Enantioselective fluorination of β-ketoesters using tartrate derived bidentate bioxazoline-Cu(II) complexes

Article abstract of DOI:10.1016/j.tetasy.2013.07.004

Enantioselective fluorination of aliphatic cyclic and acyclic β-ketoesters was achieved in excellent yield (up to 98%) with moderate to good enantioselectivities (up to 86% ee) using tartrate derived bidentate bioxazoline-Cu(II) complexes. This is the fir

Full text of DOI:10.1016/j.tetasy.2013.07.004

Tetrahedron: Asymmetry 24 (2013) 919–924
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Enantioselective fluorination of b-ketoesters using tartrate derived
bidentate bioxazoline-Cu(II) complexes
⇑
Kaluvu Balaraman, Ravichandran Vasanthan, Venkitasamy Kesavan
Chemical Biology Laboratory, Bhupat and Jyothi Mehta School of Biosciences Building, Indian Institute of Technology Madras, Chennai 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 May 2013
Accepted 4 July 2013
Enantioselective fluorination of aliphatic cyclic and acyclic b-ketoesters was achieved in excellent yield
(up to 98%) with moderate to good enantioselectivities (up to 86% ee) using tartrate derived bidentate
bioxazoline-Cu(II) complexes. This is the first report of a bioxazoline which forms a 5-membered chelate
inducing enantioselectivity in the asymmetric fluorination of b-ketoesters.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
enantioselective fluorinations. For example Togni5 and Sodeoka6
independently continued their efforts in synthesizing enantioselec-
Access to stereogenic fluorinated carbon centers can be
achieved by enantioselective electrophilic fluorination. Fluorinated
molecules can often interact with biological targets more effec-
tively than their non-fluorinated analogues, thus playing a key role
in pharmacokinetics.1 As a result, the development of chiral ligands
for electrophilic fluorination to construct a stereogenic fluorinated
carbon center is a prominent area of research in the field of asym-
metric catalysis.2
tive fluorinated b-ketoesters and oxindoles. In addition to these
findings, enantioselective fluorination using chiral organophos-
phate-Sc complexes by Inanaga,7a 2,20-bipyridine-3,30-dicarboxylic
esters and amides with copper by Queneau et al.,7b sulphoximines-
copper complexes by Bolm,7c chiral diamine-nickel complexes by
Kim,7d Co-salen by Itoh et al.,7e and most recently Pd/SPANphos
by Leeuwen7f was reported to synthesize fluorinated b-ketoesters.
Chiral organocatalysts such as cinchona alkaloids, chiral quarterna-
ry ammonium salts, and chiral thioureas were also utilized in order
to make optically active fluorinated molecules.8
Shibata initiated the use of bis(oxazoline) ligand 1 (Fig. 1) with
Ni(II) or Cu(II) for the enantioselective fluorination of various
1-indanone-2-carboxylates and achieved up to 93% enantioselec-
tivity.9 Independently Cahard also utilized the same catalytic sys-
tem for the asymmetric fluorination of various b-ketoesters using
The first enantioselective fluorination of b-ketoesters was devel-
oped by Togni using [TiCl2(TADDOLato)]-complex and achieved up
to 90% enantioselectivity using Selectfluor.3 The Pd/BINAP com-
plexes in combination with N-fluorobenzene sulfonimide (NFSI)
were used by Sodeoka for an efficient enantioselective synthesis
of various
tions paved the way for the development of several catalytic
a
-fluoro-b-ketoesters.4 These two successful investiga-
O
O
O
O
O
O
N
N
N
N
N
N
N
N
Ph
R
Ph
R
O
1
O
O
N
N
O
N
Ph
Ph
2
4a
R = Ph
4b
R = 2-FC6H4
4c
R = adamantyl
3
4d
2-Naph-(S,S)-Box
Figure 1. Oxazoline ligands.
⇑
Corresponding author. Tel.: +91 44 2257 4124; fax: +91 44 2257 4102.
