Synthesis of Optically Pure 3,3′-Disubstituted-1,1′-Bi-6-Methoxy-2-Phenol (BIPhOL) Derivatives via Diastereomeric Resolution

Article abstract of DOI:10.1021/acs.joc.6b01645

A new protocol for the enantioselective synthesis of 3,3′-disubstituted-1,1′-bi-6-methoxy-2-phenol (BIPhOL) derivatives is described. Diastereomeric resolution of racemic BIPhOL boronic acid using a boronic acid moiety as a resolving group generated two diastereomers and subsequent Suzuki-Miyaura coupling reaction of the resulting diastereomers with aryl halides provided BIPhOL derivatives without any loss of enantioselectivity. In addition, the absolute stereochemistry of chiral BIPhOL was determined by comparison of the optical rotation with the reported value.

Full text of DOI:10.1021/acs.joc.6b01645

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Article
Synthesis of Optically Pure 3,3’-Disubstituted-1,1’-Bi-6-Methoxy-2-
Phenol (BIPhOL) Derivatives via Diastereomeric Resolution
Jung Min Yoon, Chun-Young Lee, Young-In Jo, and Cheol-Hong Cheon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01645 • Publication Date (Web): 25 Aug 2016
Downloaded from http://pubs.acs.org on August 26, 2016
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Synthesis of Optically Pure 3,3’-Disubstituted-1,1’-Bi-6-
Methoxy-2-Phenol (BIPhOL) Derivatives via
Diastereomeric Resolution
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Jung-Min Yoon, Chun-Young Lee, Young-In Jo, and Cheol-Hong Cheon*
Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841,
Republic of Korea, Phone: +82-2-3290-3147; Fax: +82-2-3290-3121; E-mail:
cheon@korea.ac.kr
Abstract: A new protocol for the enantioselective synthesis of 3,3’-disubstituted-1,1’-bi-6-
methoxy-2-phenol (BIPhOL) derivatives is described. Diastereomeric resolution of racemic
BIPhOL boronic acid using a boronic acid moiety as a resolving group generated two
diastereomers and subsequent Suzuki-Miyaura coupling reaction of the resulting
diastereomers with aryl halides provided BIPhOL derivatives without any loss of
enantioselectivity. In addition, the absolute stereochemistry of chiral BIPhOL was determined
by comparison of the optical rotation with the reported value.
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Introduction
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Since the first use of chiral 1,1’-bi-2-naphthol (BINOL, 1) as a ligand in metal-
mediated asymmetric catalysis in 1979,1 optically active 2,2’-dihydroxy-1,1’-biaryls (A,
Figure 1) have been widely used as privileged ligands in various transition metal-catalyzed
asymmetric reactions.2,3 More recently, they have been utilized in asymmetric organocatalysis
as either hydrogen bonding catalysts or chiral frameworks in chiral phosphoric acid
catalysts.4,5 Since the outcomes of given asymmetric transformations with axially chiral biaryl
diols (A) show a strong dependence on their steric and electronic natures, considerable efforts
have been made to control the steric and electronic properties of these axially chiral
compounds.
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A
(a) general structure of axially chiral biaryl diols ( )
Y
R
Controlling Parameters
1. Effect of substituents
well studied
X
X
OH
OH
Effect of dihedral angles
2.
far less investigated
Y
R
A
(b) examples of axially chiral biaryl diols with different dihedral angles
R
R
R
R
O
O
O
OH MeO
OH MeO
OH
OH
OH
OH
OH
OH
O
R
R
R
R
2
3 4
(R)-BIPhOL ( ) (R)-BISESAMOL ( )
(R)-[H]8-BINOL ( )
1
(R)-BINOL ( )
Figure 1. (a) General Structure of Axially Chiral Biaryl Diols (A) and (b) Representative
Examples of Axially Chiral Biaryl Diols
One of the ways to tune the steric and electronic natures of axially chiral biaryl diols
(A) is incorporation of different substituents at the periphery of the chiral axis, particularly at
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the 3,3’-positions; as such, various axially chiral biaryl diol derivatives bearing different
substituents have been prepared and applied to a number of asymmetric protocols.6 In
addition to substituent effects, the dihedral angle along the chiral axis in axially chiral biaryl
diols has been found to exert a pronounced influence on the outcome of asymmetric
transformations with these compounds. For instance, chiral phosphoric acids, derived from
BINOL (1) and 1,1’-bi(5,5,6,6,7,7,8,8-octahydro-2-naphthol) ([H]8-BINOL, 2) derivatives
bearing the same substituents at the 3,3’-positions afforded significantly different results in
asymmetric synthesis.7
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However, the effects of the dihedral angles on the efficiency of asymmetric reactions
with axially chiral biaryl diols (A) have been far less investigated as compared to substituent
effects on the efficiency of asymmetric reactions. This poor exploration of the influence of
dihedral angles in axially chiral biaryl diols (A) on the asymmetric reactions might be due to
the lack of reliable synthetic routes to access axially chiral biaryl diol derivatives other than
BINOL and [H]8-BINOL derivatives; although the enantioselective synthesis of the parent
1,1’-bi-6-methoxy-2-phenol (BIPhOL, 3) and 1,1’-bi-2-sesamol (BISESAMOL, 4) have been
reported a couple of times,8-11 there are few general synthetic routes that can be used to access
these axially chiral biaryl diol derivatives, and thus few derivatives of chiral BIPhOL 3 and
BISESAMOL 4 have been prepared.
