Study for the determination of the absolute configuration of fluoromethylated secondary alcohols by the modified Mosher method

Article abstract of DOI:10.1016/S0022-1139(97)00026-2

Application of the modified Mosher method using high-field FT ¹H NMR to the 2-methoxy-2-phenyl-2-trifluoromethyl acetic acid (MTPA) derivatives of fluorinated secondary alcohols indicates that this method may be generally used to determine the absolute configurations of these materials.

Full text of DOI:10.1016/S0022-1139(97)00026-2

Journal of Fluorine Chemistry 84 (1997) 19–23
Study for the determination of the absolute configuration of
fluoromethylated secondary alcohols by the modified Mosher method
U
Ling Xiao a, Takashi Yamazaki a, Tomoya Kitazume a, , Tetsuo Yonezawa b,
Yoshitake Sakamoto b, Kouji Nogawa b
a Department of Bioengineering, Tokyo Institute of Technology, Nagatsuta, Midori-ku Yokohama 226, Japan
b Department of Research and Development, Morita Chemical Industries Co. Ltd., Higasi-mikuni, Yadogawa-ku, Osaka 532, Japan
Received 6 September 1996; accepted 15 February 1997
Abstract
Application of the modified Mosher method using high-field FT 1H NMR to the 2-methoxy-2-phenyl-2-trifluoromethyl aceticacid(MTPA)
derivatives of fluorinated secondary alcohols indicates that this method may be generally used to determine the absolute configurations of
these materials. q 1997 Elsevier Science S.A.
Keywords: Fluorinated secondary alcohols; Absolute configuration
1. Introduction
appear upfield relative to those of the (S)-MTPA ester
(MTPA is the 2-methoxy-2-phenyl-2-trifluoromethyl acetyl
unit). When DdsdSydR, protons on the right side of the
MTPA plane (Fig. 1) must have positive values (Dd)0)
and protons on the left side of the plane must have negative
values (Dd-0). This is illustrated in Fig. 2 [4].
In the references by Kakisawa and coworkers [4], when
the following conditions (1–4) are all satisfied, the model
shown in Fig. 1 will indicate the correct absolute configura-
tion of the compound. The conditions can be extended as
follows. (1) Assign as many proton signals as possible with
One objective of research in fluorine chemistry, required
to support applications in fluorine analogs of bioactive [1]
and/or functionalized materials [2], is the development of
methodology suitable for determination of the absolute con-
figuration. There are a few physical methods, e.g. the exciton
chirality method [3] and X-ray crystallography, however
they have some limitations. Recently, in hydrocarbon chem-
istry, Kakisawa and coworkers have reported that a modifi-
cation of Mosher’s method is useful to elucidate the absolute
configuration of secondary alcohols [4].
Accordingly, we have devoted our attention to application
of the modified Mosher methodtofluorinatedsecondaryalco-
hols possessing a monofluoro-, difluoro- and/or trifluoro-
methyl group to determine the absolute configuration.
2. Results and discussion
Fig. 1. MTPA plane of an MTPA ester. HA,B,C and HX,Y,Z are on the left and
right sides of the plane respectively.
Recently, Kakisawa and coworkers [4] have revealed that
the high-field FT NMR application of Mosher’s method is
very convenient to elucidate the absolute configuration of
chiral secondary alcohols using high-field 1H NMR spectros-
copy. Owing to the diamagnetic effect of the benzene ring,
the HA,B,C NMR signals of the (R)-MTPA ester should
Fig. 2. Model used to determine the absolute configurations of secondary
alcohols.
U Corresponding author.
0022-1139/97/$17.00 q 1997 Elsevier Science S.A. All rights reserved
PII S0022-1139(97)00026-2

20
L. Xiao et al. / Journal of Fluorine Chemistry 84 (1997) 19–23
respect to each of the (R)- and (S)-MTPA esters. (2) Obtain
Dd values for the protons. (3) Put the protons with positive
Dd on the right side and those with negative Dd on the left
side of the model shown in Fig. 1. (4) Construct a molecular
model of the compound in question and confirm that all the
assigned protons with positive and negative Dd values are
actually found on the right and left sides of the MTPA plane
respectively. This methodology is widely accepted to apply
to elucidation of the absolute stereochemistries of various
types of materials [5].
