Improved asymmetric synthesis of 3,4-dihydro-2-[3-(1,1,2,2- tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-α- (trifluoromethyl)-1(2H)-quinolineethanol, a potent cholesteryl ester transfer protein inhibitor

Article abstract of DOI:10.1021/ol900639j

The asymmetric synthesis of 3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy) phenyl]-5-[3-(trifluoromethoxy)phenyl]-α-(trifluoromethyl)-1(2H) -quinolineethanol (compound 11), a cholesteryl ester transfer protein inhibitor, Is accomplished. The asymmetric cent

Full text of DOI:10.1021/ol900639j

1
An Improved Asymmetric Synthesis of 4-dihydro-2-[3-(1,1,2,2-
tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)-phenyl]-α-
(
trifluoromethyl)-1(2H)-quinolineethanol,
a Potent Cholesteryl Ester Transfer Protein (CETP) Inhibitor
Thomas A. Rano*, Gee-Hong Kuo
Supporting Information

2
Scheme 1
EtO C
2
Br
Br
NaCl
DMSO/H O
Br
Na
3N NaOH
CO Et
2
CO Et
2
EtO C
2
2
Br
CO Et
o
THF
reflux
DMF
2
1
80 C
15
Br
Br
5%
Br
1
00%
7
Br
O
Br
1
2
) ClCOCOCl/DCM
)
NaBH4
CO H
2
4
Br
66%
Me Sn
OCF CF H
2 2
Br
00%
3
Pd DBA
DIEA/THF
2
3
OCF CF H
2
2
,
1
3
Br
N3
1
) MsCl/TEA/DCM
Quantitative
Br
OH
OCF CF H
2
2
OCF CF H
2
2
Br
2
) NaN /DMF
3
Br
9
7%
9
4%
O O
S
Cl
Br
NHNs
Br
NH2
+O
Me SBHCl
N
2
2
OCF CF H
2 2
OCF CF H
O
DCE
2
2
Br
9
5
DCM/TEA
Br
2%
9
1%
Br
Br
2
eq. CuI
HO C
SH
2
OCF CF H
2
2
5
eq. CsOAc
OCF2CF2H
N
H
LiOH/DMF
N
Ns
o
DMSO/90 C
8
8%
6
89%

3
OCF3
(
HO) B
OCF3
2
2
5 mol % Yb(SO CF )
3 3 3
o
DCE/50 C
Pd(PPh ) /2M K CO
OCF CF H
2 2
3
4
2
3
N
H
O
Dioxane/reflux
5
eq.
CF3
9
1%
OCF3
OCF3
+
OCF CF H
2
2
OCF CF H
2
2
N
N
F3C
F3C
OH
OH
7
(29%)
Higher Rf compound
Lower Rf compound
Alternate Route to 4
O
O
Me SiCHN
3
2
HO
H CO
3
MeOH/DCM
86%)
(
OCF CF H
OCF CF H
2 2
2
2
16
O
TiCl4 / 5 mol % TMS-Cl
Br
O
Br
CO Et
Bu3N / DCM
2
H CO
3
o
-
78 C
CO Et
2
Br
+
Br
(
70%)
OCF CF H
OCF CF H
2
2
2
2
1
5
16
17
AcOH/HCl
Br
O
(
2:1)
o
1
00 C
(
98%)
Br
OCF CF H
2
2
4

4
Br
CO Et
2
CO Et
2
Br
2
-(2,6-Dibromo-benzyl)-malonic acid diethyl ester
To a solution of sodium diethyl malonate (2.40 g, 13.2 mmol) in DMF (15
mL) under a N atmosphere was added 1,3-dibromo-2-bromomethyl-benzene
4.56 g, 13.9 mmol). After stirring at room temperature for 2 h, ether was added
and the solution was washed with H O and brine, dried (MgSO ), concentrated
2
(
2
4
and purified by column chromatography to afford 4.28 g (75%) the bis-ester as
1
an oil: H NMR (300 MHz, CDCl
3
) δ 7.51 (d, J = 8.0 Hz, 2 H), 6.95 (t, J = 8.0 Hz,
1
1
H), 4.18 (q, J = 7.1 Hz, 4 H), 3.84 (t, J = 7.7 Hz, 1 H), 3.63 (d, J = 7.7 Hz, 2 H),
+
.21 (t, J = 7.1 Hz, 6 H); MS (ES) m/z: 409 (M+H ).
Br
CO Et
2
15
Br
3
-(2,6-Dibromo-phenyl)-propionic acid ethyl ester
A mixture of the bis-ester (4.2 g, 10.3 mmol), sodium chloride (602 mg,
0.3 mmol) and H O (371 mg, 20.6 mmol) in DMSO (75 mL) was heated at 180
1
2
o
C for 1 h. After cooling to room temperature, the reaction mixture was poured
into EtOAc (500 mL) and washed with H
2
4
O and brine, dried (MgSO ) and
1
concentrated to afford 3.49 g (100%) of 15 as an oil : H NMR (300 MHz, CDCl
3
)
δ 7.51 (d, J = 8.0 Hz, 2 H), 6.93 (t, J = 8.0 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H),
+
3
.33 (m, 2 H), 2.57 (m, 2 H), 1.28 (t, J = 7.1 Hz, 3 H); MS (ES) m/z: 337 (M+H ).
Br
CO H
2
Br
-(2,6-Dibromo-phenyl)-propionic acid
3

