Enantiodivergent Synthesis of Axially Chiral Biphenyls from σ-Symmetric 1,1'-Biphenyl-2,6-diol Derivatives by Single Lipase-Catalyzed Acylative and Hydrolytic Desymmetrization

Article abstract of DOI:10.1002/ejoc.201901583

The enzymatic acylative desymmetrization of σ-symmetric 2'-halo-1,1'-biphenyl-2,6-diols was achieved for the first time using commercially available Burkholderia cepacia lipase immobilized on diatomaceous earth to give (S)-mono esters. The hydrolytic desymmetrization of the corresponding diacetates was also achieved using the same lipase to give (R)-mono esters. Our results, therefore, demonstrate that a single lipase can conduct the enantiodivergent synthesis of axially chiral biphenyl compounds in high chemical and optical yields.

Full text of DOI:10.1002/ejoc.201901583

A Journal of
Accepted Article
Title: Enantiodivergent synthesis of axially chiral biphenyls from σ-
symmetric 1,1ʹ-biphenyl-2,6-diol derivatives by single lipase-
catalyzed acylative and hydrolytic desymmetrization
Authors: Kengo Kasama, Hiroshi Aoyama, and Shuji Akai
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901583
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901583
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10.1002/ejoc.201901583
European Journal of Organic Chemistry
FULL PAPER
Enantiodivergent synthesis of axially chiral biphenyls from σ-
symmetric 1,1ʹ-biphenyl-2,6-diol derivatives by single lipase-
catalyzed acylative and hydrolytic desymmetrization
Kengo Kasama[a], Hiroshi Aoyama[a] and Shuji Akai*[a]
Abstract: The enzymatic acylative desymmetrization of σ-symmetric
2’-halo-1,1ʹ-biphenyl-2,6-diols was achieved for the first time using
commercially available Burkholderia cepacia lipase immobilized on
diatomaceous earth to give (S)-mono esters. The hydrolytic
desymmetrization of the corresponding diacetates was also achieved
using the same lipase to give (R)-mono esters. Our results therefore
demonstrate that a single lipase can conduct the enantiodivergent
synthesis of axially chiral biphenyl compounds in high chemical and
optical yields.
KR with in situ racemization to produce optically pure 1,1ʹ-biaryl-
2,2ʹ-diols in up to 98% yields.[10b]
The lipase-catalyzed asymmetric desymmetrization of σ-
symmetric biaryl diols and their esters can also be employed to
obtain axially chiral biaryl compounds in up to quantitative yields,
with Matsumoto et al. reporting some excellent examples of the
hydrolytic desymmetrization of σ-symmetric 1,1ʹ-biphenyl-2,6-diyl
diesters.[11] They also described the preparation of both
enantiomers by the use of different lipases.[11a] Very recently, the
N-heterocyclic-carbene-catalyzed atroposelective acylation of σ-
symmetric 2ʹ-amino-1,1ʹ-biphenyl-2,6-diols was reported.[12]
However, to the best of our knowledge, the atroposelective
desymmetrization of σ-symmetric biaryl diols 1 by enzymatic
esterification has yet to be reported. We also expect that the
enantiodivergent synthesis of both enantiomers will be possible
through the use of a single lipase since lipases can conduct both
the esterification and hydrolysis of σ-symmetric biaryl compounds
(1 and 3) through very similar transition states, in which the only
difference is the R2 substituent (R2 = H for 1 and Ac for 3) (Figure
1).
Introduction
Axially chiral biaryl compounds have received increasing attention
in organic chemistry because of their abundance, their important
roles in natural products and biologically active molecules, and
their use as chiral catalysts and chiral ligands of transition metal
catalysts.[1,2] Therefore, the asymmetric synthesis of these biaryl
compounds has been intensively studied, with reported methods
including the enantioselective coupling of phenols and their
congeners using optically active transition metal catalysts[3] and
organo-catalysts.[4] In addition, the kinetic resolution (KR) and
dynamic kinetic resolution (DKR) of racemic biaryl compounds
using metal catalysts[5] and organo-catalysts[6] to produce biaryl
compounds have also been reported.
In contrast, due to excellent enantio- and chemo-
selectivities of enzymes under mild conditions, the enzymatic
asymmetric synthesis of axially chiral biaryls is also highly
attractive.[7] Among the various enzymes examined to date,
lipases are commonly employed in such enzymatic
transformations due to their high stabilities, high catalytic activities
in both aqueous and organic media, ease of handling, and lack of
a requirement for cofactors. Indeed, they are able to catalyze not
only hydrolysis but also (trans)esterification reactions.[8] Although
the lipase-catalyzed acylative KR of axially chiral 1,1ʹ-biaryl-2,2ʹ-
diols has been reported, there remained room for improvement in
terms of the reaction rate and the substrate scope.[9] We
previously addressed these issues by the dramatic acceleration
of the lipase-catalyzed esterification of biaryl diols using a weak
inorganic base, namely Na2CO3.[10a] We also reported a solution
for the inherent limitation of KR (i.e., a maximum 50% yield of
each enantiomer) by achieving DKR through the combination of
R1
R1
vinyl acetate
Acylation
X
X
OH
Na2CO3
org. solvent
AcO
OH
HO
N
H
N
R1
Me
(S)-2
H
O-
1
X
OR2
O
O
Ser
O
H
+ single lipase
Enantiomer
N
Asp
N
H
O
R1
HO
His
R1
Similer Transition States
buffer/
X
X
OAc
pentane
AcO
OAc
Hydrolysis
(
)-2
R
3
Figure 1. A concept of the enantiodivergent synthesis of both
enantiomers (S)- and (R)-2 by atroposelective desymmetrization
of σ-symmetric biphenyl compounds 1 and 3 using a single lipase
Thus, in this study, our attention was focused on the
preparation of 2ʹ-halo-1,1ʹ-biphenyl diol derivatives 2, since the
halogen atoms present on the benzene ring can be easily
converted into other substituents, thereby enabling the
preparation of a wider range of multi-substituted biphenyls.[5a,b] As
such, we herein present the first example of the lipase-catalyzed
acylative desymmetrization of σ-symmetric 1,1ʹ-biphenyl-2,6-diols
1 using the commercially available Burkholderia cepacia lipase
immobilized on diatomaceous earth (Amano PS-IM)[13,14] in the
presence of Na2CO3. We also report the hydrolytic
desymmetrization of diesters 3 using the same lipase. With these
two types of desymmetrization reaction in hand, the
enantiodivergent synthesis of both enantiomers of optically active
mono acetates 2 (98–99% ee) is also carried out.
