Enantioselective synthesis of α-halo-α-alkylmalonates via phase-transfer catalytic α-alkylation

Article abstract of DOI:10.1039/c3ob42107d

A new enantioselective synthetic method for α-halo-α- alkylmalonates is reported. α-Alkylation of diphenylmethyl tert-butyl α-halomalonates under phase-transfer catalytic conditions (solid KOH, toluene, -40 °C) in the presence of (S,S)-3,4,5-trifluorophen

Full text of DOI:10.1039/c3ob42107d

Organic &
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Enantioselective synthesis of
α-halo-α-alkylmalonates via phase-transfer
Cite this: Org. Biomol. Chem., 2014,
12, 1510
catalytic α-alkylation†
Suckchang Hong,a Minsik Kim,a Myunggi Jung,a Min Woo Ha,a Myungmo Lee,a
Yohan Park,b Mi-hyun Kim,c Taek-Soo Kim,a Jihoon Leea and Hyeung-geun Park*a
Received 22nd October 2013,
Accepted 28th November 2013
A new enantioselective synthetic method for α-halo-α-alkylmalonates is reported. α-Alkylation of diphenyl-
methyl tert-butyl α-halomalonates under phase-transfer catalytic conditions (solid KOH, toluene, −40 °C) in
the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (5 mol%) afforded diphenylmethyl tert-butyl
α-halo-α-alkylmalonates in very high chemical yields (up to 99%) and optical yields (up to 93% ee).
DOI: 10.1039/c3ob42107d
www.rsc.org/obc
diarylmalonamide esters (1) in the presence of Maruoka cata-
lyst (S,S)-3,4,5-trifluorophenyl-NAS bromide (5) and success-
Introduction
Malonates possessing α-halogenated quaternary carbon center fully proved its usefulness in applications involving synthesis
have been recognized as privileged elements in organic syn- of various chiral building blocks (Scheme 1).5 We could also
thesis for the following reasons. First, α-halogenated quater- expand the PTC alkylation to the malonate system for the con-
nary carbon center cannot be racemized. Second, the high struction of quaternary carbon center. The enantioselective
electronegativity of halogens provides molecules with biophysi- α-alkylation of diphenylmethyl tert-butyl α-methylmalonates
cal features such as increased bond energy and lipophilicity. (3) under the condition of phase-transfer catalysis afforded
Especially, because fluorine has the highest electronegativity α-methyl-α-alkylmalonates (4) in high chemical and optical
among all elements and the second smallest van der Waals yields.6 Based on a series of our previous studies, we
radius after hydrogen, fluorine can replace hydrogen without attempted to further extend the PTC alkylation to the enantio-
changing its steric environment, however it greatly changes the selective construction of the quaternary α-halomalonate
electronic environment by the bioisostere mimic effect.1 Third, system.7 Here we report a new and highly efficient enantio-
malonate can be easily modified according to the chemical selective synthetic method for α-halo-α-alkylmalonates under
conversion of the two esters. Although construction of chiral phase-transfer catalytic conditions8 (Scheme 2).
α-halogenated quaternary carbon centers by enantioselective
α-halogenation or α-alkylation of a β-ketoester system2 and
chiral induction from a stereogenic center in β-position of
malonates by enantioselective conjugate addition3 have been
frequently reported, to date, the enantioselective synthesis of
the α-halomalonate system has not yet been extensively
studied, with only few reported studies using organometallic
catalysts or chiral auxiliaries.4
Recently, we reported a new enantioselective synthetic
method for chiral α-mono-alkylmalonamide esters (2) by
phase-transfer catalytic (PTC) mono-α-alkylation of N,N-
aResearch Institute of Pharmaceutical Science and College of Pharmacy, Seoul
National University, Seoul 151-742, S. Korea. E-mail: hgpk@snu.ac.kr
bCollege of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam
621-749, S. Korea
cCollege of Pharmacy, Gachon University, Incheon 406-799, S. Korea
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Previous chiral phase-transfer catalysis of malonate type
c3ob42107d
substrates.
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Table 1 Optimization of reaction conditions of temperature and base
Scheme 2 PTC α-alkylation of α-halomalonates.
Entry
Base
T (°C)
Time (h)
Yielda (%)
eeb (%)
Results and discussion
1
2
3
4
5
6c
7
50% KOH
50% KOH
Solid KOH
Solid KOH
Solid KOH
Solid KOH
Solid CsOH
0
−20
0
−20
−40
−78
−78
13
14
2
80
99
98
98
99
0
87
89
87
88
90
—
92
First, we needed to synthesize α-halomalonates as substrates
for the initial study. Since both diphenylmethyl and tert-butyl
ester groups shown to be necessary for high enantioselectivity
in a previous report,6 we chose diphenylmethyl tert-butyl malo-
nate (6) as a template of substrates (12, 14, 15). Substrate 12
could be prepared from commercially available dimethyl
3
20
96
96
99
a Yield of isolated product. b The enantiopurity was determined by
HPLC analysis of α-benzylated product using
a chiral column
α-fluoromalonate (8) in 4 steps (Scheme 3).6 Partial hydrolysis (Chiralpak AD-H) with hexanes/2-propanol as eluents. c No reaction.
of dimethyl α-fluoromalonate (8) using KOH in methanol
afforded the corresponding mono-acid 9 (82%). DCC coupling
of 9 with tert-BuOH in the presence of DMAP (74%), followed
of non-substituted diphenylmethyl tert-butyl malonate (13)
under PTC condition in the presence of weak base K2CO3
by methyl ester hydrolysis using LiOH in THF (73%) provided
gave the corresponding mono-benzylated product in 65% ee.11
mono-acid 11. Finally, the treatment of 11 with diphenylmethyl
Also, the electronic property of fluorine might be responsible
for the difference of enantioselectivity. The optimization of
base and temperature conditions was performed. As shown
in Table 1, solid alkali base (solid–liquid PTC system)
and 50% alkali base (liquid–liquid PTC system) provided com-
parable enantioselectivity (entries 1–4). Generally, a lower
bromide under triethylamine basic condition gave α-fluoro sub-
strate 12 (76%). α-Chloromalonate 14 and α-bromomalonate 15
were successfully prepared from malonate 13 via direct α-halo-
genation by following the procedure developed by Yang and co-
workers.9 The efficiency of the prepared α-halosubstrates was
examined by α-benzylation of 12 under typical PTC conditions.
temperature affords a slightly higher enantioselectivity, but no
The enantioselective PTC benzylation of 12 was performed in
reaction was observed at −78 °C with solid KOH (entries 3–6).