Herein, we describe the development of a new synthetic route to access optically pure
3,3’-disubstituted BIPhOL derivatives 3. Diastereomeric resolution of racemic BIPhOL
boronic acid using a boronic acid moiety as a resolving group generated two diastereomers,
which could be readily separable by a conventional separation technique. Subsequent Suzuki-
Miyaura coupling reaction of the resulting diastereomers with aryl halides provided the
desired BIPhOL derivatives in good yields. The absolute stereochemistry of chiral BIPhOL
was determined by comparison of the optical rotation of the resulting optically active BIPhOL
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with the reported value and the absolute stereochemistry of all other derivatives was assigned
by analogy.
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Results and Discussion
To date, the enantioselective synthesis of chiral BIPhOL itself has been reported
several times8-11 mainly via diastereoselective resolution8,9 or kinetic resolution10 of rac-
BIPhOL, where the phenolic hydroxy groups are used as resolving groups. However, it might
be difficult to develop a protocol to access optically pure BIPhOL derivatives bearing
substituents at the 3,3’-positions based on previous methods since these previous methods
required multistep synthetic sequences to access parent chiral BIPhOL and additional
synthetic steps are needed to introduce substituents at the 3,3’-positions. Thus, it is desired to
develop a new approach to access these derivatives.
Our group developed a new approach to access axially chiral biaryl compounds via the
diastereomeric resolution where a boronic acid moiety acts as a diastereomeric resolving
group and a masked functional group to introduce other functional groups.12 This protocol
was successfully applied to the synthesis of (R)- and (S)-3,3’-diaryl BINOL derivatives12(a)
,
and oxidation-divergent total syntheses of some natural products,12(b) respectively. In an effort
to enantioselectively synthesize biaryl compounds bearing an axial chirality using this
approach, we attempted to further apply our diastereomeric resolution protocol to the
synthesis of chiral 3,3’-disubstituted BIPhOL derivatives 3.
The retrosynthetic analysis of the enantioselective synthesis of 3,3’-disubstituted
BIPhOL derivatives 3 is depicted in Scheme 1. Both (R)- and (S)-BIPhOL derivatives could
be prepared by Suzuki-Miyaura coupling reaction of the optically pure boronic acids, (R)- and
(S)-5, which could be prepared by the diastereomeric resolution of racemic biaryl boronic acid
(rac-5) using a boronic acid moiety as a resolving group. rac-5 could be prepared via
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dimerization of resorcinol 6 with a proper protecting group, followed by the installation of
boronic acid moieties at the 3,3’-position. We initially planned to introduce the boronic acid
functional groups at the 3,3’-positions in rac-5 via directed ortho-metalation followed by
electrophilic borylation with a trialkyl borate. Since a methoxymethyl (MOM) group is
known to exhibit a stronger ortho directing ability than a methoxy group,13 we decided to use
a MOM group as the protecting group in compound 6.
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R
R
MeO
MeO
OH
OH
MeO
MeO
OH
OH
+
MeO
OP
R
R
6
(R)-3
3
(S)-
Suzuki reaction;
then, deprotection
dimerization
B(
OH
)
B(
OH
)
B( )
OH
2
2
2
diastereomeric
resolution
MeO
MeO
OP
OP
MeO
MeO
OP
OP
MeO
MeO
OP
OP
+
B(OH)2
B(OH)2
B(OH)2
5
(S)-
(R)-5
5
rac-
Scheme 1. Retrosynthetic Analysis
Based on these considerations, our synthesis commenced with the preparation of rac-5
(Scheme 2). The reaction of methoxy-protected resorcinol 7 with MOM chloride in the
presence of a base provided MOM-protected compound 6 in 92% yield. Directed lithiation at
the 2-position of 6 with n-BuLi and subsequent dimerization of the resulting organolithium
species in the presence of FeCl3 afforded biaryl compound 814 after an acidic aqueous work-
up. Unfortunately, some of the MOM group in compound 8 was hydrolyzed under the acidic
conditions, leading to the concomitant formation of rac-BIPhOL (rac-3).
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Scheme 2. Synthesis of rac-Boronic Acid, rac-5. TMEDA
=
1,1,2,2-
tetramethylethylenediamine, NBS = N-bromosuccinimide, DMF = N,N-dimethylformamide,
Bn = benzyl.
Next, we investigated the possibility of introducing a boronic acid moiety via directed
ortho-metalation of 8 with n-BuLi using the MOM group as the ortho-directing group
followed by trapping the resulting organolithium species with trimethyl borate. However, the
directed ortho-metalation protocol was not successful; most of starting compound 8 remained
unreacted and only a trace amount of mono-boronic acid was obtained. Alternatively, a
boronic acid functional group could be introduced from the corresponding halide via metal-
halogen exchange followed by electrophilic borylation of the resulting organometallic species
with a trialkyl borate, and thus we decided to introduce bromide groups at the 3,3’-positions
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as precursors for boronic acid moieties. When compound 8 was treated with NBS,
unfortunately, bromination took place without any regioselectivity, leading to a complex
mixture of different regioisomers.
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Since a phenolic hydroxy group is known as a better directing group than the
corresponding alkoxy group in electrophilic aromatic substitution (EAS) reactions15 and some
of the MOM group in compound 8 was hydrolyzed during the acidic work-up, the MOM
group was converted into a free hydroxy group via treatment with aqueous acidic solution
affording parent BIPhOL 3 as a racemate in 83% yield from compound 6 over two steps.