[a]
K. Kasama, Prof. Dr. H. Aoyama and Prof. Dr. S. Akai
Graduate School of Pharmaceutical Sciences, Osaka University
1-6, Yamadaoka, Suita, Osaka 565-0871, Japan,
E-mail: akai@phs.osaka-u.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201901583
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Results and Discussion
A similar reaction was then conducted using 1a on the 0.50
mmol scale with a slightly reduced quantity of PS-IM (0.27 g, 2.0
w/w) in addition to Burkholderia cepacia lipase immobilized on
diatomaceous earth,[14] Na2CO3 (1.5 mol equiv), and vinyl acetate
(10 equiv) in toluene (0.1 M). In this case, complete conversion
was achieved within 17 h at 35 °C, and optically pure (S)-2a was
obtained in 91% yield after purification by column
chromatography (Table 2, entry 1). We also reaffirmed the
significant acceleration of the enzymatic acylation of 1a by
Na2CO3, since a similar reaction in the absence of Na2CO3
required 48 h to reach 98% conversion (entry 2).
As
a
model compound for the enzymatic acylative
desymmetrization reaction, we selected 2ʹ-bromo-1,1ʹ-biphenyl-
2,6-diol 1a. After screening a range of commercially available
hydrolases under typical conditions[10a] [1a (5 mg, 0.02 mmol),
hydrolase (3 w/w), vinyl acetate (10 equiv), Na2CO3 (1.5 mol
equiv), organic solvent (0.1 M), 35 °C, 24 h (Table 1)], we were
pleased to find that Pseudomonas fluorescens lipase (Amano AK),
Pseudomonas sp. lipase (Toyobo LIP301), and Burkholderia
cepacia lipase (Amano PS-IM) efficiently catalyzed the
atroposelective acylation of 1a to give the optically pure
monoester (S)-2a (97–99% ee, >60% ratio based on HPLC
analysis) along with diester 3a (4–17% ratio based on HPLC
analysis) (entries 7–9). Among them, PS-IM produced a perfect
conversion and gave the highest ratio (88%) of (S)-2a. Using PS-
IM, we also examined a number of other reaction solvents, but no
improvements in the yield or the optical purity of (S)-2a were
observed compared to those obtained using toluene (entries 10–
13), and so a combination of PS-IM and toluene was selected for
the reaction.
Examples of similar desymmetrization reactions of other σ-
symmetric biphenyl diols 1 (see Table 2) demonstrate the good
substrate scope of our method, in which the reactions of 2ʹ-
halogenated diols 1b–1e (0.50 mmol) reached complete
conversion in 13–26 h at 35 °C to give optically pure monoesters
(S)-2b–2e (98–99% ee) in 76–91% isolated yields (entries 3–6).
In general, substrates bearing smaller substituent(s) on the upper
phenyl moiety, such as 1a, 1b, 1d, and 1e, had a tendency to
react faster, although a similar reaction of 1f bearing three
substituents on the upper phenyl moiety resulted in 77%
conversion in 24 h at 35 °C. Such a low reactivity was improved
by conducting the reaction with a higher loading of PS-IM (3 w/w)
and at a higher temperature (50 °C) to achieve 99% conversion
in 26 h to give (S)-2f (94% isolated yield, 99% ee) (entry 7).
In all cases, the corresponding diacetates 3b–3f were also
obtained. In particular, 2ʹ-chloro compounds 1b and 1e produced
3b and 3e, respectively, in higher ratios (17–18%) than those
obtained for other substrates (4–7%). We also examined the time
course of the PS-IM-catalyzed second esterification reaction (2b
→3b) using a racemic 2b and found that 3b was gradually formed
over time along with an increase in the optical purity of (S)-2b.
Thus, after 24 h at 35 ºC, (S)-2b (41% yield, 77% ee) was
obtained (Figure 2). This result demonstrated that PS-IM
conducted the kinetic resolution of racemic 2b under the
desymmetrization conditions employed herein, in which the
esterification of (R)-2b took place preferentially. This
phenomenon contributes to the formation of optically pure mono
ester (S)-2b.
Table 1. Screening of hydrolases and solvents for the acylative
desymmetrization of diol 1a.[a]
hydrolase (3 w/w)
Na2CO3 (1.5 mol equiv)
vinyl acetate (10 equiv)
Br
Br
Br
+
HO
OAc
HO
OH
AcO
OAc
solv. (0.1 M)
35 °C, 24 h
1a
(S)-2a
3a
(S)-2a
3a
Conver-
Entry Hydrolase[b] Solvent
sion,[c]
%
Ratio,[d]
%
Ee,[e]
%
Ratio,[d]
%
1
2
3
PLE
PPL
toluene
toluene
0
0
0
0
-
0
0
-
-
-
lipase AY
CAL-A
toluene
toluene
toluene
toluene
toluene
toluene
0
0
0
0
0
0
4
5
6
7
8
CAL-B
2
2
99
82
97
99
0
lipase AH
lipase AK
LIP301
7
7
0
61
95
57
78
4
17
lipase
PS-IM
lipase
PS-IM
lipase
PS-IM
lipase
PS-IM
lipase
PS-IM
9
toluene
heptane
iPr2O
99
89
79
64
27
88
84
75
62
26
98
83
93
96
94
11
5
10
11
12
13
4
CH2Cl2
MeCN
2
1
[a] Reaction scale; 1a (5 mg, 0.02 mmol), enzyme (15 mg). [b] PLE = pig
liver esterase, PPL = porcine pancreatic lipase, lipase AY = Candida rugosa
lipase, CAL-A = Candida antarctica lipase A, CAL-B = Candida antarctica
lipase B, lipase AH
= Burkholderia cepacia lipase, lipase AK =
Pseudomonas fluorescens lipase, LIP301 = Pseudomonas sp. lipase, PS-
IM = Burkholderia cepacia lipase. [c] Ratio of the compounds (2a + 3a) out
of the total of 1a, 2a and 3a determined by HPLC analysis using a Daicel
CHIRALPAK IE column, detection: 254 nm. [d] Ratio of 3a out of the total of
1a, 2a and 3a determined by HPLC analysis shown in footnote c. [e] Optical
purity (ee %) was determined by HPLC analysis shown in footnote c.