Also the lower amount of solid KOH or benzyl bromide gave
lower chemical yield with longer reaction time. The best
enantioselectivity was observed in the case of solid CsOH base
the presence of Maruoka catalyst 510 optimized in our previous
study, along with benzyl bromide (5.0 equiv.) and 50% KOH
(aq. 5.0 equiv.) at 0 °C in toluene (Table 1).6
As shown in Table 1, the α-benzylated product 12c could be
condition at −78 °C (entry 7, 99%, 92% ee), however, the reac-
obtained in 87% ee which is slightly less than that of the
tion time was quite long (96 h). We finally chose solid KOH at
corresponding α-benzylated product of α-methyl substrate 3
−40 °C as the optimal reaction condition (entry 5).12 The
(95% ee in Scheme 1).6 We speculated that the smaller size of
α-benzylation of 14 and 15 were also performed under the opti-
mized PTC condition. Similar enantioselectivities and chemi-
cal yields were observed as shown in Table 2. The scope and
the α-substituent might provide less benefit to form optimal
tight binding conformation with catalyst 5. In fact, α-benzylation
limitations of enantioselective PTC alkylation with various
electrophiles (Table 3) was investigated. As shown in Table 3,
high enantioselectivities were observed except for methylation
of 12 (entry 1, 30% ee) and allylation of 15 (entry 4, 42% ee).
Table 2 PTC benzylation of α-halomalonates (12, 14, 15)
Entry
X
Time (h)
Yielda (%)
eeb (%)
1
2
3
F (12)
Cl (14)
Br (15)
20
5
9
99
98
99
90
93
86
a Yield of isolated product. b The enantiopurity was determined by
chiral column
HPLC analysis of α-benzylated product using
a
(Chiralcel OJ-H or Chiralpak AD-H) with hexanes/2-propanol as
eluents.
Scheme 3 Preparation of α-halomalonates (12, 14, 15).
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Table 3 Enantioselective phase-transfer α-alkylation of α-halomalonates with various alkyl halides
Entry
1
X
F
E+
Product
Time (h)
48
Yielda (%)
38
eeb (%)
30 (+)
CH3I (a)
2
3
4
5
F
48
7
82
99
78
99
87 (+)
Cl
Br
F
70 (+)
4
42 (+)
20
90 (+) (R)c
6
7
8
Cl
Br
F
5
9
98
99
91
93 (+)
86 (+)
91 (+)
18
9
F
F
14
16
86
97
80 (+)
93 (+)
10
a Yield of isolated product. b The enantiopurity was determined by HPLC analysis of α-alkylated products (12a–f, 14b–c, 15b–c) using a chiral
column (Chiralcel OJ-H or Chiralpak AD-H) with hexanes/2-propanol as eluents. c The absolute configuration was confirmed as R by comparison
of the specific optical rotation value of 17 derivatized from 12c with a reported value.13a
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concentrated under reduced pressure using a Büchi rotary
evaporator. As the commercially available KOH is a pellet type,
solid KOH should be grinded to the powder form and stored
under Ar gas for successful reaction and high enantiopurity.
Phase-transfer catalysts (5) were purchased from the commer-
cial source (Wako). Flash column chromatography was carried
out using silica gel (230–400 mesh). Nuclear magnetic reson-
ance spectra were measured on 300 MHz, 400 MHz or
500 MHz instrument. All 1H-NMR spectra were reported in
ppm relative to CHCl3 (δ 7.24) or CD3OD (δ 3.30). All 13C-NMR
spectra were reported in ppm relative to the central CDCl3
(δ 77.23) or CD3OD (δ 49.15). All HPLC analyses were per-
formed using 4.6 mm × 250 mm chiral column as the station-
ary phase.
Scheme 4 Conversion of 12c into a precursor of Welch’s (R,R)-HIV-1
protease inhibitor (20).
Preparation of halomalonates (12, 14, 15)
2-Fluoro-3-methoxy-3-oxopropanoic acid (9). KOH 1.0 M in
MeOH (29.98 mL) was added to a stirred solution of dimethyl
fluoromalonate (8, 5 g, 33.31 mmol) in MeOH at room temp-
erature. After 1.5 hours, the reaction mixture was evaporated
and diluted by 5% NaHCO3, then acidified by 1N HCl in ice-
water bath. Then extracted by DCM, dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. The residue 9
The very high enantioselectivities (up to 93% ee) indicates that
this reaction method is a very efficient enantioselective syn-
thetic method for quaternary α-halo-α-alkylmalonates.
The synthetic potential of this method has been demon-
strated via the synthesis of a precursor of Welch’s (R,R)-HIV-1
protease inhibitor (2013) from 12c as outlined in Scheme 4.
Hydrogenolysis of 12c under one atmosphere of H2 in the pres-
ence of Pd/C in methanol provided the corresponding mono
acid 16 (99%). To confirm the absolute configuration of 12c,
the methyl ester 17 was prepared by treatment of 16 with an
excess of diazomethane and comparing the specific optical
rotation value of 17 {[α]2D3 = −10.9 (c 1.0, MeOH)} with a
reported value13a {(S)-17, [α]2D3 = +13.9 (c 1.0, MeOH), 98% ee}
revealed that the absolute configuration of 12c is R. The DCC
coupling of 16 with benzylamine in the presence of HOBT in
THF, followed by the deprotection of tert-butyl group afforded
the mono acid 19 (82%). Finally, the precursor of Welch’s
(R,R)-HIV-1 protease inhibitor (20) could be obtained by the
amide formation of 19 and O-benzylated (L)-valine using DCC
in the presence of HOBT in THF (60%).
1
(3.72 g, 82% yield) was obtained as a pale yellow oil. H-NMR
(300 MHz, CDCl3) δ 5.37 (d, J = 47.62 Hz, 1H), 3.86 (s, 3H)
ppm; 13C-NMR (100 MHz, CDCl3) δ 167.74 (d, J = 24.30 Hz),
164.40 (d, J = 23.80 Hz), 84.65 (d, J = 196.10 Hz), 53.68 ppm; IR
(KBr) 3542, 2965, 1965, 1757, 1631, 1442, 1267, 1117, 1014,
928, 811 cm−1; HRMS (FAB): calcd for [C4H6FO4]+: 137.0250,
found: 137.0245.
