Diastereomeric resolution of rac -1,1′-bi-2-naphthol boronic acid with a chiral boron ligand and its application to simultaneous synthesis of (R)- and (S)-3,3′-disubstituted 1,1′-bi-2-naphthol derivatives

Article abstract of DOI:10.1021/jo400928q

A new concept of diastereomeric resolution has been developed where a boronic acid functionality was employed as (1) a diastereomeric resolving group with a chiral boron ligand and (2) a masked functional group for further transformation thereafter. This new diastereomeric resolution method was successfully applied to the preparation of both (R)- and (S)-3,3′- disubstituted 1,1′-bi-2-naphthol (BINOL) derivatives in a step-ecomonical manner. Racemic BINOL boronic acid reacted with a commercially available pinene-derived iminodiacetic acid as a chiral boron ligand to generate the two diastereomers in quantitative yields over a gram-scale quantity. After the removal of the chiral boron ligand from the diastereomers under mild conditions, the subsequent Suzuki coupling reaction of the resulting chiral BINOL boronic acids with aryl halides provided a series of both (R)- and (S)-BINOL derivatives in good yields. Further, both resulting diastereomers could be directly applied to the Suzuki coupling reaction without the removal of the chiral ligand.

Full text of DOI:10.1021/jo400928q

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Article
Diastereomeric Resolution of rac-1,1‘-Bi-2-naphthol Boronic Acid with
a Chiral Boron Ligand and Its Application to Simultaneous Synthesis
of (R)- and (S)-3,3#-Disubstituted 1,1‘-Bi-2-naphthol Derivatives
Chun-Young Lee, and Cheol-Hong Cheon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400928q • Publication Date (Web): 20 Jun 2013
Downloaded from http://pubs.acs.org on June 22, 2013
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Diastereomeric Resolution of rac-1,1‘-Bi-2-naphthol Boronic Acid with a
Chiral Boron Ligand and Its Application to Simultaneous Synthesis of (R)-
and (S)-3,3′-Disubstituted 1,1‘-Bi-2-naphthol Derivatives
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Chun-Young Lee and Cheol-Hong Cheon*
Department of Chemistry, Korea University, Anam-ro, Seongbuk-gu, Seoul 136701, Republic
of Korea, Phone: +82-2-3290-3147; Fax: +82-2-3290-3121; e-mail: cheon@korea.ac.kr
Abstract: A new concept of diastereomeric resolution has been developed where a boronic
acid functionality was employed as 1) a diastereomeric resolving group with a chiral boron
ligand and 2) a masked functional group for further transformation thereafter. This new
diastereomeric resolution method was successfully applied to the preparation of both (R)- and
(S)-3,3’-disubstituted 1,1‘-bi-2-naphthol (BINOL) derivatives in a step-ecomonical manner.
Racemic BINOL boronic acid reacted with a commercially available pinene-derived
iminodiacetic acid as a chiral boron ligand to generate the two diastereomers in quantitative
yields over a gram-scale quantity. After the removal of the chiral boron ligand from the
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diastereomers under mild conditions, the subsequent Suzuki coupling reaction of the resulting
chiral BINOL boronic acids with aryl halides provided a series of both (R)- and (S)-BINOL
derivatives in good yields. Further, both resulting diastereomers could be directly applied to
the Suzuki coupling reaction without the removal of the chiral ligand.
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Introduction
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Diastereomeric resolution of racemic compounds with a chiral auxiliary has been
considered one of the most commonly used methods for the preparation of enantiomerically
pure compounds and thus is actually an important tool in the preparation of optically active
drugs in the pharmaceutical industry.1 In conventional diastereomeric resolutions, a functional
group (FG1) in a racemic compound is utilized as a diastereomeric resolving group with a
chiral auxiliary to afford two diastereomers. Subsequent removal of the auxiliary from the
resulting diastereomers furnishes the original compound in an enantiomerically pure form and
the further derivatization of the resulting enantiomers is generally performed using other
functional group than FG1 (Scheme 1(a)). In contrast, we envisioned that if a functional group
(FG1) in a racemic compound were initially utilized as a resolving group with a chiral
auxiliary and the same functional group in the resulting enantiomers and/or diastereomers
were able to be further functionalized thereafter, enantiomerically pure compounds would be
more readily derivatized (Scheme 1(b)). Furthermore, if this approach were able to be applied
to the diastereomeric resolution of an advanced intermediate derived from a racemic starting
material rather than that of the racemic starting material, both enantiomers of a product could
be readily obtained in a step-economical manner in case both enantiomers of the product need
to be prepared. In order to demonstrate the feasibility of this new diastereomeric resolution
method, we chose a diastereomeric resolution of a racemic BINOL boronic acid where a
boronic acid is utilized as a dual role functional group; the boronic acid initially acts as a
diastereomeric resolution group with a chiral boron ligand2 and then is utilized to introduce
substituents at the 3,3’-position of the BINOL backbone.
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Scheme 1. Diastereomeric resolution of racemic-compounds
Since the first use of a chiral BINOL as a ligand for metal-mediated catalysis in 1979,3
BINOL has been considered one of the commonly used privileged ligands4 in metal-based
asymmetric Lewis acid catalysis. More recently, they have been also considered as important
frameworks in asymmetric organocatalysis: chiral BINOLs have been used not only as
hydrogen bonding catalysts5 but also as key chiral scaffolds in phosphoric acid catalysis.6
Since the outcome of a given asymmetric transformation strongly depends on the electronic
and steric properties of the BINOL framework, significant efforts have been made to develop
BINOL derivatives by introducing substituents within the BINOL periphery.7 Among the
BINOL derivatives developed, 3,3’-disubstituted BINOL derivatives, (R)-1 and (S)-1 (Figure
1), have been most widely utilized in asymmetric catalysis,8 and thus the development of
efficient methods for the synthesis of enantiomerically pure 3,3’-disubstituted BINOL
derivatives is of considerable importance.