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10.1002/ejoc.201901583
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Table 2. Acylative desymmetrization of various diols 1a-f.[a]
Table 3. Hydrolytic desymmetrization of various diacetates 3a-f.[a]
PS-IM (2 w/w)
Na2CO3 (1.5 mol equiv)
vinyl acetate (10 equiv)
R1
R1
AcO
R1
R1
R1
R1
X
X
X
X
X
X
PS-IM (0.1 w/w)
HO
OH
HO
OAc
OAc
AcO
OH
+
AcO
OAc
HO
OH
+
toluene (0.1 M)
35 °C
pH 7.0 phosphate buffer
/ pentane (3 : 2),
30 °C
1
(S)-2
3
(
R
)-2
1
3
(S)-2
3
(R)-2
1
Reaction Conver-
time, h
Time, Conver-
Entry
Substrate 1
Entry
Substrate 3
sion,[b]
%
sion,[b]
%
Ee,[c] Isolated
Isolated
yield, %
Ee,[c] Isolated
h
Isolated
yield, %
%
yield, %
%
yield, %
1a
X = Br
3a
X = Br
17
48
98
98
(S)-2a, 91
(S)-2a, 90
99
3a, 7
1
18
99
(R)-2a, 99
99
1a, 0
1
3b
X = Cl
2[d]
1a
99
3a, 3
2
16
37
99
95
(R)-2b, 99
(R)-2c, 85
99
99
1b, 0
1c, 0
3c
X = I
1b
X = Cl
3[d]
3
4
16
24
99
96
(S)-2b, 82
(S)-2c, 89
98
99
3b, 17
3c, 5
1c
X = I
4
5
3d
3e
15
16
99
98
(R)-2d, 96[e] 99
1d, 0
1e, 0
5
6
1d
1e
14
13
99
99
(S)-2d, 91
(S)-2e, 76
99
99
3d, 6
(R)-2e, 98
(R)-2f, 94
99
99
3e, 18
6[f]
3f
30
99
1f, 4
7[e]
1f
26
99
(S)-2f, 94
99
3f, 4
[a] Each reaction was conducted by using 0.50 mmol of 1. [b] Same as
footnote c in Table 1. [c] Determined by HPLC analysis using a Daicel
CHIRALPAK IE column as mentioned in footnote c in Table 1. [d] Conducted
using PS-IM (0.2 w/w) at 40 °C. [e] Contaminated with 2% of 1d (1H NMR
analysis). [f] Conducted using PS-IM (0.2 w/w) at 50 °C in a mixture of pH
7.0 phosphate buffer (6.0 mL) and pentane (4.0 mL).
[a] Each reaction was conducted by using 0.50 mmol of 1. [b] Same as
footnote c in Table 1. [c] Determined by HPLC analysis using a Daicel
CHIRALPAK IE column as mentioned in footnote c in Table 1. [d] In the
absence of Na2CO3. [e] Conducted using PS-IM (3 w/w) at 50 °C.
mmol), PS-IM (0.1 w/w), a 3:2 (v/v) mixture of pH 7.0 phosphate
buffer and pentane, 30 °C (Table 3, entry 1). When ion-exchanged
water was used instead of pH 7.0 phosphate buffer with or without
pentane, overhydrolysis to give 1a was observed, and the yield of
(R)-2a was a little bit lower than that obtained by using the buffer.
This method was then applied to other diacetates 3b–3f,
and the results are presented in Table 3. The reaction was highly
chemoselective, exclusively yielding monoacetates (R)-2b–2f,
and the formation of diols 1 was generally not observed (entries
1–3 and 5), with the exception of entries 4 and 6 (up to 4%). It
should be noted that the optical purities of products (R)-2 were
99% ee in all cases. Similar to the acylation reactions, smaller
halogen substituents at the C2ʹ position gave a faster reaction
(entries 1 and 2). In the case of iodo compound 3c only 17%
conversion was achieved in 24 h. However, upon modifying the
reaction conditions through the use of PS-IM (0.2 w/w) at 40 °C,
95% conversion was achieved in 37 h to give an 85% isolated
yield of (R)-2c (entry 3). Although a similar reaction of 3f was slow
under the standard conditions, we found that conducting the
hydrolysis reaction using PS-IM (0.2 w/w) along with double the
volume of each reaction medium at 50 °C allowed the reaction to
reach completion in 30 h, giving (R)-2f in 94% yield with >99% ee
(entry 7).
Figure 2. Time-course of the PS-IM-catalyzed kinetic resolution
of racemic 2b. -- optical purity (% ee) of 2b, ■ conversion (%) of
2b.
We subsequently examined the feasibility of the hydrolytic
desymmetrization reaction of diacetates 3 by PS-IM. Optimization
of the reaction conditions using 3a in a mixture of pH 7.0
phosphate buffer (or water) and an organic solvent or in the
aqueous media only (for details, see: Supporting Information)
gave perfect conversion in 16 h producing optically pure (R)-2a in
99% isolated yield under the following conditions; 3a (0.50
It should also be noted that in all cases, the esterification
and hydrolysis reactions produced enantiomers of each other as
confirmed unambiguously by chiral HPLC analysis. The absolute
configurations of 2a, 2c, 2d, and 2e, obtained by the acylation
reaction, were determined to be S by X-ray diffraction analysis
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10.1002/ejoc.201901583
European Journal of Organic Chemistry
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are reported in δ (ppm) relative to the residual nondeuterated solvent
signal for 1H (CHCl3: δ = 7.26 ppm, DMSO: δ = 2.50 ppm, acetone:
2.05 ppm) and relative to the solvent signal for 13C (CDCl3: δ = 77.0
ppm), and those of 19F NMR spectra reported in δ (ppm) relative to
hexafluorobenzene (CDCl3: -164.9 ppm) as an internal standard. The
mass spectra (MS) were measured on a JEOL JMS-S3000 (MALDI)
with a TOF mass analyser. HPLC analyses were carried out using a
JASCO LC-2000Plus system (HPLC pump: PU-2080, UV detector:
MD-2018) equipped with a Daicel CHIRALPAK IE column with a size
of 4.6 mm x 250 mm. Optical rotations were measured on a JASCO
P-1020 polarimeter. The lipase from Burkholderia cepacia
immobilized on diatomaceous earth (commercial name; Lipase PS
IM Amano) was gifted from Amano Enzyme Inc. and used as
received. Kanto silica gel 60N was used for column chromatography.
In general, the anhydrous reactions were carried out in anhydrous
solvents.
(Figure 3), and the others were estimated to be the same based
on by similar enantiodiscrimination ability of the lipase.
(S)-2a
(S)-2c
(S)-2d
(S)-2e
Figure 3. X-Ray structure of the products (S)-2a, (S)-2c, (S)-2d,
and (S)-2e obtained by the enzymatic acylation reaction.[15]
Preparation of substrates 1 and 3
Conclusions
The preparation of 1 and 3 were performed as shown in Scheme 1. 1,3-
Bis(methoxymethyl)benzene was prepared according to the reported
procedure.[16] Other chemicals were purchased and used as received.
We
herein
reported
the
lipase-catalyzed
acylative
desymmetrization of σ-symmetric 1,1ʹ-biphenyl-2,2ʹ-diols 1 for the
first time, in which the addition of Na2CO3 was critical to
accelerate the enzymatic acylation reaction. We also
accomplished the hydrolytic desymmetrization of the
corresponding diacetates 3 using the same lipase as that
employed for the above acylation reactions (i.e., Burkholderia
cepacia lipase (Amano PS-IM)). Through the combination of
these two reactions (i.e., acylation and hydrolysis) using a single
lipase, we demonstrated the first enantiodivergent synthesis of
axially chiral biphenyls 2 in a particularly high optical purity (≥98%
ee). In addition, the presence of reactive halogen and hydroxyl
groups at the C2ʹ and C2 positions, respectively, allows the
installation of a range of substituents,[5a,b] thereby rendering
biphenyls 2 valuable precursors for the preparation of both
enantiomers of optically pure axially chiral multisubstituted
biphenyls, which are important as synthetic intermediates of
bioactive molecules, chiral catalysts, and chiral ligands.