1-tert-Butyl
3-methyl
2-fluoromalonate
(10). t-BuOH
(28.7 mL) was added to a stirred solution of 9 (1.17 g,
8.60 mmol) in dichloromethane (28.7 mL) at room tempera-
ture. And DMAP (52.52 mg, 0.43 mmol), DCC (3.55 g,
17.2 mmol) was added to the reaction mixture at 0 °C and
stirred for 1 hour. The N,N′-dicyclohexylurea formed during
the reaction was removed by filtration and the filtrate was
poured in to a mixture of EtOAc (700 mL) and brine (100 mL).
The organic phase was washed with brine and water. The solu-
tion was dried over MgSO4 and concentrated. The resulting
residue was purified by column chromatography (silica gel,
hexane–EtOAc = 15 : 1) to afford 10 (1.23 g, 74% yield) as a col-
Conclusions
In summary, enantioselective synthetic methods of α-halo-
α-alkylmalonates were developed. The enantioselective PTC
α-alkylation of diphenylmethyl tert-butyl α-halomalonates
afforded the corresponding diphenylmethyl tert-butyl α-halo-
α-alkylmalonates in high chemical (up to 99%) and optical
yields (up to 93% ee). Additionally, the synthetic potential of
this method was successfully demonstrated by the synthesis of
a precursor of Welch’s (R,R)-HIV-1 protease inhibitor.
1
orless oil. H-NMR (300 MHz, CDCl3) δ 5.14 (d, J = 48.55 Hz,
1H), 3.82 (s, 3H), 1.47 (s, 9H) ppm; 13C-NMR (100 MHz, CDCl3)
δ 164.79 (d, J = 23.8 Hz), 162.73 (d, J = 23.7 Hz), 86.46, 84.46 (d,
J = 8.3 Hz), 53.01, 27.75 ppm; IR (KBr) 2982, 2934, 2856, 1754,
1680, 1440, 1396, 1371, 1297, 1255, 1207, 1155, 1122, 1018,
842, 760 cm−1. The spectral data were identical to the reported
data.6
1-Benzhydryl 3-(tert-butyl) 2-fluoromalonate (12). LiOH 1 M
in H2O (5.20 mL) was added to a stirred solution of 10 (1.0 g,
5.20 mmol) in tetrahydrofuran (5.20 mL) at room temperature.
After 40 minutes, the reaction mixture was evaporated and
diluted by 5% NaHCO3, then acidified by 1N HCl in ice-water
Experimental section
General methods
All reagents bought from commercial sources were used bath. Then it was extracted by DCM, dried over anhydrous
without further purification. Organic solvents were MgSO4, filtered, and concentrated in vacuo. The residue (crude
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11) was diluted with acetonitrile (17.35 mL), and triethylamine trifluorophenyl-NAS bromide (5, 2.66 mg, 0.003 mmol) in
(0.73 mL, 5.72 mmol) was added at room temperature. Then toluene (0.2 mL). At the designated temperature, solid KOH
diphenylmethyl bromide was added at room temperature and (16.29 mg, 0.29 mmol) was quickly added to the reaction
refluxed for 4 hours. The reaction mixture was diluted with mixture and stirred for the designated time. EYELA PSL-1400
EtOAc (700 mL), washed with brine (2 × 100 mL), dried over was used for low temperature stirring and the stirring rate was
anhydrous MgSO4, filtered, and concentrated in vacuo. The 7. The reaction mixtures was diluted with EtOAc (10 mL),
residue was purified by column chromatography (silica gel, washed with brine (2 × 3 mL), dried over anhydrous MgSO4, fil-
hexane–EtOAc = 50 : 1) to afford 12 (985 mg, 55% yield) as a tered, and concentrated in vacuo. The residue was purified by
1
white solid. H-NMR (300 MHz, CDCl3) δ 7.34–7.28 (m, 10H), column chromatography (silica gel, hexane–EtOAc = 50 : 1) to
7.00 (s, 1H), 5.23 (d, J = 48.33 Hz, 1H), 1.38 (s, 9H) ppm; afford alkylated malonates.
13C-NMR (100 MHz, CDCl3) δ 163.28 (d, J = 24.3 Hz), 162.51 (d,
(R)-1-Benzhydryl 3-tert-butyl 2-fluoro-2-methylmalonate
J = 24.1 Hz), 138.83 (d, J = 3.1 Hz), 128.56, 128.50, 128.31, (12a). Following the general procedure, the reaction was
128.25, 127.17, 127.11, 86.59, 84.64, 84.45, 78.74, 27.65 ppm; started from 12 (20 mg, 0.058 mmol) using iodomethane
IR (KBr) 2981, 1771, 1751, 1469, 1454, 1370, 1251, 1152, 1122, (18 μL, 0.29 mmol). After 48 hours, 12a was obtained as a
987, 838, 748, 700 cm−1; HRMS (FAB): calcd for [C20H22FO4]+: yellow oil (7.90 mg, 38% yield). HPLC analysis (Chiralpak
345.1502, found: 345.1487; m.p. = 72 °C. The spectral data AD-H, hexane–2-propanol = 96 : 4, flow rate = 1.0 mL min−1
,
were identical to the reported data.6
23 °C, λ = 254 nm) retention time = major 6.70 min, minor
1
1-Benzhydryl 3-(tert-butyl) 2-chloromalonate (14). A solu- 8.82 min, 30% ee; H-NMR (300 MHz, CDCl3) δ 7.35–7.25 (m,
tion of 13 (750 mg, 2.298 mmol) in dry MeCN (23 mL) was 10H), 6.96 (s, 1H), 1.75 (d, J = 21.78 Hz, 3H), 1.32 (s, 9H) ppm;
added to N-chlorosuccinimide (368 mg, 2.757 mmol) and mag- 13C-NMR (100 MHz, CDCl3) δ 166.05 (d, J = 25.60 Hz), 165.42
nesium perchlorate (154 mg, 0.689 mmol). The reaction (d, J = 24.90 Hz), 139.13, 139.01, 128.56, 128.53, 128.26,
mixture was stirred for 4 hours. After the solvent was removed 128.20, 127.24, 127.11, 92.44 (d, J = 193.00 Hz), 83.90, 78.52,
on a rotary evaporator, the mixture was diluted with EtOAc 27.56, 20.50 (d, J = 23.20 Hz) ppm; IR (KBr) 2927, 1750, 1455,
(400 mL) and washed with brine (100 mL). The organic layers 1372, 1254, 1146, 1123, 1075, 958, 841, 743, 700 cm−1; HRMS
were dried with MgSO4, and concentrated in vacuo. The residue (CI): calcd for [C21H22FO4]+: 357.1502, found: 357.1501; [α]2D5
was purified by column chromatography (silica gel, hexane– +1.53 (c 1, CHCl3).
