Asymmetric reduction using (R)-MeCBS and determination of absolute configuration of para-substituted 2-fluoroarylethanols

Article abstract of DOI:10.1016/j.tetasy.2008.07.019

The asymmetric reduction of eight α-fluoroacetophenones has been investigated using (R)-MeCBS as a catalyst in various media. Based on a solvent screen, 1,2-dimethoxyethane, diethyl ether and dichloromethane were used in reductions of the α-fluoroacetophe

Full text of DOI:10.1016/j.tetasy.2008.07.019

Tetrahedron: Asymmetry 19 (2008) 1941–1946
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric reduction using (R)-MeCBS and determination of
absolute configuration of para-substituted 2-fluoroarylethanols
Erik Fuglseth a, Eirik Sundby b, Per Bruheim a,c, Bård Helge Hoff a,
*
a Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway
b Sør-Trøndelag University College, E. C. Dahls Gate 2, 7004 Trondheim, Norway
c SINTEF Materials and Chemistry, Department of Biotechnology, 7491 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric reduction of eight
catalyst in various media. Based on a solvent screen, 1,2-dimethoxyethane, diethyl ether and dichloro-
methane were used in reductions of the -fluoroacetophenones. The enantiomeric excess of the products
a-fluoroacetophenones has been investigated using (R)-MeCBS as a
Received 25 June 2008
Accepted 17 July 2008
Available online 12 August 2008
a
depended on the solvent and the electronic character of the aromatic substituents. Higher enantioselec-
tivity and less solvent dependency were observed in the reduction of substrates bearing electron donat-
ing substituents, whereas the opposite was the case for reduction of the substrates with electron
withdrawing substituents. The (R)-2-fluoro-1-arylethanols were obtained with enantiomeric excesses
in the range of 91–99% using 1,2-dimethoxyethane as a solvent. Six of the alcohols produced are new
chemical entities. The absolute configurations of the (R)-2-fluoro-1-arylethanols were determined by
circular dichroism using the exciton chirality method of the (S)-benzoate esters of the alcohols. The
(S)-benzoate esters were obtained by lipase-catalysed resolution using Novozym 435.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
solvents on ee in reductions of a series of para-substituted aceto-
phenones. Solvent effects have also been investigated experimen-
The importance of fluorinated compounds has been well
documented and there is a fast growing demand of optically active
fluorinated building blocks, for example, in medicinal chemistry,
biochemistry and material science.1–4 Approximately 20% of drugs
on the market contain fluorine, a number expected to grow.5 The
tally by Gilmore et al.,23 Xu et al.24 and Corey et al.25 whilst Xu
et al.,26 have investigated substrate electronic effects on the
enantioselectivity in oxazaborolidine-catalysed reductions. Several
theoretical studies of the catalyst have also been performed.27–30
1-arylethanol-skeleton is
a frequently encountered structural
2. Result and discussion
element in bioactive molecules.6–9 However, applications of
1-aryl-2-fluoroethanols are not numerous.
2.1. Asymmetric reduction
Enantioenriched (R)- and (S)-2-fluoro-1-phenylethanol are well
known and have been prepared by microbial reductions,10–13
reduction using DIP-Chlorine and Alpine-borane,14 asymmetric
epoxide opening15,16 and hydrolase catalysed resolutions.17–19
Also, (R)-1-(4-bromophenyl)-2-fluoroethanol has been prepared
by Baker’s yeast reduction.10
In order to find suitable conditions for the asymmetric
reduction of a series of
a-fluoroacetophenones, 2a–h (Scheme 1),
a solvent screen was performed. The investigation was carried
out using nine different solvents, 2a as the model substrate and
Chiral oxazaborolidine-catalysed borane reduction of prochiral
ketones to chiral secondary alcohols is one of the most important
methods in asymmetric synthesis. The present work deals with
Ph
Ph
O
O
OH
the asymmetric reduction and solvent selection for a series a-fluo-
B
N
F
F
roacetophenones using (R)-MeCBS.20 The MeCBS catalyst had pre-
viously been used for the reduction of structurally related
acetophenones, giving the corresponding alcohols in high enantio-
meric excess (ee).21,22 Mathre et al.,21 compared the effect of three
BH3
R
R
(
R
)-1a-h
2a-h
Solvent
a
b
c
d
e
f
g
h
R = OMe ( ), OBn ( ), H ( ), F ( ), Br ( ), CF3 ( ), CN ( ), NO2 ( )
* Corresponding author. Tel.: +47 73593973; fax: +47 73550877.
E-mail address: bard.helge.hoff@chem.ntnu.no (B. H. Hoff).
Scheme 1. Asymmetric reduction of 2a–h using (R)-MeCBS in various solvents.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.07.019

1942
E. Fuglseth et al. / Tetrahedron: Asymmetry 19 (2008) 1941–1946
(R)-MeCBS as the catalyst (Table 1). The catalyst was prepared
from (R)-
-diphenyl-2-pyrrolidinemethanol,21 and was used as
1a to 1h. Such effects have also been observed in similar
systems.25,26
a,a
the borane complex in equimolar amounts.
