Asymmetric α-hydroxylation of tetralone-derived β-ketoesters by using a guanidine-urea bifunctional organocatalyst in the presence of cumene hydroperoxide

Article abstract of DOI:10.1002/chem.201303006

Highly enantioselective catalytic oxidation of 1-tetralone-derived β-keto esters was achieved by using a guanidine-urea bifunctional organocatalyst in the presence of cumene hydroperoxide (CHP), a safe, commercially available oxidant. The α-hydroxylation products were obtained in 99 % yield with up to 95 % enantiomeric excess (ee). The present oxidation was successfully applied to synthesize a key intermediate of the anti-cancer agent daunorubicin (2).

Full text of DOI:10.1002/chem.201303006

DOI: 10.1002/chem.201303006
Asymmetric a-Hydroxylation of Tetralone-Derived b-Ketoesters by Using a
Guanidine–Urea Bifunctional Organocatalyst in the Presence of Cumene
Hydroperoxide
Minami Odagi, Kota Furukori, Tatsuya Watanabe, and Kazuo Nagasawa*[a]
Abstract: Highly enantioselective catalytic oxidation of 1-tetralone-derived b-keto
esters was achieved by using a guanidine–urea bifunctional organocatalyst in the
Keywords: esters · enantioselectivi-
presence of cumene hydroperoxide (CHP), a safe, commercially available oxidant.
ty · hydroxylation · organocatalysis ·
The a-hydroxylation products were obtained in 99% yield with up to 95% enan-
oxidation · synthetic methods
tiomeric excess (ee). The present oxidation was successfully applied to synthesize
a key intermediate of the anti-cancer agent daunorubicin (2).
Introduction
the presence of cumene hydroperoxide (CHP).[6a,c,e] In these
cases, moderate to high enantioselectivities were obtained,
although the substrate scope was limited to 1-indanone-de-
rived b-keto esters.[5d,f,6b–e,7] Recently, Zhong et al. reported
the selective oxidation of various b-keto esters, including 1-
indanone-, cyclopentanone-, and cyclohexanone-derived b-
keto esters, using nitrosobenzene as an oxidant with a chiral
phosphoric acid-type organocatalyst.[6b]
Intact or masked a-hydroxy-b-dicarbonyl structure is fre-
quently found in natural products, as represented by hami-
geran A (1) and daunorubicin (2; Figure 1), as well as vari-
ous pharmaceuticals,[1–3] and great efforts have been made to
achieve stereoselective synthesis of this structure.
Recently, we have developed a series of guanidine–(thio)-
urea bifunctional organocatalysts 3 bearing a conformation-
ally flexible chiral linker, and have applied them to several
asymmetric carbon–carbon bond-forming reactions as well
as oxidation reactions.[8] In the case of asymmetric nucleo-
philic epoxidation of chalcones, the guanidine–urea catalyst
3a was very effective, and the corresponding epoxides were
obtained in 99% yield with up to 99% enantiomeric excess
(ee; Scheme 1a).[9,10] It was suggested that urea and guani-
dine in the catalyst interacted with hydrogen peroxide and
a carbonyl group. Based upon this mechanism,[9] we envis-
aged that 3 would be effective for catalyzing the a-hydroxyl-
ation of b-keto esters with the aid of similar interactions be-
tween guanidine and the b-keto ester, and urea and the oxi-
dant, respectively (Scheme 1b). These interactions were ex-
pected to promote the reaction and to enhance asymmetric
induction through a synergistic proximity effect, with control
of the transition state by the chirality of the catalyst.
Herein, we describe catalytic enantioselective a-hydroxyl-
ation of b-keto esters derived from 1-tetralone, which is
a challenging substrate for a-hydroxylation,[7] by using the
guanidine–urea bifunctional organocatalyst 3.
Figure 1. Representative natural products bearing an intact or masked a-
hydroxy-b-keto ester moiety.
One of the most widely investigated approaches to the
synthesis of this structure is oxidation of the a-position of b-
keto esters, and many methods have been developed by
using appropriate oxidants in the presence of metal cata-
lysts.[4,5] On the other hand, there has been only limited
study of organocatalyts.[6] The groups of Jørgensen and
Meng independently reported the a-hydroxylation of b-keto
esters by using cinchona alkaloid-derived organocatalysts in
[a] M. Odagi, K. Furukori, T. Watanabe, Prof. Dr. K. Nagasawa
Department of Biotechnology and Life Science
Faculty of Engineering, Tokyo University of
Agriculture and Technology, 2-24-16, Naka-cho, Koganei
Tokyo 184-8588 (Japan)
Results and Discussion
We commenced our investigation of a-hydroxylation with
the 1-tetralone-derived b-keto methyl ester 4a in the pres-
ence of 3a and CHP in toluene (Table 1). First, several
bases (1 equiv) were examined. In the case of organic bases
Fax : (+81)42-388-7295
E-mail: knaga@cc.tuat.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303006.