=
EtOAc = 40 : 1–20 : 1) to afford α-chloromalonate substrates as a
(R)-1-Benzhydryl 3-tert-butyl 2-fluoro-2-allylmalonate (12b).
colorless oil (373 mg, 45% yield). 1H-NMR (300 MHz, CDCl3) Following the general procedure, the reaction was started from
δ 7.34–7.25 (m, 10H), 6.96 (s, 1H), 4.84 (s, 1H), 1.36 (s, 9H) ppm; 12 (20 mg, 0.058 mmol) using allyl bromide (25 μL,
13C-NMR (125 MHz, CDCl3) δ 163.79, 162.90, 138.89, 138.86, 0.29 mmol). After 48 hours, 12b was obtained as a colorless oil
128.58, 128.53, 128.35, 128.23, 127.34, 127.08, 84.55, 79.22, (18.30 mg, 82% yield). HPLC analysis (Chiralpak AD-H,
56.70, 27.54 ppm; IR (KBr) 2921, 2850, 1745, 1598, 1457, 1371, hexane–2-propanol = 96 : 4, flow rate = 1.0 mL min−1, 23 °C,
1299, 1252, 1147, 988, 753, 699 cm−1; HRMS (CI): calcd for λ = 254 nm) retention time = major 7.38 min, minor
[C20H20ClO4]+: 359.1050, found: 359.1046.
10.96 min, 87% ee; H-NMR (300 MHz, CDCl3) δ 7.33–7.26 (m,
1
1-Benzhydryl 3-(tert-butyl) 2-bromomalonate (15). A solu- 10H), 6.96 (s, 1H), 5.78–5.64 (m, 1H), 5.10 (d, J = 11.55 Hz,
tion of 13 (750 mg, 2.298 mmol) in dry MeCN (23 mL) was 2H), 2.87 (dd, J1 = 23.61 Hz, J2 = 7.14 Hz, 2H), 1.33 (s, 9H)
added to N-bromosuccinimide (490 mg, 2.757 mmol) and ppm; 13C-NMR (100 MHz, CDCl3) δ 165.14 (d, J = 25.7 Hz),
magnesium perchlorate (154 mg, 0.69 mmol). The reaction 164.36 (d, J = 25.2 Hz), 139.05, 138.96, 129.13 (d, J = 2.9 Hz),
mixture was stirred for 4 hours. After the solvent was removed 128.53, 128.50, 128.30, 128.17, 127.40, 127.05, 120.64, 93.95 (d,
on a rotary evaporator, the mixture was diluted with EtOAc J = 197.4 Hz), 84.09, 78.60, 38.51 (d, J = 21.2 Hz), 27.64 ppm; IR
(400 mL) and washed with brine (100 mL). The organic layers (KBr) 2981, 2930, 1750, 1455, 1371, 1303, 1249, 1150, 1032,
were dried with MgSO4, and concentrated in vacuo. The 928, 840, 743, 700 cm−1; HRMS (CI): calcd for [C23H24FO4]+:
residue was purified by column chromatography (silica gel, 383.1659, found: 383.1654; [α]2D5 = +13.57 (c 1, CHCl3).
hexane–EtOAc = 40 : 1–20 : 1) to afford α-bromomalonate sub-
(R)-1-Benzhydryl 3-tert-butyl 2-chloro-2-allylmalonate (14b).
strates as a colorless oil (736 mg, 79% yield). 1H-NMR Following the general procedure, the reaction was started from
(300 MHz, CDCl3) δ 7.35–7.27 (m, 10H), 6.94 (s, 1H), 4.48 (s, 14 (21 mg, 0.058 mmol) using allyl bromide (25 μL,
1H), 1.36 (s, 9H) ppm; 13C-NMR (125 MHz, CDCl3) δ 163.77, 0.29 mmol). After 7 hours, 14b was obtained as a colorless oil
162.90, 138.91, 138.89, 128.52, 128.48, 128.28, 128.17, 127.29, (23 mg, 99% yield). HPLC analysis (Chiralpak AD-H, hexane–
127.04, 84.40, 79.26, 44.24, 27.47 ppm; IR (KBr) 2981, 1740, 2-propanol = 99 : 1, flow rate = 1.0 mL min−1, 23 °C, λ = 254 nm)
1496, 1455, 1370, 1294, 1256, 1139, 989, 848, 748, 699 cm−1
HRMS (CI): calcd for [C20H20FO4]+: 403.0545, found: 403.0545.
;
retention time = major 15.82 min, minor 18.06 min, 69% ee;
1H-NMR (300 MHz, CDCl3) δ 7.35–7.26 (m, 10H), 6.93 (s, 1H),
5.81–5.67 (m, 1H), 5.11–5.01 (m, 2H), 2.96 (d, J = 6.96 Hz, 2H),
1.28 (s, 9H) ppm; 13C-NMR (100 MHz, CDCl3) δ 165.72, 164.71,
139.03, 138.96, 130.28, 128.51, 128.48, 128.34, 128.11, 127.62,
General procedure for enantioselective phase-transfer catalytic
alkylation
Alkyl halides (0.29 mmol) was added to a solution of α-halo- 126.97, 120.45, 84.19, 79.07, 70.56, 42.02, 27.46 ppm; IR (KBr)
malonate substrates (0.058 mmol) and (S,S)-3,4,5- 2981, 2929, 1744, 1456, 1371, 1278, 1237, 1155, 1029, 972, 839,
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742, 699 cm−1
;
HRMS (ESI): calcd for [C23H25ClO4Na]+: 23 °C, λ = 254 nm) retention time = major 15.54 min, minor
1
423.1334, found: 423.1336; [α]2D0 = +8.97 (c 1, CHCl3).