When compound 3 was subjected to bromination with NBS, 3,3’-dibrominated compound 9
was obtained in 70% yield with perfect regioselectivity. Subsequent protection of the phenolic
hydroxy group with benzyl bromide afforded compound 10 in 95% yield. Bromide-lithium
exchange of 10 with n-BuLi followed by trapping of the resulting organolithium species with
B(Oi-Pr)3 afforded rac-5 in 77% yield.
With rac-5 in hand, we explored the diastereomeric resolution of rac-5 with chiral
ligand 1116-18 using a boronic acid as a resolving group (Scheme 3).12 To our delight, the
reaction of rac-5 with chiral ligand 11 provided the two diastereomers (12 and 12’), both in
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43 % yields, which could be readily separated by column chromatography on silica.
Furthermore, this diastereomeric resolution could be performed on a gram-scale (10 mmol
scale) without any loss in efficiency.20
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*R
*R
N
N
O
O
B
11 (3 equiv)
DMSO/toluene
4A MS, 120 oC, 12 h
B
O
O
O
O
O
O
MeO
MeO
OBn
OBn
MeO
MeO
OBn
OBn
rac-5
+
Dean-Stark distillation
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R*
O
O
O
O
B
N
B
N
O
O
N
CO2H
HO2C
R* =
*R
*R
O
O
12 (43%)
12' (43%)
OBn
11
Scheme 3. Diastereomeric Resolution of rac-5 with Chiral Ligand 11.
In order to determine the absolute stereochemistry of the resulting diastereomeric
compounds (12 and 12’), the resulting diastereomers were converted into the enantiomers of
BIPhOL 3, since the absolute stereochemistry of the parent chiral BIPhOL was reported11
(Scheme 4).
a
Scheme 4. Determination of Absolute Stereochemistry of the Resulting Enantiomers.
A
b
mixture of hexanes/ethyl acetate (1:1) was used as the eluent. % ee was determined by
HPLC analysis using a Chiralcel AS-H column. c For the reported [α]D value of (S)-3, see ref.
11.
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Treatment of each diastereomer (either 12 or 12’) with a basic solution provided the
corresponding chiral boronic acid. Subsequent thermal protodeboronation of the resulting
boronic acid with acetic acid in 1,4-dioxane,21 followed by the removal of a benzyl group via
hydrogenolysis provided the parent BIPhOL with excellent enantioselectivity (>98% ee for
each enantiomer). Comparison of the optical rotation of the resulting enantiomer with the
reported value of the known enantiomer22 allowed us to assign the absolute stereochemistry of
the resulting enantiomers of the parent BIPhOL; the less polar diastereomer 12 was derived
from (R)-BIPhOL, while the more polar diastereomer 12’ was from (S)-BIPhOL.
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a
Scheme 5. Synthesis of Chiral BIPhOL Derivatives. Ee was determined by HPLC analysis
using a Chiralcel AD-H column.
Next, we further attempted to prepare chiral BIPhOL derivatives through Suzuki-
Miyaura coupling reaction of the resulting diastereomers with aryl bromides, followed by
deprotection of the benzyl group (Scheme 5). When chiral boronate 12 was subjected to
Suzuki-Miyaura coupling reaction with phenyl bromide, to our delight, the Suzuki reaction
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proceeded smoothly to provide the desired (R)-BIPhOL derivative, (R)-3a, in a good yield and
excellent enantiopurity12a after the removal of the benzyl group. In addition, when the other
diastereomer 12’ was subjected to Suzuki-Miyaura coupling reaction with phenyl bromide,
the (S)-BIPhOL derivative, (S)-3a, was obtained with a similar efficiency. It should be noted
that all transformations could be accomplished without any loss of enantioselectivity. Under
these conditions, other aryl bromides were subjected to Suzuki-Miyaura coupling reaction
with 12 and the chiral BIPhOL derivatives, (R)-3b and (R)-3c, were obtained in similar
efficiencies regardless of electronic natures of the aryl groups. Furthermore, chiral ligand 11
used for the resolution could be readily recovered in quantitative yield by re-dissolving chiral
ligand 11 with acetone from the concentrated crude product of 11 from the aqueous layer after
the extraction.20 The recovered chiral ligand could be directly re-applied to diastereomeric
resolution of rac-5 without any loss of efficiency.
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Conclusions
In conclusion, we have developed a new synthetic protocol to access chiral 3,3’-disubstituted
BIPhOL derivatives via the diastereomeric resolution of racemic BIPhOL boronic acid using
a boronic acid moiety as a resolving group followed by Suzuki-Miyaura coupling reaction of
the resulting diastereomers with aryl bromides. The desired BIPhOL derivatives bearing aryl
groups at the 3,3’-positions were obtained in good yields and with excellent
enantioselectivities. Furthermore, the absolute stereochemistry of the resulting chiral BIPhOL
derivatives was determined by comparison of the optical rotation of the resulting BIPhOLs
with the reported value. Further development of the synthesis of novel axially chiral biaryl
diols and novel asymmetric transformations with these diol compounds are currently
underway in our laboratory.