5
A mixture of 15 (3.46 g, 10.3 mmol) and 3 M sodium hydroxide (25 mL, 75
o
mmol) in THF (25 mL) was heated at reflux for 5 h. Upon cooling to 0 C, the
reaction mixture was acidified with concentrated HCl followed by extraction with
EtOAc. The combined organic phases were then washed with brine, dried
1
(MgSO
4
) and concentrated to afford 3.29 g (100%) the acid as a white solid: H
NMR (300 MHz, CDCl
3
) δ 7.52 (d, J = 8.0 Hz, 2 H), 6.95 (t, J = 8.0 Hz, 1 H), 3.35
+
(
m, 2 H), 2.65 (m, 2 H); MS (ES) m/z: 307 (M-H ).
Me Sn
OCF CF H
2 2
3
3
Trimethyl-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-stannane
A mixture of 1-bromo-3-(1,1,2,2-tetrafluoro-ethoxy)-benzene (3.87 g, 14.1
mmol), hexamethylditin (5.11 g, 15.6 mmol), PPh
toluene (70 mL) under a N atmosphere was degassed by bubbling N
the solution for 15 min. Pd(PPh (814 mg, 0.7 mmol) was added and the
3
(110 mg, 0.423 mmol) in
2
2
through
3 4
)
o
reaction mixture was heated at 80 C for 2 h. After cooling to room temperature,
the reaction mixture was poured into EtOAc (500 mL). The solution was then
washed with H
2
O and brine, dried (MgSO
4
), concentrated and purified by column
1
chromatography (2% EtOAc/Hex) to afford 3.76 g (67%) 3 as an oil: H NMR
(300 MHz, CDCl
3
) δ 7.37 – 7.29 (m, 3 H), 7.16 – 7.13 (m, 1 H), 5.91 (tt, J = 53.2,
2.9 Hz, 1 H), 0.31 (s, 9 H).
Br
O
Br
OCF CF H
2
2
4
3-(2,6-Dibromo-phenyl)-1-[3-(1,1,2,2-tetrafluoro-
ethoxy)-phenyl]-propan-1-one
To a solution of the acid (3.27 g, 10.6 mmol) in CH Cl (45 mL) under a N
2
2
2
2 2
atmosphere was added 2M oxalyl chloride in CH Cl (7.95 mL, 15.9 mmol). After

6
stirring at room temperature for 18 h, the solution was concentrated to give 3.26
g of acid chloride 2 which was used without further purification.
To a solution of the above intermediate (3.26 g, 9.98 mmol) in dry THF (50
o
mL) at 0 C under a N atmosphere was added N,N-diisopropylethylamine (2.6
2
2 3
mL, 15.0 mmol), 3 (4.27 g, 12.0 mmol) and Pd (dba) (456 mg, 0.499 mmol).
o
After heating at 50 C for about 30 min, the reaction mixture was cooled and
poured into EtOAc (300 mL) and washed with saturated NaHCO
dried (MgSO ), concentrated and purified by column chromatography (5%
EtOAc/Hex) to afford 3.20 g (66%) of 4 as an oil: H NMR (300 MHz, CDCl
3 2
, H O and brine,
4
1
3
) δ
7
5
.94 – 7.89 (m, 1 H), 7.83 (s, 1 H), 7.55 – 7.40 (m, 4 H), 6.96 (t, J = 8.0 Hz, 1 H),
.93 (tt, J = 53.0, 2.8 Hz, 1 H), 3.47 – 3.40 (m, 2 H), 3.25 – 3.20 (m, 2 H); MS
+
(
ES) m/z: 485 (M+H ).
Br
OH
OCF CF H
2
2
Br
-(2,6-Dibromo-phenyl)-1-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-propan-1-ol
3
To a solution of 4 (3.04 g, 6.27 mmol) in EtOH (50 mL) under a N2
4
atmosphere was added NaBH (118 mg, 12.5 mmol). After 1 h the reaction was
o
cooled to 0 C and quenched with several drops of glacial AcOH. The EtOH was
evaporated and the residue was dissolved in EtOAc. The organic phase was
3 4
washed with saturated NaHCO , water and brine, dried (MgSO ), concentrated
and purified by column chromatography (10%-15%-20% EtOAc/Hex) to provide
1
2
.89 g (95%) of the alcohol as an oil: H NMR (300 MHz, CDCl
3
) δ 7.48 (d, J =
8.0 Hz, 2 H), 7.41 – 7.28 (m, 3 H), 7.14 (d, J = 7.7 Hz, 1 H), 6.89 (t, J = 8.0 Hz, 1
H), 5.91 (tt, J = 53.1, 2.8 Hz, 1 H), 4.86 (dd, J = 10.1, 6.2 Hz, 1 H), 3.19 – 3.05
+
(
m, 1 H), 3.03 – 2.92 (m, 1 H), 2.09 – 1.95 (m, 3 H); MS (ES) m/z: 509 (M+Na ).