For the purpose of confirming whether the chemical shift
behaviors of the protons of fluoromethylated materials actu-
ally accord with Kakisawa’s rule (new Mosher method),
fluoromethylated 2-alkanols (4–21), the absolute configu-
rations of which are known, were examined. At first, we
prepared various kinds of fluorinated 2-alkanols using the
following procedures: (1) (q)-1,1,1-trifluoro-2-alkanols
(compounds 4–11) were prepared by asymmetric hydrolysis
[6,7]; (2) other types of optically active 1,1,1-trifluoroal-
kanol derivatives (compounds 12–17) were prepared by
reported synthetic procedures [6,8,9]; (3) 1-fluoro- and 1,1-
difluoro-2-alkanols (compounds 18–21) were also prepared
by known synthetic procedures [10].
Scheme 1. (a) DHP, CH2Cl2; (b) LiAH4, Et2O; (c) TsCl, pyridine; (d) n-
PrMgBr, Et2O; (e) n-BuMgBr, Et2O; (f) n-C5H11MgBr, Et2O; (g) (n-
C6H13)2CuLi, Et2O.
(y)-trifluoropropene oxide (3) which were confirmed by
X-ray analysis [6–8,10–14]. We established the absolute
configurations of optically active compounds 8,9,10 by syn-
thesis from (R)-2 as shown in Scheme 1. Further, the abso-
lute configurations of trifluorinated alkanols (4,5,6,7), and
monofluoro- and difluoromethylated alkanols (18–21) are
known [6,10].
(R)- and (S)-MTPA derivatives of fluorinated 2-alkanols
were prepared by treatment of the corresponding optically
active 2-alkanols with (R)- and (S)-2-methoxy-2-phenyl-2-
trifluoromethyl acetic acid in the presence of N,N9-dicycloh-
exyl-carbodiimide (DCC) and 4-(dimethylamino)pyridine
(DMAP) in dichloromethane (CH2Cl2). The Dd values
(dSydR) obtained for these complexes are summarized in
Figs. 3–5.
It is evident from the figures that protons with Dd)0 are
located on the right side of the MTPA plane, while those
oriented on the left side of MTPA plane have Dd-0. Also,
Dd values are almost proportional to the distance between
the protons and the MTPA moiety. In Fig. 1, DdsdSydR
obtained from (R)- and (S)-MTPA derivatives of (q)-
trifluorinated 2-alkanols is Dd)0. These results suggest that
the absolute configuration of all (q)-trifluorinated 2-alkan-
The absolute stereochemistries of the prepared trifluorome-
thylated alkanols 4–17, except compounds8,9,10, arealready
determined from those of the synthetic intermediates (R)-
(q)-ethyl 4,4,4-trifluoro-3-hydroxybutanoate (1) and S-
Fig. 3. Dd (dSydR) values obtained for the MTPA esters of (R)-(q)-trifluoromethylated 2-alkanols. Dd values are expressed in hertz (500 MHz).

L. Xiao et al. / Journal of Fluorine Chemistry 84 (1997) 19–23
21
13C NMR spectra were recorded in ppm (d) downfield from
the following internal standards (Me4Si, d 0.00, or CHCl3, d
7.24). The 19F (470 MHz) NMR spectra were recorded in
ppm downfield from external trifluoroacetic acid in CDCl3
using a VXR 500 instrument. Yields quoted are those of the
products actually isolated.