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R
R
5
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OH
OH
OH
OH
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R
R
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(R)-1
(S)-1
Figure 1. Structures of (R)- and (S)-3,3’-disubstituted BINOL derivatives ((R)-1 and (S)-1)
In conventional methods for the synthesis of 3,3’-disubstituted chiral BINOL
derivatives via diastereomeric resolution, racemic-BINOL, rac-2, is resolved with a chiral
auxiliary using the hydroxyl functionality on the BINOL backbone. After the isolation of one
enantiomer of BINOL, the subsequent introduction of substituents at the 3,3’-positions of the
BINOL backbone is carried out to access optically pure 3,3’-disubstituted BINOLs (Scheme
2(a)). However, in order to access the other enantiomers of BINOL derivatives, the same
synthetic sequence must be performed with the other enantiomer of BINOL.9 On the other
hand, racemic-BINOL derivative, rac-3, bearing a boronic acid functionality at the 3,3’-
position10 could undergo diastereomeric resolution with a chiral ligand on the boron.2 After
the separation of the resulting diastereomers, subsequent Suzuki reaction of the boronic acid
functionality in the diastereomers and/or enantiomers would provide both (R)-1 and (S)-1
after deprotection of the methyl ether group (Scheme 2(b)). Furthermore, since an advanced
intermediate derived from racemic-BINOL rather than racemic-BINOL itself is applied to
diastereomeric resolution, both (R)-1 and (S)-1 can be more readily accessed in a step-
economical manner as compared to the conventional diastereomeric resolution.
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Scheme 2. a) Conventional approach to access both (R)-1 and (S)-1 via diastereomeric
resolution. b) Our approach for both (R)-1 and (S)-1 via diastereomeric resolution of rac-3.
Herein we would like to report a novel diasteromeric resolution method using a
boronic acid functionality as a diastereomeric resolving group and a latent functional group
for further transformation. In addition, this diastereomeric resolution has been successfully
applied to the step-economical synthesis of both (R)- and (S)-BINOL derivatives from rac-
BINOL boronic acid. To the best of our knowledge, this is the first example of utilizing a
boronic acid functionality to resolve the racemic-BINOL compounds rather than the hydroxy
group. Furthermore, this is the first example of the preparation of chiral BINOL derivatives
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via diastereoselective resolution of an advanced intermediate stage from racemic-BINOL
rather than racemic-BINOL stage.
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Results/Discussion
The key for the success of this approach is the choice of a chiral ligand on the boron
atom in the boronic acid in rac-3. The chiral ligand (1) should generate the two stable
diastereomers with rac-3, displaying large difference in their physical properties, which
enables us to separate them by conventional separation methods, (2) should be easily removed,
and (3) should be recovered by a simple work-up procedure if possible.
Considering these requirements, we commenced with our studies to find a suitable
chiral ligand on the boronic acid moiety in rac-3. First, we focused on finding a suitable
scaffold to provide enough stability to the resulting boronates. Recently, the Burke group has
developed a trivalent N-methyliminodiacetate (MIDA) ligand,11 which significanlty increases
the stability of boronic acids for Suzuki coupling reactions that would have otherwise resulted
in poor or negligible yields.12,13,14 Furthermore, the increased stability of MIDA boronates
allowed the isolation and storage of problematic heteroaromatic boronic acids.15 Based on
these results, we chose the MIDA motif as a basic scaffold for the chiral ligand on the boron
in rac-3 to provide stability of the resulting boronates. Next, we moved our attention to the
design of the chiral ligands by incorportating chirality on the MIDA scaffold, which should be
critical in achieving better diastereomeric resolution. X-ray structures of MIDA boronates
showed that the methyl group in the MIDA ligand is closely positioned to the π-aryl
substrates.12 Thus, we expected that chiral ligands incorporating chirality on the N-alkyl group
in the MIDA scaffold might lead to better diastereomeric resolution of rac-3 due to the
proximity betwen the chiral motif and the axially chiral center in the BINOL backbone.
Furthermore, very recently the Burke group has developed new chiral boron ligands bearing
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chirality in the N-alkyl moiety and applied the chiral MIDA ligands to the diastereoselective
epoxidation of alkenyl boronates.16 Based on these considerations, we decided to first explore
the diastereomeric resolution of rac-3 using chiral boron ligands 5a-d developed by the Burke
group. Chiral boron ligands 5a-d could be readily prepared by following the literature
procedure with slight modifications on a multigram scale from commodity chemicals, such as
chiral amines, t-butyl bromoacetate, and trifluoroacetic acid (Scheme 3).16
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O
Br
R*
N
R*
N
TFA, rt
O
HO2C
CO2H
H
H
DMF, K2CO3, rt
5
Me
OBn
R* =
5a
5c
5d
5b
Scheme 3. Preparation of chiral boron ligands 5a-d bearing chirality on the N-alkyl moiety
With these chiral boron ligands 5a-d in hand, the diastereomeric resolution of rac-3
with these ligands was investigated (Table 1). The chiral scaffold in the ligands was found to
have a significant effect on the resolution of the resulting diastereomers. The chiral ligands 5a
and 5b, derived from pinene and cyclopentyl amines, respectively, afforded the two
diastereomers in high yields after column chromatography (entries 1 and 2), while the
diastereomers with other chiral ligands 5c and 5d were obtained as inseparable mixtures
(entries 3 and 4).17 Although both chiral ligand 5a or 5b were effective in the diastereomeric
resolution of rac-3, we decided to use pinene-derived iminodiacetic acid ligand 5a as the
chiral boron ligand because of its commercial availability.18
Table 1. Diastereomeric Resolution of rac-3 with Chiral Boron Ligands 5a-da
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*R
*R
N
O
N
O
O
R*
N
O
B
B
O
O
O
O
O
O
HO
OH
5
( )
OMe
OMe
OMe
OMe
rac-3
+
DMSO, toluene
dean-stark
distillation
O
O
O
O
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B
B
O
O
N
N
*R
*R
O
O
4
4
(S)-
(R)-
Entry
1
5
eluent
productb
Rf
yield (%)
45
[α]D
-230.7
(-158.5)c
234.8
(R)-4a
0.4
0.3
0.6
0.3
Hx:EtOAc
(1:2)
5a
(S)-4a
(R)-4b
(S)-4b
41
47
45
N.D.d
N.D.d
N.D.d
N.D.d
(159.4)c
-90.0
(-157.9)c
88.5
Hx:EtOAc
(1:3)
2
5b
(158.8)c
N.D.d
(R)-4c
(S)-4c
(R)-4d
(S)-4d
0.3
0.3
0.3
0.3
Hx:EtOAc
(1:1)
Hx:EtOAc
(1:2)
3
4
5c
N.D.d
N.D.d
5d
N.D.d
a Conditions: rac-3 (0.25 mmol), ligand 5 (0.75 mmol), DMSO/toluene (1:10), reflux, 12 h.