E-mail address: vkesavan@iitm.ac.in (V. Kesavan).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.004

920
K. Balaraman et al. / Tetrahedron: Asymmetry 24 (2013) 919–924
O
O
O
O
O
O
N
N
N
N
N
N
OCH3
H3CO
5a
OCH3
H3CO
OCH3
H3CO
5b
(R,R)-Nap-(S,S)-Box
(S,S)-Nap-(R,R)-Box 5c
(S,S)-Nap-(S,S)-Box
O
O
O
O
O
O
N
N
N
N
N
N
OCH3
(R,R)-Nap-(R,R)-Box
H3CO
5d
5f
(S,S)-Ibu-(R,R)-Box
5e
(S,S)-Ibu-(S,S)-Box
Figure 2. Bidentate bioxazoline ligands from tartaric acid.
several electrophilic fluorinating agents.10 Despite the good enanti-
oselectivity, the efficiency of the method was not demonstrated
using various substrates. Moreover good selectivity was only possi-
ble with b-ketoesters, which possessed bulky ester constituents
such as t-butyl/adamantyl or menthyl. Since the well known bisox-
azolines failed to mediate enantioselective fluorinations with a
broad substrate scope, DBFOX-Ph 2 (Fig. 1) was applied for the same
reactions with good substrate scope.11 N,N,N-Tridentate ligand 3
was exploited with various Lewis acids for asymmetric fluorination
of b-ketoesters.12 DBFOX-Ph 2 was the most effective catalyst for
the construction of fluorinated stereogenic centers. Although
ligands 2 and 3 showed excellent enantioselectivity in the asym-
metric fluorination reaction, the synthesis of DBFOX-Ph 2 precursor
demands tedious reaction conditions such as s-BuLi, while the syn-
thesis of ligand 3 involves a resolution. Any catalytic system which
could overcome some of these difficulties discussed would be
desirable.
influence the stereochemical outcome of the products.15 Shibata
et al. also made a similar observation in the case of the asymmetric
fluorination of b-ketoesters.9 On similar lines, the asymmetric fluo-
rination of b-ketoesters using ligand 5a with Cu salts furnished the
(S)-isomer (Table 1, entries 1–3), while the use of a Zn salt resulted
in the (R)-isomer (Table 1, entry 4). Among the various metal salts
screened Cu(ClO4)2ꢀ6H2O was observed to be the best in terms of
enantioselectivity (Table 1, entry 3).
Table 1
Optimization of the conditions for (S,S)-Nap-(S,S)-Box 5a-catalyzed enantioselective
fluorination of ethyl 2-oxocyclopentanecarboxylate 6aa
O
O
F
PhO2S
PhO2S
COOEt
5a / metal salt
COOEt
+
N
F
*
DCM
6a
7a
Due to poor chiral induction, ligand 4 (Fig. 1) has been less
explored.13 The poor chirality transfer of tartrate derived bioxazo-
line 4 was overcome by the introduction of an additional chiral
appendage near the coordination sphere. This new class of chiral li-
gand 5 (Fig. 2) was used efficiently in various asymmetric transfor-
mations such as asymmetric Henry reactions,14a enantioselective
propargylamine synthesis,14b and asymmetric allylic alkylations.14c
The paucity of synthetic methods to synthesize a stereogenic center
with fluorine prompted us to explore the efficiency of ligand 5
(Fig. 2) in asymmetric fluorinations, since it can be obtained from
commercially available and inexpensive chiral sources through
simple organic transformations.
Entry
Metal source
Time (h)
Temp (°C)
Yieldb (%)
eec (%)
1
2
3
4
Cu(OTf)2
Cu(OTf)2
4
10
3
25
0
25
25
97
89
91
73
28 (S)
26 (S)
34 (S)
22 (R)
Cu(ClO4)2ꢀ6H2O
Zn(OTf)2
6
a
Reaction conditions: 5a (7.5 mol %), metal salt (5 mol %), 6a (1 equiv), and NFSI
(1.1 equiv) in 1 mL of dichloromethane.
b
Isolated yield.