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Chem. Eur. J. 2013, 19, 16740 – 16745

FULL PAPER
liquid–solid biphasic conditions also gave high yields, and
high selectivity (72% ee) was obtained in the case of potas-
sium carbonate (Table 1, entry 4), though only low selectivi-
ty (36% ee) was observed with cesium carbonate as a base
(Table 1, entry 5). Next, the oxidants were varied under the
conditions of entry 4 (Table 1). tert-Butyl hydroperoxide
(TBHP) is frequently used for this oxidation reaction, as
well as CHP, but here the yield and enantioselectivity were
decreased (Table 1, entry 6). meta-chloroperoxybenzoic acid
(mCPBA) and 2-p-toluenesulfonyl-3-phenyl oxaziridine
(Davis oxaziridine)[11] each gave 99% yield, but the selectiv-
ity was drastically decreased, and almost racemic 5a was ob-
tained with mCPBA (Table 1, entries 7 and 8). Hydrogen
peroxide and urea hydrogen peroxide (UHP) were ineffec-
tive for the oxidation (Table 1, entries 9 and 10). Thus, we
adopted the reaction conditions of entry 4 in Table 1 as the
optimized conditions, with the catalyst 3a.[12]
Next, we carried out structure–activity relationship studies
of catalyst 3 focusing on the R3 substituent on the chiral
spacer (Table 2, entries 1–5). Changing the R3 group to
methyl, isopropyl, or isobutyl drastically reduced the selec-
tivity to 13, 49, and 38% ee, respectively, although the yields
were moderate to high (Table 2, entries 2–4). In the case of
a phenyl group at R3, selectivity was similar to that with 3a,
but the yield was decreased to 55% (Table 2, entry 5). The
effects of the R1 and R2 groups in catalyst 3 were also exam-
Scheme 1. Asymmetric epoxidation catalyzed by 3a, and catalytic asym-
metric a-hydroxylation of b-keto ester showing the proposed transition
model.
Table 1. Optimization of the reaction conditions with catalyst 3a.[a]
Table 2. Structure–activity relationship studies of catalyst 3.[a]
Entry Solvent
Base
Oxidant
Product 5a
Yield
ee
[%][b] [%][c]
Catalyst 3
5a
Entry
R1, R2
R3
Yield
[%][b]
ee
1
2
3
4
5
6
7
8
9
Toluene DBU
Toluene TEA
Toluene 2n NaOH (aq) CHP
Toluene K2CO3
Toluene CsCO3
Toluene K2CO3
Toluene K2CO3
Toluene K2CO3
Toluene K2CO3
Toluene K2CO3
CHP
CHP
57
58
86
88
80
47
99
59
60
62
72
36
50
3
[%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3e
–
H, C18H37
H, C18H37
H, C18H37
H, C18H37
H, C18H37
Bn
Me
iPr
iBu
Ph
Bn
Bn
Bn
Bn
88
66
94
80
55
70
67
57
93
65
13
72
13
49
38
69
-7
1
CHP
CHP
TBHP
mCPBA
Davis oxaziridine 99
H2O2
UHP
18
À
À
(CH2)4
trace
trace
À
À
ACHTUGNTERN(NUNG CH2)5
10
Et, Et
0
82
9[d]
10[e]
11[f]
H, C18H37
[a] These reactions were carried out with 4a (0.1 mmol), oxidant
(120 mol%), base (100 mol%), and 3a (5 mol%) in solvent (0.1m) at
08C for 24 h. [b] Determined by 1H NMR spectroscopy. [c] Determined
by chiral HPLC.
–
[a] Unless otherwise noted, reactions were carried out with 4a
(0.1 mmol), cumene hydroperoxide (120 mol%), K2CO3 (100 mol%),
and catalyst 3 (5 mol%) in solvent (0.1m) at 08C for 24 h. [b] Deter-
1
mined by H NMR spectroscopy. [c] Determined by chiral HPLC. [d] Re-
(1,8-diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU) and triethyla-
actions were carried out with 4a (0.1 mmol), cumene hydroperoxide
(120 mol%), K2CO3 (20 mol%), and catalyst (5 mol%) in toluene
(0.05m) at 08C for 24 h. [e] Reaction was carried out with 4a (0.1 mmol),
cumene hydroperoxide (120 mol%), and K2CO3 (100 mol%) in toluene
(0.1m) at 08C for 24 h without catalyst. [f] Reactions were carried out
with 4a (0.1 mmol), cumene hydroperoxide (120 mol%) and K2CO3
(20 mol%) in toluene (0.05m) at 08C for 24 h without catalyst.
mine (TEA)), moderate yields (57–58%) and enantioselec-
tivities (59–60% ee) were obtained (Table 1, entries 1 and
2). Under biphasic conditions with NaOH (aq, 2n), the
chemical yield of 5a increased to 86%, but the selectivity
was still only moderate (Table 1, entry 3). Interestingly,
Chem. Eur. J. 2013, 19, 16740 – 16745
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16741

K. Nagasawa et al.
Table 4. Substrate scope of the a-hydroxylation of 4.[a]
ined.[8f,h] Interestingly, selectivity was drastically reduced
with 3 f–3h bearing disubstituted guanidines, even though
R3 was a benzyl group, and almost racemic 5a was obtained
(Table 2, entries 6–8). Thus, the catalyst 3a appeared to be
optimal for the present oxidation reaction. With the catalyst
3a in hand, we fine-tuned the reaction conditions based
upon entry 1 in Table 1, and finally found that the selectivity
could be improved to 82% ee without affecting the yield by
decreasing the amount of base (K2CO3) to 20 mol%
(Table 2, entry 9). This condition was effective for suppress-
ing the background oxidation reaction of 4a (Table 2, en-
tries 10 and 11).