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Experimental Section
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General. All reactions were carried out in oven- or flame-dried glassware under an argon
atmosphere unless otherwise noted. Except as otherwise indicated, all reactions were
magnetically stirred and monitored by analytical thin layer chromatography (TLC) using pre-
coated silica gel glass plates (0.25 mm) with F254 indicator. Visualization was accomplished
by UV light (254 nm), with combination of potassium permanganate and/or phosphomolybdic
acid solution as an indicator. Flash column chromatography was performed using silica gel 60
(230 – 400 mesh). Yields refer to chromatographically and spectroscopically pure
compounds, unless otherwise noted. Commercial grade reagents and solvents were used
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without further purification. H NMR and C{1H} NMR spectra were recorded on 300/400
MHz, 75/100 MHz, respectively. Tetramethylsilane and CDCl3 were used as internal
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standards for H NMR (δ: 0.0 ppm) and C NMR (δ: 77.0 ppm), respectively. The proton
spectra are reported as follows: chemical shift ppm, multiplicity, coupling constant J, number
of protons. Multiplicities are indicated by s (singlet), d (doublet), t (triplet), m (multiplet) and
br (broad). High performance liquid chromatography (HPLC) was performed by using chiral
columns (0.46 cm x 250 mm) with 2-propanol/hexane as the eluent. High resolution mass
spectra (HRMS) were measured on a Q-TOF spectrometer using electron spray ionization
(ESI) as the ionization method. Optical rotations were measured using a 1 mL cell with 10
mm path length on an automatic polarimeter and reported as follows: [α]25 (c: g/100 mL, in
D
solvent).
Synthesis of 1-methoxy-3-(methoxymethoxy)benzene (6): To a solution of 3-methoxyphenol 7
(12.4 g, 100 mmol) in DMF (300 mL) was added NaH (4.8 g, 120 mmol; 60 wt% powder) at
0 oC and the reaction mixture was warmed up to room temperature and stirred for additional 1
h. Then, methoxymethyl (MOM) chloride (8.4 mL, 110 mmol) was added dropwise to the
reaction mixture. After complete consumption of compound 7, the reaction mixture was
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quenched by the addition of H2O and extracted with ethyl acetate. The organic layer was
combined, dried over MgSO4, and concentrated. The crude mixture was purified by short
flash column chromatography on silica (hexanes/ethyl acetate=3:1) to provide the desired
product 6 as colorless oil in 92% yield (16 g). The spectroscopic data were in good agreement
with the literature.23 1H NMR (300 MHz, CDCl3, ppm) δ 7.18 (t, J = 8.1 Hz, 1H), 6.52 - 6.68
(m, 3H), 5.16 (s, 2H), 3.78 (s, 3H), 3.47 (s, 3H).
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Synthesis of rac-BIPhOL (rac-3): To a mixture of compound 6 (7.1 g, 42 mmol) and TMEDA
(6.9 mL, 46 mmol) in THF was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL,
46 mmol) at -78 oC. Then, the reaction mixture was warmed up to room temperature and
stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0
oC and FeCl3 (8.2 g, 50 mmol) was added to the reaction mixture in one portion at 0 oC. The
reaction mixture was warmed to room temperature and stirred for 12 h. After 12 h, aqueous
HCl solution (1 N, 50 mL) was added to the reaction mixture to quench the remaining FeCl3.
The organic phase was extracted with ethyl acetate and the organic layers were combined,
dried over MgSO4, and concentrated to provide the desired product 8 along with rac-BIPhOL
(rac-3). To a solution of the crude mixture in MeOH was added 3N HCl solution, and the
o
reaction mixture was stirred at 70 C for 1 h. After complete conversion of compound 8 into
rac-3, the reaction mixture was cooled to room temperature, concentrated under reduced
pressure, and extracted with ethyl acetate. The organic layer was combined, dried over
MgSO4, and concentrated. The crude mixture was purified by short flash column
chromatography on silica (hexanes/ethyl acetate=3:1) to afford the desired product rac-3 as a
yellowish green solid in 83% yield from compound 6 over two steps (4.3 g). The
o
1
spectroscopic data were in good agreement with the literature.8-11 mp 144-146 C. H NMR
(300 MHz, CDCl3, ppm) δ 7.31 (t, J = 8.3 Hz, 2H), 6.72 (d, J = 8.3 Hz, 2H), 6.62 (d, J = 8.3
Hz, 2H), 5.05 (s, 2H), 3.77 (s, 6H).
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Synthesis of 3,3'-dibromo-6,6'-dimethoxy-(1,1'-biphenyl)-2,2'-diol (9): A solution of N-
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bromosuccimide (NBS, 5.7 g, 32 mmol) in dichloromethane (50 mL) was added dropwise to a
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suspension of in rac-3 (3.9 g, 16 mmol) in dichloromethane (100 mL) at 0 C. The reaction
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mixture stirred at 0 C for 1 h and monitored by TLC. After complete consumption of rac-3,
the reaction mixture was quenched with saturated NaHSO4 aqueous solution and extracted
with dichloromethane. The organic layer was combined, dried over MgSO4, and concentrated.
The crude mixture was purified by flash column chromatography on silica (hexanes/ethyl
acetate=3:1) to provide the desired product 9 in 70% yield (4.5 g). The spectroscopic data
were in good agreement with the literature.9a mp 186-188 C. H NMR (300 MHz, CDCl3,
ppm) δ 7.48 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 9.1 Hz, 2H), 5.44 (s, 2H), 3.74 (s, 6H).
