mol %) were added to a test tube
equipped with a stirring bar and dissolved in toluene (1 mL). Cumyl
hydroperoxide (0.3 mmol in toluene solution, 1.5 equiv, 1 mL) was
added; the resulting mixture was cooled to −5 °C before precooled
50% aq K2HPO4 (1 mL) was added, and the reaction was stirred at
this temperature for 60 h. After completion of the reaction, the
reaction mixture was diluted with Et2O (10 mL), washed with water (3
× 5 mL), dried with anhydrous Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography (silica gel;
petroleum ether/EtOAc, 13:1−5:1) to afford products.
1-Adamantyl 2-Hydroxy-1-oxoindan-2-carboxylate (3a): Color-
less oil (58.7 mg, 90% yield, 88% ee); [α]D25 12.5 (c 0.11, MeOH); 1H
NMR (400 MHz, CDCl3) δ 7.78 (1 H, d, J = 7.7), 7.64 (1 H, dd, J =
10.9, 4.1), 7.47 (1 H, d, J = 7.7), 7.40 (1 H, t, J = 7.5), 4.10 (1 H, s),
3.66 (1 H, d, J = 17.1), 3.21 (1 H, d, J = 17.1), 2.11 (3 H, s), 1.96 (6
H, d, J = 2.9), 1.59 (6 H, s); 13C NMR (100 MHz, CDCl3) δ 201.5,
170.2, 152.4, 135.8, 134.0, 127.9, 126.3, 125.0, 83.9, 80.6, 40.9, 39.6,
35.9, 30.8. HPLC conditions: Chiralcel AD-H column (250 × 4.6
mm), hexane/i-PrOH = 80/20, 1 mL/min, 254 nm, τR (major) = 12.0
min, τR (minor) = 20.7 min.
1-Adamantyl 6-Methoxyl-2-hydroxy-1-indanone-2-carboxylate
20
(3b): Colorless oil (60.7 mg, 85% yield, 86% ee); [α]D 17.3 (c
1
3-Ethyl Amyl-1-indanone-2-carboxylate (1k): Colorless crystal
(0.86 g, 59.8% yield); mp 61−63 °C; 1H NMR (400 MHz, CDCl3) δ
7.77 (d, J = 7.7 Hz, 1H), 7.61 (td, J = 7.6, 1.2 Hz, 1H), 7.52−7.46 (m,
1H), 7.42−7.34 (m, 1H), 3.64 (dd, J = 8.2, 3.9 Hz, 1H), 3.49 (dd, J =
17.1, 3.9 Hz, 1H), 3.35 (dd, J = 17.1, 8.2 Hz, 1H), 1.89−1.77 (m, 6H),
0.83 (t, J = 7.5 Hz, 9H), minor peaks due to enol observed at 3.49 (s,
1H), 1.94 (q, J = 7.5 Hz, 3H), 0.88 (t, J = 7.5 Hz, 5H); 13C NMR (100
MHz, CDCl3) δ 200.0, 167.9, 153.7, 135.6, 135.2, 127.7, 126.5, 124.6,
90.2, 54.6, 30.6, 26.8, 7.6, minor peaks due to enol observed at 143.0,
129.0, 126.7, 120.5, 32.8, 27.3; HRMS (ES+) calcd for [C17H22O4 +
Na]+ 297.1467, found 297.1462.
0.10, MeOH); H NMR (400 MHz, CDCl3) δ 7.36 (1 H, d, J = 8.2),
7.26−7.19 (2 H, m), 4.11 (1 H, s), 3.84 (3 H, s), 3.58 (1 H, d, J =
16.8), 3.13 (1 H, d, J =16.8), 2.12 (3 H, s), 1.98 (6 H, d, J = 2.5), 1.60
(6 H, s); 13C NMR (100 MHz, CDCl3) δ 201.4, 170.3, 159.6, 145.3,
135.1, 127.0, 125.1, 106.1, 83.8, 81.2, 55.6, 40.9, 39.0, 35.9, 30.8.
HPLC conditions: Chiralcel AD-H column (250 × 4.6 mm), hexane/i-
PrOH = 90/10, 1 mL/min, 254 nm, τR (major) = 24.8 min, τR
(minor) = 48.1 min.