Using the optimized conditions together with catalyst 3a,
we next focused on the ester group of the substrates (Ta-
ble 3).[6a,d] Changing the methyl ester group to an isopropyl
or tert-butyl group improved the selectivity, and the corre-
sponding alcohol 5d or 5e was obtained with 90 and 94% ee
in 94 and 60% yield, respectively (Table 3, entries 4 and 5).
Interestingly, the yield of tert-butyl ester 5e was improved
to 90% without loss of enantioselectivity simply by employ-
ing one equivalent of potassium carbonate (Table 3,
entry 6).[13]
b-Keto ester 4
Product 5
Yield
Entry
R
t
ee
[h]
[%][b]
[%][c]
1
2
4 f
4g
4h
4i
4j
4k
4l
6-OMe
24
16
48
36
20
16
20
23
5 f
5g
5h
5i
5j
5k
5l
91
99
92
88
83
94
82
90
87
92
95
95
85
93
89
90
6-OBn
6-NMe2
6-Cl
6-Br
7-OMe
7-Br
3[d]
4
5[d]
6
7
8
4m
7-F
5m
[a] Unless otherwise noted, reactions were carried out with 4 (0.1 mmol),
cumene hydroperoxide (120 mol%), K2CO3 (100 mol%), and 3a
(5 mol%) in toluene (0.05m) at 08C. [b] Determined by 1H NMR spec-
troscopy. [c] Determined by chiral HPLC. [d] Reactions were carried out
with
4
(0.1 mmol), cumene hydroperoxide (120 mol%), K2CO3
(20 mol%), and catalyst (5 mol%) in toluene (0.05m) at 08.
Table 3. Optimization of ester group of 4.[a]
lating the target DNA. Because of its remarkable antitumor
activity, compound 2 has attracted much synthetic interest,
and various derivatives of 2 have been developed for anti-
cancer chemotherapy. a-Hydroxy-ketone 6 (Scheme 2) is
a key intermediate in a Friedel–Crafts reaction-based syn-
thesis of 2,[15] and therefore the present a-hydroxylation of
the b-keto ester was applied to the synthesis of ent-6.
Oxidation of 4n with CHP in the presence of 3a
(5 mol%) gave 5n in 92% yield with 84% ee. Reduction of
the ketone moiety of 5n with NaBH4 afforded the benzylic
alcohol, which was selectively reduced with triethylsilyl hy-
dride in the presence of BF3·Et2O. The tert-butyl group was
simultaneously removed to generate carboxylic acid 7. This
was treated with methyllithium to furnish ent-6 in 19% yield
from 5n. The optical purity of the product was improved to
99% ee by a single recrystallization from hexane/ether
(Scheme 2).
b-Keto ester 4
Product 5
Yield
Entry
R
ee
[%][b]
[%][c]
1
2
3
4
4a
4b
4c
4d
4e
4e
Me
Et
Bn
iPr
tBu
tBu
5a
5b
5c
5d
5e
5e
93
95
87
94
60
90
81
81
78
90
94
93
5
6[d]
[a] Unless otherwise noted, reactions were run with 4a (0.1 mmol),
cumene hydroperoxide (120 mol%), K2CO3 (20 mol%), and 3a
(5 mol%) in toluene (0.05m) at 08C for 24 h. [b] Determined by
1H NMR spectroscopy. [c] Determined by chiral HPLC. [d] The reaction
was run with 4a (0.1 mmol), cumene hydroperoxide (120 mol%), K2CO3
(100 mol%), and 3a (5 mol%) in toluene (0.05m) at 08C for 24 h.
As either an isopropyl or a tert-butyl group was suitable
as the ester, the scope of the reaction was investigated for
a-hydroxylation using 1-tetralone-derived b-keto tert-butyl
esters. As depicted in Table 4, substituents on the aromatic
ring of 4 did not affect the yield or selectivity, and deriva-
tives with both electron-donating and electron-withdrawing
groups 4 f–4m gave the corresponding 5 f–5m in high yields
(82–99%) with high enantioselectivities (87–95% ee).[14]
Daunorubicin (2; Figure 1) is an anthracycline antibiotic
isolated from Streptomyces peucetius. It shows potent antitu-
mor activity by inhibiting topoisomerase II through interca-
Scheme 2. Synthesis of key intermediate ent-6 for synthesis of ent-daunor-
ubicin (2).