11.68 min, 86% ee; H-NMR (300 MHz, CDCl3) δ 7.47–7.36 (m,
(R)-1-Benzhydryl 3-tert-butyl 2-bromo-2-allylmalonate (15b). 10H), 7.32–7.22 (m, 5H), 7.04 (s, 1H), 3.73 (d, J = 1.65 Hz, 2H),
Following the general procedure, the reaction was started from 1.39 (s, 9H) ppm; 13C-NMR (100 MHz, CDCl3) δ 165.95, 165.07,
15 (23.50 mg, 0.058 mmol) using allyl bromide (25 μL, 139.00, 138.92, 134.42, 130.52, 128.54, 128.43, 128.33, 128.05,
0.29 mmol). After 4 hours, 15b was obtained as a colorless oil 128.01, 127.72, 127.41, 127.05, 84.26, 79.41, 64.51, 43.43,
(20.20 mg, 99% yield). HPLC analysis (Chiralpak AD-H, 27.38 ppm; IR (KBr) 3033, 2980, 1745, 1496, 1455, 1370, 1272,
hexane–2-propanol = 99 : 1, flow rate = 1.0 mL min−1, 23 °C, 1149, 984, 840, 743, 699 cm−1
; HRMS (ESI): calcd for
λ = 254 nm) retention time = major 11.45 min, minor [C27H27BrO4Na]+: 517.0985, found: 517.0889; [α]D20 = +6.91 (c 1,
1
10.07 min, 42% ee; H-NMR (300 MHz, CDCl3) δ 7.37–7.25 (m, CHCl3).
10H), 6.92 (s, 1H), 5.81–5.67 (m, 1H), 5.11–5.02 (m, 2H), 3.02
(R)-1-Benzhydryl 3-tert-butyl 2-fluoro-2-(4-methylbenzyl)-
(d, J = 6.6 Hz, 2H), 1.28 (s, 9H) ppm; 13C-NMR (100 MHz, malonate (12d). Following the general procedure, the reaction
CDCl3) δ 165.81, 164.74, 139.09, 138.99, 131.20, 128.49, 128.45, was started from 12 (20 mg, 0.058 mmol) using 4-methylbenzyl
128.30, 128.09, 127.59, 127.03, 120.25, 84.16, 79.21, 63.35, bromide (53.70 mg, 0.29 mmol). After 18 hours, 12d was
42.64, 27.43 ppm; IR (KBr) 2980, 2929, 1740, 1496, 1455, 1370, obtained as a white solid (23.80 mg, 91% yield). HPLC analysis
1271, 1234, 1154, 1130, 964, 927, 842, 759, 699, 649 cm−1
;
(Chiralpak AD-H, hexane–2-propanol = 96 : 4, flow rate =
HRMS (CI): calcd for [C23H26BrO4]+: 445.1014, found: 1.0 mL min−1, 23 °C, λ = 254 nm) retention time = major
445.1008; [α]2D0 = +0.57 (c 1, CHCl3).
(R)-1-Benzhydryl 3-tert-butyl
14.54 min, minor 18.27 min, 91% ee; 1H-NMR (300 MHz,
2-fluoro-2-benzylmalonate CDCl3) δ 7.62–7.45 (m, 10H), 7.35–7.24 (m, 5H), 7.19 (s, 1H),
(12c). Following the general procedure, the reaction was 3.67 (d, J = 25.48 Hz, 2H), 2.55 (s, 3H), 1.57 (s, 9H) ppm;
started from 12 (20 mg, 0.058 mmol) using benzyl bromide 13C-NMR (100 MHz, CDCl3) δ 165.26 (d, J = 25.90 Hz), 164.36
(34.5 μL, 0.29 mmol). After 20 hours, 12c was obtained as a (d, J = 25.10 Hz), 139.04, 138.95, 136.87, 130.17, 129.92,
yellow oil (25 mg, 99% yield). HPLC analysis (Chiralpak AD-H, 128.94, 128.52, 128.41, 128.27, 128.03, 127.51, 126.98, 94.65 (d,
hexane–2-propanol = 96 : 4, flow rate = 1.0 mL min−1, 23 °C, J = 199.00 Hz), 84.03, 78.59, 39.55 (d, J = 20.80 Hz), 27.59,
λ = 254 nm) retention time = major 13.82 min, minor 21.05 ppm; IR (KBr) 2979, 2925, 1752, 1517, 1454, 1371, 1251,
1
24.40 min, 90% ee; H-NMR (400 MHz, CDCl3) δ 7.31–7.16 (m, 1157, 1061, 953, 841, 745, 699 cm−1; HRMS (FAB): calcd for
15H), 6.92 (s, 1H), 3.44 (d, J = 15.33 Hz, 2H), 1.28 (s, 9H) ppm; [C28H30FO4]+: 449.2128, found: 449.2143; [α]D25 = +14.29 (c 1,
13C-NMR (100 MHz, CDCl3) δ 165.20 (d, J = 25.8 Hz), 164.30 (d, CHCl3); m.p. = 82 °C.