Synthesis of 2,2'-bis(benzyloxy)-3,3'-dibromo-6,6'-dimethoxy-1,1'-biphenyl (10): A solution of
compound 9 (4.4 g, 11 mmol) and CsCO3 (7.5 g, 23 mmol) in DMF (100 mL) was stirred for
30 min at room temperature. Benzyl bromide (2.8 mL, 23 mmol) was added dropwise to the
above reaction mixture, and the reaction mixture was stirred at room temperature. After
complete consumption of compound 9, the reaction mixture was poured into H2O, and
extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, and
concentrated. The crude mixture was purified by short column chromatography flash on silica
(hexanes/ethyl acetate=4:1) to yield the desired product 10 in 95% yield as a white solid (6.1
g). mp 92-94 oC. 1H NMR (300 MHz, CDCl3, ppm) δ 7.55 (d, J = 8.8 Hz, 2H), 7.15 - 7.25 (m,
6H), 6.95 - 7.05 (m, J = 2.6, 6.5 Hz, 4H), 6.64 (d, J = 9.1 Hz, 2H), 4.89 (d, J = 10.4 Hz, 2H),
4.67 (d, J = 10.7 Hz, 2H), 3.65 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 157.5,
154.3, 136.6, 132.3, 127.7, 127.6, 127.3, 119.4, 108.3, 108.0, 74.3, 55.7. HRMS (ESI) calcd
for C28H24Br2O4Na 604.9941, found 604.9937.
o
1
Synthesis of (2,2'-bis(benzyloxy)-6,6'-dimethoxy-[1,1'-biphenyl]-3,3'-diyl)diboronic acid (rac-
5): To a solution of compound 10 (11 g, 19 mmol) in Et2O was added slowly a solution of n-
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BuLi (2.5 M in hexane, 16 mL, 39 mmol) at -78 oC and the reaction mixture was stirred for 3
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h at -78 C. After complete consumption of compound 10, triisopropyl borate (10 mL, 94
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mmol) was added dropwise to the reaction mixture at -78 C. After the reaction mixture was
stirred for 1 h at -78 oC, the reaction mixture was warmed up to room temperature and stirred
for additional 6 h. After 6 h, the reaction mixture was quenched with H2O, and extracted with
ethyl acetate. The organic layers were combined, dried over MgSO4, and concentrated. The
crude mixture was purified by flash column chromatography on silica (hexanes/ethyl
acetate=1:1) to provide the desired product rac-5 in 77% yield as a white solid (7.4 g). mp not
10
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unavailable due to decomposition of 10 during the measurement. H NMR (300 MHz,
acetone-d6, ppm) 7.94 (d, J = 8.2 Hz, 2H), 7.20 (m, J = 5.8 Hz, 4H), 6.98 - 7.05 (m, 4H), 6.88
13
- 6.94 (m, 4H), 4.65 (d, J = 10.2 Hz, 2H), 4.51 (d, J = 10.2 Hz, 2H), 3.83 (s, 6H). C{1H}
NMR (100 MHz, acetone-d6, ppm) 205.6, 163.9, 161.6, 137.2, 136.8, 128.7, 128.4, 128.3,
117.4, 107.6, 76.4, 55.7. HRMS (ESI) calcd for C28H28B2O8 514.1970, unable to be measured
due to decomposition of compound 10 during the analysis.
Synthesis of Compounds 12 and 12’: Chiral ligand 11 (9.2 g, 30 mmol) and 4 Å molecular
sieves were added to a solution of rac-5 (5.1 g, 10 mmol) in a mixture of DMSO and toluene
(1:20) (200 mL). The reaction mixture was refluxed with azeotropic removal of water using a
Dean-stark condenser under an argon atmosphere. After stirring for 12 h, the reaction mixture
was cooled to room temperature. The reaction mixture was quenched by water and extracted
with ethyl acetate. The organic layer was combined, dried over MgSO4, and concentrated. The
crude mixture was purified by flash silica gel column chromatography (hexanes/ethyl
acetate=1:2) to provide the desired products 12 and 12’ in both 43% yields (4.5 g).
In order to recover unreacting chiral ligand 11 used for the diastereomeric resolution, the
aqueous layer was combined and concentrated under reduced procedure. Then, chiral ligand
11 in the resulting crude solid mixture was separated by re-dissolving it with excess of
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acetone. The acetone solution was combined and concentrated in vacuo to provide chiral
lignad 11 in a pure form without further purification (2.8 g, 91%).
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Compound 12: a white solid. mp 150-152 oC. 1H NMR (300 MHz, CDCl3, ppm) δ 7.74 (d, J =
8.5 Hz, 2H), 7.27 - 7.37 (m, 6H), 7.04 - 7.20 (m, 6H), 6.84 - 7.01 (m, 8H), 6.79 (d, J = 8.0 Hz,
2H), 4.83 - 5.10 (m, 4H), 4.27 (d, J = 11.3 Hz, 2H), 3.93 - 4.16 (m, 4H), 3.73 - 3.83 (m, 2H),
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3.71 (br. s., 6H), 3.29 (d, J = 16.5 Hz, 8H), 0.73 - 2.02 (m, 12H). C{1H} NMR (100 MHz,
CDCl3, ppm) 168.4, 161.4, 160.8, 137.6, 137.0, 136.6, 128.9, 128.8, 128.7, 128.4, 128.3,
128.0, 127.9, 126.9, 118.0, 107.0, 79.8, 74.3, 71.2, 62.0, 56.0, 29.7, 26.2, 21.8. HRMS (ESI)
calcd for C60H62B2N2O14Na 1079.4287, found 1079.4299.
