Facile and highly enantioselective synthesis of axially chiral biaryls by enzymatic desymmetrization

Article abstract of DOI:10.1055/s-2002-19349

The axially chiral biaryls 2 were obtained in high enantioselectivity by desymmetrization of the σ-symmetric biaryl diacetates 1 by lipase-catalyzed hydrolysis.

Full text of DOI:10.1055/s-2002-19349

122
LETTER
Facile and Highly Enantioselective Synthesis of Axially Chiral Biaryls by
Enzymatic Desymmetrization
F
acile and High
a
ly Enantios
k
e
lective
S
yn
a
thesis of
A
s
hal Biaryls i Matsumoto,* Tadayoshi Konegawa, Takeshi Nakamura, Keisuke Suzuki
Department of Chemistry, Tokyo Institute of Technology, and CREST, Japan Science and Technology Corporation (JST), Tokyo 152-8551,
Japan
Fax +81(3)57343531; E-mail: tmatsumo@chem.titech.ac.jp
Received 18 September 2001
Substrates for the enzymatic hydrolysis, the diacetates
Abstract: The axially chiral biaryls 2 were obtained in high enanti-
1a–1d, were synthesized via the Suzuki coupling
oselectivity by desymmetrization of the -symmetric biaryl diace-
tates 1 by lipase-catalyzed hydrolysis.
reaction6 of the boronic acid 4 with the bromoarenes
5a–5d, respectively (Scheme).
Key words: asymmetrization, hydrolysis, enzyme, axial chirality,
biaryl
B(OH)2
MOMO
OMOM
MOMO
OMOM
1) n-BuLi, Et2O
Axially chiral non-racemic biaryls are of current interest
due to their importance as chiral ligands and auxiliaries in
asymmetric synthesis. Also, they constitute a structural
feature of many natural products.1,2
2) B(OMe)3; then
3 M HCl
65%
3
4
Ar-Br (5a–5d)
Pd(PPh3)4 (10 mol%)
2 M Na2CO3 aq., benzene
reflux
Among the approaches to such chiral biaryls, ones based
on the desymmetrization of achiral biaryl derivatives, e.g.
the palladium-catalyzed cross-coupling of 2-aryl-1,3-phe-
nylene ditriflates by Hayashi3a and the acetalization of
2,2’,6,6’-biphenyltetrol with L-menthone by Harada,3b are
unique and convenient in terms of the ready accessibility
to the achiral precursors. Surprisingly, however, there
have been no reports on the application of an enzyme to
such desymmetrization,4 although the ability of enzymes
to recognize the axial chiralities of a biaryl has been well
documented in the kinetic resolution of racemic biaryls.5
1) TsOH, MeOH
AcO
OAc
MOMO
OMOM
2) Ac2O, DMAP
pyridine
1a: 94%, 1b: 75%
1c: 78%, 1d: 89%
6a: 38%, 6b: 79%
6c: 74%, 6d: 31%
5b: R = Me
In this communication, we wish to report the first example
of the enzymatic asymmetric desymmetrization of biaryl
compounds: The -symmetric biaryl diacetate 1 can be ef-
ficiently desymmetrized by lipase-catalyzed hydrolysis to
give the chiral biaryls 2 in high enantioselectivity (Equa-
tion 1).
R
5c:
5d:
R = Et
R = CH2OBn
5a
Br
Br
Scheme
The boronic acid 4 was easily prepared from the resorci-
nol derivative 3 via (1) lithiation, (2) trapping by
B(OMe)3, (3) acid workup, and (4) purification of the
crude material by trituration with hexane. A single batch
of the operations starting from 50 g of 3 gave 40 g of col-
orless, pure crystals of 4 [mp 79–80 °C]. The biaryl bond
formations with the boronic acid 4 and the bromoarenes,
5a–5d, proceeded in moderate to good yields under the
standard conditions of the Suzuki coupling. Removal of
the MOM groups under acidic conditions followed by
acetylation gave the diacetates 1a–1d in high yields.
Lipase
AcO
OH
AcO
OAc
1
2
Equation 1
With the diacetates in hand, we examined several com-
mercially available lipases for the hydrolysis of 1a. Thus,
1a (50 mg) was treated with the lipases (10 mg) in a
3:2-mixture of pH 7 phosphate buffer (0.1 M)–acetone at
30 °C. As shown in Table, it turned out that CAL and PCL
were effective for the purpose. Both enzymes gave the
mono-acetate (+)-2a in high enantioselectivity in high
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0122,0124,ftx,en;Y19501ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Facile and Highly Enantioselective Synthesis of Axially Chiral Biaryls
123
Both PCL and CAL exhibited high enantioselectivities in
all cases.7 However, in terms of the reaction rate, PCL was
preferable in the reactions of 1b and 1c, and CAL was
preferable in the reaction of 1d.
Table Hydrolysis of 1a using Various Lipases
enzyme (10 mg)
AcO
OAc
phosphate buffer (pH 7),
acetone (3:2), 30 °C
1a 50 mg
Me
Me
OH
PCL (100 mg)
30 ºC, 3 d
AcO
AcO
OAc
AcO
OH
HO
OH
(–)-2b
86% (99% ee)
cf) CAL (200mg), 7 d → 80% (97% ee)
1b 1.00 g
(+)-2a
7a
Yield %
Equation 3
Run Enzymea Period/day (+)-2a (ee/%) Recovery 7a
of 1a
1
2
3
4
5
6
PFL
CRL
PPL
PLE
CAL
PCL
2
82 (79)
4 (80)
7
93
60
51
11
1
5
0
Et
Et
OH
PCL (200 mg)
30 ºC, 3 d
2
AcO
AcO
OAc
2.5
2.5
2.5
1
12 (94)
12 (95)
72 (97)
94 (98)
2
1c 1.00 g
(–)-2c
67% (96% ee)
cf) CAL, 7 d → 57% (99% ee)
20
3
1
Equation 4
a PFL: Pseudomonas fluorescence lipase (Amano Pharm. Co., lipase
AK), CRL: Candida rugosa lipase (Amano Pharm. Co., lipase AY),
PPL: porcine pancreas lipase (Sigma, Type II), PLE: pig liver esterase
(Sigma), CAL: Candida antarctica lipase (Roche Diagnostics,
Chirazyme L-2), PCL: Pseudomonas cepacia lipase (Amano Pharm.
Co., lipase PS)
OBn
OBn
CAL (200 mg)
AcO
OH
AcO
OAc
35 ºC, 7 d
yield,7 while the reaction rate was slower with CAL than
that with PCL. By contrast, the enantioselectivity was un-
satisfactory with PFL, and the reaction rate was too slow
with CRL, PPL, or PLE.
1d 1.00 g
(–)-2d
68% (99% ee)
cf) PCL, 7 d → 51% (98% ee)
Equation 5
Equation 2 shows the 1g scale reaction with PCL under
the optimized conditions (100 mg catalyst), where (+)-2a
with 99% ee was obtained in 93% yield.7
The chiral biaryls, 2a–2d, thus obtained, were configura-
tionally stable at room temperature. Even the compound
2b, which should have the lowest barrier to the biaryl
bond rotation among these compounds, underwent virtu-
ally no racemization during storage as a solution in CHCl3
for one week or as crystals for some months.8
PCL (100 mg)
AcO
OH
0.1 M phosphate buffer (pH 7),
acetone (40 ml/26 ml)
30 °C, 24 h
AcO
OAc
The absolute configurations of 2a–2d were determined by
X-ray crystallography after derivations as shown below
(Figure). Thus, the sense of the stereoselection proved
identical in all the cases. Namely, the pro-R acetates were
predominantly hydrolyzed, although we can not give a ra-
tional explanation based on the enzyme structure.
1a 1.00 g
(+)-2a
93% (99% ee)
Equation 2
In summary, the symmetric diacetates 1 were efficiently
desymmetrized by hydrolysis with a suitable lipase, i.e.
PCL or CAL, to give the corresponding mono-acetates 2
in high enantioselectivity. This desymmetrization will
have considerable value as a synthetic method for axially
chiral biaryls because of its convenience and high enantio-
selectivity.
The reactions of diacetates 1b–1d were carried out under
the similar conditions by employing PCL and CAL as the
catalyst (Equations 3–5).
Synlett 2002, No. 1, 122–124 ISSN 0936-5214 © Thieme Stuttgart · New York

