An efficient method for the preparation of Chiral Mosher's acid analogues

Article abstract of DOI:10.1246/cl.2006.304

A diastereoselective trifluoromethylation of chiral α-keto esters derived from isosorbide with TMSCF₃ in the presence of a Lewis-base catalyst gave the corresponding trifluoromethylated α-hydroxy esters in good yields with moderate to high dias

Full text of DOI:10.1246/cl.2006.304

304
Chemistry Letters Vol.35, No.3 (2006)
An Efficient Method for the Preparation of Chiral Mosher’s Acid Analogues
Yoshikazu Kawano, Nobuya Kaneko, and Teruaki MukaiyamaÃ
Center for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received December 14, 2005; CL-051532; E-mail: mukaiyam@abeam.ocn.ne.jp)
A diastereoselective trifluoromethylation of chiral ꢀ-keto
Table 1. Trifluoromethylation of chiral ꢀ-keto esters
esters derived from isosorbide with TMSCF3 in the presence
of a Lewis-base catalyst gave the corresponding trifluoromethyl-
ated ꢀ-hydroxy esters in good yields with moderate to high dia-
stereomeric excesses.
O
F3C OSiMe3
R*
Cat. (5 mol%)
R*
Me3SiCF3
+
Ph
1a–1c
Ph
DMF, Temp, 30 min
(1.2 equiv.)
O
O
2a–2c
Temp/°C Yielda/% (S:R)b
Entry
R*
Cat.
O
Recently, organofluorine compounds have focused increas-
ed attention in the field of pharmaceutical and agricultural chem-
icals because of their unique physical and biological properties.1
Out of many, a trifluoromethyl group of organofluorine com-
pounds is one of the most important fluorine-containing func-
tional groups that has the electronegativity similar to that of oxy-
gen and also has a large hydrophobic nature. Mosher’s acid
(MTPA), for example, is a valuable reagent for determining
enantiomeric excesses of alcohols or amines and examples for
its preparation have therefore been reported ever since.2 Howev-
er, this convenient reagent is not fully used because the signals of
certain diastereotopic groups from the MTPA overlap with an-
other one. Then, some MTPA analogues that might solve this
problem were developed, but yet there were only a few chiral
ones.3,4 Therefore, it remains to be an important topic to find
more efficient and convenient procedure for the preparation of
chiral MTPA analogues (Scheme 1).
H
1
2
82
77
56:44
55:45
AcOLi
0–rt
0
O
5
2
3
1
1a
4
O
AcONBu4
H
OBn
O
O
H
H
88
75
79:21
79:21
3
4
AcOLi
0–rt
0
O
1b
1c
AcONBu4
OBn
O
O
5
6
7
AcOLi
AcONBu4
CsF
0–rt
0
84
81
84
83:17
83:17
49:51c
H
O
H
OBn
0
aYield was determined by 19F NMR analysis (270 MHz) using
PhOCF3 as an internal standard. bRatio was determined by 19F NMR
c
analysis. DME was used as a solvent.
of Lewis bases in DMF (Table 1). The reaction of 1a was carried
out in the presence of 5 mol % of lithium acetate at 0 ꢀC to room
temperature in DMF and the corresponding product was ob-
tained in moderate yield with low diastereoselectivity (Entry
1). The effect of counter cations of the acetate was also examined
so as to improve the diastereoselectivity of this reaction. Howev-
er, there was no improvement observed (Entry 2). On the other
hand, the desired products were obtained in good yields with
moderate diastereoselectivities when chiral ꢀ-keto esters 1b or
1c derived from 2-endo-hydroxy carbohydrate were used as sub-
strates (Entries 3 and 5). It was found that the substituents at C-2
position of carbohydrate played an important role in controlling
the stereoselectivity in this reaction. Interestingly, it showed
no selectivity when it was carried out in the presence of cesium
fluoride as a Lewis base in DME (Entry 7).
Next, the reaction was tried by using a phenoxide anion
instead of an acetate one because Lewis-base catalyst could
activate TMSCF3 at low temperatures (Table 2). Consequently,
the corresponding trifluoromethylated adducts were obtained in
high yields with good diastereoselectivities when the reactions
were carried out at À45 ꢀC, and the diastereoselectivity increas-
ed at the lower temperature (Entry 3). The yields depended on
the nature of a counter cation and the lithium was found most
effective (Entries 3–5).