Scheme 1
Based on our previous study using Pseudomonas sp. lipase
(Toyobo LIP301)[10a] and our current observations using
Burkholderia cepacia lipase (Amano PS-IM), the acceleration
effect of Na2CO3 on the lipase-catalyzed acylation of phenolic
hydroxyl groups seems to be generally applicable.
Further studies into expanding the substrate scope of these
reactions and the synthetic applications of the products are in
progress in our laboratory, and the results will be presented in due
course.
2'-Bromo-2,6-dimethoxy-1,1'-biphenyl (6a): 6a was synthesized from
1,3-dimethoxybenene and 1-bromo-2-chlorobenzene 4a according to the
reported procedure.[17] Its 1H NMR data ([D6]DMSO) are in good
agreement with those reported.[16] 1H NMR (500 MHz, CDCl3) δ 7.66 (dd,
J = 8.0, 1.0 Hz, 1H), 7.33-7.37 (m, 2H), 7.18-7.24 (m, 2H), 6.66 (d, J = 8.0
Hz, 2H), 3.74 (s, 6H).
2'-Iodo-2,6-dimethoxy-1,1'-biphenyl (6c): 6c was synthesized from 1,3-
dimethoxybenene and 1,3-diiodobenzene 4b according to the reported
procedure.[17] Its spectroscopic data are in good agreement with those
reported.[18]
Experimental Section
General considerations
2'-Chloro-2,6-dimethoxy-1,1'-biphenyl (6b); a typical procedure
for the coupling of bromobenzene 5 and (2,6-dimethoxyphenyl)-
boronic acid to give biphenyl 6 (Procedure A): A mixture of 1-
bromo-2-chlorobenzene (5b) (1.0 g, 5.2 mmol), (2,6-dimethoxy-
phenyl)boronic acid (1.1 g, 6.3 mmol), Pd(PPh3)4 (0.30 g, 0.16 mmol),
and K3PO4 (2.4 g, 11.5 mmol) in 1,4-dioxane (0.1 M) was stirred at
90 ºC for 4 h. After being cooled to ambient temperature, the mixture
Melting points were determined on a Yanagimoto melting point
apparatus and are uncorrected. Infrared (IR) absorption spectra were
1
recorded on a SHIMADZU FTIR-8400S spectrophotometer. H and
13C NMR spectra were measured on JEOL JNM-ECA500 (1H: 500
MHz, 13C: 126 MHz) and JEOL JNM-ECS400 (13C: 101 MHz and19F:
376 MHz) instruments. Chemical shifts of H and 13C NMR spectra
1
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10.1002/ejoc.201901583
European Journal of Organic Chemistry
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was concentrated in vacuo. Water and CH2Cl2 were added to the
residue, and the product was extracted with CH2Cl2 three times. The
combined organic layer was washed with water, dried over MgSO4,
and filtered. The filtrate was concentrated in vacuo, and the residue
was purified by column chromatography (hexanes/EtOAc = 10:1) to
1H), 6.96-7.03 (m, 2H), 6.56 (d, J = 8.0 Hz, 2H), 4.66 (s, 2H)., 13C NMR
(126 MHz, CDCl3) δ 162.1 (dd, JCF = 234, 13 Hz), 160.1 (dd, JCF = 234, 13
Hz), 153.3, 136.6 (d, JCF = 10 Hz), 130.6, 115.4 (dd, JCF = 21, 4.0 Hz),
113.7, 108.2, 107.9 (dd, JCF = 21, 4.0 Hz), 105.3 (t, JCF = 26 Hz). 19F-NMR
(376 MHz, CDCl3) δ -105.7 (m, 1F), -117.5 (m, 1F). IR (neat) ν 3397, 1622,
1587 cm-1. HRMS (MALDI) m/z calcd for C12H779BrF2O2 [M]+: 300.9670,
found: 300.9673.
1
give 6b (1.08 g, 83% yield). A colourless solid. Mp. 134-136 °C. H
NMR (500 MHz, [D6]acetone) δ 7.44-7.46 (m, 1H), 7.30-7.36 (m, 3H),
7.20-7.22 (m, 1H), 6.74 (d, J = 8.0 Hz, 2H), 3.70 (s, 6H). 13C NMR
(126 MHz, CDCl3) δ 157.8, 134.6, 133.8, 132.4, 129.4, 129.1, 128.4,
126.2, 117.0, 104.0, 56.0. IR (neat) ν 1586 cm-1. HRMS (MALDI) m/z
calcd for C14H1535ClO2 [M+H]+: 249.0677, found: 249.0676.
2',3'-Dichloro-1,1'-biphenyl-2,6-diol (1e): By following Procedure B, 6e
(0.85 g, 3.0 mmol) was converted to 1e (0.68 g, 89% yield). A colourless
solid. Mp. 62-65 °C. 1H NMR (500 MHz, CDCl3) δ 7.59 (dd, J = 8.0, 2.0 Hz,
1H), 7.37 (t, J = 8.0 Hz, 1H), 7.30 (dd, J = 8.0, 2.0 Hz, 1H), 7.19 (t, J = 8.0
Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.66 (s, 2H). 13C NMR (126 MHz, CDCl3)
δ 153.5, 134.5, 134.2, 132.9, 131.2, 131.0, 130.3, 128.1, 113.5, 108.0. IR
(neat) ν 3406, 1621, 1591 cm-1. HRMS (MALDI) m/z calcd for C12H935Cl2O2
[M+H]+: 254.9975, found: 254.9974.
2,3-Dichloro-2',6'-dimethoxy-1,1'-biphenyl
(6e):
By
following
Procedure A (reaction time: 2 h), 1-bromo-2,3-dichlorobenzene (5e) (0.90
g, 4.0 mmol) was converted to 6e (0.94 g, 83% yield). A colourless solid.
1
Mp. 124-126 °C. H NMR (500 MHz, CDCl3) δ 7.44 (dd, J = 8.0, 2.0 Hz,
1H), 7.35 (t, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.15 (dd, J = 8.0, 2.0
Hz, 1H), 6.65 (d, J = 8.0 Hz, 2H), 3.74 (s, 6H). 13C NMR (101 MHz, CDCl3)
δ 157.6, 136.2, 133.1, 132.8, 130.6, 129.7, 129.2, 126.7, 116.7, 103.9,
55.9. IR (neat) ν 1591 cm-1. HRMS (MALDI) m/z calcd for C14H1235Cl2O2
[M]+: 283.0287, found: 283.0290.