The enantioselectivity of (R)-MeCBS-catalysed asymmetric
reductions has been observed to be dependant on the reaction
temperature24 and the addition time of the substrate. The effects
of these two parameters were investigated in the reduction of 2a.
The reaction temperature was varied between –20 °C and +40 °C,
and the substrate addition time was varied from 0 to 4 h. The re-
sults are given in Table 3.
Table 1
Effect of solvent on ee (%) in reduction of 2a at 25 °C
Solvent
ee (%)
Absolute configuration
Diethyl ether
t-BuOMe
DME
THF
CH2Cl2
Toluene
i-Pr ether
Hexane
MeCN
98.0
97.0
97.0
96.0
94.5
86.5
86.0
81.0
74.5
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
Table 3
Effect of reaction temperature and addition time on ee in reduction of 2a
Reaction temperature (°C)
Addition time (h)
ee (%)
40
40
10
0
4
2
2
0
4
92.5
93.5
98.0
98.5
98.5
98.5
10
ꢀ20
The enantioselectivity of the reductions depended on the sol-
vent. The product (R)-1a was obtained in high ee when the reaction
was performed in diethyl ether, tert-butyl methyl ether (t-BuOMe)
and 1,2-dimethoxyethane (DME). Acyclic ethers had previously
been found to be suitable solvents for the asymmetric reduction
of structurally related ketones.31,32 The reductions of 2a in dichlo-
romethane and THF also gave acceptable ee-values, whereas the
reductions in the other solvents resulted in moderate enantioselec-
tivity. Surprisingly, reductions in diisopropyl ether gave low selec-
tivity. The reason for this is not clear; however, both the catalyst
and the substrate had a low solubility in the reaction medium.
To investigate the effect of solvents on the enantioselectivity
further, the whole series of substrates, 2a–2h, were reduced in
diethyl ether, dichloromethane and DME. t-BuOMe was not
included due to the low solubility of the catalyst in this medium.
Dichloromethane was included to ensure a larger variability in sol-
vent properties. The reductions of 2a–h in the three solvents were
performed using (R)-MeCBS at 25 °C. The results are summarised in
Table 2.
ꢀ20
The ee of the product, (R)-1a, depended on the reaction temper-
ature. Lower enantioselectivity was experienced at 40 °C. The sub-
strate addition time seemed to be less important, but a minor
effect was observed at a higher reaction temperature.
Based on the above findings, all the substrates were reduced on
a 1 mmol scale using (R)-MeCBS at ꢀ20 °C in DME. The addition of
the substrates was carried out over 20 min; the results are given in
Table 4.
Table 4
Asymmetric reduction of 2a–h at ꢀ20 °C using (R)-MeCBS in DME
Product
Reaction time (min)
ee (%)
Isolated yield (%)
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1e
(R)-1f
(R)-1g
(R)-1h
30
15
20
20
20
20
20
20
99.5
97.0
96.5
99.0
98.5
93.0
91.5
92.5
88
88
84
76
82
84
74
80
Table 2
Effect of solvent on ee in reduction of 2a–h at 25 o
C
Product
ee (%)
CH2Cl2
Diethyl ether
DME
All the products were obtained in good to excellent ee, but a
slight decrease in enantioselectivity was observed going from
(R)-1a to (R)-1h. Comparing the reactions in DME performed at
ꢀ20 °C with those at +25 °C, only minor changes in enantioselec-
tivity were observed for most substrates. However, the enantio-
selectivity in the reduction of 2e increased from 93.5% to 98.5%.
This effect was not investigated, but might be due to either a tem-
perature effect, addition time or a scale effect.
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1e
(R)-1f
(R)-1g
(R)-1h
98.0
98.0
91.5
94.5
90.0
94.5
98.0
78.0
92.0
81.5
65.0
74.0
68.0
97.0
97.0
96.5
97.5
93.5
90.0
89.0
93.5
85.5
a
75.0
a
Low solubility of substrate resulted in slow conversion.
2.2. Determination of the absolute configuration
The effect of the solvent on the enantioselectivity varied be-
tween the substrates. For the whole series, reductions in DME on
average gave the highest ee-values, whilst reactions in dichloro-
methane gave the lowest enantioselectivity. Only minor effects of
the solvent on the ee were observed in the reduction of 2a–b,
whereas for the reduction of 2c–2h the choice of solvent was very
important.
Optical rotation data had previously only been reported for (R)-
1c,10,18 and (R)-1e.10 The absolute configuration of the remaining
alcohols was determined by circular dichroism spectroscopy (CD)
of the benzoates (S)-3a–h, (Scheme 2). The CD exciton chirality
method,33,34 had previously been used for assigning the absolute
configuration of similar compounds.35
Solvent effects on enantioselectivity in similar reaction systems
had previously been explained by changes in the equilibrium
between the monomer and dimer species of the catalyst,23 reduc-
tion caused by free borane,21,24 and stabilisation of the reactive
intermediates.27,28 The solvent effect observed in this study is
likely to be caused by a combination of all the above-mentioned
mechanisms.
The stereopreference of lipase B from Candida antarctica is well
documented.36,37 Therefore, this lipase (Novozym 435) was used to
obtain the benzoates, (S)-3a–h, from the racemic alcohols, rac-1a–
h, by kinetic resolution via a 0.1 mmol scale. Vinyl benzoate was
used as acyl donor and t-BuOMe as a solvent (Scheme 2).