c
Determined by a chiralpak AS-H column; the absolute configuration of 7a was
assigned by comparison of the specific rotation.7c
Since Cu(ClO4)2ꢀ6H2O gave the best enantioselectivity, it was
chosen for further optimization of the reaction conditions. There
is no literature precedence of utilizing ligand 4 in the asymmetric
fluorination of b-ketoesters. As a result, the substituent effect of
bioxazoline ligands 4 was investigated. Tartrate derived bioxazo-
line ligands 4a–4d, which do not possess an additional chiral
appendage, failed to induce good enantioselectivity. Although the
reaction was efficient, poor enantioselectivity was obtained when
using these ligands (Table 2, entries 1–4). It is unambiguous from
these observations that an attachment of a chiral appendage is
essential for asymmetric induction. Since ligand 5 contains two
stereogenic centers, there is a possibility of four diastereomeric
2. Results and discussion
It was reported that (S,S)-Nap-(S,S)-Box 5a (Fig. 2) efficiently
mediated enantioselective Henry reactions and the addition of al-
kynes to imines. Hence, our initial attempt at enantioselective fluo-
rination was carried out using 5a in combination with various
metal salts in order to find the most suitable metal partner. Fluori-
nation of ethyl 2-oxocyclopentanecarboxylate 6a using NFSI as an
electrophilic fluorinating agent was chosen as a model reaction. It
is reported in the literature that the nature of the metal ion may

K. Balaraman et al. / Tetrahedron: Asymmetry 24 (2013) 919–924
921
ligands 5a–5d. It is important to identify which diastereomeric
ligand might catalyze the enantioselective fluorination the best.
Evaluation of 5a–5d in the presence of Cu(ClO4)2ꢀ6H2O using NFSI
afforded the corresponding fluorinated product 7a in very good
yield. From the results (Table 2, entries 4–8) one can deduce that
the combination of (R) and (S) is required for better enantioselec-
tivity. From Table 2 it can be seen that bioxazoline ligands 5b
and 5c, which are enantiomers, afforded the product with identical
enantioselectivity (Table 2, entries 6–7).
of the (S)-isomer. In the case of ligand 5c, Re-face attack and the
lack of a steric interaction are proposed for the observed enhance-
ment in enantioselectivity as well as the stereochemical outcome.
It was shown in the previous results that the absolute configura-
tion of the product was effectively dictated by the chirality of the
oxazoline backbone,14a while similar observations were made in
the enantioselective fluorination. Chimeric ligands 5e and 5f
derived from tartaric acid and ibuprofen failed to induce good
enantioselectivity (Table 2, entries 9–10). Since the asymmetric
induction by ligand 5c was better than the other ligands, further
optimization studies were performed using this ligand.
Table 2
Under the standard reaction conditions, the fluorination of ethyl
2-oxocyclopentanecarboxylate 6a in chlorinated solvents such as
chloroform (CHCl3) and dichloroethane proceeded very efficiently
to afford 7a in excellent yield but with moderate enantioselectivity
(60% and 77% ee) (Table 3, entries 1–2). Use of ether solvents such
as diethylether, dioxane, and tetrahydrofuran (THF) did not in-
crease the enantioselectivity (Table 3, entries 3–5). Although excel-
lent yields (87–95%) were obtained in the case of polar solvents
such as acetonitrile (CH3CN), hexafluoro-2-propanol (HFIP), and
acetone, only moderate enantioselectivity was observed (Table 3,
entries 6–8). The use of a non-polar solvent, such as toluene, affor-
ded the product with good enantioselectivity (82% ee, Table 3, en-
try 9). Toluene was thus identified as a suitable reaction medium.
Identification of bioxazoline ligands in the enantioselective fluorination of ethyl
2-oxocyclopentanecarboxylate 6aa
O
O
F
PhO2S
PhO2S
COOEt
L
/ Cu(ClO4)·2H2O
DCM, 25 °C
COOEt
+
N
F
*
6a
7a
Entry
Ligand
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
5a
5b
5c
5d
5e
5f
4
4
8
4
3
3
3
3
5
5
92
88
79
90
91
87
89
73
91
77
7 (S)
5 (S)
12 (S)
4 (S)
34 (S)
68 (S)
70 (R)
33 (R)
52 (S)
29 (R)
Table 3
Effect of solvents on enantioselectivity in the formation of 7aa
O
O
a
Reaction conditions: ligand (7.5 mol %), Cu(ClO4)2ꢀ6H2O (5 mol %), 6a (1 equiv),
F
5c
·
/ Cu(ClO4) 2H2O
and NFSI (1.1 equiv) in 1 mL of dichloromethane at 25 °C.
COOEt
COOEt
b
Isolated yield.