2-Bromo-4,5-dimethoxy-2',6'-bis(methoxymethoxy)-1,1'-biphenyl (6f)
and 2'-Bromo-4',5'-dimethoxy-1,1'-biphenyl-2,6-diol (1f): To an ice-cold,
stirred solution of 1,3-bis(methoxymethyl)benzene (3.6 g, 18.1 mmol) in
Et2O (40mL) was dropwise added n-BuLi (2.8 M solution in hexanes, 7.2
mL, 19.9 mmol) over 25 min. The reaction mixture was stirred at ambient
temperature for 4 h and was cooled to 0 °C, to which was dropwise added
1,2-dibromo-4,5-dimethoxybenzene 4f (5.4 g, 18.1 mmol) over 5 min with
vigorous stirring. The mixture was stirred at 0 °C overnight, and MeOH (1.0
mL) and H2O (40 mL) were added. The resulting mixture was extracted
with EtOAc three times, and the combined organic layer was dried over
MgSO4 and concentrated in vacuo. The residue was purified by column
chromatography (hexanes/EtOAc = 4:1) to give 6f (5.0 g) which contained
some impurities. Further purification of the product by column
chromatography (hexanes/EtOAc = 4:1) produced pure 6f. A colourless
2'-bromo-1,1'-biphenyl-2,6-diol (1a): 1a was synthesized according to
the reported procedure.[19] Its spectroscopic data are in good agreement
with those reported.[19]
2'-Chloro-1,1'-biphenyl-2,6-diol (1b); a typical procedure for the
demethylation of 6 to give 1 (Procedure B): A 1.0 M solution of
BBr3 (20 mL, 20 mmol) in CH2Cl2 was dropwise added to an ice-cold
solution of 6b (1.0 g, 4.0 mmol) in CH2Cl2 (0.07 M) over 10 min. The
resulting solution was stirred at ambient temperature overnight and
cooled again to 0 ºC. MeOH (1.0 mL) was added, Water and CH2Cl2
were added to the residue, and the mixture was extracted with
CH2Cl2 three times. The combined organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified
by column chromatography (hexanes/EtOAc = 4:1) to give 1b (0.67
g, 83% yield). A colourless solid. Mp. 145-146 °C. 1H-NMR (500 MHz,
CDCl3) δ 7.61-7.63 (m, 1H), 7.39-7.46 (m, 3H), 7.20 (t, J = 8.0 Hz,
1H), 6.60 (d, J = 8.0 Hz, 2H), 4.61 (s, 2H). 13C-NMR (126 MHz,
CDCl3) δ 153.5, 135.8, 133.0, 130.7, 130.2, 130.1, 128.0, 113.4,
107.9. Two 13C signals are overlapped. IR (neat) ν 3401. 1622, 1592
cm-1. HRMS (MALDI) m/z calcd for C12H1035ClO2 [M+H]+: 221.0364,
found: 221.0364.
1
solid. Mp. 104-106 °C. H-NMR (500 MHz, CDCl3) δ 7.29 (t, J = 8.0 Hz,
1H), 7.13 (s, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.76 (s, 1H), 5.09 and 5.06 (ABq,
J = 7.0 Hz, 4H), 3.91 (s, 3H), 3.83 (s, 3H), 3.37 (s, 6H). 13C-NMR (126
MHz, CDCl3) δ 155.5, 148.6, 147.9, 129.4, 128.0, 121.2, 115.0, 114.9,
114.6, 108.7, 94.7, 56.04, 56.02, 55.99. IR (neat) ν 1595 cm-1. HRMS
(MALDI) m/z calcd for C18H2179BrO6Na[M+Na]+: 435.0414, found:
435.0414.
A solution of the aforementioned 6f (5.0 g) and p-TsOH (2.3 g, 24 mmol)
in MeOH (30 mL) was stirred at ambient temperature for 10 h and was
concentrated under vacuo. The residue was purified by column
chromatography (hexanes/EtOAc = 4:1 to 1:1) to give 1f (3.9 g), which was
recrystallized from MeOH to give pure 1f (2.4 g, 40% yield for 2 steps).
Colorless needles. Mp. 236-237 °C. 1H NMR (500 MHz, CDCl3) δ 7.24 (s,
1H), 7.20 (t, J = 8.0 Hz, 1H), 6.84 (s, 1H), 6.60 (d, J = 8.0 Hz, 2H), 4.68 (s,
2H), 3.94 (s, 3H), 3.86 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 153.6, 150.5,
149.5, 130.1, 123.0, 116.33, 116.31, 115.1, 114.6, 107.7, 56.3, 56.2. IR
(neat) ν 3446, 1622, 1599. HRMS (MALDI) m/z calcd for C14H1379BrO4Na
[M+Na]+: 346.9889, found: 346.9887.
2'-Iodo-1,1'-biphenyl-2,6-diol (1c): By following Procedure B, 6c (0.68
g, 2.0 mmol) was converted to 1c (0.50 g, 79% yield). A colourless solid.
1
Mp. 172-174 °C. H NMR (500 MHz, CDCl3) δ 8.07 (dd, J = 8.0, 1.0 Hz,
1H), 7.53 (td, J = 8.0, 1.0 Hz, 1H), 7.37 (dd, J = 7.0, 2.0 Hz, 1H), 7.17-7.23
(m, 2H), 6.59 (d, J = 8.0 Hz, 2H), 4.55 (s, 2H)., 13C NMR (126 MHz, CDCl3)
δ 153.1, 140.4, 136.6, 132.2, 130.9, 130.2, 129.5, 118.7, 107.9, 102.5. IR
(neat) ν 3405, 1622, 1590 cm-1. HRMS (MALDI) m/z calcd for C12H10IO2
[M+H]+: 312.9719, found: 312.9720.
2'-Bromo-1,1'-biphenyl-2,6-diyl diacetate (3a);
a
typical
procedure for the acetylation of 1 to give 3 (Procedure C):
A
solution of 1a (0.30 g, 1.1 mmol), Ac2O (0.31 mL, 3.3 mmol, 3.0
equiv), 4-(dimethyamino)pridine (DMAP) (13.8 mg, 0.10 mmol, 0.1
equiv), and Et3N (0.31 mL, 2.3 mmol. 2.0 equiv) in CH2Cl2 (0.1 M)
was stirred at ambient temperature for 1 h and was concentrated in
vacuo. The residue was purified by column chromatography
(hexanes/EtOAc = 4:1) to give 3a (0.31 g, 80% yield). A colourless
solid. Mp. 81-83 °C. 1H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 8.0,
1.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.32 (td, J = 8.0, 1.0 Hz, 1H),
2'-Bromo-3',5'-difluoro-1,1'-biphenyl-2,6-diol
(1d):
2'-Bromo-3',5'-
difluoro-2,2’-dimethoxy-1,1'-biphenyl-2,6-diol 6d was prepared from 1,2-
dibromo-3,5-difluorobenzene 5d (1.1 g, 4.0 mmol) by following Procedure
A with the following modifications: Cs2CO3 was used instead of K3PO4 and
the reaction was conducted for 13 h. Then, the crude product 6d was
subjected to method B, and the follwoing recrystallization of a crude
product from CHCl3 gave 1d (0.50 g, 55% yield for 2 steps). A colourless
1
solid. Mp. 188-190 °C. H NMR (500 MHz, CDCl3) δ 7.20 (t, J = 8.0 Hz,
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10.1002/ejoc.201901583
European Journal of Organic Chemistry
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7.23 (td, J = 8.0, 2.0 Hz, 1H), 7.18 (dd, J = 8.0, 2.0 Hz, 1H), 7.12 (d,
J = 8.0 Hz, 2H), 1.94 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 168.8,
149.0, 133.64, 132.5, 131.8, 129.5, 129.3, 127.9, 126.9, 124.2, 120.2,
20.5. IR (neat) ν 1769 cm-1. HRMS (MALDI) m/z calcd for
C16H1379BrO4Na [M+Na]+: 370.9889, found: 370.9886.
consumption of 1, the mixture was filtered through a pad of Celite with
EtOAc, and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (hexanes/EtOAc = 8:1) to give (S)-2.
