New approach to a novel axially chiral ligand showing spontaneous enrichment of axial chirality.

Article abstract of DOI:10.1248/cpb.51.265

We have synthesized novel axially chiral ligand with two chiral centers, (R)-(R)(2)- and (S)-(S)(2)-2,2'-bis(2,2,2-trifluoro-1-hydroxyethyl)biphenyl (1), which showed a high asymmetric induction when used as ligand. Here, another new approach to 1 by kine

Full text of DOI:10.1248/cpb.51.265

March 2003
Chem. Pharm. Bull. 51(3) 265—267 (2003)
265
New Approach to a Novel Axially Chiral Ligand Showing Spontaneous
Enrichment of Axial Chirality
Tomokuni HASEGAWA, Masaaki OMOTE, Kazuyuki SATO, Akira ANDO, and Itsumaro KUMADAKI*
Faculty of Pharmaceutical Sciences; 45–1 Nagaotoge-cho, Hirakata 573–0101, Japan.
Received October 10, 2002; accepted December 17, 2002
We have synthesized novel axially chiral ligand with two chiral centers, (R)-(R) - and (S)-(S) -2,2؅-bis(2,2,2-
2
2
trifluoro-1-hydroxyethyl)biphenyl (1), which showed a high asymmetric induction when used as ligand. Here, an-
other new approach to 1 by kinetic and thermodynamic resolution is presented which gave these ligands in a
much shorter steps, in a higher yield, and in a higher enantiomeric excess.
Key words chiral ligand; trifluorohydroxyethyl group; biphenyl; kinetic resolution; chirality enhancement
Nowadays, the importance of asymmetric synthesis has shows the chirality of the TFHE groups. This was a mixture
been increasing especially in biomedicinal fields to obtain of the axially chiral isomers. Optical purities of (R)-(R) -1
2
bioactive stereoisomers of chiral compounds selectively. Axi- and (S)-(R) -1 were estimated to be more than 99% by the
2
ally chiral ligands, such as BINAP and BINOL, have been Mosher method, respectively. These optical purities are better
used for syntheses of a variety of chiral compounds.
than those obtained by the method shown in Chart 1.
In the course of our study of fluorine analogs of chiral
In the above synthesis, (R)-(R) -1 was obtained as a major
2
hematoporphyrin, we found that a chiral 2,2,2-trifluoro-1-hy- product, but (S)-(R) -1 was formed in a considerable amount.
2
droxyethyl (TFHE) group was obtained in a high yield and a To clarify this point, we examined the conformations of 9
high enantiomeric excess by asymmetric reduction of a triflu- (see Fig. 1).
1
)
oroacetyl group. The chiral TFHE group was found to be
Between two conformers of the trifluoroacetyl groups of
very stable to many reagents and its chirality was maintained the (R)-9 conformer, one that has two CF groups in exo to
3
through harsh reaction conditions. The hydroxyl group of the each other must be more stable than the endo counterpart. To
TFHE group is more acidic than common alcohols, and was afford an (R)-TFHE group from a trifluoroacetyl group, a hy-
expected to show a moderate chelating ability. We synthe- dride ion must approach from si-face of the trifluoroacetyl
sized (R)-(R) -2,2Ј-bis(2,2,2-trifluoro-1-hydroxyethyl)biphenyl group. This attack is unfavorable for the more stable CF -exo
2
3
2
)
(
(R)-(R) -1), where the first (R) shows the axial chirality conformer of the (R)-9 conformer, since this face is blocked
2
and (R) shows the chiralities of the TFHE groups. This is an by the other benzene ring. The si-face attack seems to be fa-
2
axially chiral ligand with two chiral centers. This showed a vorable for (S)-9 CF -exo conformer. If so, (S)-(R) -1 must
3
2
little better asymmetric induction for the reaction of diethyl- be formed preferentially. Namely, our working hypothesis
zinc with benzaldehyde in the presence of titanium tetraiso- must be corrected as shown in Chart 3.
