Synthesis of axially chiral 1,8-diarylnaphthalene ligands and application in asymmetric catalysis: An intriguing fluorine effect

Article abstract of DOI:10.1016/j.tetasy.2014.12.008

A fluorinated and a non-fluorinated axially chiral 1,8-diarylnaphthalene ligand have been synthesized through an Ullmann and Suzuki coupling reaction based strategy. A practical methodology for the successful chiral resolution of the newly synthesized catechol based moiety is presented. We also disclose the preliminary application of these axially chiral molecules as ligands in asymmetric transformation reactions.

Full text of DOI:10.1016/j.tetasy.2014.12.008

Tetrahedron: Asymmetry 26 (2015) 79–84
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of axially chiral 1,8-diarylnaphthalene ligands and
application in asymmetric catalysis: an intriguing fluorine effect
⇑
Harisadhan Ghosh, Ravishashidhar Vavilala, Alex M. Szpilman
Schulich Faculty of Chemistry, Technion—Israel Institute of Technology, Haifa 3200008, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
A fluorinated and a non-fluorinated axially chiral 1,8-diarylnaphthalene ligand have been synthesized
through an Ullmann and Suzuki coupling reaction based strategy. A practical methodology for the suc-
cessful chiral resolution of the newly synthesized catechol based moiety is presented. We also disclose
the preliminary application of these axially chiral molecules as ligands in asymmetric transformation
reactions.
Received 29 October 2014
Accepted 30 November 2014
Available online 16 January 2015
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
catalysis,25 new ligands must be designed and tested in order to
escape the confines defined by the reactivity profiles of existing
The 1,8-diaryl substituted naphthalene scaffold possesses inter-
esting properties due to the unique orientation of the two-aryl
moieties in a parallel-stacked geometry. Molecules of this type
ligands. Herein we report a short and efficient synthesis of a new
type of axially chiral 1,8-diarylnaphthalene based catechol ligand
with both fluorinated and non-fluorinated substituents. The enan-
tiomers were resolved using chiral pool based techniques. These
compounds should be of interest, both as chiral ligands for asym-
metric catalysis as well as chiral detector systems and charge
transfer complexes. We also report an application in the asymmet-
ric Mukaiyama aldol reaction in which the perfluorinated ligand 2
shows higher enantioselectivity than the non-fluorinated ligand
1.26,27
have consequently found applications in the study of
p–p interac-
tions,1–10 parallel displaced aromatic -interactions,11 through-
p
space spin–spin coupling12 and in studies of the through-space
control of the kinetic decay of ortho-quinonoid intermediates.13
Chemical sensors based on this scaffold have been developed as
fluorescence based detectors of dicarboxylic acids,14 for the enan-
tioselective CD analysis of chiral amino alcohols,15 as an intra-
molecular excimer emitting compound,16 as well as stereodynamic
chemosensors.17,18
2. Results and discussion
Catechols are important in biological settings where they are
ubiquitous in siderophores that control iron absorption; they also
have high affinity for metal ions in high oxidation states or with
high charge/radius ratios.19 Some catechol siderophores even
undergo chiral recognition during enzymatic reactions as part of
the iron transport pathway.20
In asymmetric catalysis, axially chiral ligands hold a unique
place among privileged ligand structures such as BINOL, BINAP
and their derivatives.21,22 In spite of the many potential uses men-
tioned, the application of 1,8-diarylnaphthalene based scaffolds as
ligands in asymmetric catalysis is relatively unexplored.23,24
The development of new ligand scaffolds remains important in
modern synthetic organic chemistry in order to increase the scope
and efficiency of catalytic asymmetric reactions. While known
privileged ligands have a wide range of applications in asymmetric
Herein, we report the preparation of two ligands; ligand 1 with
an electron rich benzene ring and ligand 2 with five strongly elec-
tron withdrawing fluorine groups and an inverted quadrupole
(Fig. 1). We hypothesized that these effects might result in differ-
ences in reactivity and chiral induction. The aryl groups are in a par-
allel-stacked geometry, but can rotate around the aryl–naphthalene
prevents free rotation
1, R=
OH
OH
coordination site
Me
F
O
R
F
F
F
F
2
, R=
⇑
Corresponding author. Tel.: +972 48295953; fax: +972 4 8295703.