16742
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Chem. Eur. J. 2013, 19, 16740 – 16745

Asymmetric a-Hydroxylation
FULL PAPER
8.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 0.4H), 7.31–7.23 (m, 1.4H), 3.49 (dd, J=
9.3, 4.7 Hz, 1H), 3.07–2,91 (m, 2H), 2.77 (t, J=7.3 Hz, 0.8H), 2.53–2.42
(m, 1.4H), 2.37–2.29 (m, 1H), 1.47 ppm (s, 13H); 13C NMR (100 MHz,
CDCl3): d=192.3, 192.2, 172.2, 168.9, 163.3, 151.9, 144.9, 140.8, 139.7,
135.7, 130.2, 129.0, 128.6, 128.4, 127.2, 126.4, 125.3, 98.2, 81.7, 81.5, 81.2,
80.7, 80.5, 7 77.2, 54.8, 28.1, 27.8, 27.6, 27.4, 27.1, 26.0, 20.6 ppm; HRMS
(ESI): m/z calcd for C15H17ClNaO3: 303.0763 [M+Na]; found: 303.0752.
Conclusion
We have developed a catalytic enantioselective a-hydroxyl-
ation reaction of b-keto esters of 1-tetralone derivatives by
using a guanidine–urea bifunctional organocatalyst 3a and
cumene hydroperoxide (CHP), a safe, commercially avail-
able oxidant. The corresponding a-hydroxy-b-keto esters
were obtained in 82–99% yield with high enantioselectivity
(84–95% ee). The usefulness of this reaction was confirmed
by applying it to the synthesis of ent-6, a key intermediate
for ent-daunorubicin (4).
tert-Butyl 5,8-dimethoxy-1-tetralone-2-carboxylate (4n): 60% yield;
1
(mixtures of enol and keto form (1:99)): H NMR (400 MHz, CDCl3): d=
8.08 (s, 1H), 7.37 (br, 1H), 7.04 (br, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.80
(d, J=8.7 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.45 (dd, 10.0, 4.6 Hz, 1H),
3.08–3.00 (m, 1H), 2.81–2.67 (m, 1H), 2.41–2.23 (m, 1H), 1.62 ppm (s,
9H); 13C NMR (75 MHz, CDCl3): d=193.2, 172.5, 169.5, 166.0, 154.1,
152.4, 150.0, 149.8, 134.0, 130.9, 122.3, 120.3, 115.4, 113.5, 111.3, 110.0,
99.3, 81.3, 81.0, 77.2, 57.0, 56.4, 56.3, 56.0, 55.8, 31.0, 28.2, 27.9, 25.2, 21.8,
21.3, 20.4 ppm; HRMS (ESI): m/z calcd for C17H22NaO5: 329.1364 [M+
Na]; found: 329.1343.
Experimental Section
General procedure: The catalytic asymmetric a-hydroxylation of 1-tetra-
lone derivatives 4 using guanidine–urea bifunctional organocatalyst 3a: A
mixture of 3a (5.6 mg, 0.005 mmol), 4a (20.4 mg, 0.1 mmol), and K2CO3
(2.7 mg, 0.02 mmol) in toluene (2.0 mL) was cooled to 08C, and cumene
hydroperoxide (22 mL, 0.12 mmol, contains ca. 20% aromatic hydrocar-
bon) was added to the solution. After stirring for 24 h at 08C, the reac-
tion was quenched by addition of 10% Na2S2O3 solution (2 mL), and the
mixture was vigorously stirred for 1 h. The organic layer was separated
and the aqueous layer was extracted with ethyl acetate (three times). The
combined extracts were dried over MgSO4, and the filtrates were concen-
trated in vacuo. The residue was purified by column chromatography on
silica gel (n-hexane/ethyl acetate 10:1 to 5:1) to give 5a[7] with insepara-
ble 2-phenyl-2-propanol derived from CHP (the yield of 3a (93%) was
determined by using 1H NMR spectroscopy).[22] [a]2D5 =À13.2 (c=0.8,
CHCl3); the enantiomeric excess of 5a was determined to be 81% ee by
chiral HPLC analysis. DAICEL CHIRALPAK OD-H column (250ꢁ
General remarks: Flash chromatography was performed using silica gel
60 (spherical, particle size 0.040–0.100 mm. Kanto Co., Inc., Japan). Opti-
cal rotations were measured on a JASCO P-2200 polarimeter. 1H and
13C NMR spectra were recorded on AL300, ECX400 (JEOL) and
AVANCE 400 (Bruker) instruments. Chemical shifts in [D]chloroform
and [D4]MeOH were reported on the scale relative to [D]chloroform
(d=7.26 ppm), [D4]MeOH (d=3.30 ppm) and [D6]dimethylsulfoxide
(d=2.50 ppm) for 1H NMR spectroscopy, respectively. For 13C NMR
spectroscopy, chemical shifts were reported on the scale relative to
[D]chloroform
(d=77.0 ppm),
[D4]MeOH
(d=49.0 ppm),
and
[D6]dimethylsulfoxide (d=39.5 ppm) as internal references, respectively.
Mass spectra were recorded on JMS-T100 LC (JEOL) spectrometer.
Synthesis of b-keto tert-butyl esters (4a–4 f, 4j-4m): b-Keto esters 4a,
4b, and 4d,[16] 4c,[17] 4e,[5b] 4 f,[18] 4j,[19] 4k–4m[20] were prepared according
to the literature.