2
)
propoxide than BINOL. The synthesis of 1 and its applica-
Analysis of the reaction mixture by TLC showed that only
tion for asymmetric reaction are summarized in Chart 1.
one isomer was formed primarily. This must be (S)-(R) -1. To
2
This synthesis needs five steps from dibromobenzene (2) clarify the reason why (R)-(R) -1 was isolated preferentially,
2
and the yield of coupling reaction of 5 to 6 was unsatisfac- we examined the difference in the stabilities between (R)-
tory probably due to the large steric hindrance of the 1-ace- (R) -1 and (S)-(R) -1. A solution of (S)-(R) -1 in toluene was
2
2
2
toxy-2,2,2-trifluoroethyl group. We planned a new approach heated, and the equilibrium was followed by TLC. The peak
to (R)-(R) -1. Our working hypothesis is shown in Chart 2. of (S)-(R) -1 decreased gradually, and that of (R)-(R) -1 in-
2
2
2
Since a trifluoroacetyl group is much smaller than the 1-ace- creased. After 2 h, the mixture was separated by a column
toxy-2,2,2-trifluoroethyl group, coupling of 3 would give a chromatography to give (R)-(R) -1 and (S)-(R) -1 (6.8 : 1).
2
2
better yield of bis(trifluoroacetyl)biphenyl (9). Further, if the
thermodynamic equilibrium between axial isomers of 9 was
fast and (R)-9 was reduced kinetically faster by asymmetric
reduction using the (S)-oxazaborolidine catalyst than (S)-9,
(
R)-(R) -1 would be formed selectively by kinetic resolution.
2
As the biphenyl part of 9 is much larger than the phenyl
group of 3, we expected that the asymmetric reduction of 9
would give a higher enantiomeric excess than that of 3.
The coupling of 3 in the presence of Cu powder and a cat-
alytic amount of CuI gave the biphenyl compound 9 in 85%
yield, much better than the coupling of 5, as expected. The
asymmetric reduction of 9 with catecholborane in the pres-
ence of (S)-2-methyl-5,5-diphenyl-3,4-propano-1,3,2-oxaza-
borolidine, which had been found to give (R)-TFHE com-
1
)
pounds from trifluoroacetyl compounds, gave (R)-(R) -1
2
(
39%), (S)-(R) -1 (27%), and (R,S)-1 (27%), where (R,S)
Chart 1
2
*
To whom correspondence should be addressed. e-mail: kumadaki@pharm.setsunan.ac.jp
© 2003 Pharmaceutical Society of Japan

2
66
Vol. 51, No. 3
Fig. 1. Comparison of Conformers
This means that (R)-(R) -1 is more stable than (S)-(R) -1, and
2
2
suggests that the primary product, (S)-(R) -1, isomerized
2
partly to (R)-(R) -1 during workup. We name this sponta-
2
neous increase of active conformer as “spontaneous enrich-
ment.” After this separation, 62% of (R)-(R) -1 was obtained
2
in total.
In conclusion, both axially chiral isomers are stable
enough to be separated by a collumn chromatography and
recrystallized from hexane. Thus, by thermal equilibrium,
separation, and recrystallization, (R)-(R) -1 was obtained
2
from 3 in a shorter steps, in a higher yield, and in higher
Chart 2
enantiomeric excess than by our previous procedure. As
shown above, (R)-(R) -1 was found to be effective for asym-
2
metric induction, while (S)-(R) -1 was not. Thus, this new
2
procedure gives the effective chiral ligands more efficiently.
Experimental
3
)
2
,2؅-Bis(2,2,2-trifluoroacetyl)biphenyl (9) Copper powder, formed
according to literature, (7.4 g) and CuI (0.500 g, 2.63 mmol) was dried by
heating in a Schlenk tube (20 ml) under vacuum. Ar was introduced to the
tube and a solution of 2Ј-bromo-2,2,2-trifluoroacetophenone (3) (3.208 g,
1
2.7 mmol) in N,N-dimethylformamide (DMF) (3 ml) was added. The mix-
ture was stirred at 180 °C for 47.5 h. After cooled to room temperature, the
mixture was passed through a Celite layer, and the layer was washed with
Et O. Combined organic layer was concentrated under vacuum, and the
2
Chart 3
residue was separated by a column chromatography (SiO , hexane–CH Cl ,
2
2
2
7
0 : 30). The effluent was recrystallized from hexane to give 2,2Ј-bis(2,2,2-
trifluoroacetyl)biphenyl (9) (1.866 g, 85%).
: Pale yellow crystals. mp 82.0—82.5 °C. MS m/z: 346 (M ). High reso- 54.87; H, 3.45. Found: C, 55.13; H, 3.61. [a] ϭϪ8.35° (cϭ1.00, CHCl ).