(S)-2'-Bromo-6-hydroxy-1,1'-biphenyl-2-yl
acetate
[(S)-2a]:
By
following Procedure D, (S)-2a (138 mg, 90% yield) was obtained from 1a
(133 mg, 0.50 mmol). A colourless solid. Mp. 95-97 °C. [α]ꢁꢀꢁ +37.8 (c 0.50,
CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.74 (dd, J = 8.0, 1.0 Hz, 1H), 7.41
(td, J = 8.0, 1.0 Hz, 1H), 7.28-7.35 (m, 3H), 6.92 (dd, J = 8.0, 1.0 Hz, 1H),
6.79 (dd, J = 8.0, 1.0 Hz, 1H), 4.73 (s, 1H), 1.93 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 169.1, 153.6, 148.7, 133.3, 132.7, 132.4, 130.4, 129.8,
127.8, 125.2, 121.3, 114.5, 113.4, 20.5. IR (neat) ν 3429, 1738, 1619, 1590
cm-1. HRMS (MALDI) m/z calcd for C14H1179BrO3Na [M+Na]+: 328.9784,
found: 328.9783. Its optical purity (>99% ee) was determined by HPLC
analysis at 20 °C using a CHIRALPAK IE column (hexanes/2-propanol =
97.5:2.5; flow rate: 1.0 mL/min; UV detection: 220 nm; retention times: 13.1
min (R), 14.7 min (S)).
2'-Chloro-1,1'-biphenyl-2,6-diyl diacetate (3b): By following Procedure
C, 1b (0.22 g, 1.0 mmol) was converted to 3b (0.30 g, 98% yield). A
colourless solid. Mp. 71-73 °C. 1H NMR (500 MHz, CDCl3) δ 7.44-7.47 (m,
2H), 7.27-7.33 (m, 2H), 7.19 (dd, J = 8.0, 2.0 Hz, 1H), 7.12 (d, J = 8.0 Hz,
2H), 1.95 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 168.8, 149.1, 134.2, 131.7,
131.4, 129.4, 129.3, 126.3, 126.2, 120.2, 20.47. Two 13C signals are
overlapped. IR (neat) ν 1771, 1639, 1615 cm-1. HRMS (MALDI) m/z calcd
for C16H1335ClO4Na [M+Na]+: 327.0395 , found: 327.0397.
2'-Iodo-1,1'-biphenyl-2,6-diyl diacetate (3c): By following Procedure C,
1c (0.31 g, 1.0 mmol) was converted to 3c (0.38 g, 95% yield). A colourless
solid. Mp. 122-124 °C. 1H-NMR (500 MHz, CDCl3) δ 7.92 (dd, J = 8.0, 1.0
Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.36 (td, J = 8.0, 1.0 Hz, 1H), 7.11-7.15
(m, 3H), 7.05 (td, J = 8.0, 2.0 Hz, 1H), 1.93 (s, 6H)., 13C-NMR (126 MHz,
CDCl3) δ 168.7, 148.8, 138.8, 137.9, 130.9, 129.4, 129.3, 127.7, 120.3,
99.7, 20.49. Two 13C signals are overlapped. IR (neat) ν 1768, 1613 cm-1.
HRMS (MALDI) m/z calcd for C16H13IO4Na [M+Na]+: 418.9751, found:
418.9748.
(S)-2'-Chloro-6-hydroxy-1,1'-biphenyl-2-yl
acetate [(S)-2b]:
By
following Procedure D, (S)-2b (108 mg, 82% yield) was obtained from 1b
(110 mg, 0.50 mmol). A colourless solid. Mp. 87-88 °C. [α]ꢁꢀꢂ +47.6 (c 0.50,
CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.54-7.56 (m, 1H), 7.29-7.41 (m, 4H),
6.91 (dd, J = 8.0, 1.0 Hz, 1H), 6.79 (dd, J = 8.0, 1.0 Hz, 1H), 4.79 (s, 1H),
1.93 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.1, 153.8, 148.9, 135.0,
132.4, 130.5, 130.2, 130.1, 129.8, 127.2, 119.5, 114.5, 113.4, 20.5. IR
(neat) ν 3438, 1738, 1615, 1591 cm-1. HRMS (MALDI) m/z calcd for
C14H1135ClO3Na [M+Na]+: 285.0289, found: 285.0289. Its optical purity
(99% ee) was determined by HPLC analysis at 20 °C using a CHIRALPAK
IE column (hexanes/2-propanol = 97.5:2.5; flow rate: 1.0 mL/min; UV
detection: 254 nm; retention times: 13.0 min (R), 14.1 min (S)).
2'-Bromo-3',5'-difluoro-1,1'-biphenyl-2,6-diyl diacetate (3d): By
following Procedure C, 1d (0.31 g, 1.0 mmol) was converted to 3d (0.38
g, quantitative yield). A colourless solid. Mp. 116-118 °C. 1H NMR (500
MHz, CDCl3) δ 7.49 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 6.94 (td,
J = 8.0, 3.0 Hz, 1H), 6.79-6.82 (m, 1H), 2.01 (s, 6H). 13C NMR (126 MHz,
CDCl3) δ 168.5, 161.2 (dd, JCF = 242, 12 Hz), 159.1 (dd, JCF = 242, 12 Hz),
148.7, 137.0 (d, JCF = 9 Hz), 130.0, 125.7, 120.3, 114.4 (dd, JCF = 22, 4
Hz), 106.6 (dd, JCF = 22, 4 Hz), 104.6 (t, JCF = 26 Hz), 20.6. 19F NMR (376
MHz, CDCl3) δ -102.8 (m, 1F), -114.1 (m, 1F). IR (neat) ν 1775, 1615, 1589
cm-1. HRMS (MALDI) m/z calcd for C16H1179BrO4F2Na [M+Na]+: 406.9701,
found: 406.9698.