Synthesis of b-keto tert-butyl esters (4g–4i, 4n): b-Keto esters 4g–4i and
4n were prepared by the following procedure reported by Jørgensen,[21]
and 4g was synthesized as follows. Lithium hexamethyldisilazide
(LHMDS; 3 mL, 4 mmol, 1.3m in THF) at À788C was added to a solution
of 6-benzyloxy-1-tetralones (250 mg, 1 mmol) in THF (3 mL) and hexam-
ethylphosphoramide (720 mL, 4 mmol), and the mixture was stirred for
90 min. 1-(tert-butoxycarbonyl)-imidazole (670 mg, 4 mmol) was added to
the resulting mixture, then the mixture was allowed to warm to RT and
stirred for additional 24 h. A saturated NH4Cl solution was then added to
the reaction mixture, and the organic layer was extracted with ethyl ace-
tate (three times). The combined extracts were dried over MgSO4, and
the filtrates were concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel to give tert-butyl 6-benzyloxy-
1-tetralone-2-carboxylate 4g (256 mg, 72% yield). The ratio of enol form
to keto form is 5:1. 1H NMR (400 MHz, CDCl3): d=12.64 (dr, 1H), 8.02
(d, J=8.8 Hz, 0.2H), 7.72 (d, J=8.3 Hz, 1H), 7.45–7.31 (m, 5H), 6.92–
6.89 (m, 0.2H), 6.87–6.85 (m, 1H), 6.78–6.77 (m, 1.2H), 5.51 (s, 0.4H),
5.09 (s, 2H), 3.45 (dd, J=9.86, 4.67, 0.2H), 3.02–2.93 (m, 0.4H), 2.76 (t,
J=7.3 Hz, 2H), 2.52–2.48 (t, J=8.3 Hz, 2H), 2.45–2.39 (m, 0.2H), 2.34–
2.27 (m, 0.2H), 1.54 (s, 9H), 1.48 ppm (s, 2.5H); 13C NMR (75 MHz,
CDCl3): d=192.3, 169.6, 164.7, 162.8, 160.3, 146.0, 141.5, 136.5, 136.0,
130.0, 128.6, 128.5, 1281, 127.9, 127.3, 125.8, 125.6, 123.3, 113.9, 113.4,
112.2, 96.3, 81.5, 80.8, 70.0, 69.8, 55.0, 28.2, 28.1, 27.9, 27.8, 26.4,
20.9 ppm; HRMS (ESI): m/z calcd for C22H24NaO4 375.1572: [M+Na];
found: 375.1569.
4.6 mm), n-hexane/2-propanol=90:10, flow rate 1 mLminÀ1, t1
9.5, t2 (minor)=10.9.
ACHTUNGTRENNUNG(major)=
Ethyl 2-hydroxy-1-tetralone-2-carboxylate (5b):[7] [a]D25 =À12.1 (c=0.9,
CHCl3); the enantiomeric excess of 5b was determined to be 81% ee by
chiral HPLC analysis. DAICEL CHIRALPAK OD-H column (250ꢁ
4.6 mm), n-hexane/2-propanol=90:10, flow rate 1 mLminÀ1, t1
ACHTUNGTRENNUNG(major)=
8.7, t2 (minor)=9.7.
Benzyl 2-hydroxy-1-tetralone-2-carboxylate (5c):[7] [a]D25 =À8.3 (c=0.7,
CHCl3); the enantiomeric excess of 5c was determined to be 78% ee by
chiral HPLC analysis. DAICEL CHIRALPAK OD-H column (250ꢁ
4.6 mm), n-hexane/2-propanol=90:10, flow rate 1 mLminÀ1, t1
ACHTUNGTRENNUNG(major)=
14.8, t2 (minor)=17.3.
Isopropyl 2-hydroxy-1-tetralone-2-carboxylate (5d):[5d] [a]D25 =À11.6 (c=
1.0, CHCl3); the enantiomeric excess of 5d was determined to be 90% ee
by chiral HPLC analysis. DAICEL CHIRALPAK OD-H column (250ꢁ
4.6 mm), n-hexane/2-propanol=95:5, flow rate 1 mLminÀ1, t1
7.7, t2 (minor)=8.5.
ACHTUNGTRENNUNG(major)=
tert-Butyl 2-hydroxy-1-tetralone-2-carboxylate (5e):[5b] [a]D25 =À7.6 (c=
0.7, CHCl3); the enantiomeric excess of 5e was determined to be 93% ee
by chiral HPLC analysis. DAICEL CHIRALPAK OD-H column (250ꢁ
4.6 mm), n-hexane/2-propanol=95:5, flow rate 1 mLminÀ1, t1
6.7, t2 (minor)=7.3.