1-Adamantyl 4-Methoxyl-2-hydroxy-1-indanone-2-carboxylate
25
(3c): Colorless solid (59.2 mg, 83% yield, 90% ee); [α]D 32.2 (c
1
0.08, MeOH); H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 1.5 Hz,
3-Ethyl Amyl 4-Methoxyl-1-indanone-2-carboxylate (1l): Color-
less crystal (0.91 g, 65.9% yield); mp 52−53 °C; 1H NMR (400 MHz,
CDCl3) δ 7.36 (s, 1H), 7.35−7.34 (m, 1H), 7.04 (p, J = 4.1 Hz, 1H),
3.91 (s, 3H), 3.61 (dd, J = 8.0, 3.9 Hz, 1H), 3.36 (dd, J = 17.6, 3.9 Hz,
1H), 3.26 (dd, J = 17.6, 8.0 Hz, 1H), 1.88−1.77 (m, 6H), 0.83 (t, J =
7.5 Hz, 9H), minor peaks due to enol observed at 6.92 (d, J = 8.0 Hz,
1H), 3.43 (s, 2H), 1.93 (q, J = 7.5 Hz, 6H), 0.88 (t, J = 7.5 Hz, 9H);
13C NMR (100 MHz, CDCl3) δ 200.3, 168.0, 156.9, 142.6, 137.1,
129.2, 116.0, 115.3, 90.1, 55.5, 54.5, 27.5, 27.3, 26.8, 7.7, 7.6, minor
peaks due to enol observed at 155.6, 138.9, 130.3, 128.8, 128.5, 114.7,
113.3, 110.9, 104.0, 36.2, 30.1, 22.5; HRMS (ES+) calcd for
[C18H24O4 + Na]+ 327.1572, found 327.1577.
1H), 7.36 (s, 1H), 7.10−7.07 (m, 1H), 4.04 (s, 1H), 3.91 (s, 3H), 3.59
(d, J = 17.5 Hz, 1H), 3.07 (d, J = 17.6 Hz, 1H), 2.11 (s, 3H), 1.98 (d, J
= 2.8 Hz, 6H), 1.60 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 201.6,
170.4, 156.6, 141.4, 135.3, 129.4, 116.4, 116.0, 83.8, 80.3, 55.6, 40.9,
36.4, 35.9, 30.8. HPLC conditions: Chiralcel OD-H column (250 ×
4.6 mm), hexane/i-PrOH = 98/2, 1 mL/min, 254 nm, τR (major) =
28.5 min, τR (minor) = 32.8 min.
1-Adamantyl 5,6-Dimethoxy-2-hydroxy-1-indanone-2-carboxy-
25
late (3d): Colorless solid (42.5 mg, 61% yield, 90% ee); [α]D 56.3
1
(c 0.08, MeOH); H NMR (400 MHz, CHCl3) δ 7.19 (1 H, s), 6.89
(1 H, s), 4.02 (1 H, s), 3.99 (3 H, s), 3.92 (3 H, s), 3.57 (1 H, d, J =
16.9), 3.12 (1 H, d, J = 16.9), 2.13 (3 H, s), 2.00 (6 H, s), 1.61 (6 H,
s); 13C NMR (100 MHz, CHCl3) δ 199.8, 170.5, 156.4, 149.8, 148.2,
126.6, 107.2, 105.3, 83.7, 80.8, 56.3, 56.1, 41.0, 39.3, 35.9, 30.8. HPLC
conditions: Chiralcel AD-H column (250 × 4.6 mm), hexane/i-PrOH
= 80/20, 1 mL/min, 254 nm, τR (major) = 23.6 min, τR (minor) =
42.6 min.