J = 25.1 Hz), 139.02, 138.92, 133.08, 130.33, 128.54, 128.45,
(R)-1-Benzhydryl 3-tert-butyl 2-fluoro-2-(4-fluorobenzyl)malo-
128.30, 128.24, 128.06, 127.51, 127.32, 126.95, 94.57 (d, J = nate (12e). Following the general procedure, the reaction was
199.6 Hz), 84.10, 78.67, 39.94 (d, J = 20.5 Hz), 27.56 ppm; IR started from 12 (20 mg, 0.058 mmol) using 4-fluorobenzyl
(KBr) 3033, 2979, 2929, 1752, 1469, 1455, 1370, 1302, 1251, bromide (36.2 μL, 0.29 mmol). After 14 hours, 12e was
1156, 1085, 1053, 953, 840, 742, 699 cm−1; HRMS (CI): calcd obtained as a yellow solid (22.60 mg, 86% yield). HPLC analy-
for [C27H26FO4]+: 433.1815, found: 433.1828; [α]2D5 = +16.69 (c 1, sis (Chiralpak AD-H, hexane–2-propanol = 96 : 4, flow rate =
CHCl3). The spectral data were identical to the reported data.6
1.0 mL min−1, 23 °C, λ = 254 nm) retention time = major
(R)-1-Benzhydryl 3-tert-butyl 2-chloro-2-benzylmalonate 14.24 min, minor 22.01 min, 80% ee; 1H-NMR (300 MHz,
(14c). Following the general procedure, the reaction was CDCl3) δ 7.31–7.06 (m, 15H), 6.91 (s, 1H), 3.39 (d, J = 25.30 Hz,
started from 14 (21 mg, 0.058 mmol) using benzyl bromide 2H), 1.30 (s, 9H) ppm; 13C-NMR (100 MHz, CDCl3) δ 165.07 (d,
(34.5 μL, 0.29 mmol). After 5 hours, 14c was obtained as a col- J = 25.50 Hz), 164.22 (d, J = 25.00 Hz), 138.95, 138.81, 131.94,
orless oil (25.60 mg, 98% yield). HPLC analysis (Chiralpak 131.85, 128.57, 128.46, 128.36, 128.13, 127.52, 126.93, 115.21
AD-H, hexane–2-propanol = 99 : 1, flow rate = 1.0 mL min−1
,
115.00, 94.49 (d, J = 199.60 Hz), 84.27, 78.71, 39.12 (d, J = 20.70
23 °C, λ = 254 nm) retention time = major 23.44 min, minor Hz), 27.59 ppm; IR (KBr) 2927, 1751, 1606, 1511, 1455, 1371,
1
21.80 min, 93% ee; H-NMR (300 MHz, CDCl3) δ 7.29–7.04 (m, 1289, 1226, 1157, 1101, 1059, 953, 841, 795, 744, 700,
15H), 6.87 (s, 1H), 3.48 (s, 2H), 1.21 (s, 9H) ppm; 13C-NMR 647 cm−1; HRMS (FAB): calcd for [C27H25F2O4]+: 451.1721,
(100 MHz, CDCl3) δ 165.85, 164.88, 138.94, 138.89, 133.74, found: 451.1719; [α]2D5 = +11.68 (c 1, CHCl3); m.p. = 99 °C.
130.60, 128.54, 128.42, 128.36, 128.03, 127.74, 127.39, 126.95,
(R)-1-Benzhydryl 3-tert-butyl 2-fluoro-2-(naphthalen-2-yl-
84.25, 79.20, 71.44, 42.89, 27.40 ppm; IR (KBr) 3032, 2980, methyl)malonate (12f). Following the general procedure, the
1745, 1496, 1455, 1370, 1272, 1149, 1082, 984, 840, 743, reaction was started from 12 (20 mg, 0.058 mmol) using 2-(bro-
699 cm−1; HRMS (CI): calcd for [C27H26ClO4]+: 449.1520, momethyl) naphthalene (64.10 mg, 0.29 mmol). After
found: 449.1518; [α]2D0 = +20.10 (c 1, CHCl3).
16 hours, 12f was obtained as a white solid (27.30 mg, 97%
(R)-1-Benzhydryl 3-tert-butyl 2-bromo-2-benzylmalonate yield). HPLC analysis (Chiralpak AD-H, hexane–2-propanol =
(15c). Following the general procedure, the reaction was 96 : 4, flow rate = 1.0 mL min−1, 23 °C, λ = 254 nm) retention
started from 15 (23.5 mg, 0.058 mmol) using benzyl bromide time = major 19.39 min, minor 27.39 min, 93% ee; 1H-NMR
(34.5 μL, 0.29 mmol). After 9 hours, 15c was obtained as a col- (300 MHz, CDCl3) δ 7.78–7.16 (m, 22H), 6.90 (s, 1H), 3.60 (d,
orless oil (28.50 mg, 99% yield). HPLC analysis (Chiralcel J = 25.26 Hz, 2H), 1.28 (s, 9H) ppm; 13C-NMR (100 MHz,
OJ-H, hexane–2-propanol = 99 : 1, flow rate = 1.0 mL min−1
,
CDCl3) δ 165.21 (d, J = 25.70 Hz), 164.34 (d, J = 25.10 Hz),
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138.98, 138.85, 133.21, 132.63, 130.67, 129.29, 128.55, 128.38, (d, J = 21.38 Hz), 165.06 (d, J = 24.60 Hz), 137.24, 133.64,
128.30, 128.04, 127.85, 127.77, 127.55, 127.45, 126.90, 125.90, 130.54, 128.59, 128.27, 127.51, 127.49, 127.23, 96.92 (d, J =
125.77, 94.77 (d, J = 199.90 Hz), 84.20, 78.71, 40.08 (d, J = 20.50 199.66 Hz), 84.00, 43.17, 39.68 (d, J = 19.96 Hz), 27.73 ppm; IR
Hz), 27.59 ppm; IR (KBr) 2928, 1751, 1496, 1455, 1370, 1255, (KBr) 3330, 2925, 2852, 1739, 1684, 1542, 1454, 1365, 1217,
1155, 1063, 951, 839, 746, 699 cm−1; HRMS (FAB): calcd for 1085, 697 cm−1
;
HRMS (FAB): calcd for [C21H25FNO3]+:
[C31H29FO4]+: 484.2050, found: 484.2059; [α]D25 = +16.88 (c 1, 358.1818, found: 358.1816; [α]D25 = +29.02 (c 1, CHCl3); m.p. =
CHCl3); m.p. = 76 °C.