7
N–
+
N
Br
N
OCF CF H
2
2
Br
To a solution of the alcohol (2.89 g, 5.94 mmol) in CH Cl (30 mL) under a
2
2
o
2
N atmosphere at 0 C was added triethylamine (1.66 mL, 11.9 mmol) and
methanesulfonyl chloride (0.690 mL, 8.9 mmol). The cooling bath was removed
and the solution was stirred at room temperature for 2 h. The reaction mixture
3
was poured into EtOAc and washed with 1 N HCl, water, saturated NaHCO and
brine. The organic layer was dried (MgSO ) and concentrated to give the
4
mesylate as a crude intermediate.
A mixture of the above crude mesylate and sodium azide (1.93 g, 29.7
o
mmol) in DMF (45 mL) under a N atmosphere was heated at 50 C for ~ 1 h.
2
After cooling to room temperature, the reaction mixture was poured into EtOAc
(
500 mL), the solution was then washed with H
2
O, saturated NaHCO
) and concentrated to afford 2.90 g (95% for two steps)
) δ 7.48 (d, J = 8.0 Hz, 2 H), 7.42 (t,
3
solution
and brine, dried (MgSO
4
1
the azide as an oil: H NMR (300 MHz, CDCl
3
J = 7.9 Hz, 1 H), 7.31 – 7.19 (m, 3 H), 6.90 (t, J = 8.0 Hz, 1 H), 5.92 (tt, J = 53.1,
2
2
.8 Hz, 1 H), 4.60 (t, J = 6.9 Hz, 1 H), 3.15 – 3.05 (m, 1 H), 2.99 – 2.82 (m, 1 H),
+
.09 – 1.97 (m, 2 H); MS (ES) m/z: 484 (M-N
2
+H ).
Br
NH2
OCF CF H
2
2
Br
-(2,6-Dibromo-phenyl)-1-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-propylamine
3
To a solution of the azide (2.90 g, 5.67 mmol) in 1,2-dichloroethane (38
mL) under a N atmosphere was added Me S⋅BHCl (1.64 mL, 14.2 mmol)
2
2
2
dropwise. The solution was stirred at room temperature for 0.5 h and then
o
o
heated at 50 C for 1.5 h. The reaction was cooled to 0 C, then 6 N HCl (10 mL)
was added. The reaction mixture was then heated at reflux for 1 h. Upon cooling
o
to 0 C, the solution was basified with 3 N NaOH and extracted several times with

8
CHCl . The combined organic phases were dried (MgSO ), concentrated and
3
4
purified by column chromatography (100% EtOAc) to provide 2.69 g (98%) the
1
amine as an oil: H NMR (300 MHz, CDCl ) δ 7.46 (d, J = 8.2 Hz, 2 H), 7.39 –
3
7.26 (m, 3 H), 7.14 – 7.10 (m, 1 H), 6.88 (t, J = 8.0 Hz, 1 H), 5.91 (tt, J = 53.1, 2.9
Hz, 1 H), 4.08 (t, J = 6.6 Hz, 1 H), 3.09 – 3.00 (m, 1 H), 2.90 – 2.80 (m, 1 H), 1.98
+
–
1.88 (m, 2 H), 1.57 (brs, 2 H); MS (ES) m/z: 486 (M+H ).
Br
NHNs
OCF CF H
2
2
Br
5
N-{3-(2,6-Dibromo-phenyl)-1-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-propyl}-2-nitro-benzenesulfonamide
To a solution of the amine (2.67 g, 5.50 mmol) and triethylamine (1.53 mL,
1
1.0 mmol) in dichloromethane (27 mL) under a N
1.34 g, 6.05 mmol) under N . The reaction mixture was stirred at room
temperature for 1 h and then poured into EtOAc / Et O. The solution was
washed with saturated NaHCO , H O and brine, dried (MgSO ), concentrated
2
atmosphere was added NsCl
(
2
2
3
2
4
and purified by column chromatography (5%-10%-15%-20% EtOAc/Hex) to
1
afford 3.54 g (95%) 5 as an oil: H NMR (400 MHz, CDCl
3
) δ 7.72 (d, J = 8.0 Hz,
1
1
H), 7.66 (d, J = 7.9 Hz, 1 H), 7.55 – 7.33 (m, 4 H), 7.13 – 7.08 (m, 2 H), 7.01 (s,
H), 6.95 – 6.88 (m, 2 H), 5.96 (d, J = 8.9 Hz, 1 H), 5.86 (tt, J = 53.1, 2.8 Hz, 1
H), 4.69 (dd, J = 16.0, 7.8 Hz, 1 H), 3.19 – 3.11 (m, 1 H), 2.88 – 2.80 (m, 1 H),
+
2
.14 – 1.94 (m, 2 H); MS (ES) m/z: 693 (M+Na ).
Br
OCF CF H
2
2
N
Ns
5
-Bromo-1-(2-nitro-benzenesulfonyl)-2-[3-(1,1,2,2-tetrafluoro-ethoxy)-
phenyl]-1,2,3,4-tetrahydro-quinoline