3-Ethyl Amyl 5,6-Dimethoxy-1-indanone-2-carboxylate (1m):
1
Colorless crystal (0 8 g, 59.9% yield); mp 104−106 °C; H NMR
(400 MHz, CDCl3) δ 7.17 (s, 1H), 6.91 (s, 1H), 3.97 (s, 4H), 3.90 (s,
3H), 3.62 (dd, J = 7.8, 3.5 Hz, 1H), 3.38 (dd, J = 16.9, 3.4 Hz, 1H),
3.25 (dd, J = 16.9, 7.8 Hz, 1H), 1.92−1.78 (m, 7H), 0.84 (t, J = 7.5 Hz,
10H), minor peaks due to enol observed at 3.09−3.00 (m, 1H), 2.69−
2.63 (m, 1H), 1.46 (q, J = 7.5 Hz, 3H), 0.87 (s, 7H); 13C NMR (100
MHz, CDCl3) δ 198.57, 168.25, 155.86, 149.67, 149.17, 128.25,
1-Adamantyl 6-Bromo-2-hydroxy-1-indanone-2-carboxylate
25
(3e): Colorless oil (35.8 mg, 45% yield, 58% ee); [α]D −15.5 (c
1
0.084, MeOH); H NMR (400 MHz, CDCl3) δ 77.91 (1 H, d, J =
9606
dx.doi.org/10.1021/jo3016242 | J. Org. Chem. 2012, 77, 9601−9608

The Journal of Organic Chemistry
Article
1.3), 7.74 (1 H, dd, J = 8.1, 1.7), 7.36 (1 H, d, J = 8.1), 4.07 (1 H, s),
3.59 (1 H, d, J = 17.3), 3.15 (1 H, d, J = 17.3), 2.13 (3 H, s), 1.96 (6
H, d, J = 2.5), 1.60 (6 H, s); 13C NMR (100 MHz, CHCl3) δ 200.1,
169.7, 150.8, 138.5, 135.8, 127.8, 127.8, 122.0, 84.3, 80.7, 40.9, 39.2,
35.8, 30.8. HPLC conditions: Chiralcel AD-H column (250 × 4.6
mm), hexane/i-PrOH = 80/20, 1 mL/min, 254 nm, τR (major) = 11.1
min, τR (minor) = 21.8 min.
Hz), 7.37 (1 H, s), 7.11−7.07 (1 H, m), 4.03 (1 H, s), 3.91 (4 H, s),
3.59 (1 H, d, J = 17.4 Hz), 3.09 (1 H, d, J = 17.4 Hz), 1.71 (6H, q, J =
7.4 Hz), 0.67 (9 H, t, J = 7.5 Hz); 13C NMR (100 MHz, CDCl3) δ
197.9, 166.5, 152.9, 137.4, 131.8, 125.7, 112.6, 112.3, 88.3, 76.9, 51.9,
32.7, 23.2, 3.7; HRMS (ES+) calcd for [C18H24O5 + Na]+ 343.1521,
found 343.1533. HPLC conditions: Chiralcel AD-H column (250 ×
4.6 mm), hexane/i-PrOH = 90/10, 1 mL/min, 254 nm, τR (major) =
26.1 min, τR (minor) = 19.6 min.
1-Adamantyl 4-Bromo-2-hydroxy-1-indanone-2-carboxylate
25
(3f): Colorless oil (58.2 mg, 73% yield,76% ee); [α]D 34.5 (c
3-Ethyl Amyl 5,6-Dimethoxy-2-hydroxy-1-indanone-2-carboxy-
1
0.116, MeOH); H NMR (400 MHz, DMSO) δ 7.98 (d, J = 7.7 Hz,
25
late (3m): Colorless oil (51.7 mg, 82% yield, 85% ee); [α]D 7.1 (c
1H), 7.74 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 6.67 (br s, 1H),
3.45 (d, J = 17.5 Hz, 1H), 2.99 (d, J = 17.5 Hz, 1H), 2.05 (br s, 3H),
1.88 (br s, 6H), 1.53 (br s, 6H); 13C NMR (100 MHz, DMSO) δ
201.3, 169.8, 151.7, 138.9, 136.3, 130.9, 123.9, 121.6, 82.0, 80.4, 42.5,
41.0, 35.8, 30.6. HPLC conditions: Chiralcel AD-H column (250 × 4.6
mm), hexane/i-PrOH = 90/10, 1 mL/min, 254 nm, τR (major) = 16.4
min, τR (minor) = 19.5 min.
1
0.08, MeOH); H NMR (400 MHz, CDCl3) δ 7.20 (s, 1H), 6.89 (s,
1H), 4.06 (s, 1H), 4.00 (s, 1H), 3.92 (s, 3H), 3.56 (d, J = 16.8 Hz,
1H), 3.15 (d, J = 16.9 Hz, 1H), 1.73 (q, J = 7.5 Hz, 6H), 0.70 (t, J =
7.5 Hz, 9H); 13C NMR (101 MHz, CDCl3) δ 199.8, 170.4, 156.4,
149.8, 148.1, 126.7, 107.1, 105.2, 91.9, 80.9, 56.3, 56.1, 39.4, 26.8, 7.4;
HRMS(ES+) calcd for [C19H26O6 + Na]+ 373.1627, found 373.1642.