E-mail address: szpilman@tx.technion.ac.il (A.M. Szpilman).
Figure 1. Design of axially chiral molecules 1 and 2.
http://dx.doi.org/10.1016/j.tetasy.2014.12.008
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

80
H. Ghosh et al. / Tetrahedron: Asymmetry 26 (2015) 79–84
bond depending on the strength of parallel-stacked
p
–
p
interac-
Unfortunately, the inclusion complex of 1 with (S)-proline was
not amenable to X-ray analysis. However, the complex was
characterized by NMR.
tions. In the neighbouring catechol aryl group, a methoxy group
was incorporated into the design in order to prevent free rotation
around the aryl-naphthyl C–C bond. The catechol would serve the
double function of preventing free rotation as well being a metal
coordination site for detector or catalytic applications.
In order to investigate the applicability of ligand 1 in asymmet-
ric catalysis, we performed an asymmetric Mukaiyama aldol
reaction (Scheme 2). A titanium complex of ligand 1 was generated
in situ. Ligand 1 was dissolved in dry dichloromethane, after which
molecular sieves (4 Å) were added followed by freshly prepared
diisopropoxide-titanium(IV) dichloride 7. Upon the addition of 7,
the reaction mixture turned red, which indicated complex forma-
tion with 1. The putative complex 8 was left for one hour and then
phenol and aldehyde were added. The reaction mixture was cooled
to À42 °C and then silyl enol ether was added. After 4 days reac-
tion, product 11 was isolated in 30% yield, with the mass balance
being unreacted starting material. Disappointingly, the aldol
product was isolated as a racemic mixture. We hypothesized that
the lack of stereochemical induction from the ligand might be
due to too many degrees of freedom in the catalyst–aldehyde
complex. Taking note of the recent finding that fluorine, when
appropriately situated in a chiral catalyst, might have a positive
effect on the chiral induction,31 we prepared fluorinated ligand 2
(Fig. 1 and Scheme 3). In this ligand, the fluorines are situated in
such an orientation that they might interact orthogonally with
the titanium-complexed aldehyde through polar interactions as
Our synthesis of 1 started from 1,8-diiodonaphthalene 3.28
Suzuki coupling of 3 and phenylboronic acid gave the mono arylat-
ed product 4 in 40% yield (Scheme 1). This is presumably due to the
known propensity of the second iodine to react more rapidly than
the first29 leading to 1,8-diphenylnaphthalene as a by-product.
Indeed, a second Suzuki coupling using trimethoxy boronic acid
5 afforded 6 in 70% yield. Selective deprotection of the methylated
catechol functionality was achieved in 78% yield using BBr3 to give
the chiral racemic catechol rac-1.
Resolution of rac-1 was achieved via chiral recognition by
(S)-proline in acetonitrile at 90 °C.30 Rac-1 and (S)-proline were
added to acetonitrile in equimolar amounts and refluxed for 3 h.
Upon cooling to room temperature, the inclusion complex precip-
itated from solution as a white solid precipitated from the solution.
The precipitate was hydrolysed in a mixture of ethyl acetate and
water, after which crystallization from toluene furnished ligand 1
in 45% yield and with >99% ee. The enantiomer ent-1 was
recovered from the mother liquor in 40% yield and with 86% ee.
OMe
MeO
OMe
B(OH)2
5
I
I
phenylboronic acid
Na2CO3, Pd(PPh3)4
I
K3PO4, Pd(PPh3)4
DMF, 4Å MS
24h, 100 °C
DME/EtOH (2.5:1, V/V)
H2O, reflux 24h
40% yield
3
4
70% yield
OH
OH
resolution:
(S)-proline in
CH3CN
MeO
MeO
OMe
OH
R
BBr3
90 °C,3h
CH2Cl2
-78 °C to rt, 12h
78% yield
OMe
OH
R=OMe
, 45%, 99% ee
6
1
rac-1
1,
ent- 40%, 86 % ee
Scheme 1. Synthesis of the axially chiral catechol 1 and ent-1.