ACHTUNGTRENNUNG(major)=
tert-Butyl 6-methoxy-2-hydroxy-1-tetralone-2-carboxylate (5 f): [a]2D5 = +
11.1 (c=1.04, CHCl3); 1H NMR (400 MHz, CDCl3): d=8.01 (d, J=
8.7 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.70 (s, 1H), 4.25 (brs, 1H), 3.87 (s,
3H), 3.08 (t, J=6.9 Hz, 2H), 2.19 (dt, J=13.3, 5.5 Hz, 1H), 2.63 (dt, J=
13.7, 7.3 Hz, 1H), 1.40 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=
193.5, 170.4, 164.3, 146.6, 130.6, 124.1, 113.8, 112.7, 83.3, 77.7, 55.6, 32.9,
27.9, 26.1 ppm; HRMS (ESI): m/z calcd for C16H20NaO5: 315.1208 [M+
Na]; found: 315.1257; enantiomeric excess of 5 f was determined to be
87% ee by chiral HPLC analysis. DAICEL CHIRALPAK OD-H column
tert-Butyl 6-(dimethylamino)-1-tetralone-2-carboxylate (4h): 51% yield
(mixture of enol and keto form (1:99)). 1H NMR (400 MHz, CDCl3): d=
7.95 (d, J=8.7 Hz, 1H), 6.60 (dd, J=8.7, 2.3 Hz, 1H), 6.36 (d, J=2.3 Hz,
1H), 3.41 (dd, J=10.7, 5.0 Hz, 1H), 3.05 (s, 6H), 2.99–2.84 (m, 2H),
2.44–2.35 (m, 1H), 2.30–2.23 (m, 1H), 1.48 ppm (s, 9H); 13C NMR
(75 MHz, CDCl3): d=191.8, 170.2, 153.5, 145.6, 129.7, 120.7, 110.3, 109.1,
81.1, 55.1, 40.0, 39.9, 28.3, 27.9, 26.7 ppm; HRMS (ESI): m/z calcd for
C17H23NNaO3: 312.1575 [M+Na]; found: 375.1538.
(250ꢁ4.6 mm), n-hexane/2-propanol=95:5, flow rate 1 mLminÀ1
(major)=10.2, t2 (minor)=12.6.
, t1-
tert-Butyl 6-chloro-1-tetralone-2-carboxylate (4i): 89% yield; mixtures of
enol and keto form (2.5:1). 1H NMR (400 MHz, CDCl3): d=7.98 (d, J=
AHCTUNGTRENNUNG
Chem. Eur. J. 2013, 19, 16740 – 16745
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16743

K. Nagasawa et al.
tert-Butyl 6-benzyloxy-2-hydroxy-1-tetralone-2-carboxylate (5g): [a]D25
=
(100 MHz, CDCl3): d=194.0, 170.0, 162.9, 160.4, 139.7, 132.3, 130.8,
121.8, 121.6, 113.9, 113.7, 83.8, 77.6, 32.9, 27.9, 25.1 ppm; HRMS (ESI):
m/z calcd for C16H20FNaO5: 303.1009 [M+Na]; found: 303.0993; the
enantiomeric excess of 5m was determined to be 90% ee by means of
chiral HPLC analysis. DAICEL CHIRALPAK AD-H column (250ꢁ
4.6 mm), n-hexane/2-propanol=95:5, flow rate 1 mLminÀ1, t1 (major)=
15.7, t2 (minor)=21.2.
+9.7 (c=2.7, CHCl3); 1H NMR (400 MHz, CDCl3): d=8.02 (d, J=
8.7 Hz, 1H), 7.43–7.34 (m, 5H), 6.93 (d, J=8.7 Hz, 1H), 6.79 (s, 1H),
5.13 (s, 2H), 4.27 (brs, 1H), 3.07 (t, J=6.4 Hz, 2H), 2.62 (dt, J=13.3,
5.5 Hz, 1H), 2.19 (dt, J=13.7, 7.3 Hz, 1H), 1.40 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=193.5, 170.4, 163.5, 146.6, 136.1, 130.7, 128.9,
128.4, 127.9, 127.6, 127.4, 126.8, 124.3, 114.4, 13.7, 83.4, 77.7, 77.5, 55.6,
32.8, 27.9, 26.1 ppm; HRMS (ESI): m/z calcd for C22H24NaO5: 391.1521
[M+Na], found: 391.1551; enantiomeric excess of 5g was determined to
be 92% ee by chiral HPLC analysis. DAICEL CHIRALPAK OD-H
tert-Butyl
5,8-dimethoxy-2-hydroxy-1-tetralone-2-carboxylate
(5n):
[a]2D5 =À48.5 (c=1.0, CHCl3); Spectral data for 3n: 1H NMR (400 MHz,
CDCl3): d=6.99 (d, J=8.7 Hz, 1H), 6.80 (d, J=9.2 Hz, 1H), 4.54 (brs,
1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.08–3.01 (m, 1H), 2.92–2.83 (m, 1H),
2.69–2.63 (m, 1H), 2.08–2.00 (m, 1H), 1.33 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=194.4, 169.4, 154.2, 150.3, 134.1, 121.0, 116.1,
110.1, 82.8, 78,4, 56.5, 56.1, 31.6, 27.8, 20.5 ppm; HRMS (ESI): m/z calcd
for C17H22NaO6: 345.1314 [M+Na]; found: 345.1266; the enantiomeric
excess of 5n was determined to be 84% ee by chiral HPLC analysis.