b The absolute configuration was determined by comparison of Rf value and optical rotation of
(R)-4 derived from optically pure (R)-3.
c
The values in parentheses are optical rotation of (R)-3 and (S)-3 after removal of chiral
ligand 5.
d Not determined.
To test the practicality of this method, we carried out the diastereomeric resolution of
rac-3 with 5a on a gram scale (Scheme 4). To our satisfaction, both diastereomers (R)-4a and
(S)-4a were obtained in high yields without any loss of efficiency (eq 1). Furthermore, 5a was
easily removed from (R)-4a under mild aqueous basic solution, and quantitatively recovered
by simple aqueous extraction (eq 2). Moreover, the recovered 5a could be directly re-applied
to diastereomeric resolution of rac-3 without any loss of efficiency.
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*R
*R
O
R*
N
O
N
N
O
O
B
B
O
O
HO
OH
O
O
O
O
5a
(
)
rac-3
OMe
OMe
OMe
OMe
DMSO, toluene
( 1 )
+
1.0 g scale
dean-stark
distillation
O
O
O
O
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B
B
O
O
R* =
N
N
*R
*R
O
O
4a
4a
(R)-
(1.02 g; 47%)
(S)-
(0.95 g; 44 %)
*R
N
O
O
O
B
B(OH)2
OMe
O
R*
NaOH
OMe
OMe
( 2 )
+
HO2C
N
CO2H
OMe
O
O
B
B(OH)2
O
N
(R)-3 : 94 %
5a : 92 %
*R
4a
O
(R)-
Scheme 4. Diastereomeric resolution of rac-3a with 5a in a gram scale and removal of 5a
After successful diastereomeric resolution, we attempted to introduce substitutents at
the 3,3‘-position through direct application of the resulting (R)- and (S)-enantiomers of the
BINOL boronic acid to Suzuki coupling reaction with aryl bromides 6 (Table 2),19 which
could be one of the advantages of our new diasteromeric resolution method as compared to
the previously developed methods. Delightedly, both BINOL derivatives, (R)-1a and (S)-1a,
bearing a 4-biphenyl group were obtained in good yields (entries 1 and 2). Under these
conditions, various aromatic bromides were successfully applied to Suzuki reaction with (R)-
3. Electronic properties had little effect on the reaction yields; both electron-rich and electron-
deficient aryl halides provided the desired Suzuki coupling products in good yields (entries 1,
3-7). However, steric bulkiness produced a detrimental effect on the cross-coupling reaction:
2,6-disubstituted aryl bromides, such as mesityl bromide, provided the desired product in only
moderate yield along with the mono coupled as well as deboronated products (entry 8).20 In
order to demonstrate the effectiveness of this method, we needed to varify that the BINOL
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derivatives obtained by this method must be enantiomerically pure; there is no racemization
during the hydrolysis of chiral boron ligand 5a and/or cross-coupling reaction of the resulting
boronic acids. Thus, we decided to determine the enantiopurity of the resulting BINOL
derivatives. Initially, we attempted to determine the enantiopurity of of compounds (R)-1a
and (S)-1a, but were not able to separate the two enantiomers using our chiral HPLC system.
When the hydroxy groups in (R)-1a and (S)-1a were protected as a methyl group, the both
compounds were obtained as a single enantiomer and the other enantiomer was not observed
in the HPLC analysis. Thus, there was no racemization during hydrolysis of chiral boron
ligand 5a and/or cross-coupling reaction of the resulting boronic acids.17
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Table 2. Preparation of Chiral 3,3’-Disubstituted BINOL via Suzuki Coupling Reactiona
B(OH)2
Ar
6
ArBr ( )
BBr3
DCM
OMe
OMe
OH
OH
Pd(PPh3)4
Ba(OH)2 8H2O
B(OH)2
Ar
dioxane/H2O
3
(R)-
1
(R)-
entry
ArBr (6)
4-PhC6H4
4-PhC6H4
C6H5
Product
Yield (%)b
1
2c
3
4
5
6
7
8
(R)-1a
(S)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1e
(R)-1f
(R)-1g
79
77
71
76
78
79
70
28
3,5-(CH3)2C6H3
4-(NO2)C6H4
3,5-(CF3)2C6H3
2-naphthyl
2,4,6-(CH3)3C6H2
a Conditions: (R)-3 (0.20 mmol), aryl bromide 6 (0.64 mmol), Pd(PPh3)4 (0.01 mmol),
Ba(OH)2•8H2O (0.58 mmol) in dioxane/H2O (5:1) was refluxed for 12 h.
b Determined after deprotection of the OMe group.
c (S)-3 was used instead.