3.2. Typical procedure for chloroacetate
3.2.1. 1,1,1-trifluoro-2-butyl chloroacetate [7]
(a) Preparation of 1,1,1-trifluoro-2-butanol. To a mixture
solution of ethyl trifluoroacetate (460 g, 3.24 mol) and die-
thyl ether (1.5 l), the Grignard reagent derived from mag-
nesium (87.5 g, 3.6 mol), ethyl bromide (400 g, 3.6 mol) in
diethyl ether (1 l) was added slowly (more than 4 h) with
cooling with ice-water under a nitrogen atmosphere. The
whole mixture was stirred at room temperature for 30 min,
and then the mixture was poured into a mixture of 12 N HCl
(500 ml) and ice (700 g). Oily materials were extractedwith
diethyl ether. The extract waswashedwithsaturatedNaHCO3
solution, and brine. On removal of the solvent, the crude of
1,1,1-trifluoro-2-butanone was obtained. Into a mixture solu-
tion of the above crude of 1,1,1-trifluoro-2-butanone, diethyl
ether (3 l) and water (100 ml), a mixture solution of NaBH4
(30.7 g, 0.81 mol) and water (150 ml) was added slowly
(more than 3 h) below 20 8C, and the whole was stirred
overnight at room temperature. Oily materials were extracted
with diethyl ether. On removal ofthe solvent, distillationgave
1,1,1-trifluoro-2-butanol in 59% yield, bp 84 8C.
Fig. 4. Dd (dSydR) values obtained for the MTPA esters of trifluorome-
thylated alkanols. Dd values are expressed in hertz (500 MHz). (R)-(q)-
12 [9], (R)-(q)-13 [8], (R)-(q)-14 [6], (S)-(y)-15 [9], (S)-(y)-
16 [12], (S)-(y)-17 [6].
Fig. 5. Dd (dSydR) values obtained for the MTPA esters of (S)-(y)-
monofluoromethylated 2-alkanols and (R)-(q)-difluoromethylated 2-
alkanol. Dd values are expressed in hertz (500 MHz). (R)-(q)-18 [10],
(R)-(q)-19 [10], (R)-(q)-20 [10], (S)-(y)-21 [10].
(b) Preparation of 1,1,1-trifluoro-2-butyl chloroacetate.
To a mixture of 1,1,1-trifluoro-2-butanol (263.6 g, 1.9 mol)
and chloroacetyl chloride (282 g, 2.5 mol) in CH2Cl2 (1.8
l), pyridine (237 g, 3 mol) was added for 1.5 h at 5–10 8C.
After finishing the reaction by checking with gas chromatog-
raphy, the mixture was poured into a mixture of 12 N HCl
(400 ml) and ice (500 g). Oily materials were separated,
and then were washed with saturated NaHCO3 solution, and
brine. On removal of the solvent, distillation gave 1,1,1-
trifluoro-2-butyl chloroacetate in 93% yield (370 g, 66 8C/
32 mm Hg).
Other chloroacetates [7], such as 1,1,1-trifluoro-2-pentyl
chloroacetate, 1,1,1-trifluoro-2-hexyl chloroacetate, 1,1,1-
trifluoro-2-heptyl chloroacetate and 1,1,1-trifluoro-2-nonyl
chloroacetate, were also obtained in the sameprocedureusing
pentyl-, hexyl-, heptyl- or nonyl-magnesium bromide.
ols shown in Fig. 3 is the R-configuration from the model
indicated in Fig. 2. Furthermore, Dd values obtained for the
(q)- or(-)-trifluorinated2-alkanols(12–17)containingthe
functionalized group (carbon–carbondoublebond, cyclopro-
pyl or carbonyl group) shown in Fig. 4, are in good agree-
ment with the validity of the present methodology. For
1,1,1-trifluorinated 2-alkanols, as for non-fluorinatedsecond-
ary alcohols.