1
Compound 12’: a white solid. mp 170-172 oC. H NMR (300 MHz, CDCl3, ppm) δ 7.68 (d, J
= 8.5 Hz, 2H), 7.33 (d, J = 5.5 Hz, 6H), 7.20 (d, J = 7.2 Hz, 2H), 7.03 - 7.16 (m, 8H), 6.97 (d,
J = 7.2 Hz, 6H), 6.73 (d, J = 8.5 Hz, 2H), 4.89 (d, J = 10.2 Hz, 2H), 4.47 - 4.62 (m, 4H), 4.22
- 4.35 (m, 4H), 3.79 (d, J = 9.9 Hz, 4H), 3.71 (br. s., 2H), 3.66 (s, 6H), 3.37 - 3.51 (m, 2H),
13
3.17 (d, J = 15.95 Hz, 2H), 1.03 - 2.01 (m, 12H). C{1H} NMR (100 MHz, CDCl3, ppm)
169.2, 168.2, 161.0, 159.6, 136.9, 136.7, 136.1, 128.8, 128.5, 128.3, 128.1, 127.9, 127.8,
107.1, 80.4, 74.2, 73.7, 72.0, 62.8, 57.0, 55.9, 30.6, 26.7, 22.1. HRMS (ESI) calcd for
C60H62B2N2O14Na 1079.4287, found 1079.4299.
Synthesis of (R)-BIPhOL ((R)-3): To a suspension of compound 12 (0.11 g, 0.10 mmol) in
THF (10 mL) was added 1 N NaOH (0.50 mL), and the reaction mixture was stirred for 1 h.
The reaction mixture was quenched with saturated NH4Cl, and the crude product was
extracted with ethyl acetate. The organic layer was combined, dried over MgSO4, and
concentrated. Acetic acid (1.0 mL) was added to a solution of the crude product in 1,4-
dioxane (10 mL) and the reaction mixture was stirred at 100 oC in an open flask. After stirring
for 12 h, the reaction mixture was quenched with saturated NH4Cl, and the crude product was
extracted with ethyl acetate. The organic layer was combined, dried over MgSO4, and
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concentrated. Pd/C powder (0.050 g) was added to a solution of crude mixture in EtOH (10
mL). The above mixture was stirred at room temperature under a hydrogen atmosphere and
monitored by TLC. After stirring for 6 h, the reaction mixture was filtered through celite, and
washed with dichloromethane. Then, the filtrate was concentrated, and purified by flash
column chromatography on silica (hexanes/ethyl acetate=3:1) to provide the desired product
(R)-3 in 90% yield over three steps (0.022 g). The spectroscopic data were in good agreement
with the literature.8-11 1H NMR (300 MHz, CDCl3, ppm) δ 7.31 (t, J = 8.25 Hz, 2H), 6.72 (d, J
= 8.25 Hz, 2H), 6.62 (d, J = 8.25 Hz, 2H), 5.05 (s, 2H), 3.77 (s, 6H). Enantiomeric excess (ee)
was determined by HPLC with a Chiralcel AS-H column (hexane:2-propanol = 90:10, flow
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rate = 1.0 mL/min, λ = 254 nm), tr(major) = 20.4 min., tr(minor) = 23.2 min. [α]20 = +153.6
D
(c 0.77, CHCl3).
1
Synthesis of (S)-BIPhOL ((S)-3): Similar reaction with 12’ provided (S)-BIPhOL. H NMR
(300 MHz, CDCl3, ppm) δ 7.31 (t, J = 8.25 Hz, 2H), 6.72 (d, J = 8.25 Hz, 2H), 6.62 (d, J =
8.25 Hz, 2H), 5.05 (s, 2H), 3.77 (s, 6H). Enantiomeric excess (ee) was determined by HPLC
with a Chiralcel AS-H column (hexane:2-propanol = 90:10, flow rate = 1.0 mL/min, λ= 254
nm), tr(major) = 21.2 min., tr(minor) = 19.3 min. [α]20D= -144.0 (c 0.77, CHCl3) (Lit.11 [α]20
-144.0 (c 0.77, CHCl3)).
=
D
Synthesis of 3,3’-disubstituted-6,6’-dimethoxy-2,2’-biphenol: To a solution of compound 12
(0.21 g, 0.20 mmol), Ba(OH)2·8H2O (0.18 g, 0.58 mmol, 2.9 equiv.), and Pd(PPh3)4 (0.012 g,
0.010 mmol, 0.050 equiv) in 1,4-dioxane (5.0 mL) and H2O (2.0 mL) was added aryl bromide
(0.60 mmol, 3.0 equiv). The above mixture was stirred at room temperature under an argon
atmosphere for 10 min, then heated to 120 oC and stirred for 24 h. After stirring for 24 h, the
reaction mixture was cooled to room temperature. The reaction mixture was quenched by 1 N
HCl aqueous solution, and extracted with dichloromethane. The organic layer was combined,
dried over MgSO4, and concentrated. The crude mixture was re-dissolved in EtOH (10 mL)
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and Pd/C powder was added to the reaction mixture. The above mixture was stirred at room
temperature under a hydrogen atmosphere, and monitored by TLC. After complete
consumption of the starting material, the reaction mixture was filtered through celite, and
washed with dichloromethane. Then, the filtrate was concentrated, and the crude product was
purified by flash column chromatography on silica to provide the desired product. For the
recovery of chiral ligand 11, the aqueous layer after Suzuki-Miyaura reaction was combined
and concentrated under reduced procedure. Then, the chiral ligand 11 in the resulting crude
solid mixture was separated by re-dissolving it with excess of acetone (20 mL/mmol of 11 X
3 times). The acetone solution was combined and concentrated in vacuo to provide chiral 11
in a pure form without further purification (0.11 g, 90%).