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Next, we attempted to directly apply the diastereomer (R)-4a to the Suzuki reaction
with 4-biphenyl bromide 6a without removal of the chiral ligand (Scheme 5). Based on the
conditions developed by the Burke group,13 we investigated several reaction parameters.
Interestingly, the choice of phosphine ligand had a strong influence on the reaction yield.
Among the phosphine ligands tested, XPhos provided the best result21 and the desired product
(R)-1a was obtained in comparable yield with that from (R)-3 even without further
optimization of reaction conditions (eq 3). Furthermore, the Suzuki coupling reaction of the
other diastereomer (S)-4a with 6a also provided (S)-1a in yield similar to that obtained with
the reaction with (R)-4a (eq 3’).
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Br
BBr3
DCM
6a
(
)
1a
4a
(R)-
( 3 )
(R)-
Pd(OAc)2
74 % yield
XPhos, K3PO4
dioxane/H2O (5:1)
4a
With (S)-
1a
:
(S)-
72 % yield
( 3' )
Scheme 5. Direct Suzuki reaction of (R)-4a with 6a without removal of 5a
In conclusion, we have demonstrated a new diastereomeric resolution where a
functional group in a racemic compound played a dual-role: 1) the diastereomeric resolution
with a chiral auxiliary and 2) further transformation in the resulting diastereomers and/or
enantiomers. The usefulness of new diastereomeric resolution method was successfully
demonstrated to the synthesis of both (R)- and (S)-3,3’-disubstituted BINOL derivatives via
the diastereomeric resolution of rac-3 with a commercially available pinene-derived
iminodiacetic acid ligand 5a, followed by a Suzuki-coupling reaction. Various aryl groups
could be easily introduced via subsequent Suzuki coupling reaction in good yields. Moreover,
both (R)- and (S)-diastereomers, (R)-4a and (S)-4a, could be directly applied to the Suzuki
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coupling reaction without the removal of the chiral ligand. It is noted that the diastereomeric
resolution of an advanced intermediate such as rac-3 and direct application of the boronic
acid functionality to the Suzuki reaction allowed us to access both (R)- and (S)-BINOL
derivatives in a step-economical manner. Moreover, ready availability of all the starting
compounds (rac-3 and 5a) and a simple procedure would render this method highly attractive
to the synthetic community. Further application of this new diastereomeric resolution methed
to asymmetric synthesis is underway in our research group.
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Experiment Section
General. All reactions were carried out in oven- or flame-dried glassware under nitrogen
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 according to the method of Still using silica gel 60 (230 – 400 mesh). Yields
refer to chromatographically and spectrographically pure compounds, unless otherwise
noted. Commercial grade reagents and solvents were used without further purification.
rac-(2,2'-Dimethoxy-[1,1'-binaphthalene]-3,3'-diyl)diboronic acid (rac-3) was synthesized
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by following literature procedure.10 1H NMR and C NMR spectra were recorded on 300
MHz and 100 MHz NMR spectrometers, respectively. Tetramethylsilane and the solvent
1
resonance were used as internal standards for H NMR (δ: 0.0 ppm) and 13C NMR,
respectively. The proton spectra are reported as follows δ (position of proton, multiplicity,
coupling constant J, number of protons). Multiplicities are indicated by s (singlet), d
(doublet), t (triplet), q (quartet), p (quintet), h (septet), m (multiplet) and br (broad). High
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resolution mass spectra (HRMS) were obtained using quadrupole instrucment with FAB as
the ionization method. The optical rotations were measured on an automatic polarimeter.
Enantiomeric excesses were determined by HPLC analysis using a chiral column
(Chiralpak OD-H, Φ 4.6 mm x 250 mm) with a mixture of hexanes and isopropyl alcohol
as an eluent.
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General Procedure for Synthesis of Chiral Boron Ligands 5. To a stirred solution of a
chiral amine (32.6 mmol; 1.00 equiv.), K2CO3 (13.5 g, 97.9 mmol; 3.00 equiv.) in DMF
(50 mL) was added t-butyl-2-bromoacetate (19.1 g, 97.9 mmol; 3.00 equiv) at room
temperature. The reaction mixture was stirred at room temperatur and monitored by TLC.
After 24 h, the reaction was quenched with water and extracted with EtOAc (3×100 mL).
The combined organic layer was dried with MgSO4, and concentrated under reduced
pressure. The residue was dissolved in dichloromethane (100 mL), and then trifluoroacetic
o
acid (25 mL, 326 mmol, 10.0 equiv) was added to the solution dropwise at 0 C. After 48
h, reaction mixture was concentrated in vacuo and recrystallized in Et2O to afford the
desired product 5.
2,2'-(((1R,2R,3R,5S)-2,6,6-Trimethylbicyclo[3.1.1]heptan-3-yl)azanediyl)diacetic acid (5a).16
Yield: 5.24 g (60.0%). White Solid. 1H NMR (300 MHz, DMSO-d6) δ 3.63 (s, 4H), 3.40-3.38
(m, 1H), 2.30-2.22 (m, 2H), 1.90-1.67 (m, 4H), 1.16 (s, 3H), 1.07 (d, J = 6.6 Hz, 3H), 0.93 (s,
3H), 0.86 (d, J = 9.9 Hz, 1H).
2,2'-(((1S,2S)-2-(Benzyloxy)cyclopentyl)azanediyl)diacetic acid (5b).16 Yield: 4.43 g (44.2%).