In the next step, we examined the validity of this rule for
other types of fluoromethylated compounds, (R)-(q)-1,1-
difluoro-2-octanol (18), (R)-(q)-1,1-difluoro-2-decanol
(19), (R)-(q)-1,1-difluoro-4-phenyl-2-butanol (20) and
(S)-(y)-1-fluoro-2-decanol (21), the absolute configura-
tions of which are known. Based on the comparison with
Fig. 2 and Dd values in Fig. 5, the absolute configuration of
samples with Dd)0 is the R-enantiomer.
In conclusion, the new methodology is also valid for deter-
mination of the absolute configuration of fluoromethylated
alkanols.
3.2.2. Typical procedure of asymmetric hydrolysis
A mixture of 1,1,1-trifluoro-2-octylchloroacetate (50 g),
lipase MY (0.02 g, Candida rugosa, Meito Sangyo Co. Ltd.)
in buffer solution (made from 0.5 M KH2PO4 (250 ml) and
0.5 M NaOH (145 ml)) was stirred for 6 h at 38 8C. After
quenching with 1 N HCl, organic materials were extracted
with methylene chloride (500 ml), and then the extract was
dried over MgSO4. Removal of the solvent and distillation
gave (R)-(q)-1,1,1-trifluoro-2-octanol 9 (13.1 g, bp 55–56
8C/20 mm Hg, )98% ee) [6,7].
3. Experimental details
3.1. General
All commercially available reagents were used without
1
further purification. Chemical shifts of H (500 MHz) and

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L. Xiao et al. / Journal of Fluorine Chemistry 84 (1997) 19–23
3.2.3. 1,1,1-Trifluoro-2-nonyn-4-ol [9]
column chromatography, (S)-1,1,1-trifluoro-(E)-2-nonen-
To a solution of lithium diisopropylamine (44 mmol) in
THF (40 ml) was added dropwise a precooled (y78 8C)
solution of 2-bromo-3,3,3-trifluoropropene (3.5 g, 20 mmol)
in THF (20 ml) at y78 8C. After stirring for 5 min, n-
C5H11CHO (2.5 ml, 24 mmol) was added to this solution
and the whole was stirred for 30 min. The reaction mixture
was quenched with 1 N HCl aq (100 ml) and extracted with
AcOEt three times. The organic layer was dried over MgSO4
and concentrated. The residue was chromatographedonsilica
gel to afford 3.96 g (19.8 mmol) of 1,1,1-trifluoro-2-nonyn-
4-ol in 93% yield, bp 100 8C/2 mm Hg. 1H NMR (CDCl3):
d 0.8–1.0 (3 H, m), 1.2–2.0 (8 H, m), 2.6–3.0 (1 H, br),
4.454 (1 H, tq, Js6.69, 2.98 Hz). 13C NMR (CDCl3): d
13.838, 22.411, 24.467, 31.202, 36.576 (q, Js1.22 Hz),
61.77 (q, Js1.48 Hz), 71.957 (q, Js52.88 Hz), 87.947 (q,
Js6.30 Hz), 114.041 (q, Js257.15 Hz). 19F NMR
(CDCl3): d 28.4 (s) from ext. CF3CO2H. lR (neat) 3325
4-ol was obtained in 79% yield.
3.2.6. Preparation of compounds 8–10
(R)-(q)-1,1,1-Trifluoro-2-heptanol (8). Into a solution
of n-propyl magnesium bromide (1.5 mmol) in freshly dried
diethyl ether (5 ml), was added R-tosylate 2 (1 mmol) [6]
in diethyl ether (5 ml) slowly at y70 8C. After 1.5 h of
stirring at that temperature, the mixture was warmed to room
temperature, and the whole was stirred overnight at that tem-
perature. The mixture was poured into water, and then the
ethereal layer was separated. (R)-(q)-1,1,1-Trifluoro-2-
heptanol 8 was purified by column chromatography on silica
gel.
(R)-(q)-1,1,1-Trifluoro-2-octanol (9). In the above
reaction, n-butyl magnesium bromide was used, and then
worked up similarly. (R)-(q)-1,1,1-Trifluoro-2-octanol 9
was purified by column chromatography on silica gel.