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(R)-3,3'-Diphenyl BIPhOL ((R)-3a): The product was obtained in 82% yield as an off-white
solid (0.065 g) with 99.1% ee. mp 134-136 oC. 1H NMR (300 MHz, CDCl3, ppm) 7.58 (d, J =
7.4 Hz, 4H), 7.18 - 7.50 (m, 8H), 6.72 (d, J = 8.5 Hz, 2H), 5.31 (s, 2H), 3.80 (s, 6H). 13C{1H}
NMR (100 MHz, CDCl3, ppm) δ 157.8, 152.0, 138.1, 131.7, 129.5, 128.6, 127.1, 122.4, 107.9,
104.0, 56.3. HRMS (ESI) calcd for C26H22O4Na 421.1418, found 421.1410. Enantiomeric
excess (ee) was determined by HPLC with a Chiralcel AD-H column (hexane:2-propanol =
90:10, flow rate = 1.0 mL/min, λ= 254 nm), tr(major) = 19.7 min., tr(minor) = 29.8 min. [α]20
D
= -17.3 (c 1.0, CHCl3).
(S)-3,3'-Diphenyl BIPhOL ((S)-3a): The reaction of the other diastereomer 12’ under the
above conditions provided (S)-3a. The product was obtained in 80% yield (0.063 g) as an off-
white solid with 98.6% ee. mp 133-135 oC. 1H NMR (300 MHz, CDCl3, ppm) 7.58 (d, J = 7.4
13
Hz, 4H), 7.18 - 7.50 (m, 8H), 6.72 (d, J = 8.5 Hz, 2H), 5.31 (s, 2H), 3.80 (s, 6H). C{1H}
NMR (100 MHz, CDCl3, ppm) δ 157.8, 152.0, 138.1, 131.7, 129.5, 128.6, 127.1, 122.4, 107.9,
104.0, 56.3. HRMS (ESI) calcd for C26H22O4Na 421.1418, found 421.1410. Enantiomeric
excess (ee) was determined by HPLC with a Chiralcel AD-H column (hexane:2-propanol =
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90:10, flow rate = 1.0 mL/min, λ= 254 nm), tr(minor) = 19.7 min., tr(major) = 29.8 min. [α]20
= +17.2 (c 1.0, CHCl3).
D
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(R)-3,3'-Di(4-methoxyphenyl) BIPhOL ((R)-3b): The product was obtained as an off-white
solid in 67% yield (0.061 g). mp 120-122 oC. 1H NMR (300 MHz, CDCl3, ppm) 7.50 (d, J =
8.8 Hz, 4H), 7.34 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.5 Hz, 4H), 6.70 (d, J = 8.5 Hz, 2H), 5.29
(s, 2H), 3.84 (s, 6H), 3.79 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3, ppm) 158.8, 157.5,
152.0, 131.4, 130.6, 130.4, 122.1, 114.1, 107.9, 103.9, 56.3, 55.5. HRMS (ESI) calcd for
C28H26O6Na 481.1629, found 481.1623. [α]20D = +11.3 (c 0.20, CHCl3).
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(R)-3,3'-Di(4-(ethoxycarbonyl)phenyl) BIPhOL ((R)-3c): The product was obtained in 60%
(0.065 g) yield as an off-white solid. mp 110-112 oC. 1H NMR (300 MHz, CDCl3, ppm) 8.09
(d, J = 8.0 Hz, 4H), 7.67 (d, J = 7.7 Hz, 4H), 7.43 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H),
5.33 (br. s., 2H), 4.39 (q, J = 6.7 Hz, 4H), 3.81 (s, 6H), 1.40 (t, J = 7.0 Hz, 6H). 13C{1H}
NMR (100 MHz, CDCl3, ppm) 166.8, 158.3, 152.3, 142.8, 132.1, 129.8, 129.4, 128.9, 121.5,
107.5, 104.2, 61.1, 56.3, 14.6. HRMS (ESI) calcd for C32H30O8Na 565.1841, found 565.1832.
[α]20D = +4.5 (c 0.50, CHCl3).
Notes
The authors declare no competing financial interests.
Acknowledgements
This work was supported by National Research Foundation of Korea (NRF) grants funded by
the Korean Government (NRF-2015R1D1A1A01057200 and NRF-20100020209). C.-H.C.
thanks the financial support from an NRF grant funded by the Korean Government (NRF-
2014-011165, Center for New Directions in Organic Synthesis).
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Supporting Information
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1H NMR and C{1H} NMR spectra for compounds 3, 5, 6, 8, 9,10, 12, and 12’ and HPLC
traces for compounds 3 and 3a. The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
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References
1. Noyori, R.; Tomino, I.; Tanimoto, Y. J. Am. Chem. Soc. 1979, 101, 3129-3131.
2. Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008-2022, and references therein.
3. For a review on privileged chiral ligands, see: Yoon, T. P.; Jacobsen, E. N. Science
2003, 299, 1691-1693.
4. For the use of axially chiral biaryl diols as hydrogen bonding catalysts, see: (a)
Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165-2169. (b) McDougal,
N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 12094-12095. (c) McDougal, N. T.;
Trevellini, W. L.; Rodgen, S. A.; Kliman, L. T.; Schaus, S. E. Adv. Synth. Catal. 2004,
346, 1231-1240.