9
A mixture of 5 (3.54 g, 5.26 mmol), CuI (2.00 g, 10.5 mmol) and CsOAc
(
5.04 g, 26.3 mmol) in DMSO (52 mL) under a N atmosphere was heated at 95
2
o
C for 24 h. After cooling to room temperature, the reaction mixture was poured
into EtOAc (400 mL), washed with saturated NH Cl (3x), water, Na solution
4
2 2 3
S O
and brine, dried (MgSO
4
) concentrated and purified by column chromatography
1
(
25% EtOAc/Hex) to afford 2.99 g (96%) Ns-THQ as an oil: H NMR (400 MHz,
CDCl ) δ 7.81 (d, J = 8.1 Hz, 1 H), 7.73 – 7.69 (m, 1 H), 7.63 – 7.50 (m, 3 H),
3
7
.43 (d, J = 8.0 Hz, 1 H), 7.39 – 7.09 (m, 5 H), 5.88 (tt, J = 53.1, 2.9 Hz, 1 H),
.62 (t, J = 6.9 Hz, 1 H), 2.74 – 2.66 (m, 1 H), 2.47 – 2.39 (m, 1 H), 2.35 – 2.27
5
(m, 1 H), 2.05 – 1.96 (m, 1 H); MS (ES) m/z: 589 (M).
Br
OCF CF H
2
2
N
H
6
5
-Bromo-2-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-1,2,3,4-
tetrahydro-quinoline
To a solution of the Ns-THQ (2.99 g, 5.06 mmol) in DMF (25 mL) under a
2
atmosphere was added thioacetic acid (0.707 mL, 10.1 mmol) and powdered
N
LiOH (485 mg, 20.2 mmol). The reaction mixture was stirred at room
temperature for ~ 6 h and then poured into EtOAc, washed with saturated
3 2 4
NaHCO , H O and brine, dried (MgSO ), concentrated and purified by column
chromatography (25% EtOAc/Hex) to afford 1.80 g (88%) racemic THQ 6 as an
1
oil: H NMR (300 MHz, CDCl ) δ 7.37 (t, J = 7.8 Hz, 1 H), 7.30 – 7.21 (m, 2 H),
3
7
.15 (d, J = 7.9 Hz, 1 H), 6.95 – 6.71 (m, 2 H), 6.51 (d, J = 7.8 Hz, 1 H), 5.90 (tt,
J = 53.1, 2.8 Hz, 1 H), 4.40 (dd, J = 9.3, 3.1 Hz, 1 H), 4.13 (brs, 1 H), 2.88 – 2.79
m, 2 H), 2.21 – 2.11 (m, 1 H), 2.05 – 1.90 (m, 1 H); MS (ES) m/z: 406 (M+2).
(

10
OCF3
OCF CF H
2
2
N
H
2-[3-(1,1,2,2-Tetrafluoro-ethoxy)-phenyl]-5-(3-trifluoromethoxy-phenyl)-
1
,2,3,4-tetrahydro-quinoline
Under a N atmosphere, a mixture of the 6 (30 mg, 0.074 mmol), 3-
2
trifluoromethoxy-phenyl-boronic acid (30 mg, 0.148 mmol), Pd(PPh
.0074 mmol) and 2 N K CO (0.11 mL, 0.22 mmol) in 1,4-dioxane (0.75 mL)
was heated at reflux for 2 h. After cooling to room temperature, EtOAc was
added and the solution was washed with Na HCO , H O and brine. The organic
3 4
) (9 mg,
0
2
3
2
3
2
layer was dried (MgSO
4
), concentrated and purified by column chromatography
1
to give 33 mg (91%) of the biphenyl-THQ as a clear oil: H NMR (400 MHz,
CDCl
3
) δ 7.42 – 7.30 (m, 4 H), 7.25 (m, 1 H), 7.21 – 7.08 (m, 4 H), 6.62 (s, 1 H),
6.60 (s, 1 H), 5.90 (tt, J = 53.1, 2.8 Hz, 1 H), 4.51 (dd, J = 8.9, 3.3 Hz, 1 H), 4.20
(brs, 1 H), 2.81 – 2.71 (m, 1 H), 2.53 (dt, J = 16.6, 4.8 Hz, 1 H), 2.10 – 2.02 (m, 1
+
H), 1.92 – 1.82 (m, 1 H); MS (ES) m/z: 486 (M+H ).
O
OCF CF H
2
2
H CO
3
16
3
-(1,1,2,2-Tetrafluoro-ethoxy)-benzoic acid methyl ester
To 3-(1,1,2,2-tetrafluoro-ethoxy)-benzoic acid (10 g; 41.9 mmol) in 20 mL
o
of DCM and 30 mL of MeOH cooled to 0 C was added TMS-diazomethane (2M;
35 mL). The reaction was stirred for 10 minutes, followed by removal of the
solvent in vacuo. Purification by column chromatography provided 9.1 g (86%) of
1
1
6: H NMR (400 MHz, CDCl
3
) δ 3.94 (s, 3H), 5.93 (tt, J = 53.1, 2.8 Hz, 1
H),7.40-7.50 (m. 2H), 7.88 (s, 1H), 7.97 (d, J=8.9 Hz, 1H).

11
Br
O
CO Et
2
Br
OCF CF H
2
2
17
2-(2,6-Dibromo-benzyl)-3-oxo-3-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-propionic acid ethyl ester
To the mono ester (308 mg; 0.95 mmol) and 16 (725 mg; 2.87 mmol) in
o
anhydrous PhMe (2.5 mL) under an atmosphere of N
2
cooled to 0 C was added
TiCl (2.87 mL; 2.87 mmol), TMSOTf (8.6 uL; 0.0475 mmol) and Bu N (1.01 mL;
4
3
4.27 mmol). The ice bath was removed. After 10 minutes, A2 was completely
consumed. The ice bath was replaced and the reaction was quenched with
water. EtOAc was added and the mixture separated. The organic layer was
washed with water (2X), saturated sodium bicarbonate solution (2X), water and
4
brine. The organic layer was dried (MgSO ), concentrated and purified by
column chromatography (0-5% EtOAc/Hexanes) to provide 17 (364 mg) in 70%
1
yield; H NMR (400 MHz, CDCl
3
) δ 1.09(t, 3H), 3.69 ½ ABX (Jab=14.4 Hz, Jax=5.9
Hz, 1H), 3.80 ½ ABX (Jab=14.4 Hz, Jax=8.6 Hz, 1H), 4.08-4.15 (m, 2H), 4.70 (dd,
J=8.5, 6.1 Hz, 1H), 5.93 (tt, J = 53.1, 2.8 Hz, 1 H), 6.91 (t, J=8.0 Hz, 1H), 7.37-
7.50 (m, 4H), 7.75 (s, 1H), 7.78 (d, J=7.46 Hz 1H).
Br
O
Br
OCF CF H
2
2
4
3
-(2,6-Dibromo-phenyl)-1-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-propan-1-one
17 (369 mg; 0.663 mmol) was heated in a 2:1 mixture of glacial AcOH and
concentrated HCl (5 mL) for 1 hour under an atmosphere of N . After cooling,
2
water was added and extraction with EtOAc followed. The organic layer was
washed with water (3X), 1N NaOH (1X), water (1X) and brine. The organic layer