HPLC conditions: Chiralcel AD-H column (250 × 4.6 mm), hexane/i-
PrOH = 90/10, 1 mL/min, 254 nm, τR (major) = 42.7 min, τR
(minor) = 36.0 min.
1-Adamantyl 5-Chloro-2-hydroxy-1-indanone-2-carboxylate
25
(3g): White solid (64.1 mg, 88% yield, 82% ee); [α]D 41.7 (c
1
0.156, MeOH); H NMR (400 MHz, CDCl3) δ 7.72 (1 H, d, J = 8.2
Hz), 7.47 (1 H, s), 7.39 (1 H, d, J = 8.2 Hz), 4.14 (1 H, s), 3.63 (1 H,
d, J = 17.3 Hz), 3.20 (1 H, d, J = 17.3 Hz), 2.12 (3 H, s), 1.97 (6 H, s),
1.60 (6 H, s); 13C NMR (100 MHz, CDCl3) δ 200.0, 169.8, 153.7,
142.4, 132.5, 128.8, 126.5, 126.1, 84.2, 80.5, 40.9, 39.3, 35.8, 30.8.
HPLC conditions: Chiralcel AD-H column (250 × 4.6 mm), hexane/i-
PrOH = 80/20, 1 mL/min, 254 nm, τR (major) = 12.5 min, τR
(minor) = 22.1 min.
2-Adamantyl 2-Hydroxy-1-indanone-2-carboxylate (3h). Color-
less solid (62.1 mg, 95% yield, 75% ee); [α]D25 3.2(c 0.16, MeOH); 1H
NMR (400 MHz, CHCl3) δ 7.80 (1 H, d, J = 7.7 Hz), 7.71−7.61 (1 H,
m), 7.50 (1 H, d, J = 7.7 Hz), 7.42 (1 H, t, J = 7.5 Hz), 4.95 (1 H, s),
4.15 (1 H, s), 3.71 (1 H, d, J = 17.0 Hz), 3.30 (1 H, d, J = 17.0 Hz),
1.87 (2 H, d, J = 28.3 Hz), 1.81−1.21 (12 H, m); 13C NMR (100
MHz, CHCl3) δ 201.2, 170.6, 152.0, 135.9, 134.1, 128.0, 126.3, 125.0,
81.0, 79.7, 39.6, 37.1, 36.1, 36.0, 31.7, 31.5, 31.3, 26.8, 26.7. HPLC
conditions: Chiralcel AD-H column (250 × 4.6 mm), hexane/i-PrOH
= 80/20, 1 mL/min, 254 nm, τR (major) = 11.3 min, τR (minor) =
14.4 min.
3-Ethyl Amyl 5-Chloro-2-hydroxy-1-indanone-2-carboxylate
25
(3n): Colorless oil (44.7 mg, 69% yield, 79% ee); [α]D 25.0 (c
1
0.12, MeOH); H NMR (400 MHz, CDCl3) δ 7.72 (1 H, d, J = 8.2
Hz), 7.48 (1 H, s), 7.40 (1 H, d, J = 7.4 Hz), 4.08 (1 H, s), 3.61 (1 H,
d, J = 17.3 Hz), 3.23 (1 H, d, J = 17.3 Hz), 1.71 (6 H, q, J = 7.5 Hz),
0.67 (9 H, t, J = 7.5 Hz); 13C NMR (100 MHz, CDCl3) δ 200.0, 169.7,
153.5, 142.4, 132.6, 128.8, 126.5, 126.0, 92.5, 80.7, 39.3, 26.9, 7.4;
HRMS (ES+) calcd for [C17H21ClO4 + Na]+ 347.1026, found
347.1019. HPLC conditions: AS-H column (250 × 4.6 mm),
hexane/i-PrOH = 90/10, 1 mL/min, 254 nm, τR (major) = 11.6
min, τR (minor) = 9.1 min.
Methyl 2-Hydroxy-1-tetralone-2-carboxylate (3o): Colorless solid
(15.7 mg, 35% yield, 63% ee); [α]D25 20.0 (c 0.015, MeOH); 1H NMR
(400 MHz, CDCl3) δ 8.05 (1 H, d, J = 7.9 Hz), 7.53 (1 H, t, J = 7.5
Hz), 7.34 (1 H, t, J = 7.5 Hz), 7.26 (1 H, d, J = 7.7 Hz), 4.36 (1 H, s),
3.74 (3 H, s), 3.13 (2 H, m), 2.71 (1 H, dt, J = 13.6, 5.1 Hz), 2.25 (1
H, ddd, J = 13.6, 8.9, 6.3 Hz); 13C NMR (100 MHz, CDCl3) δ 194.6,
171.1, 144.0, 134.4, 130.2, 129.0, 128.2, 127.0, 77.7, 53.0, 32.7, 25.6.