Determined by a chiralpak AS-H column.
(R)
NFSI, 25 °C
c
6a
7a
Entry
Solvent
CHCl3
Dichloroethane
Diethylether
Dioxane
THF
CH3CN
HFIP
Acetone
Toluene
Time (h)
Yieldb (%)
eec (%)
It should be noted that while ligands 5a and 5d provided very
good enantioselectivities in asymmetric Henry reactions, alkyne
additions to imines and asymmetric allylic alkylations, in the case
of asymmetric fluorinations the diastereomeric pair of 5a and 5d,
that is bioxazoline ligands 5b and 5c, was better in inducing
enantioselectivity. The observed difference in the ability of these
ligands 5a and 5c to induce asymmetric induction is explained
by the proposed transition-state model in Figure 3. In order to
obtain the (S)-isomer of the fluorinated molecule, b-ketoester 6a
might approach the metal coordination site of ligand 5a, as
depicted in Figure 3a, although it is sterically not favored. The
Si-face attack of the electrophile is responsible for the formation
1
2
3
4
5
6
7
8
9
3
3
5
4
3
4
6
3
3
97
96
77
82
93
88
87
91
95
77
60
74
61
71
52
57
54
82
a
Reaction conditions: 5c (7.5 mol %), Cu(ClO4)2ꢀ6H2O (5 mol %), 6a (1 equiv), and
NFSI (1.1 equiv) in 1 mL of solvent at 25 °C.
b
Isolated yield.
Determined by a chiralpak AS-H column.
c
(PhO2S)2N
F
(a)
(b)
F
N(SO2Ph)2
Table 4
Additive effects on the enantioselective formation of 7aa
O
O
O
O
O
O
R
R
R
R
F
N
N
N
N
5c
·
/ Cu(ClO4) 2H2O
Cu
COOEt
Cu
COOEt
Me
Me
Me
Me
O
NFSI, toluene
O
O
O
6a
Additiveb
7a
R'O
OR'
(S,S)-Nap-(S,S)-Box 5a
Entry
Time (h)
Temp (sC)
Yieldc (%)
eed (%)
5c
(S,S)-Nap-(R,R)-Box
1
2
3
4
5
MS (4 Å)
NaBArF
HFIP
HFIP
HFIP
3
3
4
8
12
25
25
25
0
ꢁ20
93
78
94
93
88
82
31
80
86
86
Re-face attack
Si-face attack
O
O
COOR'
F
R'OOC
F
a
Reaction conditions: 5c (7.5 mol %), Cu(ClO4)2ꢀ6H2O (5 mol %), 6a (1 equiv), and
NFSI (1.1 equiv) in 1 mL of toluene.
b
10 mol % of additives was added.
Isolated yield.
Determined by chiralpak AS-H column.
(S)-isomer with 34% ee
(R)-isomer with 70% ee
c
d
Figure 3. Proposed transition state models for enantioselective fluorinations.

922
K. Balaraman et al. / Tetrahedron: Asymmetry 24 (2013) 919–924
In order to improve the enantioselectivity of the fluorination
The optimizedreaction conditionswere then appliedto theenan-
tioselective fluorination reactions of various b-ketoesters and the re-
sults are shown in Table 5. As shown in Table 5, various aliphatic b-
reaction further, we evaluated the effect of additives due to earlier
reports on enhanced enantioselectivity with additives.16The use of
molecular sieves did not improve the enantioselectivity (Table 4,
entry 1). The use of a borate salt as an additive dramatically
reduced the enantiomeric excess of 7a (Table 4, entry 2). Cahard
reported an increase in enantioselectivity in the asymmetric
fluorination with the addition of a trace amount of HFIP.10a Katsuki
and Shibasaki independently found that HFIP promoted the release
of the fluorinated product from the catalyst, thus assisting catalyst
turnover.17
These observations encouraged us to use 10 mol % of HFIP as an
additive in the formation of 7a. Carrying out the reaction at room
temperature did not enhance the enantioselectivity (Table 4, entry
3). Lowering the temperature to 0 °C with HFIP as the additives in-
creases the enantioselectivity marginally to 86% (Table 4, entry 4).