DAICEL CHIRALPAK OJ-H column (250ꢁ4.6 mm), n-hexane/2-propa-
nol=95:5, flow rate 1 mLminÀ1, t1 (major)=24.8, t2 (minor)=33.0.
column
(250ꢁ4.6 mm),
n-hexane/2-propanol=90:10,
flow
rate
1 mLminÀ1, t1
(major)=13.4, t2 (minor)=16.2.
tert-Butyl 6-(dimethylamino)-2-hydroxy-1-tetralone-2-carboxylate (5h):
[a]2D5 = +60.2 (c=1.1, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.94 (d,
J=8.7 Hz, 1H), 6.61 (d, J=8.9 Hz, 1H), 6.63–6.60ACTHNUTRGNE(NUG m, 1H), 6.37–6.36 (m,
1H), 4.31 (s, 1H), 3.10–2.96 (m, 8H), 2.63–2.57 (m, 1H), 2.19–2.11 (m,
1H), 1.41 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=192.5, 170.6,
153.9, 145.9, 130.2, 118.9, 110.5, 109.1, 82.6, 77.4, 39.9, 32.9, 27.7,
26.3 ppm; HRMS (ESI): m/z calcd for C17H23NNaO4: 328.1525 [M+Na],
found 328.1543; enantiomeric excess of 5h was determined to be 95% ee
by chiral HPLC analysis. DAICEL CHIRALPAK OD-H column (250ꢁ
4.6 mm), n-hexane/2-propanol=90:10, flow rate 1 mLminÀ1, t1 (major)=
12.07, t2 (minor)=16.9.
tert-Butyl 6-chloro-2-hydroxy-1-tetralone-2-carboxylate (5i): [a]2D5 = +8.8
(c=0.9, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.97 (d, J=8.2 Hz,
1H), 7.33–7.23 (m, 2H), 4.18 (brs, 1H), 3.16–2.99 (m, 2H), 2.66–2.58 (m,
1H), 2.26–2.16 (m, 1H), 1.40 ppm (s, 9H); 13C NMR (100 MHz, CDCl3):
d=193.8, 170.0, 145.5, 140.7, 129.7, 129.2, 128.8, 127.6, 83.8, 77.7, 32.6,
27.9, 25.6 ppm; HRMS (ESI): m/z calcd for C15H17ClO4: 319.0713 [M+
Na]; found: 319.0706; the enantiomeric excess of 5i was determined to
be 95% ee by chiral HPLC analysis. DAICEL CHIRALPAK OD-H
column (250ꢁ4.6 mm), n-hexane/ethanol=99:1, flow rate 1 mLminÀ1, t1
(major)=11.6, t2 (minor)=12.3.
Synthesis of ent-6: Cumene hydroperoxide (670 mL, 3.66 mmol) was
added to a mixture of 4n (936 mg, 3.05 mmol), 3a (171 mg, 0.15 mmol),
and K2CO3 (84 mg, 0.61 mmol) in toluene (60 mL) at 08C, and the mix-
ture was stirred for 18 h. A solution of 10% Na2S2O3 was added to the
reaction mixture, and the resultant was stirred for 1 h vigorously. The or-
ganic layer was separated and the aqueous layer was extracted with ethyl
acetate. The combined extracts were dried over MgSO4, and the filtrates
were concentrated in vacuo. The residue was purified by column chroma-
tography on silica gel (hexane/ethyl acetate=10:1 to 5:1) to give 5n
(968 mg, 98% yield, 84% ee). NaBH4 (29 mg, 0.8 mmol) was added to
a solution of 5n (500 mg, 1.5 mmol) in MeOH (15 mL) at 08C. After stir-
ring for 30 min at the same temperature, H2O was added to the reaction
mixture, and the organic layer was extracted with ethyl acetate. The ex-
tracts were dried over MgSO4, and the filtrates were concentrated in
vacuo to give diol, which was directly used in the next step. BF3·Et2O
(195 mL, 1.5 mmol) was then added dropwise at 08C to the solution of
diol and triethylsilane (2.5 mL, 15.5 mmol) in dichloromethane (15 mL),
and the resultant solution was allowed to RT. After stirring for 30 min, to
the reaction mixture was added H2O, and organic layer was extracted
with dichloromethane. The combined extracts were dried over MgSO4,
and the filtrates were concentrated in vacuo to give a-hydroxy carboxylic
acid 7. Methyllithium (3.3 mL, 4.5 mmol, 1.36m in 2-Me THF) was then
added dropwise at 08C to a solution of a-hydroxy carboxylic acid 7 in
THF (10 mL), and the resulting mixture was allowed to RT. After stirring
for 2 h, to the reaction mixture was added saturated NH4Cl solution, and
the organic layer was extracted with ethyl acetate. The extracts were
dried over MgSO4, and the filtrates were concentrated in vacuo. The resi-
due was purified by column chromatography on silica gel (n-hexane/ethyl
acetate=20:1 to 2:1) to give a-hydroxy ketone ent-6 as a colorless solid
(80 mg, 19%, 3 steps), whose optical purity was increased to 99% ee by
a single recrystallization from n-hexane/ethyl acetate. [a]2D5 = +46.2 (c=
1.1, CHCl3) (lit. [a]D25 =À22 (c=0.8, CHCl3), 66% ee);[23] 1H NMR
(400 MHz, CDCl3): d=6.67 (d, J=9.1 Hz, 1H), 6.64 (d, J=8.7 Hz, 1H),
3.79 (s, 3H), 3.75 (s, 3H), 2.99–2.92 (m, 2H), 2.81–2.73 (m, 2H), 2.32 (s,
3H), 1.99–1.92 (m, 1H), 1.87–1.82 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d=212.2, 151.5, 151.0, 125.4, 122.6, 107.3, 106.9, 76.4, 55.6, 55.4,
32.3, 29.6, 23.9, 19.1 ppm; HRMS (ESI): m/z calcd for C14H18NaO4:
273.11028 [M+Na]; found: 273.10863; the enantiomeric excess of ent-5
was determined to be 99% ee by chiral HPLC analysis. DAICEL CHIR-
ALPAK OJ-H column (250ꢁ4.6 mm), n-hexane/2-propanol=95:5, flow
rate 1 mLminÀ1, t1 (major)=26.1, t2 (minor)=28.8.