12
was dried (MgSO ) and concentrated to provide 4 (~305 mg) in 95% yield. The
4
compound was identical in all respects to 4 which was prepared employing the
original method.
OCF3
OCF CF H
2
2
N
F3C
OH
7
Higher Rf compound
,1,1-Trifluoro-3-[2-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-5-(3-trifluoromethoxy-phenyl)-
,4-dihydro-2H-quinolin-1-yl]-propan-2-ol
1
3
To a solution of the biphenyl-THQ (33 mg, 0.068 mmol) and 1,1,1-trifluoro-
,3-epoxy-propane (38 mg, 0.34 mmol) in DCE (0.45 mL) under a N atmosphere
(10.5 mg, 0.0169 mmol). The reaction mixture was heated
2
2
was added Yb(OTf)
3
o
at 50 C for 48 h and then cooled to ambient temperature. EtOAc was added
and the solution was washed with saturated NaHCO
3
2
, H O and brine, dried
(
MgSO
29%) of 7 as an oil: H NMR (400 MHz, CDCl
4
), concentrated and purified by column chromatography to afford 12 mg
1
(
3
) δ 7.40 – 7.20 (m, 2 H), 7.28 –
7
5
=
2
5
.10 (m, 6 H), 7.04 (s, 1 H), 6.73 (d, J = 8.3 Hz, 1 H), 6.67 (d, J = 7.4 Hz, 1 H),
.89 (tt, J = 53.1, 2.8 Hz, 1 H), 4.89 (t, J = 4.4 Hz, 1 H), 4.42 (m, 1 H), 3.91 (d, J
15.5 Hz, 1 H), 3.30 (dd, J = 15.6, 9.7 Hz, 1 H), 2.48 (dt, J = 16.3, 4.4 Hz, 1 H),
.42 – 2.31 (m, 2 H), 2.19 – 2.09 (m, 1 H), 2.00 – 1.92 (m, 1 H); MS (ES) m/z:
+
98 (M+H ).

13
OCF3
OCF CF H
2
2
N
F3C
OH
Lower Rf compound
,1,1-Trifluoro-3-[2-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-5-(3-trifluoromethoxy-phenyl)-
,4-dihydro-2H-quinolin-1-yl]-propan-2-ol
1
3
The lower Rf compound was isolated as the other diasteriomer (27%) in
1
the synthesis of 7. H NMR (400 MHz, CDCl
3
) δ 7.40 – 7.32 (m, 2 H), 7.28 –
7
5
=
.09 (m, 6 H), 7.02 (s, 1 H), 6.89 (d, J = 8.3 Hz, 1 H), 6.68 (d, J = 7.4 Hz, 1 H),
.89 (tt, J = 53.1, 2.8 Hz, 1 H), 4.61 (t, J = 4.3 Hz, 1 H), 4.34 (m, 1 H), 3.80 (dd, J
15.7, 6.5 Hz, 1 H), 3.51 (dd, J = 15.7, 5.4 Hz, 1 H), 2.48 – 2.33 (m, 2 H), 2.24
(
(
d, J = 5.0 Hz, 1 H), 2.17 – 2.08 (m, 1 H), 1.99 – 1.91 (m, 1 H); MS (ES) m/z: 598
+
M+H ).

14
Scheme 2
Ph Ph
H
Br
O
Br
OH
0.75 equiv.
O
OCF CF H
2
2
N
B
S
Br
Br
8
OCF2CF2H
Br
1.0 equiv. BH3 Me2S
4
o
THF/-15 C
(82%)
Br
NH2
N3
Me2SBHCl2
DCE
1
) MsCl/TEA/DCM
Quantitative
OCF2CF2H
OCF CF H
2
2
R
(99%)
2
) NaN /DMF
94% for 2 steps)
Br
3
Br
(
O O
Br
S
Cl
Br
NHNs
2
eq. CuI
+
O
N
O
OCF2CF2H
OCF2CF2H
N
5
eq. CsOAc
DMSO/90 C
Quantitative
Ns
o
Br
DCM/TEA
81%)
9
(
OCF3
Br
(
HO) B
OCF3
2
HO2C
SH
OCF2CF2H
N
H
LiOH/DMF
91%)
Pd(PPh ) /2M K CO
OCF CF H
2 2
3
4
2
3
N
H
Dioxane/reflux
91%)
(
(
1
0
25 mol % Yb(SO CF )
3 3 3
OCF3
OCF3
o
DCE/50 C
+
O
5
eq.
CF3
OCF CF H
OCF CF H
2 2
2
2
N
N
F3C
F C
3
11
12
OH
OH
Br
OH
OCF CF H
2
2
Br
αS)-2,6-Dibromo-α-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]benzenepropanol
8
(