Lowering the temperature further did not lead to an increase in the
enantioselectivity (Table 4, entry 5). From these optimization stud-
ies, we concluded that (S,S)-Nap-(R,R)-Box 5c was the most suit-
able ligand in combination with Cu(ClO4)2ꢀ6H2O in toluene and
10 mol % of HFIP at 0 °C for the effective asymmetric fluorination
reactions of b-ketoesters.
ketoesters were successfully converted into their corresponding a-
fluoro-b-ketoesters 7a–7e in excellent yields and with good enanti-
oselectivities. However, in the case of aromatic b-ketoesters, low
enantioselectivities were observed. These observations are in agree-
ment with similar results reported by Itoh et al.7e The enantioselec-
tive fluorination using (S,S)-ip-pybox and (R,R)-Jacobson’s salen
ligands showed high enantioselectivity for aliphatic substrates com-
pared to aromatic substrates. It is noteworthy that the most readily
available and inexpensive substrate 6a was identified as the most
suitable substrate, giving the expected fluorinated product 7a in
93% yield with 86% ee (Table 5, entry 1). The methyl ester of cyclo-
pentanone-2-carboxylate also showed 72% enantioselectivity with
96% yield (Table 5, entry 2). The notable advantage of our catalytic
system over existing methods is that most of the reported catalysts
need bulky tert-butyl ester substrates in order to achieve high
enantioselectivity. We also utilized t-butyl-2-cyclopentanonecarb-
oxylate 6c and found that the bulkiness did not enhance the enanti-
oselectivity (83% ee) further (Table 5, entry 3). Enlarging the ring size
to a 6-membered size decreased the enantioselectivity to 52%
although the yield was excellent (Table 5, entry 4). This protocol
worksverywellforacyclicb-ketoester6e. Ethyl2-methyl-3-oxobut-
anoate 6e underwent fluorination in 84% yield and with 70% enanti-
oselectivity (Table 5, entry 5). Only ketoesters containing aromatic
rings afforded the corresponding fluorinated product in low to poor
enantioselectivity (Table 5, entries 6–7). In summary this is the first
report of a bioxazoline which forms a 5-membered chelate catalyz-
ing the asymmetric fluorination of b-ketoesters with fair to very
good enantioselectivity.
Table 5
Enantioselective fluorination of b-ketoesters using bioxazoline 5ca
O
O
F
PhO2S
PhO2S
5c
·
/ Cu(ClO4)2 6H2O
COOR3
COOR3
R1
R1
N
F
toluene, 0 °C
HFIP
R2
R2
6
7
Entry Substrate Product
Time (h) Yieldb (%) eec (%)
O
F
3. Conclusion
COOEt
1
2
3
6a
6b
6c
8
6
93 86
96 72
97 83
In conclusion, tartrate derived bioxazolines containing a chiral
appendage were successfully applied for the asymmetric fluorina-
tions of b-ketoesters. (S,S)-Nap-(R,R)-Box 5c was identified as the
most suitable diastereomeric ligand to construct a stereogenic
C–F bond. The use of these ligands in other asymmetric transfor-
mations is currently being developed in our laboratory.
7a
O
F
F
COOMe
7b
O
O
COOtBu
10
4. Experimental
4.1. General
7c
F
4
5
6d
6e
8
8
90 52
COOEt
7d
Tartrate derived bioxazoline ligands 4a–4d and 4e and bioxaz-
olines with an additional stereogenic center 5a–5f were synthe-
sized according to the literature.13,14a 1H and 13C NMR spectra
were recorded in CDCl3 solution on a Bruker AVANCE III 500 MHz
spectrometer operating at 500 and 125 MHz. Chemical shifts are
expressed in ppm values using TMS as an internal standard. Infra-
red spectra were recorded on a Perkin Elmer FT-IR spectrometer.
The enantiomeric excess (ee) was determined by HPLC using a chi-
ral column on a SHIMADZU liquid chromatography equipped with
PDA detector. The chiral columns used were Chiralpak AS-H, Chi-
ralcel OD-H, Chiralpak AD-H, and RESTEK Rt-bDEXsm chiral col-
umns. Optical rotations were determined on Rudolph, Autopol IV
digital polarimeter. TLC was carried out using Kieselgel 60 F254
aluminum sheets (Merck 1.05554).