The remaining substrate from the resolution had the same con-
figuration as the alcohols, (R)-1a–h, obtained by the asymmetric
reduction using (R)-MeCBS. Thus, the benzoates obtained, (S)-3a–
h, had the opposite configuration.
Clearly, the substrate structure has an effect on the outcome of
the reaction. In all solvents, there was a decrease in ee going from

E. Fuglseth et al. / Tetrahedron: Asymmetry 19 (2008) 1941–1946
1943
O
OH
OH
O
O
Ph
F
F
+
Novozym 435
F
+
Ph
O
t-BuOMe
R
R
R
1a-h
(R)-1a-h
(S)-3a-h
Scheme 2. Kinetic resolution of racemic 1a–h using Novozym 435 and vinyl benzoate as acyl donor.
The exciton chirality method depends on the conformation of
the molecule. Therefore, an energy minimisation using Molecular
Modelling Pro (MM2) was performed. The benzoates, (S)-3a–h,
had similar preferred conformations, with the hydrogen atom at
the stereogenic centre arranged in the same plane as the disubsti-
tuted aromatic ring, see Figure 1.
The CD chirality exciton method predicts that upon looking
through the centres of the two interacting dipoles, a negative sign
is defined when an anticlockwise rotation brings the dipole in the
front onto that in the back, and vice-versa.38
For the benzoates, (S)-3a–h, an anticlockwise rotation of the
disubstituted phenyl ring brings it onto the benzoate dipole, thus
a negative first Cotton effect was predicted. This was confirmed
by CD measurements. The ee of the benzoates, (S)-3a–h, the molar
extinction (De) and UV absorption maximum (kmax) are summa-
rised in Table 5.
The second Cotton effect at lower wavelength was not observed
because the CD spectrum is perturbed by other electronic transi-
tions and effects caused by solvents, see Figure 2.
3. Conclusion
Eight
a-fluoroacetophenones have been reduced with good to
excellent enantioselectivity, using the (R)-MeCBS borane complex
as catalyst. The enantiomeric excess of the products depended on
the choice of solvent, DME being the preferred reaction medium.
The enantioselectivity of the reactions was also affected by sub-
strate structure. High enantioselectivity was obtained in the reduc-
tion of substrates having electron donating substituents, whereas a
slight decrease in ee of the products were observed in reductions of
substrates having electron withdrawing substituents.
Six of the prepared 2-fluoro-1-arylethanols had not previously
been described. The absolute configuration of the alcohols, (R)-
1a–h, was determined by CD spectroscopy using the exciton chiral-
ity method.
Figure 1. Favoured conformation of (S)-3h.
Table 5
Enantiomeric excess,
D
e
and k for (S)-3a–h
ee (%)
73
Compound
R
D
e
ka (nm)
(S)-3a
(S)-3b
(S)-3c
(S)-3d
(S)-3e
(S)-3f
(S)-3g
(S)-3h
OMe
OBn
H
F
Br
CF3
CN
NO2
ꢀ5.9
ꢀ14.2
ꢀ9.0
233
234
228
228
232
227
237
265
99
88
79
94
96
90
94
ꢀ7.1
ꢀ22.3
ꢀ6.0
4. Experimental
4.1. General
ꢀ19.6
ꢀ9.0
a
Maximum of first Cotton effect.
The
ously.39 The (R)-MeCBS borane complex was prepared according
to Mathre et al.21 starting with (R)-
-diphenyl-2-pyrolidinemeth-
anol. Trimethylboroxine, borane dimethyl sulfide complex, vinyl
benzoate and NaBH4 were purchased from Aldrich. (R)- -Diphe-
a-fluoroacetophenones were prepared as described previ-
a,a
a,a
nyl-2-pyrrolidinemethanol was a gift from Borregaard (Norway).
Novozym 435 was from Novozymes A/S (Denmark). Column chro-
matography was performed using Silica Gel 60A from Fluka, pore
size 40–63 lm. Preparative TLC plates were made by known proce-
dures. Solvents were dried by standard procedures before use.
4.2. Analyses
NMR spectra were recorded with Bruker Avance DPX 400 oper-
ating at 400 MHz for 1H, 375 MHz for 19F and 100 MHz for 13C. 1H
and 13C NMR chemical shifts are in ppm relative to TMS, whilst for
19F NMR, the shift values are relative to hexafluorobenzene. Cou-
pling constants are in Hertz. Mass spectroscopy (EI): Finnigan
MAT 95 XL Mass Spectrometer (EI/70 eV). Accurate mass determi-
nation (ESI) was performed on an Agilent 6520 QTOF MS instru-
ment equipped with a dual electrospray ion source. Samples
Figure 2. CD and UV spectra of (S)-3e.