(R)-(q)-1,1,1-Trifluoro-2-nonanol (10). In the above
reaction, n-pentyl magnesium bromide was used, and then
worked up similarly. (R)-(q)-1,1,1-Trifluoro-2-nonanol10
was purified by column chromatography on silica gel.
cmy1
.
3.2.4. (R)-1,1,1-Trifluoro-2-nonyn-4-ol [9]
To a 0.17 M solution of a racemic 1,1,1-trifluoro-2-nonyn-
4-ol (4.03 mmol) in n-hexane (24 ml) were added vinyl
acetate (8.10 ml, 97.4 mmol) and lipase PL (0.548 g, 49320
U; Alcaligenes sp. Meito Sangyo Co., Ltd., Japan), and the
whole was stirred at 30 8C for 24 h. After removal of the
residue by filtration and concentration of this solution, sepa-
ration by silica gel column chromatography afforded an opti-
cally active (S)-1,1,1-trifluoro-2-nonyn-4-ol (yield 45%)
and (R)-1,1,1-trifluoro-4-acetoxy-2-nonyn. (R)-1,1,1-tri-
fluoro-2-nonyn-4-ol ()80% ee) was obtained by thehydrol-
ysis of (R)-1,1,1-trifluoro-4-acetoxy-2-nonyn in the aq.
NaOH (5%)–acetone system. (S)-1,1,1-trifluoro-2-nonyn-
References
[1]
R. Filler, Y. Kobayashi, Biomedicinal Aspects of Fluorine Chemistry,
Kodansha and Elsevier Biomedical, Amsterdam, 1983. C. Walsh,
Tetrahedron, 38 (1982) 871. J.T. Welch, S. Eswarakrishman, Fluorine
in Bioorganic Chemistry, Wiley, New York, 1990. J.T. Welch,
Tetrahedron, 43 (1987) 3123.
[2]
Y. Suzuki, O. Nonaka, Y. Koide, N. Okabe, T. Hagiwara, I. Kawamura,
N. Yamamoto, Y. Yamada, T. Kitazume, Ferroelectrics, 147 (1993)
109. K. Itoh, M. Takeda, M. Namekawa, S. Nayuri, Y. Murayama, T.
Yamazaki, T. Kitazume, Ferroelectrics, 148 (1993) 85. M. Koden, T.
Kaneko, K. Tamai, H. Takeda, S. Miyoshi, T. Wada, M. Takeda, K.
Itoh, T. Yamazaki, T. Kitazume, Jpn. J. Appl. Phys., 33 (1994) 1096.
K. Itoh, M. Takeda, M. Namekawa, S. Nayuri, Y. Murayama, T.
Yamazaki, T. Kitazume, Chem Lett., (1994) 839. K. Itoh, M. Takeda,
M. Namekawa, S. Nayuki, Y. Murayama, T. Yamazaki, T. Kitazume,
Chem. Lett., (1995) 641.
1
4-ol: [a]1D4 y4.1 (c 0.8, CHCl3) ()99% ee). H NMR
(CDCl3): d 0.8–1.0 (3 H, m), 1.2–2.0 (8 H, m), 2.6–3.0 (1
H, br), 4.454 (1 H, tq, Js6.69, 2.98 Hz). 13C NMR
(CDCl3): d 13.838, 22.411, 24.467, 31.202, 36.576 (q,
Js1.22 Hz), 61.77 (q, Js1.48 Hz), 71.957 (q, Js52.88
Hz), 87.947 (q, Js6.30 Hz), 114.041 (q, Js257.15 Hz).
19F NMR (CDCl3): d 28.4 (s) from ext. CF3CO2H. IR(neat)
.
3325 cmy1 (R)-1,1,1-trifluoro-4-acetoxy-2-nonyn. 1H
[3]
[4]
N. Harada, K. Nakanishi, Circular Dichroic Spectroscopy—Exciton
Coupling In Organic Stereochemistry, University Science Books, Mill
Valley, CA, 1983.