10 mol%
O
O
Cl
Cl
1
(10 mol%)
O
Cl
Cl
MS (4Å), DCM
RT, 1 hour
Ti
Ti
or
+
MeO
O
(Sa)-2, (10 mol%)
7
8
O
OSiMe3
OH
O
H
+
8
(10 mol%)
phenol, dry DCM, Ar
-42 oC, 4 days
O2N
11
10
0.15 mmol
O2N
9
0.1 mmol
1: 30% yield, 0% ee
2
(Sa)- : 34% yield, 28% ee
Scheme 2. Asymmetric catalytic Mukaiyama aldol reaction using 1 and 2.

H. Ghosh et al. / Tetrahedron: Asymmetry 26 (2015) 79–84
81
F
F
F
F
F
F
F
OMe
OMe
F
F
F
F
MeO
F
F
F
F
I
I
OMe
OMe
10 mol%
Pd(Ph3P)4,
K3PO4,
I
Cu powder
160oC, DMSO
85%
MeO
+
dry DMF, 4 Å MS,
100oC, 24 hours
25%
I
B(OH)2
3
12
13
5
14
-78oC to RT,
overnight
BBr3,
DCM
83%
R* =
O
F5
R*
O
S
OH
OH
F
F
R*
O
O
F
F
OH
HO
O
O
O
F
F
F
F
F
S
separation of
Cl
O
diastereomers
R
F
Et3N, MeCN
then
OMe
OMe
0oC to RT, 2h
NaBH4, EtOH
0oC to RT, 2h
R=OMe
quantitative yield
(Sa)-2, >99% ee
15 and 16
rac-2
2
(Ra)- , >99% ee
80%
Scheme 3. Synthesis of the axially chiral perfluorinated catechols 2. See Figure 3 for the absolute configuration of 15.
described by Diederich.32 Compound 2 could also have other inter-
esting properties and applications in non-chiral settings.
Accordingly, we attempted to attach various fluorinated phenyl
systems to 1,8-diiodonaphthalene through various coupling reac-
tions (Scheme 3). All of our initial attempts to achieve Suzuki cou-
pling between ortho- and meta-bis-fluoro-phenyl boronic acid with
1,8-diiodonaphthalene
3 failed. The ortho-bis-fluorine phenyl
boronic acid underwent rapid proto-deboronation. This is a com-
mon problem in Suzuki coupling with electron poor aryl boronic
acids.33 In contrast, Suzuki coupling between 3 and meta-bis-flu-
oro-phenyl boronic acid always led to the bis-arylated product.
Attempts to perform Suzuki couplings between pentafluoro-
phenylboronic acid and 3 afforded product 13 in yields of less than
10%. After exhaustive experimentation using modern catalytic pro-
cedures, we decided to attempt the classical Ullmann coupling of
iodo-pentafluoro-benzene 12 and 3 using copper metal.8 To a solu-
tion of 1,8-diiodonaphthalene 3 in DMSO and iodo-pentafluoro-
benzene 12 (2 equiv) copper powder (2.5 equiv) was added and
the reaction mixture was heated to 160 °C for 5 h with constant
stirring. Product 13 was successfully obtained in 85% isolated yield.
We then performed the Suzuki coupling of 1,3,5-trimethoxy-
phenyl boronic acid 5 with 13 to give product 14. In contrast to
the second Suzuki coupling in the synthesis of ligand 1, the yield
for this transformation was 25% with the rest of the material being
mostly proto-deboronated 5, that is, 1,2,4-trimethoxy-benzene.
The fluorinated juxtaposed aromatic ring, must somehow reduce
the reactivity of the second iodine. This material could be recov-
ered and converted back into boronic acid 5. Racemic product 14
can be crystallized from acetonitrile solvent. The crystals obtained
provided proof of the structure (Fig. 2).
Figure 2. ORTEP diagram of X-ray data for 14 (CCDC-1035718). Ellipsoids are at
50% probability and hydrogen atoms are omitted for the sake of clarity.
We next performed the selective deprotection of the methyl-
ated catechol function to obtain the racemic catechol ligand rac-
2. In this case, our efforts to form diastereomeric salts using a vari-
ety of chiral amines and amino-acid esters failed. We also
attempted the preparation of esters of various amino acids, but
none of the products could be separated by crystallization or col-
umn chromatography.