(S)-6-hydroxy-2'-iodo-1,1'-biphenyl-2-yl acetate [(S)-2c]: By following
Procedure D, (S)-2c (160 mg, 90% yield) was obtained from 1c (156 mg,
0.50 mmol). A colourless solid. Mp. 117-121 °C. [α]ꢁꢀꢁ +30.8 (c 0.49,
CHCl3). 1H NMR (500 MHz, [D6]acetone) δ 8.45 (s, 1H), 7.95 (dd, J = 8.0,
1.0 Hz, 1H), 7.42 (td, J = 8.0, 1.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.15
(dd, J = 8.0, 2.0 Hz, 1H), 7.10 (td, J = 8.0, 2.0 Hz, 1H), 6.88 (dd, J = 8.0,
1.0 Hz, 1H), 6.70 (dd, J = 8.0, 1.0 Hz, 1H), 1.84 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 169.1, 153.4, 148.6, 139.7, 137.0, 131.6, 130.3, 129.9,
128.7, 124.6, 114.5, 113.5, 101.1, 20.5. IR (neat) ν 3434, 1738, 1615 cm-
1. HRMS (MALDI) m/z calcd for C14H11IO3Na [M+Na]+: 376.9645, found:
376.9646. Its optical purity (99% ee) was determined by HPLC analysis at
20 °C using a CHIRALPAK IE column (hexanes/2-propanol = 97.5:2.5;
flow rate: 1.0 mL/min; UV detection: 254 nm; retention times: 13.0 min (R),
14.5 min (S)).
2',3'-Dichloro-1,1'-biphenyl-2,6-diyl diacetate (3e): By following
Procedure C, 1e (0.26 g, 1.0 mmol) was converted to 3e (0.32 g, 95%
1
yield). A colourless solid. Mp. 102-104 °C. H NMR (500 MHz, CDCl3) δ
7.45-7.50 (m, 2H), 7.22 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.11
(dd, J = 8.0, 2.0 Hz, 1H), 1.97 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 168.7,
148.8, 138.8, 137.9, 130.9, 129.4, 129.3, 127.7, 120.3, 99.7, 20.49. Two
13C signals are overlapped. IR (neat) ν 1771, 1613, 1583 cm-1. HRMS
(MALDI) m/z calcd for C16H1235Cl2O4Na [M+Na]+: 361.0005, found:
361.0003.
(S)-2'-Bromo-3',5'-difluoro-6-hydroxy-1,1'-biphenyl-2-yl acetate [(S)-
2d]: By following Procedure D, (S)-2d (156 mg, 91% yield) was obtained
from 1d (151 mg, 0.50 mmol). A colourless solid. Mp. 136-140 °C. [α]ꢀꢁꢃ
+19.6 (c 0.44, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.35 (t, J = 8.0 Hz,
1H), 6.98 (td, J = 8.0, 3.0 Hz, 1H), 6.86-6.90 (m, 2H), 6.81 (dd, J = 8.0, 1.0
Hz, 1H), 4.78 (s, 1H), 2.00 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.1,
161.6 (dd, JCF = 250, 12 Hz), 159.7 (dd, JCF = 250, 12 Hz), 153.5, 148.6,
136.7 (d, JCF = 10 Hz), 130.3, 119.6, 114.83 (dd, JCF = 21, 4.0 Hz), 114.81,
113.6, 107.2 (dd, JCF = 21, 4.0 Hz), 104.9 (t, JCF = 26 Hz), 20.6. 19F NMR
(376 MHz, CDCl3) δ -101.9 (m, 1F), -113.4 (m, 1F). IR (neat) ν 3415, 1738,
1619, 1588 cm-1. HRMS (FAB+) m/z calcd for C14H1079BrF2O3 [M+H]+:
342.9781, found: 342.9776. Its optical purity (>99% ee) was determined
by HPLC analysis at 20 °C using a CHIRALPAK IE column (hexanes/2-
2'-Bromo-4',5'-dimethoxy-1,1'-biphenyl-2,6-diyl diacetate (3f): By
following Procedure C, 1f (1.0 g, 3.1 mmol) was converted to 3f (1.16 g,
92% yield). A colourless solid. Mp. 160-162 °C. 1H NMR (500 MHz, CDCl3)
δ 7.44 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.10 (s, 1H), 6.68 (s,
1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.00 (s, 6H). 13C NMR (126 MHz, CDCl3) δ
168.9, 149.3, 149.1, 147.8, 129.2, 127.8, 125.4, 120.2, 114.9, 114.3, 114.0,
56.11, 56.06, 20.6. IR (neat) ν 1765, 1599, 1509 cm-1. HRMS (MALDI) m/z
calcd for C18H1779BrO6Na [M+Na]+: 431.0101, found: 431.0100.
A general procedure for lipase-catalyzed acylative desymmetrization
of 1 (Procedure D): To a solution of biaryl diol 1 (0.50 mmol) in toluene
(0.1 M) was added PS-IM (2.0 w/w), vinyl acetate (0.46 mL, 5.0 mmol) and
Na2CO3 (50 mg, 0.75 mmol) at 35 °C. The progress of the reaction was
monitored by HPLC analysis of an aliquot of the reaction mixture. After the
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10.1002/ejoc.201901583
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propanol = 98.75:1.25; flow rate: 1.0 mL/min; UV detection: 220 nm;
(R)-6-Hydroxy-2'-iodo-1,1'-biphenyl-2-yl acetate [(R)-2c]: (R)-2c (150
mg, 85% yield) was obtained from 3c (198 mg, 0.50 mmol) by following
Procedure E with the following modification; the crude product was
purified by column chromatography (hexanes/EtOAc = 8:1). A colourless
solid. Mp. 117-121 °C. [α]ꢀꢁꢁ -31.6 (c 0.58, CHCl3). Its 1H NMR, 13C NMR,
and IR data are in good agreement with those for (S)-2b. HRMS (MALDI)
m/z calcd for C14H11IO3Na [M+Na]+: 376.9645, found: 376.9642. Its optical
purity (>99% ee) was determined by HPLC analysis as shown for (S)-2c.
retention times: 12.2 min (R), 13.7 min (S)).
(S)-2',3'-Dichloro-6-hydroxy-1,1'-biphenyl-2-yl acetate [(S)-2e]: By
following Procedure D, (S)-2e (113 mg, 76% yield) was obtained from 1e
(128 mg, 0.50 mmol). A colourless solid. Mp. 136-138°C. [α]ꢁꢀꢃ +48.7 (c
0.50, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.55 (dd, J = 8.0, 2.0 Hz, 1H),
7.28-7.36 (m, 2H), 7.21 (dd, J = 8.0, 2.0 Hz, 1H), 6.90 (dd, J = 8.0, 1.0 Hz,
1H), 6.79 (dd, J = 8.0, 1.0 Hz, 1H), 4.81 (s, 1H), 1.96 (s, 3H)., 13C NMR
(126 MHz, CDCl3) δ 169.1, 153.6, 148.8, 133.8, 133.4, 133.1, 130.8, 130.4,
130.0, 127.6, 119.5, 114.7, 113.5, 20.6. IR (neat) ν 3415, 1737, 1617, 1589
cm-1. HRMS (MALDI) m/z calcd for C14H1035Cl2O3Na [M+Na]+: 318.9899,
found: 318.9897. Its optical purity (>99% ee) was determined by HPLC
analysis at 20 °C using a CHIRALPAK IE column (hexanes/2-propanol =
97.5:2.5; flow rate: 1.0 mL/min; UV detection: 220 nm; retention times: 18.9
min (R), 22.3 min (S)).