O
F
O
H3C
OEt
CH3
84 70
7e
O
O
F
COOEt
6
7
6f
6
6
98 34
7f
F
COOEt
6g
90 16
7g
4.2. General experimental procedure for the catalytic enantio-
selective fluorination reaction
a
Reaction conditions: 5c (7.5 mol %), Cu(ClO4)2ꢀ6H2O (5 mol %), 6 (1 equiv), and
NFSI (1.1 equiv) in 1 mL of toluene and 10 mol % of HFIP at 0 °C.
b
Isolated yield.
Determined by chiral HPLC.
Reactions were performed on a 0.5 mmol scale: Cu(ClO4)2ꢀ6H2O
(7 mg, 5 mol %) and ligand 5c (14 mg, 7.5 mol %) were stirred in
c

K. Balaraman et al. / Tetrahedron: Asymmetry 24 (2013) 919–924
923
toluene (1 mL) and HFIP (0.1 mL) under Ar at 25 °C. After stirring
for 2 h, ketoester 6 (1 equiv) and NFSI (1 equiv) were added at
0 °C and the reaction mixture was stirred for 6–10 h at the same
temperature. Completion of the reaction was monitored by TLC
and then it was directly loaded onto a column. Elution with 10%
EtOAc in hexanes afforded the fluorinated ketoester 7 in 84–98%
of yield.
13C NMR (125.7 MHz, CDCl3): d = 202.2 (d, J = 28.5 Hz), 166.7 (d,
J = 25.1 Hz), 97.6 (d, J = 193.3 Hz), 25.1, 62.7, 19.9 (d, J = 22.8 Hz),
14.1 ppm; enantiomeric excess was determined by GC with (RESTEK
Rt-bDEXsm, isotherm 120 °C, H2) major enantiomer tr = 13.2 min,
minor enantiomer tr = 12.5 min; 70%; ½a D25
¼ ꢁ62:1 (c 0.70, CHCl3).
ꢂ
The absolute stereochemistry was assigned as (R) based on the anal-
ogous optical rotation values.7c
4.3. (R)-Ethyl 1-fluoro-2-oxocyclopentanecarboxylate 7a
4.8. (R)-Ethyl 2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carbox-
ylate 7f
1H NMR (500 MHz, CDCl3): d = 4.28 (dq, J = 10.8, 7.2 Hz, 1H),
4.26 (dq, J = 10.9, 7.2 Hz, 1H), 2.60–2.44 (m, 3H), 2.38–2.22 (m,
1H), 2.20–2.04 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H) ppm; 13C NMR
(125.7 MHz, CDCl3): d = 207.39 (d, J = 17.1 Hz), 167.3 (d,
J = 27.0 Hz), 94.7 (d, J = 199.9 Hz), 62.4, 35.8, 34.0 (d, J = 20.9),
18.2 (d, J = 3.3 Hz), 14.2 ppm; enantiomeric excess was determined
by HPLC with a Chiralpak AS-H column (98:2 hexanes:isopropanol,
0.5 mL/min, 190 nm); major enantiomer tr = 23.3 min, minor enan-
1H NMR (500 MHz, CDCl3): d = 7.83 (d, J = 7.5 Hz, 1H), 7.69 (td,
J = 7.2, 1.0 Hz, 1H), 7.50–7.46 (m, 2H), 4.27 (q, J = 7.0 Hz, 2H), 3.78
(dd, J = 17.5, 17.5 Hz, 1H), 3.42 (dd, J = 17.5, 17.5 Hz, 1H), 1.26 (t,
J = 7.0 Hz, 3H) ppm; 13C NMR (125.7 MHz, CDCl3): d = 195.2 (d,
J = 18.8 Hz), 167.2 (d, J = 27.6 Hz), 150.8 (d, J = 3.7 Hz), 136.6,
133.2, 128.5, 126.5, 125.6, 94.4 (d, J = 201.1 Hz), 62.5, 38.2 (d,
J = 23.8 Hz), 13.9 ppm; enantiomeric excess was determined by
HPLC with a Chiralcel OD-H column (90:10 hexanes:isopropanol,
1.0 mL/min, 254 nm); major enantiomer tr = 8.6 min, minor enan-
tiomer tr = 26.3 min; 86%; ½a D25
¼ þ73:2 (c 1.50, CHCl3). The abso-
ꢂ
lute stereochemistry was assigned as (R) based on comparison of