We were able to form separable diastereomeric (S)-camphor
sulfonyl esters 15 and 16. These diastereoisomers were separated
by column chromatography. The less polar diastereomer 15 could
be crystallized from tetrahydrofuran and allowed us to establish
the absolute stereochemistry of this diastereomer as Sa (Fig. 3).
Figure 3. ORTEP diagram of the (Sa)-diastereomer of bis-(S)-camphor-sulfonyl ester
15 (CCDC-1035719). Ellipsoids are at 50% probability and hydrogen atoms are
omitted for the sake of clarity.
Removal of the camphor sulfonyl group was performed using
NaBH4 in an ethanol medium at 0 °C to room temperature. This
reaction presumably takes place via reduction of the ketone. The

82
H. Ghosh et al. / Tetrahedron: Asymmetry 26 (2015) 79–84
resulting alcohol then attacks the camphorsulfonic ester leading to
the free catechol 2 and the cyclic sulfonic ester. Thus, we were able
to obtain both (Sa)-2 and (Ra)-2 in higher than 99% ee and 80%
yield.
With ligand 2 in hand the asymmetric aldol reaction shown in
Scheme 2 was again used as a testing ground. The reaction lasted
four days and afforded the product in 34% yield. However, in this
instance the ee of the product was 28%. While the yield and enan-
tiomeric excess for this reaction are not satisfactory, these results
do show the effect of a fluorinated versus non-fluorinated ligand.
This may be attributed to the effects suggested earlier33 or simply
to the higher Lewis acidity of complex 8 with ligand 2 as compared
to the one with ligand 1.
After stirring at room temperature for a period of 30 min under
an argon atmosphere, the reaction vessel was placed in a preheated
oil bath (100 °C) and heating was continued for 24 h under an
argon atmosphere. The progress of the reaction was monitored
by TLC. After completion of the reaction, it was diluted with
10 mL of ethylacetate and filtered through a Celite pad. The organic
layer was then evaporated and extracted with ethylacetate (10 mL)
from water. The organic layer was dried over anhydrous sodium
sulfate and the pure product was purified by silica gel column
chromatography using hexane and ethyl acetate as eluent and iso-
lated as a solid (0.259 g and 70% yield). 1H NMR (400 MHz, CDCl3) d
7.90 (m, 2H), 7.51 (t, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.24 (m,
1H), 7.17 (t, J = 8.0 Hz, 2H), 6.96 (m, 4H), 6.44 (d, J = 8.0 Hz, 1H),
6.09 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 3.40 (s, 3H), 13C
NMR (100 MHz, CDCl3) d 150.9, 146.8, 146.6, 142.9, 141.0, 134.8,
132.2, 130.6, 130.1, 129.1, 128.9, 128.8, 128.6, 127.2, 126.3,
126.1, 126.0, 124.8, 124.6, 112.2, 104.7, 60.2, 56.6, 55.3, HRMS
(ES+) calcd for C25H23O3 (M+H) 371.1647, found 371.1598.
3. Conclusion
In conclusion, we have synthesized new types of axially chiral
catechol 1,8-diaryl naphthalene ligands, which were resolved in
an efficient and practical manner. There are very few methods
known for the resolution of this type of molecule. The fluorinated
ligand 2 shows chiral induction in the titanium catalysed asym-
metric Mukaiyama Aldol reaction whereas the non-fluorinated
ligand 1 lacks any chiral induction. This result indicates that fur-
ther studies into the use of fluorinated ligands in catalytic asym-
metric synthesis would be of scientific value.
4.1.2. Procedure for the deprotection of 6 to rac-1
The reactant 6 (0.37 g, 1 mmol and 1 equiv) was dissolved in
dry DCM (10 mL) under an argon atmosphere and was cooled to
À78 °C with the help of a dry ice-acetone bath. Next BBr3 [1(M)
solution in DCM] (1 mL, 1 mmol and 1.0 equiv) was added drop-
wise for a period of 30 min. The reaction mixture was stirred over-
night while it warmed slowly to reach room temperature. The
reaction mixture was then quenched with methanol at 0 °C and
then the solvent was evaporated. The product was extracted with
ethyl acetate from water and dried over anhydrous sodium sulfate.