O
R
OMe
OH
R
OH
O
OR*
OR*
F3C
R
F3C
O
O
MTPA
Scheme 1. Preparation of chiral MTPA derivatives.
In our previous communication, a catalytic trifluoromethyl-
ation of various carbonyl compounds or imines with TMSCF3 in
the presence of lithium acetate was reported.5 This nucleophilic
addition of a trifluoromethyl group to ꢀ-keto ester is one of the
most facile and straightforward methods for the preparation of
Mosher’s acid analogues. In order to demonstrate the usefulness
of this Lewis base-catalyzed reaction, the application of tri-
fluoromethylation to the synthesis of chiral trifluoromethylated
ꢀ-hydroxy acid, the immediate precursor of Mosher’s acid,
was then planned. In this communication, we would like to de-
scribe an efficient method for the preparation of MTPA deriva-
tives by trifluoromethylation of chiral esters that are easily pre-
pared from a commercially available chiral alcohol by using a
Lewis-base catalyst.
The starting chiral ꢀ-keto esters 1a–1c were prepared from
carbohydrate derivatives such as isomannide and isosorbide
which were commercially available and could be used in large
quantities at low cost.6–8
In the first place, trifluoromethylations of ꢀ-keto esters 1a–
1c with TMSCF3 were tried in the presence of a catalytic amount
In order to monitor the influence of protecting groups of al-
cohols on the stereoselectivity, the reaction of chiral ꢀ-keto es-
ters with various protecting groups were examined. The diaster-
eoselectivities were not improved when several benzyl groups or
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.3 (2006)
305
Table 2. Trifluoromethylation of chiral ꢀ-keto esters derived
from isosorbide
O
Me3SiCF3 (1.4 equiv.)
Cat. (10 mol%)
H
O
OSiMe
O
3 H
F3C
Ph
O
O
Ph
OBn
OH
OBn
Me3SiCF3
O
DMF,–45 °C, 30 min
O
H
H
O
O
(1.4 equiv.)
Cat. (10 mol%)
O
OSiMe
O
F3C
Ph
O
3 H
H
O
1c
2c : 82% yield (90 : 10 d.r.)
Two diastereomers were
separated by preparative TLC
O
Ph
OR
OR
DMF, Temp
3 h
O
O
H
H
O
O
H
O
F3C
Ph
2M LiOH
THF, rt
OH
HO
Cat. Temp/ꢀC Yielda/% (S:R)b
+
Entry
R
OBn
O
H
O
1
2
3
4
5
6
7
8
9
PhCH2
PhOLi
PhOLi
PhOLi
PhONa
PhOK
PhOLi
0
À20
À45
À45
À45
À45
À45
À45
À45
72
83
82
77
65
81
82
80
85
82:18
85:15
90:10
90:10
90:10
90:10
90:10
88:12
89:11
5 : 98% yield
6 : 96% recoverd
23 = − 29.8 (c 1.10, MeOH)
[
α
]
]
D
Lit.2c
[α
D = +29.8 (c 0.81, MeOH) : R-isomer
Scheme 2. Determination of absolute configuration.
4-ClPhCH2
ters were obtained in high yields with good diastereoselectivi-
ties. Further investigation on this reaction is now in progress.
1-Naphthylmethyl PhOLi
PhOLi
PhOLi
t-Bu
Me
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
aYield was determined by 19F NMR analysis (270 MHz) using
PhOCF3 as an internal standard. bRatio was determined by
19F NMR analysis.
References and Notes
1
Table 3. Synthesis of Mosher’s acid analogues
For a review on trifluoromethylation, see: a) R. P. Singh,
J. M. Shreeve, Tetrahedron 2000, 56, 7613. b) G. K. S.
Prakash, M. Mandal, J. Fluorine Chem. 2001, 112, 123.
c) J.-A. Ma, D. Cahard, Chem. Rev. 2004, 104, 6119.
a) J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969,
34, 2543. b) W. E. Hull, K. Seeholzer, M. Baumeister, I. Ugi,
Tetrahedron 1986, 42, 547. c) Y. L. Bennani, K. P. M.
Vanhessche, K. B. Sharpless, Tetrahedron: Asymmetry
1994, 5, 1473. d) C. Pareja, E. Martin-Zamora, R. Fernandez,
J. M. Lassaletta, J. Org. Chem. 1999, 64, 8846.
Me3SiCF3
(1.4 equiv.)