1944
E. Fuglseth et al. / Tetrahedron: Asymmetry 19 (2008) 1941–1946
were injected into the MS using an Agilent 1200 series HPLC, and
analysis was performed as a flow injection analysis without any
chromatographic steps. All melting points are uncorrected and
measured by a Büchi melting point instrument. FTIR spectra were
recorded on a Thermo Nicolet Avatar 330 infrared spectrophotom-
eter. CD spectra were recorded on an OLIS DSM 1000 spectropho-
tometer in a 1 cm cuvette, using acetonitrile as a solvent. Optical
rotations were measured using sodium D line at 589 nm on a Per-
kin–Elmer 243 B polarimeter. The ee of the alcohols was deter-
mined by HPLC using an Agilent 1100 series system equipped
1612, 1514, 1250, 1177 and 1089. MS (EI, m/z, %): 170 (M+, 14),
153 (29), 137 (100), 109 (27) and 77 (37). HRMS (EI): 170.0744
(calcd 170.0743).
4.6.2. (R)-1-(4-(Benzyloxy)phenyl)-2-fluoroethanol (R)-1b
White solid (216 mg, 88%), mp 71–73 °C, ee = 97.0%,
½
a 2D5
ꢂ
¼ ꢀ19:9 (c 0.60, CHCl3). 1H NMR (CDCl3) d: 2.39 (dd, J = 1.1,
2.9, 1H), 4.40 (ddd, J = 8.4, 9.5, 48.5, 1H), 4.48 (ddd, J = 3.4, 9.5,
46.8, 1H), 4.97 (m, 1H), 5.07 (s, 2H), 6.95–7.01 (m, 2H), 7.28–7.45
(m, 7H). 13C NMR (CDCl3) d: 70.3, 72.8 (d, J = 19.8), 87.4 (d,
J = 175.2), 115.3 (2C), 127.7 (2C), 127.9 (2C), 128.2, 128.8 (2C),
130.7 (d, J = 8.4), 137.0 and 159.1 19F NMR (CDCl3, C6F6) d:
ꢀ220.8 (dt, J = 13.4, 47.9). IR (KBr, cmꢀ1): 3427, 2948, 2860,
1612, 1512, 1248, 1170, 1078 and 1007. MS (EI, m/z, %): 246 (M+,
3), 91 (100), 65 (11), 43 (12). HRMS (EI): 246.1056 (calcd
246.1056).
with
a Bruker DAD detector and a Chiracel OD column
(0.46 cm ꢁ 25 cm), mobile phase: hexane/2-propanol, 98:2, flow
rate 1.0 mL/min. Retention times for the enantiomers: (S)-1a
24.7 min, (R)-1a 30.0 min, (S)-1b 46.7 min, (R)-1b 49.6 min, (S)-
1c 16.2 min, (R)-1c 21.4 min, (R)-1d 15.2 min, (S)-1d 16.2 min,
(R)-1e 17.8 min, (S)-1e 20.4 min, (R)-1f 16.3 min, (S)-1f 18.3 min,
(R)-1g 47.3 min, (S)-1g 52.7 min, (R)-1h 42.5 min, (S)-1h 47.3 min.
4.6.3. (R)-2-Fluoro-1-phenylethanol (R)-1c10,18
4.3. Screening scale (R)-MeCBS reductions
Colourless oil (174 mg, 84%), ee = 96.5%, ½a D25
¼ ꢀ64:4 (c 1.20,
ꢂ
CHCl3), Ref. ½a 2D5
ꢂ
¼ ꢀ49:9 (c 1.2, CHCl3).10 1H NMR (CDCl3) d: 2.51
Under anhydrous conditions, (R)-MeCBS (29 mg, 0.1 mmol) was
dissolved in the given solvent (0.5 mL) and added to a solution of
the a-fluoroacetophenone (0.1 mmol, 0.10 M) in the same solvent.
The reaction mixture was then stirred at the given temperature un-
(br, 1H), 4.41 (ddd, J = 8.3, 9.6, 48.5, 1H), 4.51 (ddd, J = 3.3, 9.6,
46.7, 1H), 5.01 (ddd, J = 3.3, 8.3, 14.0, 1H), 7.33–7.36 (m, 5H). 13C
NMR (CDCl3) d: 73.0 (d, J = 19.8), 87.2 (d, J = 174.1), 126.3 (d,
J = 0.7, 2C), 128.5, 128.7 (2C) and 138.1 (d, J = 8.1). 19F NMR (CDCl3,
C6F6) d: ꢀ221.2 (dt, J = 13.9, 48.5). IR (neat, cmꢀ1): 3564, 3387,
2950, 1604, 1454, 1311, 1198, 1064 and 1009. MS (EI, m/z, %):
140 (M+, 61), 123 (14), 107 (100), 105 (46), 91 (52), 79 (93) and
77 (88). HRMS (EI): 140.0639 (calcd 140.0637).
til full conversion as monitored by HPLC.
4.4. Preparative scale (R)-MeCBS reductions
The
a-fluoroacetophenone (1.5 mmol) was dissolved in DME
(10 mL) and cooled to ꢀ20 °C. Through an addition funnel was
added a solution of (R)-MeCBS (437 mg, 1.5 mmol) dissolved in
DME (5 mL) over 20 min. The mixture was kept at ꢀ20 °C and stir-
red until complete consumption of the ketone as analysed by HPLC.