The crude product was purified through a short column of silica gel
using hexane and ethyl acetate as eluent to afford a solid (0.267 g
and 78% yield). 1H NMR (400 MHz, CDCl3) d 7.92 (d, J = 8.0 Hz, 1H),
7.86 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz,
1H), 7.22 (m, 2H), 6.95 (m, 5H), 6.36 (d, J = 8.0 Hz, 1H), 5.84 (d,
J = 8.0 Hz, 1H), 4.68 (br s, 1H), 4.62 (br s, 1H), 3.43 (s, 3H), 13C
NMR (100 MHz, CDCl3) d 149.9, 142.0, 140.7, 139.8, 137.8, 135.4,
131.8, 130.2, 130.1, 129.8, 129.0, 128.7, 128.1, 126.7, 126.5,
126.4, 125.8, 125.3, 119.2, 113.6, 102.1, 55.3, HRMS (ES+) calcd
for C23H19O3 (M+H) 343.1334, found 343.1326.
4. Experimental
4.1. General
All non-aqueous reactions were carried out using oven-dried
(120 °C) or heat gun dried glassware under a positive pressure of
dry argon unless otherwise noted. All other commercially available
reagents were used without further purification. Unless indicated
otherwise, reactions were stirred magnetically and monitored by
thin layer chromatography using Merck Silica Gel 60 F254 plates
and visualized by fluorescence quenching under UV light. In addi-
tion, TLC plates were stained using potassium permanganate.
Chromatographic purification of products (flash chromatography)
was performed on silica 32–63, 60 Å using a forced flow of eluent
at 0.3–0.5 bar. Concentration under reduced pressure was per-
formed by rotary evaporation at 40 °C at the appropriate pressure.
Yields refer to chromatographically purified compounds. NMR
spectra were recorded on Bruker Avance III 400 spectrometers
operating at 400 MHz (1H) and 100 MHz (13C). Chemical shifts (d)
are reported in ppm with the solvent resonance as the internal
standard relative to chloroform (d 7.26) 1H, and chloroform (d
77.0) for 13C. All 13C NMR spectra were measured with complete
proton decoupling. Data are reported as follows: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad signal;
coupling constants in Hz. High resolution mass spectra were
recorded by the MS service at Technion. ESI-MS (m/z): was
recorded on a Waters Micromass LCT premier instrument at
70 eV in the positive or negative mode. APCI was recorded on the
same instrument using 70% acetonitrile/30% water at 0.2 mL
flowrate.
4.1.3. Procedures for the resolution of the phenylnaphthalene
ligands 1 and ent-1
The racemic diol (0.342 g and 1.0 mmol) and (S)-proline
(0.115 g and 1.0 mmol) were added to acetonitrile (2 mL). The mix-
ture was refluxed for 3 h, and then cooled to room temperature. A
white precipitate formed from the solution. The precipitate was fil-
tered through a sintered funnel. The solid was added to a 3:2 (v/v)
mixture of ethyl acetate and water and stirred at room tempera-
ture for 3 h. The solid was completely dissolved, the organic layer
was separated and the water phase was extracted with ethyl ace-
tate (10 mL). The organic layers were combined, dried over anhy-
drous Na2SO4 and evaporated to remove the solvents. The
residue was repeatedly recrystallized in toluene to afford 1 as a
shiny solid, with an overall yield of 45% and with >99% ee. The ace-
tonitrile filtrate was evaporated and the residue was repeatedly
recrystallized in toluene. The overall yield of ent-1 was 40% with
86% ee. The ee was determined by chiral stationary phase HPLC
analysis Chiral Lux 5u Cellulose-2 column, isopropanol/hexane
(10:90), 1 mL/min, k = 254 nm, tR: 20.7 min and 24.6 min.
4.1.1. Preparation of 1-phenyl-8-(2,3,6-trimethoxyphenyl)
naphthalene 6
Iodonaphthalene 4 (0.33 g, 1 mmol and 1 equiv), boronic acid 5
(1.06 g, 5 mmol and 5 equiv) and K3PO4 (1.272 g, 6 mmol and
6 equiv) were added to dry DMF (10 mL) and the mixture was
degassed for a period of 1 h. Next, granular molecular sieves
(4 Å) were added and finally tetrakis(triphenylphosphine)palla-
dium(0) catalyst (0.1155 g, 0.1 mmol and 10 mol %), was added.