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White solid. H NMR (300 MHz, DMSO-d6) δ 7.42-7.23 (m, 5H), 4.45-4.34 (m, 2H), 3.79-
3.40 (m, 1H), 3.45 (s, 4H), 3.23-3.20 (m, 1H), 1.84-1.78 (m, 2H), 1.65-1.39 (m, 3H), 1.38-
1.26 (m, 1H).
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(S)-2,2'-((1-Cyclohexylethyl)azanediyl)diacetic acid (5c).16 Yield: 3.97 g (50.1%). White
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6
1
solid. H-NMR (300 MHz, DMSO-d6) δ 3.45-3.31 (m, 4H), 2.44-2.38 (m, 1H), 1.93 (app
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d, J = 12.9 Hz, 1 H), 1.65-1.58 (m, 4H), 1.27-1.09 (m. 5H), 0.94 (d, J = 6.6 Hz, 3H), 0.86-
0.78 (m, 1H).
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2,2'-((((1R,2S,5R)-6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)methyl)azanediyl)diacetic acid
(5d).16 Yield: 5.29 g (60.3%). White solid. 1H-NMR (300 MHz, DMSO-d6) δ 3.42 (s, 4H),
2.63 (d, J = 6.6 Hz, 2H), 2.32-2.19 (m, 1H), 2.18-2.09 (m, 1H), 1.99-1.75 (m, 5H), 1.59-
1.47 (m, 1H), 1.14 (s, 3H), 0.92 (s, 3H), 0.86 (d, J = 9.1 Hz, 1H).
General Procedures for Diastereomeric Resolution of rac-3 with Chiral Boron Ligand 5
(Table 1). To a solution of rac-3 (0.10 g; 0.25 mmol; 1.0 eq) in a mixture of DMSO and
toluene (1:10, 3 mL) was added a chiral ligand 5 (0.75 mmol; 3.0 eq). The reaction
mixture was refluxed with azeotropic removal of water using Dean-Stark condenser under
air atmosphere. After 12 h, the reaction mixture was cooled to room temperature. The
reaction mixture was quenched with water, extracted with EtOAc. The organic layer was
combined, dried over MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica eluting with EtOAc/hexane to give the corresponding
(R)-4 and (S)-4.
(R)-4a. Yield: 97 mg (45 %); 1.0 g (47%) in 2.5 mmol scale reaction. Rf = 0.4
1
(EtOAc:hexanes = 2:1). A white solid. H-NMR (300 MHz, DMSO-d6) δ 8.36 (s, 2H),
8.07 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.1 Hz, 2H), 7.20 (t, J = 7.1 Hz, 2H), 7.13 (d, J = 8.3
Hz, 2H), 4.56-4.06 (m, 8H), 3.70-3.59 (m, 2H), 3.12 (s, 6H), 2.42-2.25 (m, 4H), 1.78-1.60
(m, 6H), 1.54-1.49 (m, 2H), 1.19 (d, J = 6.6 Hz, 6 H), 1.09 (s, 6 H), 1.00-0.97 (m, 2H),
0.76 (s, 6H). 13C-NMR (100 MHz, DMSO-d6) δ 170.9, 168.4, 159.8, 137.9, 136.0, 130.5,
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129.5, 128.1, 125.6, 125.5, 123.5, 68.9, 62.2, 61.2, 56.6, 49.1, 39.0, 38.0, 31.5, 30.8, 27.2,
24.8, 23.9. [α]D20 = -230.7 (c = 0.25, THF). HRMS (FAB+) calcd for C50H58B2N2O10 (M+)
868.4278, found 868.4281.
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(S)-4a. Yield: 89 mg (41 %); 0.95 g (44%) in 2.5 mmol scale reaction. Rf = 0.3
1
(EtOAc:hexanes = 2:1). A white solid. H-NMR (300 MHz, DMSO-d6) δ 8.35 (s, 2H),
8.04 (d, J = 8.2 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 6.92 (d, J = 8.5
Hz, 2H), 4.57-3.91 (m, 8H), 3.71-3.58 (m, 2H), 2.88 (s, 6H), 2.42-2.34 (m, 2H), 2.27 (m,
2H) 1.80-1.70 (m, 6H), 1.56-1.52 (m, 2H), 1.16 (d, J = 6.8 Hz, 6 H), 1.07 (s, 6 H), 0.98 (d,
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J = 10.7 H), 0.59 (s, 6H). C-NMR (100 MHz, DMSO-d6) δ 171.0, 168.7, 158.0, 137.9,
134.3, 130.5, 129.6, 127.3, 125.7, 125.2, 121.2, 68.5, 62.3, 59.6, 56.9, 49.3, 38.1, 31.4,
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30.8, 27.3, 24.2, 23.6. [α]D = 234.8 (c = 0.25, THF). HRMS (FAB+) calcd for
C50H58B2N2O10 (M+) 868.4278, found 868.4271.
(R)-4b. Yield: 110 mg (47 %). Rf = 0.6 (EtOAc:hexanes = 3:1). A white solid. 1H-NMR
(300 MHz, DMSO-d6) δ 8.27 (s, 2H), 8.04 (d, J = 8.7 Hz, 2H), 7.45-7.20 (m, 14H), 7.10
(br, 2H), 4.49-4.20 (m, 14 H), 4.06 (br, 2H), 2.79 (s, 6H), 1.60-1.31 (m, 2H), 1.24-0.95 (m,
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10H). C-NMR (100 MHz, DMSO-d6) δ171.0, 169.3, 160.5, 138.6, 137.0, 135.3, 130.7,
130.3, 129.6, 129.1, 128.6, 128.0, 125.5, 123.9, 80.5, 73.8, 72.2, 61.8, 61.0, 30.2, 25.8,
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20.3. [α]D = -90.0 (c = 0.25, THF). HRMS (FAB+) calcd for C54H54B2N2O12 (M+)
944.3863, found 944.3837.