The reaction mixture was then quenched with MeOH (5 mL) at
ꢀ20 °C and acidified with HCl (1%) at 0 °C. Water (10 mL) was
added before the reaction mixture was extracted with CH2Cl2
(3 ꢁ 15 mL). The organic phase was washed with water
(2 ꢁ 20 mL) and dried over Na2SO4 before the solvent was evapo-
rated under reduced pressure. The crude product was purified by
column chromatography (CH2Cl2/MeOH, 100:1).
4.6.4. (R)-2-Fluoro-1-(4-fluorophenyl)ethanol (R)-1d
Colourless oil (180 mg, 76%), ee = 99.0%, ½a D25
¼ ꢀ36:5 (c 0.60,
ꢂ
CHCl3). 1H NMR (CDCl3) d: 2.63 (br, 1H), 4.39 (ddd, J = 8.2, 9.6,
48.3, 1H), 4.48 (ddd, J = 3.3, 9.6, 46.7, 1H), 5.00 (ddd, J = 3.3, 8.3,
13.9, 1H), 7.00–7.08 (m, 2H), 7.32–7.36 (m, 2H). 13C NMR (CDCl3)
d: 72.3 (d, J = 19.6), 87.0 (d, J = 175.7), 115.5 (d, J = 21.6, 2C),
128.0 (d, J = 8.2, 2C), 134.7 (dd, J = 3.2, 11.3) and 162.7 (d,
J = 245.3). 19F NMR (CDCl3, C6F6) d: ꢀ114.2 (m), ꢀ221.4 (dt,
J = 13.8, 48.2). IR (neat, cmꢀ1): 3588, 3385, 2952, 2892, 1606,
1510, 1223, 1197, 1088 and 1010. MS (EI, m/z, %): M+ 158 (M+, 5)
125 (72), 109 (10), 97 (52), 95 (23). HRMS (ESI): 157.0470, (calcd
157.0471 [MꢀH+]).
4.5. Lipase-catalysed resolution
4.6.5. (R)-1-(4-Bromophenyl)-2-fluoroethanol (R)-1e10
The racemic 2-fluoro-1-arylethanols, rac-1a–h, (0.1 mmol), ob-
White solid (273 mg, 82%), mp 40–41 °C, ee = 98.5%.
tained by NaBH4 reduction of the
a
-fluoroacetophenones, 2a–h,
½
a 2D5
ꢂ
¼ ꢀ32:3 (c 0.90, CHCl3), Ref. ½a D25
ꢂ
¼ ꢀ25:9 (c 0.9 CHCl3).10 1
H
were dissolved in t-BuOMe (3 mL). Vinyl benzoate (74 mg,
0.5 mmol) and Novozym 435 (60 mg) were added. The reaction
mixture was agitated at 45 °C and monitored by HPLC. The enzyme
was filtered off, and the solvent was removed under reduced pres-
sure. The benzoate esters, (S)-3a–h, and alcohols, (R)-1a–h, were
separated by preparative TLC. Degree of conversions (c) was deter-
mined by 1H NMR spectroscopy, whilst enantiomeric excess of the
substrate alcohols (ees) was determined as described in Section
4.2. The ee of the benzoates (eep) was calculated by the formula
eep = (ees/c) ꢀ ees.40
NMR (CDCl3) d: 2.45 (dd, J = 1.1, 3.1, 1H), 4.38 (ddd, J = 8.2, 9.6,
48.3, 1H), 4.48 (ddd, J = 3.3, 9.6, 46.6, 1H), 4.97 (m, 1H), 7.27–
7.30 (m, 2H), 7.45–7.53 (m, 2H). 13C NMR (CDCl3) d: 72.3 (d,
J = 20.2), 86.9 (d, J = 174.7), 122.4, 128.0 (2C), 131.8 (2C) and
137.1 (d, J = 8.3). 19F NMR (CDCl3, C6F6) d: ꢀ221.9 (dt, J = 13.4,
47.4). IR (KBr, cmꢀ1): 3360, 2953, 2896, 1592, 1489, 1327, 1195,
1091 and 1008. MS (EI, m/z, %): 220/218 (M+, 6) 187 (47), 185
(52), 78 (50), 77 (100). HRMS (EI): 217.9737 (calcd 217.9743).
4.6.6. (R)-2-Fluoro-1-(4-(trifluoromethyl)phenyl) ethanol (R)-1f
Colourless oil (265 mg, 84%), ee = 93.0%, ½a D25
¼ ꢀ20:0 (c 0.70,
ꢂ
4.6. Analytical data for (R)-2-fluorophenylethanols
CHCl3). 1H NMR (CDCl3) d: 2.54 (d, J = 3.1, 1H), 4.41 (ddd J = 8.1,
9.6, 48.0, 1H), 4.54 (ddd, J = 3.3, 9.6, 46.7, 1H), 5.10 (m, 1H),
7.51–7.53 (m, 2H), 7.63–7.69 (m, 2H). 13C NMR (CDCl3) d: 72.4
(d, J = 20.5), 86.8 (d, J = 174.7), 124.0 (q, J = 272.3), 125.6 (q,
J = 3.9, 2C), 126.7 (d, J = 0.7, 2C), 130.7 (q, J = 32.5) and 142.1 (dq,
J = 1.4, 7.8). 19F NMR (CDCl3, C6F6) d: ꢀ63.2 (s, 3F), ꢀ222.4 (dt,
J = 13.8, 47.0). IR (neat, cmꢀ1): 3581, 3386, 2954, 2895, 1621,
1418, 1327, 1166, 1068 and 1016. MS (EI, m/z, %): M+ 208 (M+,
2), 189 (8), 175 (100), 145 (14), 127 (88), 95 (4). HRMS (EI):
208.0503 (calcd 208.0511).