HPLC conditions: Chiralcel OD-H column (250 × 4.6 mm), hexane/
i-PrOH = 90/10, 1 mL/min, 254 nm, τR (major) = 9.6 min, τR
(minor) = 10.9 min.
tert-Butyl 2-Hydroxy-1-indanone-2-carboxylate (3i): Colorless
25
solid (38.7 mg, 79% yield, 78% ee); [α]D 10.3 (c 0.15, MeOH);
1H NMR (400 MHz, CHCl3) δ 7.79 (d, J = 7.7 Hz, 1H), 7.65 (td, J =
7.6, 1.2 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H),
4.08 (s, 1H), 3.65 (d, J = 17.1 Hz, 1H), 3.22 (d, J = 17.1 Hz, 1H), 1.36
(s, 9H); 13C NMR (100 MHz, CHCl3) δ 201.4, 170.5, 152.3, 135.8,
133.9, 127.9, 126.3, 125.0, 83.9, 80.6, 39.5, 27.7. HPLC conditions:
Chiralcel OD-H column (250 × 4.6 mm), hexane/i-PrOH = 90/10, 1
mL/min, 254 nm, τR (major) = 6.5 min, τR (minor) = 7.1 min.
tert-Butyl 4-Methoxyl-2-hydroxy-1-indanone-2-carboxylate (3j):
1-Adamantyl 2-Hydroxy-1-tetralone-2-carboxylate (3p): Color-
25
less solid (26.7 mg, 35% yield, 71% ee); [α]D −34.8 (c 0.023,
1
MeOH); H NMR (400 MHz, CDCl3) δ 8.03 (1 H, d, J = 7.9 Hz),
7.53−7.46 (1 H, m), 7.33 (1H, dt, J = 13.0, 4.6 Hz), 7.28−7.20 (1 H,
m), 3.15−3.05 (2 H, m), 2.63 (1 H, m), 2.26−2.16 (1 H, m), 2.11 (3
H, s), 2.00 (6 H, s), 1.60 (6 H, s); 13C NMR (100 MHz, CDCl3) δ
194.9, 169.7, 143.8, 134.0, 130.7, 128.8, 127.9, 126.8, 83.4, 77.8, 41.0,
35.9, 32.9, 31.7, 30.8, 25.7. HPLC conditions: Chiralcel AD-H column
(250 × 4.6 mm), hexane/i-PrOH = 90/10, 1 mL/min, 254 nm, τR
(major) = 14.6 min, τR (minor) = 24.9 min.
25
Colorless solid (41.1 mg, 75% yield, 84% ee); [α]D 31.9 (c 0.16,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 2.3 Hz, 1H),
7.37 (s, 1H), 7.11−7.09 (m, 1H), 4.02 (s, 1H), 3.91 (s, 4H), 3.58 (d, J
= 17.6 Hz, 1H), 3.08 (d, J = 17.6 Hz, 1H), 1.37 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 201.5, 170.7, 156.6, 141.3, 135.2, 129.4, 116.5,
116.0, 83.9, 80.3, 55.6, 36.3, 27.7. HPLC conditions: Chiralcel OD-H
column (250 × 4.6 mm), hexane/i-PrOH = 90/10, 1 mL/min, 254
nm, τR (major) = 12.4 min, τR (minor) = 11.1 min.
ASSOCIATED CONTENT
■
S
3-Ethyl Amyl 2-Hydroxy-1-indanone-2-carboxylate (3k): Color-
* Supporting Information
25
Characterization data (including H NMR, 13C NMR, and
1
less oil (40.1 mg, 70% yield, 83% ee); [α]D −5.2 (c 0.14, MeOH);
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.7 Hz, 1H), 7.64 (td, J =
7.6, 1.1 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H),
4.08 (s, 1H), 3.64 (d, J = 17.1 Hz, 1H), 3.25 (d, J = 17.0 Hz, 1H), 1.70
(q, J = 7.5 Hz, 6H), 0.65 (t, J = 7.5 Hz, 9H); 13C NMR (100 MHz,
CDCl3) δ 201.4, 170.1, 152.2, 135.8, 134.2, 128.0, 126.2, 124.9, 92.1,
80.8, 39.7, 26.9, 7.4; HRMS (ES+) calcd for [C17H22O4 + Na]+
313.1416, found 313.1428. HPLC conditions: Chiralcel AS-H column
(250 × 4.6 mm), hexane/i-PrOH = 90/10, 1 mL/min, 254 nm, τR
(major) = 13.4 min, τR (minor) = 10.8 min.