(S)-4b. Yield: 110 mg (45 %). Rf = 0.3 (EtOAc:hexanes = 3:1). A white solid, 1H-NMR
(300 MHz, DMSO-d6) δ 8.30 (s, 2H), 7.99 (d, J=8.3 Hz, 2H), 7.35-6.97 (m, 16H), 4.49-
4.11 (m, 14 H), 3.49 (br, 2H), 3.06 (s, 6H), 1.96 (br, 2H), 1.53 (br, 4H), 1.28 (br, 6H). 13C-
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NMR (100 MHz, DMSO-d6) δ 170.8, 169.5, 158.1, 138.8, 137.2, 134.1, 132.3, 130.7,
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129.4, 129.0, 128.3, 127.6, 125.5, 125.2, 122.5, 80.8, 74.4, 71.4, 62.0, 59.8, 57.2, 30.5,
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26.7, 21.9. [α]D = 88.5 (c = 0.25, THF). HRMS (FAB+) calcd for C54H54B2N2O12 (M+)
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944.3863, found 944.3871.
General Procedure for Removal and Recovery of Ligand 5a: To a solution of (R)-4a (1.02 g;
1.17 mmol) in THF (20 mL) was added 1 N NaOH (14 mL) in one portion. The reaction
mixture was further stirred for 1 h at room temperature and monitored by TLC. After
completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4Cl,
extracted with EtOAc. Combined organic layer was concentrated and re-precipitated in Et2O
to provide 5a in 92 % yield. Remained Et2O layer was concentrated to provide (R)-3 in 94 %
yield. The spectroscopic data of (R)-3 were in good agreement with the literature.10 1H-NMR
(300 MHz, Acetone-d6) δ 8.56 (s, 2H), 8.04 (d, J = 7.97 Hz, 2H), 7.46 (t, J = 7.42 Hz, 2H),
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7.34 (t, J = 7.55 Hz, 2H), 7.11 (d, J = 8.24 Hz, 2H), 3.42 (s, 6H); [α]D = -158.5 (c = 0.10,
CHCl3), {lit.3 [α]D20 = -153.4 (c = 1, CHCl3)}.
General Procedure for Suzuki Cross-Coupling Reaction of (R)-3 with Aryl Bromides 6 (Table
2): In a 20 mL pressure vessel equipped with a magnetic stirring bar were added (R)-3 (80
mg, 0.20 mmol, 10 eq), Ba(OH)2·8H2O (180 mg, 0.58 mmol, 2.9 eq), Pd(PPh3)4 (12 mg,
0.010 mmol, 0.050 eq), and the relevant aryl bromide (0.64 mmol, 3.2 eq) in 1,4-dioxane (5.0
mL) and H2O (2.0 mL) and filled with N2. The reaction mixture was stirred for 24 h at 120 oC
and cooled to room temperature. 1 N HCl (30 mL) was added and extracted with
dichloromethane (3×50 mL). Organic layer was combined, dried over MgSO4, and
concentrated in vacuo to give crude oil. To the crude product solution in anhydrous
dichloromethane (10 mL) was added a solution of BBr3 (0.11 mL, 1.1 mmol, 5.5 eq) in
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dichloromethane dropwise at 0 C. The reaction mixture was warmed to room temperature
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combined, washed with brine (30 mL) and water (30 mL), dried over MgSO4, and
concentrated in vacuo. The residue was purified by column chromatography over silica gel to
give (R)-1.
(R)-3,3’-Bis(4-biphenyl)-2,2’-dihydroxy-1,1’-dinaphthyl ((R)-1a).19 Yield: 93 mg (79%). Rf
= 0.3 (dichloromethane:hexanes = 1:3). A white solid. 1H-NMR (300 MHz, CDCl3) δ 8.10 (s,
2H), 7.95 (d, J = 7.97 Hz, 2H), 7.86-7.83 (m, 4H), 7.73 (d, J = 8.24 Hz, 4H), 7.67 (d, J = 7.69
Hz, 4H), 7.50-7.31 (m, 12H), 5.44 (s, 2H). [α]D20 = -50.4 (c = 0.400, CHCl3), {lit.19 [α]D20 = -
70.3 (c = 1, CHCl3)}.
(S)-3,3’-Bis(4-biphenyl)-2,2’-dihydroxy-1,1’-dinaphthyl ((S)-1a).9(a) (S)-3 was used instead
1
of (S)-3. Yield: 91 mg (77%). Rf = 0.3 (dichloromethane:hexanes = 1:3). A white solid. H-
NMR (300 MHz, CDCl3) δ 8.09 (s, 2H), 7.95 (d, J = 7.97 Hz, 2H), 7.86-7.83 (m, 4H), 7.73
20
(d, J = 8.24 Hz, 4H), 7.67 (d, J = 7.69 Hz, 4H), 7.50-7.31 (m, 12H), 5.42 (s, 2H); [α]D
45.06 (c = 0.400, CHCl3), {lit.9(a) [α]D20 = 55.1 (c = 1.0, CHCl3)}.
=
(R)-3,3’-diphenyl-2,2’-dihydroxy-1,1’-dinaphthyl ((R)-1b).19 Yield: 62 mg (71%). Rf = 0.3
(dichloromethane:hexanes = 1:1). A white solid. 1H-NMR (300 MHz, CDCl3) δ 8.03 (s, 2H),
7.93 (d, J = 7.97 Hz, 2H), 7.74 (d, J = 7.14 Hz, 4H), 7.52-7.22 (m, 12H), 5.36 (s, 2H).