4.6.1. (R)-2-Fluoro-1-(4-methoxyphenyl)ethanol (R)-1a
Colourless oil (224 mg, 88%), ee = 99.5%, ½a D25
¼ ꢀ38:5 (c 0.70,
ꢂ
CHCl3). 1H NMR (CDCl3) d: 2.41 (br, 1H), 3.81 (s, 3H), 4.38 (ddd,
J = 8.3, 9.5, 48.5, 1H), 4.49 (ddd, J = 3.4, 9.5, 46.8, 1H), 4.97 (ddd,
J = 3.4, 8.3, 13.2, 1H), 6.89–6.93 (m, 2 H), 7.29–7.33 (m, 2H). 13C
NMR (CDCl3) d: 55.3, 72.5 (d, J = 19.8), 87.1 (d, J = 174.5), 114.0 (2
C), 127.6 (2 C), 130.2 (d, J = 8.1) and 159.7. 19F NMR (CDCl3, C6F6)
d: ꢀ220.8 (dt, J = 13.4, 47.4). IR (neat, cmꢀ1): 3420, 2955, 2839,

E. Fuglseth et al. / Tetrahedron: Asymmetry 19 (2008) 1941–1946
1945
4.6.7. 4-((R)-2-Fluoro-1-hydroxyethyl)benzonitrile (R)-1g
White solid (183 mg, 74%), mp 59–61 °C, ee = 91.5%.
1H), 6.24 (ddd, J = 3.5, 7.1, 16.9, 1H), 7.06–7.10 (m, 2H), 7.43–
7.48 (m, 4H), 7.57–7.61 (m, 1H), 8.10–8.12 (m, 2H). 13C NMR
(CDCl3) d: 74.0 (d, J = 20.1), 84.0 (dd, J = 1.1, 179.4), 115.8 (d,
J = 21.6, 2C), 128.5 (2C), 128.8 (d, J = 8.5, 2C), 129.69, 129.81 (2C),
131.4 (dd, J = 2.8, 3.5), 133.4, 162.9 (d, J = 248.0) and 165.5. 19F
NMR (CDCl3, C6F6) d: ꢀ113.3 (m), ꢀ223.8 (dt, J = 17.2, 47.0). HRMS
(ESI): 285.0696 (calcd 285.0698 [M+Na+]).
½
a 2D5
ꢂ
¼ ꢀ27:1 (c 0.70, CHCl3). 1H NMR (CDCl3) d: 2.63 (d, J = 3.1,
1H), 4.40 (ddd, J = 8.0, 9.5, 48.0, 1H), 4.54 (ddd, J = 3.4, 9.5, 46.7,
1H), 5.07 (m, 1H), 7.46–7.56 (m, 2H), 7.65–7.71 (m, 2H). 13C
NMR (CDCl3) d: 72.2 (d, J = 20.3), 86.5 (d, J = 173.3), 112.5, 118.5,
127.0 (2C), 132.4 (2C) and 143.3 (d, J = 7.6). 19F NMR (CDCl3,
C6F6) d: ꢀ222.9 (dt, J = 13.8, 47.0). IR (KBr, cmꢀ1): 3456, 2947,
2239, 1609, 1454, 1323, 1202, 1096, and 1009. MS (EI, m/z, %):
M+ 165 (M+, 5), 132 (100), 104 (50), 102 (14), 77 (29). HRMS (EI):
165.0589 (calcd 165.0590).
4.7.5. (S)-1-(4-Bromophenyl)-2-fluoroethyl benzoate (S)-3e
White solid (12.0 mg, 38%), mp 52–53 °C, ee = 94%,
½
a 2D5
ꢂ
¼ ꢀ49:5 (c 0.90, CHCl3). CD (acetonitrile):
D
e
= ꢀ22.3
(232 nm). 1H NMR (CDCl3) d: 4.67 (ddd, J = 3.5, 10.1, 46.7, 1H),
4.73 (ddd, J = 6.8, 10.1, 47.5, 1H), 6.20 (ddd, J = 3.5, 6.8, 17.4, 1H),
7.32–7.35 (m, 2H), 7.45–7.53 (m, 4H), 7.58–7.61 (m, 1H), 8.09–
8.11 (m, 2H). 13C NMR (CDCl3) d: 74.0 (d, J = 20.1), 83.9 (d,
J = 179.8), 122.9, 128.5 (2C), 128.6 (2C), 129.6, 129.8 (2C), 132.0
(2C), 133.5, 134.6 (d, J = 6.7) and 165.5. 19F NMR (CDCl3, C6F6) d:
ꢀ224.2 (dt, J = 17.2, 47.0). HRMS (ESI): 344.9901 (calcd 344.9897
[M+Na+]).