(R)-2'-Bromo-3',5'-difluoro-6-hydroxy-1,1'-biphenyl-2-yl acetate [(R)-
2d]: By following Procedure E, (R)-2d (162 mg, 94% yield) was obtained
from 3d (193 mg, 0.50 mmol). A colourless solid. Mp. 136-140 °C. [α]ꢀꢁꢁ
-
19.9 (c 0.48, CHCl3). Its 1H NMR, 13C NMR, 19F NMR, and IR data are in
good agreement with those for (S)-2d. HRMS (FAB+) m/z calcd for
C14H1079BrF2O3 [M+H]+: 342.9781 and 344.9762, found:342.9790 and
344.9772. Its optical purity (>99% ee) was determined by HPLC analysis
as shown for (S)-2d.
(S)-2'-Bromo-6-hydroxy-4',5'-dimethoxy-1,1'-biphenyl-2-yl
acetate
[(S)-2f]: (S)-2f (172 mg, 94% yield) was obtained from 1f (163 mg, 0.50
mmol) by following Procedure D with the following modifications: Using
PS-IM (488 mg, 3 w/w) at 50 °C for 26 h and the column chromatography
(hexanes/EtOAc = 4:1 to 2:1). An amorphous colourless solid. Mp. 43-
55 °C. [α]ꢁꢀꢄ +11.4 (c 0.56, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.32 (t, J
= 8.0 Hz, 1H), 7.17 (s, 1H), 6.92 (dd, J = 8.0, 1.0 Hz, 1H), 6.75-6.77 (m,
2H), 4.87 (s, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 1.98 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 169.4, 154.0, 149.9, 149.1, 148.8, 129.9, 124.1, 121.3,
115.7, 115.3, 114.6, 114.4, 113.5, 56.30, 56.28, 20.8. IR (neat) ν 3448,
3012, 2938, 2842, 1762, 1599, 1509 cm-1. HRMS (MALDI) m/z calcd for
C16H1579BrO5Na [M+Na]+: 388.9995, found: 388.9994. Its optical purity
(>99% ee) was determined by HPLC analysis at 20 °C using a
CHIRALPAK IE column (hexanes/2-propanol = 92.5:7.5; flow rate: 1.0
mL/min; UV detection: 254 nm; retention times: 11.0 min (R), 12.1 min (S)).
(R)-2',3'-Dichloro-6-hydroxy-1,1'-biphenyl-2-yl acetate [(R)-2e]: By
following Procedure E, (R)-2e (146 mg, 98% yield) was obtained from 3e
(170 mg, 0.50 mmol). A colourless solid. Mp. 136-138 °C. [α]ꢁꢀꢃ -49.9 (c
1
0.58, CHCl3). Its H NMR, 13C NMR, and IR data are in good agreement
with those for (S)-2e. HRMS (MALDI) m/z calcd for C14H1035Cl2O3Na
[M+Na]+: 318.9899, found: 318.9899. Its optical purity (>99% ee) was
determined by HPLC analysis as shown for (S)-2e.
(R)-2'-bromo-6-hydroxy-4',5'-dimethoxy-1,1'-biphenyl-2-yl
acetate
[(R)-2f]: (R)-2f (174 mg, 95% yield) was obtained from 3f (205 mg, 0.50
mmol) by following Procedure E with the following modifications: Using
PS-IM (41 mg, 0.20 w/w) and double volume of each solvent at 50 °C. A
colourless solid. Mp. 52-57 °C. [α]ꢁꢀꢁ -10.3 (c 0.70, CHCl3). Its 1H NMR, 13
C
NMR, and IR data are in good agreement with those for (S)-2f. HRMS
(MALDI) m/z calcd for C16H1579BrO5Na [M+Na]+: 388.9995, found:
388.9992. Its optical purity (>99% ee) was determined by HPLC analysis
as shown for (S)-2f.
A general procedure for lipase-catalyzed hydrolytic desymmetri-
zation of 3 (Procedure E): To a solution of 3 (0.50 mmol) in a mixture of
a solution pH 7.0 phosphate buffer (3.0 mL) and pentane (2.0 mL) was
added PS-IM (0.10 w/w) at 30 °C. The progress of the reaction was
monitored by HPLC analysis of an aliquot of the reaction mixture. After the
consumption of 3, the mixture was filtered through a pad of Celite with
EtOAc and extracted with EtOAc for three times. Then the filtrate was
concentrated under vacuo to give monoester (R)-2, whose purity was more
than 98% based on 1H NMR analysis.
Acknowledgements
This work was financially supported by the JSPS KAKENHI
[18HO4411 (Middle Molecular Strategy) and 18H02556] and
Platform Project for Supporting Drug Discovery and Life Science
Research (Basis for Supporting Innovative Drug Discovery and
Life Science Research (BINDS)) from AMED under Grant Number
JP19am0101084. We acknowledge Amano Enzyme Inc. for
supplying lipase PS-IM.
(R)-2'-Bromo-6-hydroxy-1,1'-biphenyl-2-yl acetate
[(R)-2a]: By
following Procedure E (R)-2a (153 mg, >99% yield) was obtained
,
from 3a (175 mg, 0.50 mmol). A colourless solid. Mp. 97-98 °C. [α]ꢀꢁꢁ
-37.8 (c 0.58, CHCl3). Its 1H NMR, 13C NMR, and IR data are in good
agreement with those for (S)-2a. HRMS (MALDI) m/z calcd for
C14H1179BrO3Na [M+Na]+: 328.9784, found: 328.9784. Its optical
purity (>99% ee) was determined by HPLC analysis as shown for (S)-
Keywords: lipase • axial chirality • enantiodivergent synthesis•
desymmetrization
2a
.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Commercially available Burkholderia
cepacia lipase was used for the
acylative desymmetrization of σ-
symmetric 2’-halo-1,1’-biphenyl-2,6-
diols 1 and the hydrolytic
Kengo Kasama, Hiroshi Aoyama and
Shuji Akai*
Page No. – Page No.
desymmetrization of their diacetates
3 to achieve the enantiodivergent
synthesis of axially chiral biphenyl
monoacetates, (S)- and (R)-2,
respectively, in high chemical and
optical yields.
Enantiodivergent synthesis of axially
chiral biphenyls from σ-symmetric
1,1ʹ-biphenyl-2,6-diol derivatives by
single lipase-catalyzed acylative and
hydrolytic desymmetrization
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