106 °C. The spectral data were identical to the reported
data.4c
(R)-2-Benzyl-3-(benzylamino)-2-fluoro-3-oxopropanoic acid
Confirmation of absolute configuration
(R)-1-tert-Butyl 3-methyl 2-fluoro-2-benzylmalonate (17). (19). A solution of 18 (35 mg, 0.098 mmol), TFA (75.4 μL,
10% Pd/C (47.50 mg) was added to a stirred solution of 12c 0.98 mmol) in DCM (1.40 mL) was stirred for 3 hours at room
(95 mg, 0.219 mmol) in MeOH (2.80 mL), and H2 gas was sub- temperature. Then, the reaction mixture was evaporated and
stituted. After 1 hour, the reaction mixture was filtered by purified by column chromatography (silica gel, DCM–MeOH =
celite 545 using MeOH, and the filtrate was evaporated to 9 : 1) to afford 19 (29.20 mg, 99% yield) as a white solid.
afford crude 16. The crude 16 was diluted by a toluene–MeOH 1H-NMR (300 MHz, CD3OD) δ 7.28–7.14 (m, 8H), 6.92–6.89 (m,
= 5 : 2 mixture (2.20 mL), and TMS-diazomethane (0.36 mL, 2H), 4.51 (d, J = 15 Hz, 1H), 4.14 (d, J = 15.21 Hz, 1H),
0.72 mmol) was added. After 1 hour, the reaction mixture was 3.70–3.55 (m, 2H) ppm; 13C-NMR (75 MHz, CD3OD) δ 169.17
quenched by AcOH (added to the mixture until the yellow (d, J = 22.28 Hz), 167.50 (d, J = 24.52 Hz), 140.23, 135.89,
color was converted to colorless) and evaporated. The residue 132.42, 130.17, 130.05, 129.12, 129.09, 128.90, 98.73 (d, J =
was diluted with EtOAc (50 mL), washed with brine (2 × 200.56 Hz), 44.51, 41.41 (d, J = 20.48 Hz) ppm; IR (KBr) 3404,
10 mL), dried over anhydrous MgSO4, filtered, and concen- 1661, 1546, 1496, 1391, 1209, 1140, 1088, 802, 742, 699 cm−1
;
trated in vacuo. Then the residue was purified by column HRMS (ESI): calcd for [C17H16FNO3Na]+: 324.1006, found:
chromatography (silica gel, hexane–EtOAc = 20 : 1) to afford 17 324.1029; {[α]2D5 = –24.26 (c 1, CHCl3); lit. [α]D25 = –24 (c 0.5,
(47.20 mg, 76% yield) as a yellow oil. 1H-NMR (300 MHz, CH2Cl2, (R)-form)}13b; m.p. = 107 °C. The spectral data were
CDCl3) δ 7.28–7.24 (m, 5H), 3.76 (s, 3H), 3.41 (d, J = 25.62 Hz, identical to the reported data.4c
2H), 1.39 (s, 9H) ppm; 13C-NMR (100 MHz, CDCl3) δ 166.64 (d,
A precursor of Welch’s (R,R)-HIV-1 protease inhibitor (20). A
J = 25.30 Hz), 164.46 (d, J = 25.10 Hz), 133.20, 130.31, 128.28, solution of acid 19 (15 mg, 0.05 mmol), D-valine benzyl ester
127.42, 94.69 (d, J = 199.80 Hz), 84.13, 53.06, 40.07 (d, J = 20.60 p-toluenesulfonate (20.78 mg, 0.055 mmol), HOBt (7.40 mg,
Hz), 27.68 ppm; IR (KBr) 2980, 2929, 1753, 1456, 1371, 1308, 0.055 mmol) and N-methylmorpholine (5.54 mg, 0.055 mmol)
1255, 1157, 1087, 1058, 842, 745, 701 cm−1; HRMS (FAB): calcd in dry THF (0.17 mL) was stirred and cooled in an ice-water
for [C15H20FO4]+: 283.1346, found: 283.1347; {[α]2D5 = –10.93 bath while DCC (11.30 mg, 0.055 mmol) was added. Stirring
(c 1, MeOH); lit. [α]2D5 = +13.92 (c 1.0, MeOH, 98% ee (S)- was continued for 2 hours at 0 °C and for an additional
form)}.4c The spectral data were identical to the reported 20 hours at room temperature. The N,N′-dicyclohexylurea
data.4c
formed during the reaction was removed by filtration and the
filtrate was poured in to a mixture of EtOAc (35 mL) and brine
(5 mL). The organic phase was washed with brine and water.
The organic solution was dried over MgSO4 and concentrated.
Conversion of 12c into a precursor of Welch’s (R,R)-HIV-1
protease inhibitor (20)4c,13
(R)-tert-Butyl
2-benzyl-3-(benzylamino)-2-fluoro-3-oxopro- The resulting residue was purified by column chromatography
panoate (18). 10% Pd/C (47.50 mg) was added to a stirred (silica gel, hexane–EtOAc = 9 : 1) to afford 20 (14.80 mg, 60%
solution of 12c (95 mg, 0.22 mmol) in MeOH (2.80 mL), and yield) as a white solid. 1H-NMR (300 MHz, CDCl3) δ 7.54 (d, J =
H2 gas was substituted. After 1 hour, the reaction mixture was 8.61 Hz, 1H), 7.35–7.21 (m, 12H), 6.96–6.95 (m, 2H), 6.82 (bs,
filtered by celite 545 using MeOH, and the filtrate was evapor- 1H), 5.11 (d, J = 2.55 Hz, 2H), 4.51 (dd, J1 = 8.91 Hz, J2 = 4.77
ated to afford crude 16. The crude 16 was vacuumed for Hz, 1H), 4.42 (dd, J1 = 14.28 Hz, J2 = 5.67 Hz, 1H), 4.22 (dd, J1 =
3 hours, and dry tetrahydrofuran (0.73 mL) was added at room 15.03 Hz, J2 = 5.31 Hz, 1H), 3.46 (d, J = 20.31 Hz, 1H), 3.37 (d,
temperature. Then, HOBt (32.60 mg, 0.24 mmol), benzylamine J = 11.16 Hz, 1H), 2.19–2.15 (m, 1H), 0.90 (d, J = 6.78 Hz, 3H),
(26.3 μL, 0.24 mmol), DCC (49.70 mg, 0.24 mmol) were added 0.85 (d, J = 6.96 Hz, 3H) ppm; 13C-NMR (125 MHz, CDCl3)
in order at 0 °C. The reaction mixture was stirred for 2 hours at δ 170.56, 166.86 (d, J = 8.44 Hz), 166.68 (d, J = 9.35 Hz), 136.79,
0 °C and then stirred for 20 h more at room temperature. The 135.18, 132.79, 130.30, 128.59, 128.54, 128.42, 128.34, 128.29,
reaction mixture was evaporated and diluted with EtOAc 127.54, 127.50, 127.47, 96.25 (d, J = 198.93 Hz), 67.01, 57.27,
(50 mL), washed with brine (2 × 10 mL), dried over anhydrous 43.34, 42.93 (d, J = 21.24 Hz), 31.23, 18.95, 17.51 ppm; IR (KBr)
MgSO4, filtered, and concentrated in vacuo. The residue was 3333, 2925, 2852, 1740, 1688, 1626, 1538, 1455, 1378, 1260,
purified by column chromatography (silica gel, hexane–EtOAc 1187, 1153, 1086, 1029, 803, 745, 698 cm−1; HRMS (EI): calcd
= 9 : 1) to afford 18 (64.20 mg, 82% yield) as a white solid. for [C29H31F N2O4]+: 490.2268, found: 490.2291; {[α]D25 = +6.43
1H-NMR (300 MHz, CDCl3) δ 7.28–7.22 (m, 8H), 7.09–7.07 (c 1.5, CHCl3); lit. [α]2D5 = +7.3 (c 1.5, CH2Cl2, (R,R)-form)}13b
;
(m, 2H), 6.57 (s, 1H), 4.40 (d, J = 5.88 Hz, 2H), 3.38 (d, J = 26.00 m.p. = 104 °C. The spectral data were identical to the reported