4.6.8. (R)-2-Fluoro-1-(4-nitrophenyl)ethanol (R)-1h
White solid (223 mg, 80%), mp 97–99 °C, ee = 92.5%,
½
a 2D5
ꢂ
¼ ꢀ17:7 (c 0.70, CHCl3). 1H NMR (CDCl3) d: 2.65 (br, 1H),
4.43 (ddd J = 7.8, 9.6, 47.9, 1H), 4.57 (ddd, J = 3.4, 9.6, 46.5, 1H),
5.16 (ddd, J = 3.4, 7.8, 14.5, 1H), 7.57–7.63 (m, 2H), 8.22–8.27 (m,
2H). 13C NMR (CDCl3) d: 72.1 (d, J = 20.5), 86.5 (d, J = 175.6),
123.8 (2C), 127.2 (2C), 145.2 (d, J = 7.4) and 147.9. 19F NMR (CDCl3,
C6F6) d: ꢀ223.2 (dt, J = 14.4, 47.4). IR (KBr, cmꢀ1): 3482, 3116,
2943, 2889, 1604, 1560, 1521, 1349, 1197, 1092, and 1002. MS
(EI, m/z, %): M+ 185(M+, 4), 152 (42), 102 (19), 83 (20). HRMS
(EI): 185.0488 (calcd 185.0488).
4.7.6. (S)-2-Fluoro-1-(4-(trifluoromethyl)phenyl)ethyl benzoate
(S)-3f
Colourless oil (13.5 mg, 40%), ee = 96%, ½a D25
¼ ꢀ40:3 (c 1.00,
ꢂ
CHCl3). CD (acetonitrile):
D
e
= ꢀ6.0 (227 nm). 1H NMR (CDCl3) d:
4.7. Analytical data for the benzoates
4.72 (ddd, J = 3.8, 10.1, 46.7, 1H), 4.76 (ddd, J = 6.3, 10.1, 47.2,
1H), 6.28 (ddd, J = 3.8, 6.3, 17.9, 1H), 7.46–7.50 (m, 2H), 7.55–
7.67 (m, 5H), 8.11–8.13 (m, 2H). 13C NMR (CDCl3) d: 74.0 (d,
J = 20.1), 83.9 (d, J = 179.8), 123.9 (d, J = 272.7), 125.8 (q, J = 3.9),
127.2 (d, J = 0.7, 2C), 128.6 (2 C), 129.4, 129.9 (2C), 131.1 (q,
J = 32.5), 133.6 (2C), 139.5–139.6 (m) and 165.5. 19F NMR (CDCl3,
C6F6) d: ꢀ63.4 (s, 3F), ꢀ226.2 (dt, J = 17.2, 47.0). HRMS (ESI):
335.0662 (calcd 335.0666 [M+Na+]).
4.7.1. (S)-2-Fluoro-1-(4-methoxyphenyl)ethyl benzoate (S)-3a
Colourless oil (11.5 mg, 43%), ee = 73%, ½a D25
¼ ꢀ15:0 (c 0.60,
ꢂ
CHCl3). CD (acetonitrile):
D
e
= ꢀ5.9 (233 nm). 1H NMR (CDCl3) d:
3.80 (s, 3H), 4.65 (ddd, J = 3.5, 10.1, 46.7, 1H), 4.75 (ddd, J = 7.6,
10.1, 47.8, 1H), 6.23 (ddd, J = 3.5, 7.6, 16.2, 1H), 6.89–6.93 (m,
2H), 7.37–7.48 (m, 4H), 7.55–7.59 (m, 1H), 8.09–8.13 (m, 2H). 13C
NMR (CDCl3) d: 55.3, 74.4 (d, J = 19.9), 84.2 (d, J = 179.3), 114.2
(2C), 127.6 (d, J = 6.8), 128.3 (2C), 128.4 (2C), 129.8 (2C), 130.0,
133.2, 160.0 and 165.7. 19F NMR (CDCl3, C6F6) d: ꢀ221.6 (dt,
J = 16.1, 47.0). HRMS (ESI): 297.0895 (calcd 297.0897 [M+Na+]).
4.7.7. (S)-1-(4-Cyanophenyl)-2-fluoroethyl benzoate (S)-3g
White solid (12.0 mg, 44%), mp 70–71 °C, ee = 90%,
½
a 2D5
ꢂ
¼ ꢀ49:5 (c 0.90, CHCl3). CD (acetonitrile):
D
e
= ꢀ19.6
4.7.2. (S)-1-(4-(Benzyloxy)phenyl)-2-fluoroethyl benzoate (S)-
3b
(237 nm). 1H NMR (CDCl3) d: 4.72 (ddd, J = 3.8, 10.1, 46.7, 1H),
4.76 (ddd, J = 5.8, 10.1, 47.0, 1H), 6.25 (ddd, J = 3.8, 5.8, 18.7,
1H), 7.44–7.71 (m, 7H), 8.10–8.12 (m, 2H). 13C NMR (CDCl3) d:
73.8 (d, J = 20.1), 83.6 (d, J = 179.8), 112.8, 118.3, 127.6 (d,
J = 0.7, 2C), 128.62 (2C), 129.2, 129.9 (2C), 132.6 (2C), 133.7,
140.9 (d, J = 5.6) and 165.4. 19F NMR (CDCl3, C6F6) d: ꢀ226.0 (dt,
J = 18.4, 47.0). HRMS (ESI): 292.0744 (M+Na+), (calcd 292.0744
[M+Na+]).