4.1.4. Characterization of the 4-methoxy-3-(8-phenylnaphthal-
ene-1-yl)benzene-1,2-diol 1 complex with (S)-proline
1H NMR (400 MHz, CD3OD) d 7.90 (m, 2H), 7.50 (m, 1H), 7.43
(m, 1H), 7.20 (m, 1H), 7.12 (m, 2H), 7.04 (m, 1H), 6.92 (m, 3H),
6.31 (t, J = 8.2 Hz, 1H), 5.81 (d, J = 8.2 Hz, 1H), 4.87 (s, 3H), 3.97
(dd, J = 8.6, 6.3 Hz, 1H), 3.41 (s, 1H), 3.37 (m, 1H), 3.22 (m, 1H),

H. Ghosh et al. / Tetrahedron: Asymmetry 26 (2015) 79–84
83
2.29 (ddd, J = 7.4 Hz, 1H), 2.11 (ddd, J = 6.5 Hz, 1H), 1.96 (m, 2H),
13C NMR (100 MHz, CD3OD) d 173.9, 144.1, 143.6, 142.5, 139.8,
136.5, 133.6, 132.5, 132.1, 130.8, 129.8, 129.6, 129.5, 129.4,
127.3, 127.1, 127.0, 126.2, 125.3, 121.4, 114.5, 101.8, 62.7, 55.4,
47.0, 30.4, 25.1.
The crude product was purified by column chromatography using
hexane and ethyl acetate as the eluent to afford a solid (0.358 g,
yield 83%). 1H NMR (400 MHz, CDCl3) d 8.06 (m, 2H), 7.61 (m,
2H), 7.40 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.69 (d,
J = 8.0 Hz, 1H), 6.09 (d, J = 8.0 Hz, 1H), 4.97 (br s, 1H), 4.81 (br s,
1H), 3.46 (s, 3H), 13C NMR (100 MHz, CDCl3) d 150.7, 140.9,
138.2, 135.5, 132.1, 131.7, 131.6, 131.1, 130.7, 128.8, 126.2,
125.4, 123.5, 117.2, 113.9, 101.2, 55.1, 19F NMR (400 MHz, CDCl3)
À138.2, À140.3, À156.1, À164.3, À164.5, HRMS (AP+) calcd for
4.1.5. Procedure for the Ullmann coupling for the preparation
of 13
To a solution of 1,8-diiodonaphthalene 3 (1.14 g, 3 mmol) in
DMSO (0.5 mL) was added iodoperfluorobenzene (1.76 g and
6 mmol). To this mixture was added copper powder (0.473 g and
7.5 mmol) and the reaction mixture was heated at 160 °C in an
oil bath for 5 h with constant stirring. The reaction mixture was
cooled and diluted with ethylacetate (30 mL) and then filtered
through a sintered funnel. The organic layer was then evaporated
onto Celite and the product was purified by column chromatogra-
phy (100% hexane as the eluent). The product was isolated as a
solid in 85% yield (1.07 g), 1H NMR (400 MHz, CDCl3) d 8.25 (d,
J = 4.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H),
7.57 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz,
1H), 13C NMR (100 MHz, CDCl3) d 146.5, 144.0, 143.1, 142.1,
142.8, 140.5, 139.2, 136.7, 135.5, 132.5, 132.1, 131.5, 130.6,
127.3, 125.4, 124.9, 115.6, 90.3, 19F NMR (400 MHz, CDCl3)
À139.1, À155.1, À163.1, HRMS (AP+) calcd for C16H6F5I (M)
419.9434, found 419.9432.
C23H14F5O3 (M+H) 433.0863, found 433.0858.
4.1.8. Procedure for the synthesis of sulfonate esters 15 and 16
Triethylamine (0.42 mL and 3 mmol) was added to a solution of
rac-2 (0.432 g, 1 mmol and 1 equiv) in DCM (10 mL) under ice-cold
conditions. (1S)-(+)-10-Camphor sulfonyl chloride (0.75 g and
3 mmol) was then added in one portion. The reaction was allowed
to reach room temperature and stirred at ambient temperature
overnight. The completion of the reaction was confirmed by TLC.