I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem. Soc.,
113 (1991) 4092. T. Kusumi, T. Hamada, M.O. Ishitsuka, I. Ohtani,
H. Kakisawa, J. Org. Chem., 57 (1992) 1033. T. Kusumi, T. Hamada,
M. Hara, M.O. Ishitsuka, H. Ginda, H. Kakisawa, Tetrahedron Lett.,
33 (1992) 2019. T. Kusumi, T. Fukushima, I. Ohtani, H. Kakisawa,
Tetrahedron Lett., 32 (1991) 2939.
NMR (CDCl3): d 0.90 (3 H, t, Js6.84 Hz) 1.30–1.50 (6
H, m) 1.70–1.90 (2 H, m) 2.11 (3 H, s) 5.86 (1 H, tq,
Js2.93, 5.86 Hz). 13C NMR (CDCl3): d 13.80, 20.61,
22.32, 24.34, 31.05, 33.62, 62.48, 72.09 (q, Js53.0 Hz),
84.66 (q, Js6.4 Hz), 113.83 (q, Js258 Hz), 169.53. 19F
NMR (CDCl3): d 11.14 (d, Js3.05 Hz) from ext. C6F6. IR
(neat) 1753 cmy1. [a]D15 q50.8 (c 0.7, CHCl3) (81% ee).
[5]
M. Kobayashi, K. Kawazoe, I. Kitagawa, Tetrahedron Lett., 30(1989)
4149. I. Kitagawa, M. Kobayashi, T. Katori, M. Yamashita, J. Tanaka,
M. Doi, T. Ishida, J. Am. Chem. Soc., 112 (1990) 3710.
J.-T. Lin, T. Yamazaki, T. Kitazume, J. Org. Chem., 52 (1987) 3211.
T. Yonezawa, Y. Sakamoto, K. Nogawa, T. Yamazaki, T. Kitazume,
Chem. Lett., (1996) 855.
3.2.5. (S)-1,1,1-Trifluoro-(E)-2-nonen-4-ol [9]
To a stirring solution of Red-Al (2.5 mmol) in toluene (3
ml) at y78 8C was added (S)-1,1,1-trifluoro-2-nonyn-4-ol
(2.1 mmol). After 3 h of stirring at that temperature, the
reaction was quenched with 1 N HCl (10 ml) and the usual
work-up gave the crude olefin. After purification by silica gel
[6]
[7]
[8]
T. Kitazume, M. Takeda, J.-T. Lin, T. Yamazaki, J. Fluorine Chem.,
43 (1989) 177.

L. Xiao et al. / Journal of Fluorine Chemistry 84 (1997) 19–23
23
[9] T. Konno, T. Kitazume, J. Org. Chem., 62 (1997) 137.
[10] T. Kitazume, M. Asai, T. Tsukamoto, T. Yamazaki, J. Fluorine Chem.,
56 (1992) 271.
[11] T. Kitazume, J.-T. Lin, J. Fluorine Chem., 34(1987)461. T. Kitazume,
M. Asai, J.-T. Lin, T. Yamazaki, J. Fluorine Chem., 35 (1987) 477.
T. Yamazaki, M. Asai, T. Ohnogi, J.-T. Lin, T. Kitazume, J. Fluorine
Chem., 35 (1987) 537.
[12] T. Yamazaki, J.-T. Lin, M. Takeda, T. Kitazume, Tetrahedron
Asymmetry, 1 (1990) 351.
[13] D. Seebach, P. Renaud, W.B. Schweizer, M.F. Zuger, M.J. Brienne,
Helv. Chim. Acta, 67 (1984) 1843.
[14] K. Furuhashi, M. Shintani, M. Takagi, Appl. Microbiol. Biotechnol.,
23 (1986) 218. O. Takahashi, K. Furuhashi, M. Fukumasa, T. Hirai,
Tetrahedron Lett., 31 (1990) 7031.