Hz, 2H), 1.54 (s, 9H) ppm; 13C-NMR (75 MHz, CDCl3) δ 165.75 data.4c
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Paper
2007, 72, 246; (c) D. S. Reddy, N. Shibata,
J. N. S. Nakamura, T. Toru and S. Kanemasa, Angew. Chem.,
Int. Ed., 2008, 47, 164; (d) K. Shibatomi, Y. Soga,
A. Narayama, I. Fujisawa and S. Iwasa, J. Am. Chem. Soc.,
2012, 134, 9836; (e) A. Narayama, K. Shibatomi, Y. Soga,
T. Muto and S. Iwasa, Synlett, 2013, 375.
Acknowledgements
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korean government
(MEST) (2007-0056817 & 2012-002956).
5 (a) M.-h. Kim, S.-H. Choi, Y.-J. Lee, J. Lee, K. Nahm,
B.-S. Jeong, H.-g. Park and S.-s. Jew, Chem. Commun., 2009,
782; (b) Y. Park, Y. J. Lee, S. Hong, M.-h. Kim, M. Lee,
T.-S. Kim, J. K. Lee, S.-s. Jew and H.-g. Park, Adv. Synth.
Catal., 2011, 353, 3313.
Notes and references
1 K. Mikami, Y. Itoh and M. Yamanaka, Chem. Rev., 2004,
104, 1.
2 (a) H. Li, S. Zhang, C. Yu, X. Song and W. Wang, Chem.
Commun., 2009, 2136; (b) X. Wang, Q. Lan, S. Shirakawa
and K. Maruoka, Chem. Commun., 2010, 46, 321.
6 S. Hong, J. Lee, M. Kim, Y. Park, C. Park, M.-h. Kim,
S.-s. Jew and H.-g. Park, J. Am.Chem. Soc., 2011, 133, 4924.
7 As a preliminary result, one sample (12c) of the enantio-
selective α-benzylation of α-fluoromalonate (12) was
reported in ref. 6.
8 For recent reviews on the phase-transfer catalysis, see:
(a) K. Maruoka and T. Ooi, Chem. Rev., 2003, 103, 3013;
(b) M. J. O’Donnell, Acc. Chem. Res., 2004, 37, 506;
(c) B. Lygo and B. I. Andrews, Acc. Chem. Res., 2004, 37, 518;
(d) T. Hashimoto and K. Maruoka, Chem. Rev., 2007, 107,
5656; (e) S.-s. Jew and H.-g. Park, Chem. Commun., 2009,
7090.
3 (a) T. Okino, Y. Hoashi, T. Furukawa, X. Xu and
Y. Takemoto, J. Am. Chem. Soc., 2005, 127, 119;
(b) P. J. Nichols, J. A. DeMattei, B. R. Barnett, N. A. LeFur,
T.-H. Chuang, A. D. Piscopio and K. Koch, Org. Lett., 2006,
8, 1495; (c) J. M. Andrés, R. Manzano and R. Pedrosa,
Chem.–Eur. J., 2008, 14, 5116; (d) Y.-n. Xuan, S.-z. Nie,
L.-t. Dong, J.-m. Zhang and M. Yan, Org. Lett., 2009, 11,
1583; (e) Z. Jiang, Y. Pan, Y. Zhao, T. Ma, R. Lee, Y. Yang,
K.-W. Huang, M. W. Wong and C.-H. Tan, Angew. Chem.,
Int. Ed., 2009, 48, 3627; (f) Z. Wang, D. Chen, Z. Yang,
9 D. Yang, Y.-L. Yan and B. Lui, J. Org. Chem., 2002, 67, 7429.
S. Bai, X. Liu, L. Lin and X. Feng, Chem.–Eur. J., 2010, 16, 10 T. Ooi, M. Kameda and K. Maruoka, J. Am. Chem. Soc.,
10130; (g) S. Kobayashi, M. M. Salter, Y. Yamazaki and
2003, 125, 5139.
Y. Yamashita, Chem.–Asian J., 2010, 5, 493; (h) M. Hatano, 11 S. Hong, J. Lee, M. Kim, Y. Park, C. Park and H.-g. Park,
T. Horibe and K. Ishihara, Org. Lett., 2010, 12, 3502;
unpublished results.
(i) N. Shibata, T. Nishimine, N. Shibata, E. Tokunaga, 12 The same chemical yield and enantioselectivity in PTC
K. Kawada, T. Kagawa, A. E. Sorochinskycde and
α-benzylation of 12 were confirmed with 0.5 g scale syn-
V. A. Soloshonok, Chem. Commun., 2012, 48, 321.
thesis under the optimized reaction conditions.
4 (a) M. Ihara, T. Kawabuchi, Y. Tokunaga and K. Fukumoto, 13 (a) A. Abouabdellah, L. Boros, F. Gyenes and J. T. Welch,
Tetrahedron: Asymmetry, 1994, 5, 1041; (b) T. Suzuki,
T. Goto, Y. Hamashima and M. Sodeoka, J. Org. Chem.,
J. Fluorine Chem., 1995, 72, 255; (b) A. Abouabdellah and
J. T. Welch, Tetrahedron: Asymmetry, 1994, 5, 1005.
This journal is © The Royal Society of Chemistry 2014
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