5. Axially chiral biaryl diols, particularly chiral BINOL derivatives, have been used as
key chiral scaffolds in phosphoric acid catalysis. For reviews on chiral phosphoric
acid catalysis, see: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744-5758. (b) Terada, M.
Chem. Commun. 2008, 4097-4112. (c) Terada, M. Synthesis 2010, 1929-1982. (d)
Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047-9153.
6. Among various axially chiral biaryl diols, BINOL and its derivatives have been most
widely utilized. For reviews on chiral BINOL ligands in asymmetric reactions, see:
(a) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155-3212. (b) Brunel, J.
M. Chem. Rev. 2005, 105, 857-898.
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7. Very recently, the relationship between dihedral angles in axially chiral biaryl diols
and their reactivity and selectivity in asymmetric reactions has been investigated, see:
Wang, Y.; Liu, W.; Ren, W.; Shi, Y. Org. Lett. 2015, 17, 4976-4979, and references
therein.
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8. For the synthesis of parent chiral BIPhOL via diastereomeric resolution, see: (a) Suda,
H.; Kanoh, S.; Umeda, N.; Nakajo, T.; Motoi, M. Tetrahedron Lett. 1983, 24, 1513-
1516. (b) Kanoh, S.; Tamura, N.; Motoi, M.; Suda, H. Bull. Chem. Soc. Jpn. 1987, 60,
2307-2309. (c) Delogu, G.; Fabbri, D. Tetrahedron: Asymmetry 1997, 8, 759-763. (d)
Nozaki, K.; Terakawa, T.; Takaya, H.; Hiyama, T. Angew. Chem. Int. Ed. 1998, 37,
131-133.
9. For the synthesis of chiral BIPhOL derivatives via diastereomeric resolution, see: (a)
Delogu, G.; Fabbri, D.; Dettori, M. A.; Forni, A.; Casalone, G. Tetrahedron:
Asymmetry 2000, 11, 4417-4427. (b) Capozzi, G.; Delogu, G.; Fabbri, D.; Marini, M.;
Menichetti, S.; Nativi, C. J. Org. Chem. 2002, 67, 2019-2026. (c) Drießen-Hölscher,
B.; Kralik, J.; Agel, F.; Steffens, C.; Hu, C. Adv. Synth. Catal. 2004, 346, 979-982.
10.For the preparation of parent chiral BIPhOL via kinetic resolution, see: (a) Sanfilippo,
C.; Nicolosi, G.; Delogu, G.; Fabbri, D.; Diettori, M. A. Tetrahedron: Asymmetry
2003, 14, 3267-3270. (b) Aoyama, H.; Tokunaga, M.; Kiyosu, J.; Iwasawa, T.; Obora,
Y.; Tsuji, Y. J. Am. Chem. Soc. 2005, 127, 10474-10475. (c) Lu, S.; Poh, S. B.; Zhao,
Y. Angew. Chem. Int. Ed. 2014, 53, 11041-11045.
11.Chiral BIPhOL has been prepared by diastereoselective coupling reaction followed by
introduction of phenolic hydroxy groups, see: Mooriag, H.; Meyers, A. I. Tetrahedron
Lett. 1993, 34, 6993-6996.
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12.(a) Lee, C.-Y.; Cheon, C.-H. J. Org. Chem. 2013, 78, 7086-7092. (b) Lee, C.-Y.;
Cheon, C.-H. Adv. Synth. Catal. 2016, 358, 549-554.
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13. For a review on directed ortho-metalation, see: Snieckus, V. Chem. Rev. 1990, 90,
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879-933.
14.For an example of dimerization of organolithium species in the presence of FeCl3, see:
Kakei, H.; Tsuji, R.; Ohshima, T.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Chem.
Asian J. 2007, 2, 257-264, and references therein.
15.For the relationship between substituent and reactivity in electrophilic aromatic
substitution (EAS) reactions, see: Carey, F. A.; Sundberg, R. J. Chapter 9 in Advanced
Organic Chemistry Part A: Structure and Mechanisms, Fifth Ed., Springer, 2007,
New York, U. S. A.
16.For the seminal report on N-methyl iminodiacetate (MIDA) boronates, see: Gillis, E.
P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716-6717.
17.For a review on the use of MIDA boronates, see: Gillis, E. P.; Burke, M. D.
Aldrichimica Acta 2009, 42, 17-27.
18.For the seminal report on the application of chiral MIDA boronates, see: Li, J.; Burke,
M. D. J. Am. Chem. Soc. 2011, 133, 13774-13777.
19.For a picture of the TLC of the resulting diastereomers, see Supporting Information.
20.Since chiral ligand 11 is soluble in water, all 11 remained in the aqueous layer after
extraction. The aqueous layer should be concentrated to provide the crude product of
11, from which 11 could be recovered by re-dissolving 11 in excess of acetone. The
acetone solution was combined and concentrated to provide chiral ligand 11.
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21.For metal-free thermal protodeboronation of electron-rich arene boronic acids, see: (a)
Lee, C.-Y.; Ahn, S.-J.; Cheon, C.-H. J. Org. Chem. 2013, 78, 12154-12160. (b) Ahn,
S.-J.; Lee, C.-Y.; Kim, N.-K.; Cheon, C.-H. J. Org. Chem. 2014, 79, 7277-7285.
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22.The optical rotation of (S)-enantiomer of compound 3 was -144 (c 0.77, CHCl3), see
ref. 11.
23.Kaufman, T. S.; Srivastava, R. P.; Sindelar, R. D. J. Med. Chem. 1996, 38, 1437-1445.
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