15
To a stirred solution of 4 (511 mg; 1.05 mmol) in anhydrous THF under nitrogen
was added (R)-2-Methyl-CBS-oxazaborolidine (792 uL; 0.792 mmol). The
o
reaction vessel was cooled to –15 C followed by the addition of borane-dimethyl
sulfide complex (528 uL; 1.05 mmol) slowly dropwise. The reaction was aged for
o
5
0 minutes before being quenched with MeOH at –20 C. The contents of the
reaction vessel were poured into EtOAc and washed with water/2N HCl (2:1),
water, saturated sodium bicarbonate solution, water and brine. The organic layer
was dried over MgSO4, filtered and the solvent removed in vacuo. Purification
employing SiO
82%) of alcohol 8 of the S absolute configuration as an oil. Analysis by chiral
HPLC (Chiralcel AS; Isocratic elution 90/10 Hexane/IPA) by area integration at
2
flash column chromatography (15%EtOAc/Hex) provided 420 mg
(
210 nm indicated the enantiomeric excess > 95%. This alcohol was identical in
2
D
0
o
all respects to the racemic alcohol, except for the optical rotation. [α]
= -12.1
3
(c1; CHCl ); The reaction was later repeated on a larger scale, employing 15.36
grams (31.7 mmol) of 4, 23.7 mL (0.75 equiv.) of (R)-2-Methyl-CBS-
oxazaborolidine, and 15.85 mL (1 equiv.; 31.7 mmol) of borane-dimethyl sulfide
complex in 130 mL of anhydrous THF under the conditions described above to
1
provide 14.33 grams (92%) of alcohol 8. H NMR (300 MHz, CDCl
3
) δ 7.48 (d, J
=
1
8.0 Hz, 2 H), 7.41 – 7.28 (m, 3 H), 7.14 (d, J = 7.7 Hz, 1 H), 6.89 (t, J = 8.0 Hz,
H), 5.91 (tt, J = 53.1, 2.8 Hz, 1 H), 4.86 (dd, J = 10.1, 6.2 Hz, 1 H), 3.19 – 3.05
+
(
m, 1 H), 3.03 – 2.92 (m, 1 H), 2.09 – 1.95 (m, 3 H); MS (ES) m/z: 509 (M+Na ).
Br
OH
OCF CF H
2
2
Br
αR)-2,6-Dibromo-α-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]benzenepropanol
(
The R alcohol 8 was prepared exactly as S alcohol 8, substituting (S)-2-Methyl-
CBS-oxazaborolidine for (R)-2-Methyl-CBS-oxazaborolidine. Analysis by chiral
HPLC (Chiralcel AS; Isocratic elution 90/10 Hexane/IPA) by area integration at

16
210 nm indicated the enantiomeric excess > 95%. This alcohol was identical in
2
0
all respects to the racemic alcohol A6, except for the optical rotation. [α]D
=
o
1
+
–
5
2
3
11.4 (c1; CHCl3); H NMR (300 MHz, CDCl ) δ 7.48 (d, J = 8.0 Hz, 2 H), 7.41
7.28 (m, 3 H), 7.14 (d, J = 7.7 Hz, 1 H), 6.89 (t, J = 8.0 Hz, 1 H), 5.91 (tt, J =
3.1, 2.8 Hz, 1 H), 4.86 (dd, J = 10.1, 6.2 Hz, 1 H), 3.19 – 3.05 (m, 1 H), 3.03 –
+
.92 (m, 1 H), 2.09 – 1.95 (m, 3 H); MS (ES) m/z: 509 (M+Na ).
OMe
F3C
O
Ph
(
R)
Br
O
OCF CF H
2
2
(
R)
Br
To a stirred solution of S alcohol 8 (7.5 mg; 0.0154 mmol) in anhydrous DCM
under nitrogen was added DIEA (8 uL; 0.046 mmol) followed by S-(+)-MTPA
(
5.76 uL; 0.031 mmol). The reaction was aged for 30 minutes before the solvent
removed in vacuo. Purification employing SiO flash column chromatography
5%EtOAc/Hex) provided quantitative yield of the R,R Mosher Ester. The R,S
2
(
Mosher Ester was prepared in exactly the same manner. The NMR spectra of
these Mosher Esters are pictured in the NMR section.
Br
N3
OCF CF H
2
2
Br
2
-[(3R)-3-Azido-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]-1,3-dibromobenzene
To a solution of the S alcohol 8 (14.33 g, 29.48 mmol) in CH
2
2
Cl (200 mL)
o
under a N
2
atmosphere at 0 C was added DIEA (10.27 mL, 58.9 mmol) and
methanesulfonyl chloride (3.42 mL, 44.22 mmol). The cooling bath was removed
and the solution was stirred at room temperature for 2 h. The reaction mixture
was poured into EtOAc and washed with 1 N HCl, water, saturated NaHCO and
3