HPLC spectra) for catalysts, β-oxo esters 1k, 1l, 1m, and 1n
and all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mengqw@dlut.edu.cn.
3-Ethyl Amyl 4-Methoxyl-2-hydroxy-1-indanone-2-carboxylate
25
Notes
(3l): Colorless oil (49.7 mg, 78% yield, 82% ee); [α]D 20.0 (c
1
0.12, MeOH); H NMR (400 MHz, CDCl3) δ 7.38 (1 H, d, J = 1.4
The authors declare no competing financial interest.
9607
dx.doi.org/10.1021/jo3016242 | J. Org. Chem. 2012, 77, 9601−9608

The Journal of Organic Chemistry
Article
ACKNOWLEDGMENTS
■
We would likely to thank the National Natural Science
Foundation of China (No. 21176041) and the State Key
Laboratory of Fine Chemicals for their support.
REFERENCES
■
(1) Christoffers, J.; Baro, A.; Werner, T. Adv. Synth. Catal. 2004, 346,
143.
(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 Manage. Sci. 2001, 57, 153−164.
(3) Acocella, M. R.; Bella, M.; Jørgensen, K. A. J. Org. Chem. 2004,
69, 8165−8167.
(4) Toullec, P. Y.; Bonaccorsi, C.; Mezzetti, A.; Togni, A. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5810−5814.
(5) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488−16489.
(6) Smith, A. M. R.; Billen, D.; Hii, K. K. Chem. Commun. 2009,
3925−3927.
(7) Lu, M.; Zhu, D.; Lu, Y. P.; Zeng, X. F.; Tan, B.; Xu, Z. J.; Zhong,
G. F. J. Am. Chem. Soc. 2009, 131, 4562−4563.
(8) Gong, B.; Meng, Q. W.; Su, T.; Lian, M. M.; Wang, Q.; Gao, Z. X.
Synlett 2009, 16, 2659−2662.
(9) Cai, Y. C.; Lian, M. M.; Li, Z.; Meng, Q. W. Tetrahedron 2012,
38, 7973−7977.
(10) (a) Hashimoto, T.; Sasaki, K.; Fukumoto, K.; Murase, Y.; Abe,
N.; Ooi, T.; Maruoka, K. Chem. Asian J. 2010, 5, 562−570. (b) Sano,
D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593−1595. (c) Erik, F. J.;
Lisette, P.; Marcello, C.; Johannes, B.; Arne, G. Tetrahedron:
Asymmetry 1995, 6, 1123−1132.
(11) Lian, M. M.; Li, Z.; Meng, Q. W.; Gao, Z. X. Eur. J. Org. Chem.
2010, 34, 6525−6530.
(12) Wolfer, J.; Weatherwax, A.; Taggi, A. E.; Lectka, T. J. Org. Chem.
2006, 71, 8946−8949.
(13) Poulsen, T. B.; Bernardi, L.; Bell, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2006, 45, 6551−6554.
(14) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488−16489.
(15) (a) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488−16489. (b) Smith,
A. M. R.; Rzepa, H. S.; White, A. J. P.; Billen, D.; Hii, K. K. J. Org.
Chem. 2010, 75, 3085−3096. (c) Cao, S. H.; Shi, M. Tetrahedron:
Asymmetry 2010, 21, 2675−2680. (d) Lian, M. M.; Li, Z.; Meng, Q.
W.; Gao, Z. X. Eur. J. Org. Chem. 2010, 34, 6525−6530.
(16) Nakajima, M.; Yamamoto, S.; Yamaguchi, Y.; Nakamura, S.;
Hashimoto, S. Tetrahedron 2003, 59, 7307−7313.
(17) Pericas, A.; Shafir, A.; Vallribera, A. Tetrahedron 2008, 64,
9258−9263.
9608
dx.doi.org/10.1021/jo3016242 | J. Org. Chem. 2012, 77, 9601−9608