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(R)-3,3’-Bis(3,5-dimethylphenyl)-2,2’-dihydroxy-1,1’-dinaphthyl ((R)-1c).19 Yield: 75 mg
(76%). Rf = 0.3 (dichloromethane:hexanes = 1:1). A white solid. 1H-NMR (300 MHz, CDCl3)
δ 7.98 (s, 2H), 7.91 (d, J = 8.00 Hz, 2H), 7.40-7.21 (m, 10H), 7.06 (s, 2H), 5.39 (s, 2H).
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(R)-3,3’-Bis(4-nitrophenyl)-2,2’-dihydroxy-1,1’-dinaphthyl ((R)-1d).22 Yield: 78 mg (74%).
Rf = 0.2 (dichloromethane:hexanes = 1:1). A white solid. 1H-NMR (300 MHz, CDCl3) δ 8.34
(d, J = 8.24 Hz, 4H), 8.11 (s, 2H), 8.03-7.92 (m, 6H), 7.50-7.37 (m, 4H), 7.22(d, J = 8.24 Hz,
2H), 5.37 (s, 2H).
(R)-3,3’-Bis(3,5-bis(trifluoromethyl)phenyl)-2,2’-dihydroxy-1,1’-dinaphthyl
((R)-1e).23
Yield: 110 mg (79%). Rf = 0.2 (dichloromethane:hexanes = 1:1). A white solid. 1H-NMR (300
MHz, CDCl3) δ 8.23 (s, 4H), 8.12 (s, 2H), 8.00 (d, J = 7.69 Hz, 2H), 7.91 (s, 2H), 7.51-7.40
(m, 4H), 7.25-7.22(m, 2H), 5.38 (s, 2H).
(R)-3,3’-Di(2-naphthyl)-2,2’-dihydroxy-1,1’-dinaphthyl ((R)-1f).19 Yield: 76 mg (70%). Rf
= 0.3 (dichloromethane:hexanes = 1:1). A white solid. 1H-NMR (300 MHz, CDCl3) δ 8.22 (s,
2H), 8.15 (s, 2H), 8.00-7.87 (m, 8H), 7.54-7.31 (m, 12H), 5.48 (s, 2H).
(R)-3,3’-Bis(2,4,6-trimethyl)-2,2’-dihydroxy-1,1’-dinaphthyl ((R)-1g).22 Yield: 29 mg
(28%). Rf = 0.3 (dichloromethane:hexanes = 1:1). A white solid. 1H-NMR (300 MHz, CDCl3)
δ 7.87 (d, J = 7.69 Hz, 2H), 7.74 (s, 2H), 7.41-7.29 (m, 6H), 7.01 (s, 4H), 5.00 (s, 2H), 2.34
(s, 6H), 2.14 (s, 6H), 2.07 (s, 6H).
General Procedures for Suzuki Coupling Reaction of (R)-4a with 4-Bromobiphenyl 6a
without Removal of Ligand 5a: In a 10 mL pressure vessel were placed (R)-4a (47 mg, 0.050
mmol, 1.0 eq), K3PO4 (0.16 g, 0.75 mmol, 15 eq), Pd(OAc)2 (1.2 mg, 0.0050 mmol, 0.10 eq),
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biphenyl bromide 6a, (23.3 mg, 0.10 mmol, 2.0 eq), and X-Phos (0.010 mmol, 0.20 eq) in
1,4-dioxane (1.0 mL) and H2O (0.20 mL) and filled with N2. The reaction mixture was stirred
for 24 h at 120 oC and cooled to room temperature. The reaction mixture was quenched with 1
N HCl (5 mL), and extracted with dichloromethane (3×10 mL). The organic layer was
combined, dried over MgSO4, and concentrated in vacuo to give crude oil. To the crude
product solution in anhydrous dichloromethane (2 mL) was added BBr3 (0.28 mL, 0.28 mmol,
5.5 eq) dropwise at 0 oC. The reaction mixture was warm to room temperature and stirred for
additional 20 h. After the completion of the reaction, the reaction mixture was quenched with
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water at 0 C, and extracted with dichloromethane. The organic layer was combined, washed
with brine (10 mL) and water (10 mL), dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica (dichloromethane/hexane 1:3) to
afford (R)-1a as a white solid (yield: 22 mg (74%)). When (S)-4a was applied to the above
procedure, (S)-1a was obtained as a white solid (yield: 21 mg (72%)).
Acknowledgements
This work was supported by Basic Science Research Program through the National
Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future
Planning (2013008434). We also would like to thank LG display (2012-2013, KU contract
No. R1205431) for the generous support to this work.
Supporting Information
Spectroscopic data for chiral boron ligands 5, diastereomers 4, and chiral BINOL derivatives
1. This material is available free of charge via the Internet at http://pubs.acs.org.
References
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1. (a) Porter, W. H. Pure & Appl. Chem. 1991, 63, 1119-1122. (b) Saigo, K.; Sakai, K.
In Chirality in Drug Research; Francotte, E.; Lindner, W. Eds; Wiley-VCH:
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2. Prior to our report, there was a conceptually related report of diastereomeric resolution
of boronic acids, see: Brown, H. C.; Gupta, A. K. J. Organomet. Chem. 1998, 341,
73-81.
3. Noyori, R.; Tomino, I.; Tanimoto, Y. J. Am. Chem. Soc. 1979, 101, 3129-3131.
4. Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.
5. For the use of BINOL derivatives as hydrogen bonding catalysis, 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.
6. 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.
7. For reviews on chiral BINOL ligands in asymmetric reactions, see: (a) Chen, Y.;
Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155-3211. (b) Brunel, J. M. Chem.
Rev. 2005, 105, 857-897.