the measured rotation with the literature value.7c
tiomer tr = 9.5 min; 34% ee; ½a D25
¼ ꢁ4:0 (c 1.0, CHCl3). The absolute
ꢂ
stereochemistry was assigned as (R) based on the retention times in
4.4. (R)-Methyl 1-fluoro-2-oxocyclopentanecarboxylate 7b
HPLC and specific rotation value reported in the literature.8c
1H NMR (500 MHz, CDCl3): d = 3.81 (s, 3H), 2.62–2.40 (m, 3H),
2.39–2.23 (m, 1H), 2.20–2.04 (m, 2H) ppm; 13C NMR (125.7 MHz,
CDCl3): d = 207.2 (d, J = 16.9 Hz), 167.8 (d, J = 27.1 Hz), 94.8 (d,
J = 199.9 Hz), 53.1, 35.8, 34.0 (d, J = 20.9 Hz), 18.2 (d, J = 3.2 Hz)
ppm; enantiomeric excess was determined by HPLC with a Chir-
alpak AS-H column (98:2 hexanes:isopropanol, 0.5 mL/min,
220 nm); major enantiomer tr = 33.1 min, minor enantiomer
4.9. (R)-Ethyl 2-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-
carboxylate 7g
1H NMR (500 MHz, CDCl3): d = 8.09–7.05 (m, 1H), 7.59–7.52 (m,
1H), 7.40–7.27 (m, 2H), 4.29 (q, J = 7.0 Hz, 2H), 3.24–3.02 (m, 2H),
2.86–2.47 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H) ppm; 13C NMR
(125.7 MHz, CDCl3): d = 188.6 (d, J = 18.4 Hz), 167.3 (d, J = 25.8 Hz),
143.1, 134.0, 130.5, 129.2, 128.7, 127.2, 93.1 (d, J = 117.4 Hz), 62.3,
31.7 (d, J = 22.0 Hz), 24.9, 13.9 ppm; enantiomeric excess was deter-
mined by HPLC with a Chiralcel OD-H column (90:10 hexanes:iso-
propanol, 0.7 mL/min, 254 nm); major enantiomer tr = 10.6 min,
tr = 36.4 min; 72%; ½a D25
¼ þ69:7 (c 1.20, CHCl3). The absolute ste-
ꢂ
reochemistry was assigned as (R) based on comparison of the mea-
sured rotation with the literature value.7c
4.5. (R)-tert-Butyl 1-fluoro-2-oxocyclopentanecarboxylate 7c
minor enantiomer tr = 11.1 min; 16% ee; ½a D25
¼ ꢁ2:0 (c 1.0, CHCl3).
ꢂ
The absolute stereochemistry was assigned as (R) based on the
retention times in HPLC and specific rotation value reported in the
literature.8c
1H NMR (500 MHz, CDCl3): d = 2.57–2.42 (m, 3H), 2.35–2.14 (m,
1H), 2.11–2.04 (m, 2H), 1.48 (s, 9H) ppm; 13C NMR (125.7 MHz,
CDCl3): d = 208.5 (d, J = 17.0 Hz), 166.8 (d, J = 27.6 Hz), 94.8 (d,
J = 199.9 Hz), 84.4, 36.1, 34.2 (d, J = 21.2 Hz), 28.3, 18.4 (d,
J = 3.5 Hz) ppm; enantiomeric excess was determined by HPLC
Acknowledgments
This work was supported by the Department of Science & Tech-
nology, Government of India, New Delhi (Grant No. SR/S1/OC-60/
2006). We thank sophisticated analytical instruments facility
(SAIF) IIT Madras for the analytical data. K.B. thanks University
Grants Commission, New Delhi for the research fellowship.
with
a Chiralpak AD-H column (99:1 hexanes:isopropanol,
0.4 mL/min, 290 nm); major enantiomer tr = 21.5 min, minor enan-
tiomer tr = 17.8 min; 83%; ½a D25
¼ þ61:4 (c 0.25, CHCl3). The abso-
ꢂ
lute stereochemistry was assigned as (R) based on the retention
times in HPLC reported in the literature.11
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