1
9
F-NMR (CDCl ) d: Ϫ72.01 (d, Jϭ7.3 Hz). Anal. Calcd for C H F O : C,
3
16 12
6
2
ϩ
25
9
D
3
ϩ
lution (HR)-MS Calcd for C H F O (M ): 346.0429. Found: 346.0431. IR
(S)-(R) -1: Colorless crystals (hexane). mp 119.9—120.2 °C. MS m/z: 350
2
ϩ ϩ
1
6
8
6
2
Ϫ1
1
(
0
1
KBr) cm : 1724 (CO). H-NMR (CDCl ) d: 7.99 (2H, ddd, Jϭ8.0, 1.3, (M ). HR-MS Calcd for C H F O (M ): 350.0742. Found: 350.0746. IR
3
16 12
6
2
Ϫ1
1
.5 Hz), 7.68 (2H, ddd, Jϭ8.0, 7.2, 1.3 Hz), 7.57 (2H, ddd, Jϭ7.6, 7.2,
(KBr) cm : 3368 (OH). H-NMR (CDCl ) d: 7.81 (2H, dd, Jϭ7.6, 1.6 Hz),
3
1
9
.3 Hz), 7.25 (2H, ddd, Jϭ7.6, 1.3, 0.5 Hz). F-NMR (CDCl ) d (from 7.52 (2H, ddd, Jϭ7.6, 7.6, 1.6 Hz), 7.46 (2H, ddd, Jϭ7.6, 7.6, 1.6 Hz), 7.29
3
13
19
CFCl ): Ϫ67.68 (s). C-NMR (CDCl ) d: 181.34 (q, Jϭ34.8 Hz), 142.97, (2H, dd, Jϭ7.6, 1.6 Hz), 4.89 (2H, m), 2.45 (2H, bd, Jϭ6.0 Hz). F-NMR
3
3
2
5
1
33.79, 131.00, 129.73 (q, Jϭ3.6 Hz), 129.00, 127.82, 116.18 (q,
(CDCl ) d: Ϫ71.61 (d, Jϭ5.8 Hz). [a] ϭ5.83° (cϭ1.00, CHCl ).
3 D 3
Jϭ290.7 Hz). Anal. Calcd for C H F O : C, 55.50; H, 2.33. Found: C,
5
(R,S)-1: Colorless crystals (hexane–Et O). mp 123.0—123.2 °C. MS m/z:
1
6
8
6
2
2
ϩ
ϩ
5.73; H, 2.63.
Asymmetric Reduction of 2,2؅-Bis(2,2,2-trifluoroacetyl)biphenyl (9) IR (KBr) cm : 3452 (OH). H-NMR (CDCl ) d: 7.82 (1H, m), 7.77 (1H,
350 (M ). HR-MS Calcd for C H F O (M ): 350.0742. Found: 350.0747.
16 12 6 2
Ϫ1
1
3
In an atmosphere of Ar, 2,2Ј-bis(2,2,2-trifluoroacetyl)biphenyl (9) (2.00 g, m), 7.53 (2H, dddd, Jϭ7.6, 7.6, 1.4, 1.6 Hz), 7.26 (2H, dddd, Jϭ7.6, 7.6,
.78 mmol) and (S)-2-methyl-5,5-diphenyl-3,4-propano-1,3,2-oxazaboroli- 2.8, 1.6 Hz), 7.24 (1H, m), 7.20 (1H, m), 4.86 (1H, m), 4.74 (1H, m), 2.41
5
1
9
dine (0.400 g, 1.75 mmol) were dissolved in tetrahydrofuran (THF) (1H, bd, Jϭ4.8 Hz), 2.31 (1H, bd, Jϭ4.8 Hz). F-NMR (CDCl ) d: Ϫ72.34
3
(
20.0 ml). At Ϫ78 °C, a solution of catecholborane in THF (37.5 mmol in (3F, d, Jϭ5.9 Hz), Ϫ72.74 (3F, d, Jϭ7.3 Hz).