8. For recent examples of the preparation of chiral 3,3-diaryl BINOL derivatives bearing
bulk substituents, see: (a) Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.;
Toste, F. D. Nature 2011, 470, 245-250. (b) Klussmann, M.; Ratjen, L.; Hoffmann,
S.; Wakchaure, V.; Goddard, R.; List, B. Synlett, 2010, 2189-2192. (c) Cheon, C. H.;
Yamamoto, H. Org. Lett. 2010, 12, 2476-2479. (d) Cheon, C. H.; Yamamoto, H. J.
Am. Chem. Soc. 2008, 130, 9246-9247. (e) Jiao, P.; Nakashima, D.; Yamamoto, H.
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Angew. Chem., Int. Ed. 2008, 47, 2411-2413. (f) Cheng, X.; Goddard, R.; Buth, G.;
List, B. Angew. Chem., Int. Ed. 2008, 47, 5079-5081. (g) Cheng, X.; Vellalath, S.;
Goddard, R.; List, B. J. Am. Chem. Soc. 2008, 130, 15786-15787.
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9. (R)- and (S)-BINOL can be prepared by diastereomeric resolution of racemic-BINOL
with a chiral auxiliary or kinetic resolution of racemic-BINOL through
functionalization at the phenolic hydroxy group of the BINOL. For recent examples,
see: (a) Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65, 6319-6337. (b) Li, Z.; Liang,
X.; Wu, F.; Wan, B. Tetrahedron: Asymmetry 2004, 15, 665-669. (c) Aoyama, H.;
Tokunaga, M.; Kiyosu, J.; Iwasawa, T.; Obara, Y.; Tsuji, Y. J. Am. Chem. Soc. 2005,
127, 10474-10475.
10.rac-3 could be easily prepared by literature procedure, see: (a) Jin, L.-M.; Li, Y.; Ma,
J.; Li, Q. Org. Lett. 2010, 12, 3552–3555. (b) Hatano, M.; Horibe, T.; Ishihara, K. J.
Am. Chem. Soc. 2010, 132, 56–57.
11.For a seminal report of MIDA boronates, see: Gillis, E. P.; Burke, M. D. J. Am. Chem.
Soc. 2007, 129, 6716-6717.
12.For a review on MIDA boronates, see: Gillis, E. P.; Burke, M. D. Aldrichimica Acta,
2009, 42, 17-27.
13.For recent examples of application of MIDA boronates, see: (a) Fujii, S.; Chang, S.
Y.; Burke, M. D. Angew. Chem., Int. Ed. 2011, 50, 7862-7864. (b) Woerly, E. M.;
Struble, J. R.; Palyam, N.; O'Hara, S. P.; Burke, M. D. Tetrahedron 2011, 67, 4333-
4343. (c) Lee, S. J.; Anderson, T. M.; Burke, M. D. Angew. Chem., Int. Ed. 2010, 49,
8860-8863. (d) Woerly, E. M.; Cherney, A. H.; Davis, E. K.; Burke, M. D. J. Am.
Chem. Soc. 2010, 132, 6941-6943. (e) Struble, J. R.; Lee, S. J.; Burke, M. D.
Tetrahedron 2010, 66, 4710-4718. (f) S. G. Ballmer, E. P. Gillis, M. D. Burke, Org.
Syn. 2009, 86, 344-359. (g) Uno, B. E.; Gillis, E. P.; Burke, M. D. Tetrahedron 2009,
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65, 3130-3138. (h) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084-
14085. (i) Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am. Chem. Soc. 2008,
130, 466-468.
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14.(a) He, Z.; Zajdlik, A.; St. Denis, J. D.; Assem, N.; Yudin, A. K. J. Am. Chem. Soc.
2012, 134, 9926-9929. (b) He, Z.; Yudin, A. K. J. Am. Chem. Soc. 2011, 133, 13770-
13773.
15.(a) Dick, G. R.; Woerly, E. M.; Burke, M. D. Angew. Chem., Int. Ed. 2012, 51, 2667-
2672. (b) Dick, G. R.; Knapp, D. M.; Gillis, E. P.; Burke, M. D. Org. Lett. 2010, 12,
2314-2317. (c) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131,
6961-6963.
16.Li, J.; Burke, M. D. J. Am. Chem. Soc. 2011, 133, 13774-13777.
17.For pictures of TLC of the resulting diastereomers and other results, see Supporting
Information.
18.Compound 5a is currently commercially available. Although the common name of
compound 5a is PIDA (Pinene-erived iminodiacetic acid, PIDA), we avioded using
this abbreviation of compound 5a to eliminate confusion using abbreviations since the
“PIDA” stands for the hypervalent iodine compound, “phenyliodine diacetate
(PIDA)”.
19.Simonsen, B.; Gothelf, K. V.; Jørgensen, K. A. J. Org. Chem. 1998, 63, 7536–7538.
20.Suzuki coupling reaction of (R)-3 with mesityl bromide yielded the desired, the mono-
coupled, and deboronated products in ca. 1:1:1 ratio.
1) ArBr
Pd(PPh3)4
Ar
Ar
H
3
(R)-
OH
OH
OH
OH
OH
OH
+
+
Ba(OH)2 8H2O
dioxane/H2O
Ar
H
H
2) BBr3
Ar = 2,4,6-mesityl
28 %
32 %
23 %
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21.We also tested other Buchwald-type ligands. BrettPhos, and t-butyl XPhos provided
the desired product in 57 % and 24 %, respectively, whereas Me-(t-butyl)-XPhos
afforded no desired product at all.
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22. Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129,
6756-6764.
23.Singh, R.; Czekelius, C.; Schrock, R. R.; Müller, P.; Hoveyda, A. H. Organometallics
2007, 26, 2528-2539.
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