17
brine. The organic layer was dried (MgSO ) and concentrated to give the
4
mesylate as a crude intermediate.
A mixture of the above crude mesylate and sodium azide (9.5 g, 65.01
o
mmol) in DMF (150 mL) under a N
2
atmosphere was heated at 50 C for ~ 1 h.
After cooling to room temperature, the reaction mixture was poured into EtOAc
1.5 L), the solution was then washed with H O, saturated NaHCO solution and
brine, dried (MgSO ) and concentrated to afford 13.91 g (92% for two steps).
This azide was identical in all respects to the racemic azide, except for the optical
(
2
3
4
2
D
0
o
1
rotation. [α]
3 3
= +39.3 (c1; CHCl ); H NMR (300 MHz, CDCl ) δ 7.48 (d, J =
8
.0 Hz, 2 H), 7.42 (t, J = 7.9 Hz, 1 H), 7.31 – 7.19 (m, 3 H), 6.90 (t, J = 8.0 Hz, 1
H), 5.92 (tt, J = 53.1, 2.8 Hz, 1 H), 4.60 (t, J = 6.9 Hz, 1 H), 3.15 – 3.05 (m, 1 H),
+
2
.99 – 2.82 (m, 1 H), 2.09 – 1.97 (m, 2 H); MS (ES) m/z: 484 (M-N
2
+H ).
Br
NH2
OCF CF H
2
2
Br
αR)-2,6-Dibromo-α-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]benzenepropanamine
(
To a solution of the azide (13.91 g, 27.2 mmol) in 1,2-dichloroethane (180
mL) under a N atmosphere was added Me S⋅BHCl (7.85 mL, 68 mmol)
dropwise. The solution was stirred at room temperature for 0.5 h and then
2
2
2
o
o
heated at 50 C for 1.5 h. The reaction was cooled to 0 C, then 6 N HCl (50 mL)
was added. The reaction mixture was then heated at reflux for 1 h. Upon cooling
o
to 0 C, the solution was basified with 3 N NaOH and extracted several times with
CHCl . The combined organic phases were dried (MgSO ), concentrated and
3
4
purified by column chromatography (100% EtOAc) to provide 13.1 g (99%) of the
1
amine as an oil. H NMR (300 MHz, CDCl
3
) δ 7.46 (d, J = 8.2 Hz, 2 H), 7.39 –
7.26 (m, 3 H), 7.14 – 7.10 (m, 1 H), 6.88 (t, J = 8.0 Hz, 1 H), 5.91 (tt, J = 53.1, 2.9
Hz, 1 H), 4.08 (t, J = 6.6 Hz, 1 H), 3.09 – 3.00 (m, 1 H), 2.90 – 2.80 (m, 1 H), 1.98
+
–
1.88 (m, 2 H), 1.57 (brs, 2 H); MS (ES) m/z: 486 (M+H ).

18
Br
NHNs
OCF CF H
2
2
Br
9
N-[(1R)-3-(2,6-Dibromophenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-propyl]
2-nitrobenzenesulfonamide
-
To a solution of the amine (13.1 g, 27.0 mmol) and triethylamine (9.4 mL,
4.0 mmol) in dichloromethane (135 mL) under a N atmosphere was added
NsCl (6.58 g, 29.7 mmol) under N . The reaction mixture was stirred at room
temperature for 1 h and then poured into EtOAc / Et O. The solution was
washed with saturated NaHCO , H O and brine, dried (MgSO ), concentrated
5
2
2
2
3
2
4
and purified by column chromatography (5%-10%-15%-20% EtOAc/Hex) to
afford 15.2 g (84%) 9 as an oil. Compound 9 was obtained of the R absolute
2
D
0
o
1
configuration. [α]
3 3
= +100.0 (c1; CHCl ); H NMR (400 MHz, CDCl ) δ 7.72 (d,
J = 8.0 Hz, 1 H), 7.66 (d, J = 7.9 Hz, 1 H), 7.55 – 7.33 (m, 4 H), 7.13 – 7.08 (m, 2
H), 7.01 (s, 1 H), 6.95 – 6.88 (m, 2 H), 5.96 (d, J = 8.9 Hz, 1 H), 5.86 (tt, J = 53.1,
2.8 Hz, 1 H), 4.69 (dd, J = 16.0, 7.8 Hz, 1 H), 3.19 – 3.11 (m, 1 H), 2.88 – 2.80
+
(
m, 1 H), 2.14 – 1.94 (m, 2 H); MS (ES) m/z: 693 (M+Na ).
Br
OCF CF H
2
2
N
Ns
(
2R)-5-Bromo-1,2,3,4-tetrahydro-1-[(2-nitrophenyl)sulfonyl]
2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]quinoline
-
A mixture of 9 (15.2 g, 22.68 mmol), CuI (8.63 g, 45.36 mmol) and CsOAc
(
21.7 g, 113.4 mmol) in DMSO (200 mL) under a N atmosphere was heated at
2
o
9
5 C for 24 h. After cooling to room temperature, the reaction mixture was
4 2 2 3
poured into EtOAc, washed with saturated NH Cl (3x), water, Na S O solution
and brine, dried (MgSO ) concentrated to provide the Ns-THQ as an oil. This
4
reaction was so clean it was carried on to the next step as a crude reaction
mixture. As small portion was purified by column chromatography (25%