tert-Butyl 6-bromo-2-hydroxy-1-tetralone-2-carboxylate (5j): [a]2D5 = +
1
15.2 (c=0.5, CHCl3); H NMR (400 MHz, CDCl3): d=7.91 (d, J=8.2 Hz,
1H), 7.51 (d, J=8.7 Hz, 1H), 7.47 (s, 1H), 4.22 (brs, 1H), 3.13–3.09 (m,
2H), 2.68–2.62 (m, 1H), 2.27–2.20 (m, 1H), 1.43 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=194.0, 170.0, 145.6, 140.7, 131.9, 130.6, 129.7,
129.6, 83.8, 77.7, 32.6, 27.9, 25.5 ppm; HRMS (ESI): m/z calcd for
C15H17BrNaO4: 363.0208 [M+Na]; found: 363.0161; the enantiomeric
excess of 5j was determined to be 85% ee by chiral HPLC analysis.
DAICEL CHIRALPAK OJ-H column (250ꢁ4.6 mm), n-hexane/2-propa-
nol=99:1, flow rate 1 mLminÀ1, t1 (major)=23.6, t2 (minor)=27.5.
tert-Butyl 7-methoxy-2-hydroxy-1-tetralone-2-carboxylate (5k): [a]D25
=
À18.5 (c=0.3, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.50 (s, 1H),
7.17 (d, J=8.7 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 4.21 (s, 1H), 3.84 (s,
3H), 3.01–2.94 (m, 2H), 2.63 (dt, J=13.7, 5.5, 1H), 2.20 (dt, J=13.3, 7.6,
1H), 1.40 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=195.0, 170.2,
158.6, 136.6, 131.5, 130.2, 122.9, 109.7, 83.5, 77.9, 55.7, 33.1, 27.9,
25.0 ppm; HRMS (ESI): m/z calcd for C16H20NaO5: 315.1208 [M+Na];
found: 315.1227; the enantiomeric excess of 5k was determined to be
93% ee by chiral HPLC analysis. DAICEL CHIRALPAK OD-H column
(250ꢁ4.6mm), n-hexane/2-propanol=95:5, flow rate 1mLminÀ1
(major)=8.0, t2 (minor)=9.0.
, t1
tert-Butyl 7-bromo-2-hydroxy-1-tetralone-2-carboxylate (5l): [a]2D5 =À16.8
(c=0.9, CHCl3); 1H NMR (300 MHz, CDCl3): d=8.15 (d, J=1.8 Hz,
1H), 7.62 (dd, J=2.2, 8.2 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 4.15 (s, 1H),
3.12–2.97 (m, 2H), 2.64–2.58 (m, 1H), 2.25–2.16 (m, 1H), 1.40 ppm (s,
9H); 13C NMR (100 MHz, CDCl3): d=193.6, 170.0, 142.7, 137.0, 132.3,
130.8, 121.0, 83.9, 77.6, 32.6, 27.9, 25.3 ppm; HRMS (ESI): m/z calcd for
C15H17BrNaO4: 363.0208 [M+Na]; found: 363.0196; the enantiomeric
excess of 5l was determined to be 89% ee by chiral HPLC analysis.
DAICEL CHIRALPAK OD-H column (250ꢁ4.6 mm), n-hexane/2-prop-
Acknowledgements
anol=95:5, flow rate 1 mLminÀ1, t1
ACTHNUGTRNE(UNG major)=16.1, t2 (minor)=21.9.
This work was supported by a Grant-in-Aid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations by Organocata-
lysts” (No. 23105013) from The Ministry of Education, Culture, Sports,
Science and Technology, Japan.
tert-Butyl 7-fluoro-2-hydroxy-1-tetralone-2-carboxylate (5m): [a]2D5 =À3.4
(c=0.9, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.68 (d, J=8.7 Hz,
1H), 7.26–7.20 (m, 2H), 7.26 (s, 1H), 4.18 (s, 1H), 3.14–2.99 (m, 2H)
2.65–2.59 (m, 1H), 2.25–2.18 (m, 1H), 1.39 ppm (s, 9H); 13C NMR
16744
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 16740 – 16745

Asymmetric a-Hydroxylation
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Chem. Eur. J. 2013, 19, 16740 – 16745
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16745