The reaction mixture was diluted with the addition of 10 mL of
DCM and washed with 10% HCl solution (10 mL). The organic layer
was dried over anhydrous sodium sulfate and evaporated. The
crude product is a mixture of two diastereomers. The diastereo-
meric mixture of the sulfonate esters 15 and 16 (Rf separation of
0.07 in the solvent mixture CHCl3/Et2O (5:0.2) ratio) was separated
by silica gel column chromatography using chloroform and diethyl
ether as the eluents. (Sa)-15: 0.344 g, 40% yield and (Ra)-16:
0.344 g, 40% yield.
4.1.6. Procedure for the Suzuki–Miyaura coupling for the pre-
paration of 14
Diastereomer 15: 1H NMR (400 MHz, CDCl3) d 8.07 (d, J = 8.0 Hz,
1H), 8.01 (d, J = 8.0 Hz, 1H), 7.58 (m, 2H), 7.41 (m, 2H), 7.32 (d,
J = 8.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 3.88 (d, J = 12.0 Hz, 1H),
3.69 (s, 3H), 3.61(d, J = 12.0 Hz, 1H), 2.86 (d, J = 16.0 Hz, 1H), 2.43
(m, 2H), 2.10 (m, 4H), 1.95 (m, 3H), 1.76 (m, 3H), 1.44 (m, 1H),
1.24 (m, 2H), 1.13 (s, 3H), 0.93 (s, 6H), 0.67 (s, 3H), 13C NMR
(100 MHz, CDCl3) d 213.7, 213.4, 155.7, 139.8, 135.7, 134.9,
132.8, 132.0, 131.5, 130.8, 130.6, 128.7, 126.5, 125.5, 125.2,
122.6, 108.3, 58.4, 57.9, 56.0, 49.4, 49.3, 48.2, 47.6, 43.2, 43.1,
42.6, 42.3, 27.0, 26.8, 25.6, 24.9, 19.9, 19.8, 19.6, 19F NMR
(400 MHz, CDCl3) À137.8, À138.7, À154.5, À159.8, À164.5, HRMS
(ES+) calcd for C43H42F5O9S2 (M+H) 861.2190, found 861.2178. The
X-ray data can be obtained from Cambridge Crystallographic Data
Centre registration number: CCDC 1035719.
Iodonaphthalene 13 (0.42 g, 1 mmol and 1 equiv), boronic acid
5 (1.06 g, 5 mmol and 5 equiv) and K3PO4 (1.27 g, 4 mmol and4 e-
quiv) were added to dry DMF (10 mL) and the mixture was
degassed for 1 h. Then, freshly activated granular molecular sieves
(4 Å) were added followed by tetrakis(triphenylphosphine)palla-
dium(0) catalyst (0.116 g, 0.1 mmol, 10 mol %). After stirring at
room temperature for 30 min under an argon atmosphere, the
reaction vessel was placed in a preheated oil bath (100 °C) and
heating was continued for 24 h under an inert atmosphere. The
progress of the reaction was monitored by TLC. After completion
of the reaction, it was diluted with 10 mL of ethyl acetate and fil-
tered through a Celite pad. The organic layer was concentrated
and extracted from water with ethyl acetate (10 mL). The organic
layer was dried over anhydrous sodium sulfate and the pure
product (0.115 g, 25% yield) was separated by silica gel column
chromatography using hexane and ethyl acetate as eluent.