THF (44 ml), 22.0 ml: 17.2 mmol as catecholborane) was added to this solu-
Equilibrium between (S)-(R) -1 and (R)-(R) -1 A solution of (S)-(R)2-
2
2
tion in 1.5 h. The mixture was stirred at Ϫ78 °C for 12.5 h, then it was al- 1 (0.040 g, 0.114 mmol) in toluene heated to its boiling point, and the equi-
lowed to warm up to Ϫ30 °C in 6 h. After the mixture was stirred at this librium was followed by TLC. After 2 h, the area ratio of two spots became
temperature for 26 h, it was treated with H O and 10% NaOH and stirred at
constant. After evaporation of the solvent, the residue was separated by a
2
room temperature for 6 h, then the mixture was extracted with Et O. The column chromatography (SiO , CH Cl –Et O, 95 : 5) to give (R)-(R) -1
2
2
2
2
2
2
Et O layer was washed with 10% HCl, and dried over MgSO . After evapo- (0.034 g), (S)-(R) -1 (0.005 g).
2
4
2
ration of the solvent under vacuum, the residue was separated by a column
Mosher Ester from (S)-(S) -1 In an atmosphere of Ar, a mixture of
2
chromatography (SiO , CH Cl –Et O, 90 : 10—70 : 30) to afford three fac- (S)-(S) -1 (0.020 g, 0.057 mmol), 4-dimethylaminopyridine (0.035 g, 0.29
2
2
2
2
2
tions. Each fraction was purified by a column chromatography (SiO2,
mmol), CH Cl (0.30 ml), (Ϫ)-2-methoxy-2-trifluoromethylphenylacetyl
2
2
4
)
CH Cl –Et O, 98 : 2—80 : 20) to give (R)-(R) -1 (0.798 g, 39%), (S)-(R) -1
chloride (0.035 ml, 0.19 mmol) was stirred at room temperature, then
CH Cl (0.10 ml) was added and stirred for further 1.5 h. After the mixture
2
2
2
2
2
(
0.541 g, 27%), and (R,S)-1 (0.549 g, 27%).
2
2
(
R)-(R) -1: Colorless crystals (hexane). mp 130.6—131.0 °C. MS m/z: was treated with 10% HCl, it was extracted with CH Cl . The CH Cl layer
2
2 2 2 2
ϩ ϩ
3
50 (M ). HR-MS Calcd for C H F O (M ): 350.0742. Found: 350.0746. was washed with saturated NaHCO , and dried over MgSO . After evapora-
1
6
12
6
2
3
4
Ϫ1
1
1
IR (KBr) cm : 3358 (OH). H-NMR (CDCl ) d: 7.72 (2H, dd, Jϭ7.2, tion of the solvent, NMR of the residue was examined. H-NMR (CDCl ) d:
.2 Hz), 7.51 (2H, ddd, Jϭ7.2, 7.2, 1.2 Hz), 7.47 (2H, ddd, Jϭ7.2, 7.2,
3
3
1
1
7.33—7.53 (14H, m), 7.17—7.24 (4H, m), 6.46 (2H, q, Jϭ5.6 Hz), 3.51
1
9
.2 Hz), 7.23 (2H, dd, Jϭ7.2, 1.2 Hz), 4.66 (2H, q, Jϭ7.3 Hz), 3.49 (2H, bs). (6H, s). F-NMR (CDCl ) d: Ϫ67.55 (6F, s), 70.46 (6F, d, Jϭ5.8 Hz). Peaks
3

March 2003
267
ascribed to another diastereomer were not detected.
Heterocycles, 47, 65—68 (1998).
Mosher Ester from (R)-(R) -1 From (R)-(R) -1, the Mosher ester was
2) Omote M., Kominato A., Sugawara M., Sato K., Ando A., Kumadaki
I., Tetrahedron Lett., 40, 5583—5585 (1999).
3) Brewster R. Q., Groening T., Org. Syntheses, Coll. Vol. II, 1948, 445—
446 (1948).
2
2
derived similarly using (Ϫ)-2-methoxy-2-trifluoromethylphenylacetyl chlo-
1
ride. H-NMR (CDCl ) d: 7.27—7.65 (18H, m), 6.11 (2H, q, Jϭ5.6 Hz),
3
19
3
.35 (6H, s). F-NMR (CDCl ) d: Ϫ67.75 (6F, s), 70.03 (6F, d, Jϭ4.4 Hz).
3
4
)
Dale J. A., Dull D. L., Mosher H. S., J. Org. Chem., 34, 2543—2549
Refernces and Notes
Omote M., Ando A., Takagi T., Koyama M., Kumadaki I., Shiro M.,
(1969).
1
)