White solid (13.5 mg, 39%), mp 91–92 °C, ee = 99%,
½
a 2D5
ꢂ
¼ ꢀ13:9 (c 1.00, CHCl3) CD (acetonitrile):
D
e
= ꢀ14.2
(234 nm). 1H NMR (CDCl3) d: 4.64 (ddd, J = 3.5, 10.1, 46.5, 1H),
4.74 (ddd, J = 7.6, 10.1, 48.0, 1H), 5.05 (s, 2H), 6.23 (ddd, J = 3.5,
7.6, 16.2, 1H), 6.97–6.99 (m, 2H), 7.25–7.47 (m, 9H), 7.55–7.59
(m, 1H), 8.09–8.11 (m, 2H). 13C NMR (CDCl3) d: 70.1, 74.3 (d,
J = 20.2), 84.2 (d, J = 179.3), 115.1 (2C), 127.4 (2C), 127.8 (d,
J = 6.7), 128.1, 128.3 (2C), 128.4 (2C), 128.6 (2C), 129.8 (2C),
130.0, 133.2, 136.7, 159.2 and 165.7. 19F NMR (CDCl3, C6F6) d:
ꢀ222.7 (dt, J = 16.1, 47.0). HRMS (ESI): 373.1207 (calcd 373.1210
[M+Na+]).
4.7.8. (S)-2-Fluoro-1-(4-nitrophenyl)ethyl benzoate (S)-3h
White solid (12.5 mg, 43%), mp 81–82 °C, ee = 94%,
½
a 2D5
ꢂ
¼ ꢀ33:4 (c 0.70, CHCl3). CD (acetonitrile):
D
e
= ꢀ9.0
(265 nm). 1H NMR (CDCl3) d: 4.75 (ddd, J = 4.3, 10.1, 47.0, 1H),
4.78 (ddd, J = 5.6, 10.1, 47.0, 1H), 6.30 (ddd, J = 4.3, 5.6, 19.0, 1H),
7.47–7.52 (m, 2H), 7.60–7.66 (m, 3H), 8.11–8.14 (m, 2H), 8.24–
8.28 (m, 2H). 13C NMR (CDCl3) d: 73.6 (d, J = 20.5), 83.6 (d,
J = 180.1), 124.0 (2C), 127.8 (d, J = 0.7, 2C), 128.7 (2C), 129.1,
129.9 (2C), 133.8, 142.8 (d, J = 5.3), 148.2 and 165.4. 19F NMR
(CDCl3, C6F6) d: ꢀ226.2 (dt, J = 19.5, 47.0). HRMS (ESI): 312.0642
(calcd 312.0643 [M+Na+]).
4.7.3. (S)-2-Fluoro-1-phenylethyl benzoate (S)-3c
Colourless oil (12.0 mg, 50%), ee = 88%, ½a D25
¼ ꢀ42:2 (c 0.70,
ꢂ
CHCl3). CD (acetonitrile):
D
e
= ꢀ9.0 (228 nm). 1H NMR (CDCl3) d:
4.68 (ddd, J = 3.4, 10.1, 46.7, 1H), 4.76 (ddd, J = 7.3, 10.1, 47.7,
1H), 6.28 (ddd, J = 3.4, 7.3, 16.7, 1H), 7.33–7.48 (m, 7H), 7.56–
7.60 (m, 1H), 8.11–8.13 (m, 2H). 13C NMR (CDCl3) d: 74.7 (d,
J = 19.8), 84.2 (d, J = 179.8), 126.8 (2C), 128.5 (2C), 128.8 (2C),
128.9, 129.8 (2C), 129.9, 133.3, 135.5 (d, J = 6.7) and 165.6. 19F
NMR (CDCl3, C6F6) d: ꢀ223.0 (dt, J = 16.1, 47.0). HRMS (ESI):
267.0791 (calcd 267.0792 [M+Na+]).
Acknowledgements
Norwegian University of Science and Technology is acknowl-
edged for a PhD grant. We thank Julie Jackson for MS support,
Novozymes for gift of Novozym 435, and Borregaard for donation
4.7.4. (S)-2-Fluoro-1-(4-fluorophenyl)ethyl benzoate (S)-3d
Colourless oil (9.0 mg, 37%), ee = 79%, ½a D25
¼ ꢀ23:3 (c 0.60,
ꢂ
CHCl3). CD (acetonitrile):
D
e
= ꢀ7.1 (228 nm). 1H NMR (CDCl3) d:
of (R)-a,a-diphenyl-2-pyrrolidinemethanol.
4.67 (ddd, J = 3.5, 10.1, 46.7, 1H), 4.74 (ddd, J = 7.1, 10.1, 47.5,

1946
E. Fuglseth et al. / Tetrahedron: Asymmetry 19 (2008) 1941–1946
23. Gilmore, N. J.; Jones, S. Tetrahedron: Asymmetry 2003, 14, 2115–2118.
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