19
EtOAc/Hex) for characterization purposes. This compound was identical in all
2
0
o
respects to the racemic Ns-THQ, except for the optical rotation. [α]D = +55.0
1
(
c1; CHCl
3
); H NMR (400 MHz, CDCl
3
) δ 7.81 (d, J = 8.1 Hz, 1 H), 7.73 – 7.69
(m, 1 H), 7.63 – 7.50 (m, 3 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.39 – 7.09 (m, 5 H),
5.88 (tt, J = 53.1, 2.9 Hz, 1 H), 5.62 (t, J = 6.9 Hz, 1 H), 2.74 – 2.66 (m, 1 H),
2.47 – 2.39 (m, 1 H), 2.35 – 2.27 (m, 1 H), 2.05 – 1.96 (m, 1 H); MS (ES) m/z:
589 (M).
Br
OCF CF H
2
2
N
H
(2R)-5-Bromo-1,2,3,4-tetrahydro-2-
[
3-(1,1,2,2-tetrafluoroethoxy)phenyl]quinoline
To a solution of the Ns-THQ (assuming quantitative yield from previous
reaction, 22.6 mmol) in DMF (100 mL) under a N atmosphere was added
2
thioacetic acid (3.16 mL, 45.36 mmol) and powdered LiOH (2.17 g, 90.72 mmol).
The reaction mixture was stirred at room temperature for ~ 6 h and then poured
into EtOAc, washed with saturated NaHCO
3 2 4
, H O and brine, dried (MgSO ),
concentrated and purified by column chromatography (25% EtOAc/Hex) to afford
8.25 g (90% yield for the two steps) the THQ as an oil, which was identical in all
2
D
0
o
in all respects to racemic 6, except for the optical rotation. [α]
= +17.6 (c1;
1
CHCl ); H NMR (300 MHz, CDCl ) δ 7.37 (t, J = 7.8 Hz, 1 H), 7.30 – 7.21 (m, 2
3
3
H), 7.15 (d, J = 7.9 Hz, 1 H), 6.95 – 6.71 (m, 2 H), 6.51 (d, J = 7.8 Hz, 1 H), 5.90
tt, J = 53.1, 2.8 Hz, 1 H), 4.40 (dd, J = 9.3, 3.1 Hz, 1 H), 4.13 (brs, 1 H), 2.88 –
.79 (m, 2 H), 2.21 – 2.11 (m, 1 H), 2.05 – 1.90 (m, 1 H); MS (ES) m/z: 406
M+2).
(
2
(

20
OCF3
OCF CF H
2
2
N
H
1
0
(2R)-1,2,3,4-Tetrahydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-
[
3-(trifluoromethoxy)phenyl]quinoline
Under a N atmosphere, a mixture of the THQ (8.25 g, 20.4 mmol), 3-
2
trifluoromethoxy-phenyl-boronic acid (8.4 g, 40.8 mmol), Pd(PPh
) and 2 N K CO (30.6 mL, 61.2 mmol) in 1,4-dioxane (200 mL) was heated at
reflux for 2 h. After cooling to room temperature, EtOAc was added and the
solution was washed with Na HCO , H O and brine. The organic layer was dried
MgSO ), concentrated and purified by gradient column chromatography (4-10%
EA/Hex) to give 8.78 g (88%) of the biphenyl-THQ 10 as a clear oil of the R
3 4
) (2.3 g, 10 mol
%
2
3
2
3
2
(
4
2
D
0
o
1
configuration: [α]
3 3
= -13.1 (c1; CHCl ); H NMR (400 MHz, CDCl ) δ 7.42 –
7
5
2
1
.30 (m, 4 H), 7.25 (m, 1 H), 7.21 – 7.08 (m, 4 H), 6.62 (s, 1 H), 6.60 (s, 1 H),
.90 (tt, J = 53.1, 2.8 Hz, 1 H), 4.51 (dd, J = 8.9, 3.3 Hz, 1 H), 4.20 (brs, 1 H),
.81 – 2.71 (m, 1 H), 2.53 (dt, J = 16.6, 4.8 Hz, 1 H), 2.10 – 2.02 (m, 1 H), 1.92 –
+
.82 (m, 1 H); MS (ES) m/z: 486 (M+H ).
OCF3
OCF CF H
2
2
N
F3C
OH
11
(
2R, αS)-3,4-Dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-
[
3-(trifluoromethoxy)phenyl]-α-(trifluoromethyl)-1(2H)-quinolineethanol

21
To a solution of the biphenyl-THQ 10 (8.78 g, 18.08 mmol) and
commercially available S isomer enriched 1,1,1-trifluoro-2,3-epoxy-propane (10.1
g, 90.4 mmol) in DCE (90 mL) under a N atmosphere was added Yb(OTf) (2.8
2
3
o
g, 10.5 mmol). The reaction mixture was heated at 50 C for 19 h and then
cooled to ambient temperature. EtOAc was added and the solution was washed
with saturated NaHCO
purified by Isco CombiFlash Companion column chromatography (330 g RediSep
Flash Column, 2-10% EA/Hex gradient) to afford 7.91 g (73%) of higher R
compound 11 as an oil. 1.95 g (18%) of lower R compound 12 was also isolated
as an oil. Several overlap fractions were discarded. The optical rotation of 11
3 2 4
, H O and brine, dried (MgSO ), concentrated and
f
f
2
D
0
o
1
was determined to be [α]
3 3
= -117.3 (c1.13; CHCl ); H NMR (400 MHz, CDCl )
δ 7.40 – 7.20 (m, 2 H), 7.28 – 7.10 (m, 6 H), 7.04 (s, 1 H), 6.73 (d, J = 8.3 Hz, 1
H), 6.67 (d, J = 7.4 Hz, 1 H), 5.89 (tt, J = 53.1, 2.8 Hz, 1 H), 4.89 (t, J = 4.4 Hz, 1
H), 4.42 (m, 1 H), 3.91 (d, J = 15.5 Hz, 1 H), 3.30 (dd, J = 15.6, 9.7 Hz, 1 H),
2
1
.48 (dt, J = 16.3, 4.4 Hz, 1 H), 2.42 – 2.31 (m, 2 H), 2.19 – 2.09 (m, 1 H), 2.00 –
+
.92 (m, 1 H); MS (ES) m/z: 598 (M+H ).
2
1

22

23

24

25

26

27

28

29

30