Diastereomer 16: 1H NMR (400 MHz, CDCl3) d 8.03 (m, 2H), 7.60
(m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.29 (m,
1H), 6.68 (d, J = 8.0 Hz, 1H), 3.90 (d, J = 16.0 Hz, 1H), 3.67 (s, 3H),
3.46 (d, J = 12.0 Hz, 1H), 2.53 (m, 1H), 2.41 (m, 1H), 2.10 (m, 5H),
1.85 (m, 5H), 1.48 (m, 2H), 1.26 (m, 2H), 1.14 (s, 3H), 0.88 (s,
3H), 0.75 (s, 3H), 0.59 (s, 3H), 13C NMR (100 MHz, CDCl3) d 213.8,
213.3, 155.8, 139.9, 135.7, 134.9, 133.2, 131.8, 131.5, 130.8,
130.5, 128.7, 126.5, 125.9, 125.1, 123.1, 122.3, 108.2, 58.2, 58.0,
55.9, 49.7, 49.1, 48.2, 47.7, 43.0, 42.6, 42.4, 31.7, 27.2, 26.8, 25.3,
25.1, 22.8, 19.7, 19.6, 19.5, 19.4, 14.3, 19F NMR (400 MHz, CDCl3)
À138.2, À138.7, À154.5, À160.4, À164.4, HRMS (ES+) calcd for
1H NMR (400 MHz, CDCl3)
d 8.04 (d, J = 8.0 Hz, 1H), 7.96
(d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H),
7.32 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz,
1H), 6.35 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 3.54 (s, 3H), 3.47 (s, 3H),
13C NMR (100 MHz, CDCl3) d 151.6, 147.9, 146.7, 135.1, 131.4,
131.3, 131.27, 131.20, 131.0, 129.4, 125.4, 125.3, 124.6, 123.5,
112.2, 103.9, 60.6, 56.4, 55.3, 19F NMR (400 MHz, CDCl3) À136.4,
À139.4, À157.7, À164.7, À165.2. HRMS (AP+) calcd for
C25H18F5O3 (M+H) 461.1176, found 461.1170. The X-ray data can
C43H42F5O9S2 (M+H) 861.2190, found 861.2184.
be obtained from the Cambridge Crystallographic Data Centre
registration number: CCDC 1035718.
4.1.9. Deprotection of the sulfonate ester 15 or 16 to
enantiopure (Sa)-2 or (Ra)-2
4.1.7. Procedure for the deprotection of 14 to rac-2
In a 25 mL round bottom flask, sulfonate ester 15 (0.43 g and
0.5 mmol) was dissolved in ethanol (10 mL). The flask was placed
in a cooling bath to maintain the temperature at À15 °C to
À20 °C with the help of ice and salt. Next sodium borohydride
(0.185 g, 5 mmol) was added portionwise. The reaction mixture
was stirred allowing the temperature to slowly reach room
temperature. The progress of the reaction was monitored by TLC.
After completion of the reaction, saturated ammonium chloride
solution (1 mL) was added to the reaction mixture and then stirred
for one hour. The product was extracted from water (10 mL) with
Compound 14 (0.460 g, 1 mmol and 1 equiv) was dissolved in
dry DCM (10 mL) under an argon atmosphere and cooled to
À78 °C with a dry ice-acetone mixture. Next, a solution of BBr3 in
DCM (1 mL, 1 mol/L, 1 mmol and 1 equiv) was added dropwise
over a period of 30 min. The reaction mixture was stirred over
night while being warmed slowly to reach room temperature.
The reaction mixture was quenched with methanol at 0 °C and
then the solvent was evaporated. The product was extracted from
water with ethyl acetate and dried over anhydrous sodium sulfate.

84
H. Ghosh et al. / Tetrahedron: Asymmetry 26 (2015) 79–84
ethyl acetate (20 mL). The organic layer was dried over anhydrous
sodium sulfate and evaporated and the product (Sa)-2 was purified
by column chromatography using hexane and ethyl acetate as elu-
ent and isolated as a solid (0.345 g, 80% yield). Compound (Ra)-2
was produced in an identical yield from 16 using this procedure.
The ee was determined by chiral stationary phase HPLC analysis
CHIRALPAKÒ OD-H HPLC Analytical Columns column, isopropa-
nol/hexane (10:90), 1 mL/min, k = 254 nm, tR: 23.0 min and
24.6 min.
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added to the reaction mixture at À42 °C. The reaction mixture
was stirred at this temperature for 4 days. The reaction mixture
was quenched with ammonium chloride solution, diluted with
dichloromethane, and filtered. The product was hydrolysed with
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out using ligand 1 on the same scale, the product was isolated in
30% yield (8 mg) in racemic form. The ee of the products were
determined by chiral stationary phase HPLC analysis using a Lux
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(15:85), 1 mL/min, k = 254 nm, tR: 19.1 min (minor), 23.9 min
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Acknowledgement
This research was supported by an Israel Science Foundation
FIRST Grant (Grant No. 1636/11).