O
F3C OSiMe3H
O
H
O
PhOLi (10 mol%)
O
O
Ar
Ar
OBn
OBn
2
DMF,–45 °C
Time
O
O
H
H
O
O
4a–4c
3a–3c
Entry
Ar
Time/h
Yielda/%
(S:R)b
1
2
3
4-MeOPh
4-ClPh
2-Naphthyl
3a
3b
3c
5
3
3
81
80
73
92:8
88:12
89:11
3
a) G. Blay, I. Fernandez, A. Marco-Aleixandre, B. Monje,
J. R. Pedro, R. Ruiz, Tetrahedron 2002, 58, 8565. b)
aYield was determined by 19F NMR analysis (270 MHz) using
PhOCF3 as an internal standard. bRatio was determined by
19F NMR analysis.
G. K. S. Prakash, P. Y. B. Torok, G. A. Olah, Synlett
2003, 527.
¨ ¨
4
5
a) W. Zhuang, N. Gathergood, R. G. Hazell, K. A. Jorgensen,
J. Org. Chem. 2001, 66, 1009.
a) T. Mukaiyama, Y. Kawano, H. Fujisawa, Chem. Lett.
2005, 34, 88. b) Y. Kawano, H. Fujisawa, T. Mukaiyama,
Chem. Lett. 2005, 34, 422. c) Y. Kawano, T. Mukaiyama,
Chem. Lett. 2005, 34, 894.
Isosorbide and isomannide are easily obtained by dehydra-
tion of sorbitol and mannitol, respectively. a) L. F. Wiggins,
R. Montgomery, J. Chem. Soc. 1945, 4. b) R. Montgomery,
L. F. Wiggins, J. Chem. Soc. 1946, 390.
For the reactions using isosorbide or isomannide, see: a) O.
Sageot, D. Monteux, Y. Langlois, C. Riche, A. Chiaroni,
Tetrahedron Lett. 1996, 37, 7019. b) A. Loupy, D. Monteux,
Tetrahedron Lett. 1996, 37, 7023. c) A. Loupy, D. A.
Monteux, Tetrahedron 2002, 58, 1541. d) M.-H. Xu, W.
Wang, L.-J. Xia, G.-Q. Lin, J. Org. Chem. 2001, 66, 3953.
e) L.-L. Huang, M.-H. Xu, G.-Q. Lin, J. Org. Chem. 2005,
70, 529.
alkyl groups such as t-butyl or methyl ones were used as
hydroxy-protecting groups (Entries 6–9). It was also found that
the stereoselectivity of this reaction was not influenced by the
nature of the protecting groups.
Next, the reaction of various chiral ꢀ-keto esters with
TMSCF3 was tried by using a catalytic amount of PhOLi in
DMF (Table 3). Chiral ꢀ-keto esters having electron-donating
or -withdrawing groups on their benzene rings reacted smoothly
to afford the trifluoromethylated adducts in high yields with
good diastereosectivities (Entries 1–3). These trifluoromethylat-
ed adducts were easily purified by column chromatography and
optically pure major diastereomers were isolated. The absolute
configuration of newly formed chiral center was assigned to be
the S configuration, which was determined by the optical rotation
of the corresponding ꢀ-hydroxy acid 5 after the complete
hydrolysis of the ꢀ-hydroxy-ꢀ-trifluoromethylated ester 2c
(Scheme 2).9 The chiral auxiliary, the monobenzylated isosor-
bide 6, was recovered in quantitative yield.
6
7
8
9
For the preparation of isosorbide or isomannide derivatives,
see: D. Abenhaim, A. Loupy, L. Munnier, R. Tamion, F.
Marsais, G. Queguiner, Carbohydr. Res. 1994, 261, 255.
The configurations of 4a–4c were assigned by comparing
19F NMR chemical shifts of 2c with that of 4a–4c.
It is noted that the chiral ꢀ-keto esters, prepared by introduc-
ing chiral auxiliary derived from isosorbide to benzoylformic
acids, were successfully applied to the asymmetric reaction
and enantiomerically pure ꢀ-hydroxy-ꢀ-trifluoromethylated es-
Published on the web (Advance View) February 11, 2006; DOI 10.1246/cl.2006.304