124
T. Matsumoto et al.
LETTER
(3) (a) Hayashi, T.; Niizuma, S.; Kamikawa, T.; Suzuki, N.;
Uozumi, Y. J. Am. Chem. Soc. 1995, 117, 9101.
(b) Harada, T.; Ueda, S.; Yoshida, T.; Inoue, A.; Takeuchi,
M.; Ogawa, N.; Oku, A. J. Org. Chem. 1994, 59, 7575.
(4) For a review of the enzymatic asymmetric
desymmetrization, see: Schoffers, E.; Golebiowski, A.;
Johnson, C. R. Tetrahedron 1996, 52, 3769.
(5) (a) Fujimoto, Y.; Iwadate, H.; Ikekawa, N. J. Chem. Soc.,
Chem. Commun. 1985, 1333. (b) Wu, S.-H.; Zhang, L.-Q.;
Chen, C.-S.; Girdaukas, G.; Sih, C. J. Tetrahedron Lett.
1985, 26, 4323. (c) Kazlauskas, R. J. J. Am. Chem. Soc.
1989, 111, 4953. (d) Miyano, S.; Kawahara, K.; Inoue, Y.;
Hashimoto, H. Chem. Lett. 1987, 355.
(6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(7) Enantiomeric purities of the biaryls 2a-2d were determined
by chiral HPLC analyses. Enantiomerically pure samples of
2a–2c could be obtained by recrystallization. Data for the
compounds 2a–2d follow; (+)-2a (>99% e.e.): Mp 97–98 °C
(hexane–EtOAc); [ ]18D +101 (c 1.03, CHCl3); 1H NMR
(CDCl3) 1.69 (s, 3 H), 4.77 (s, 1 H), 6.83 (dd, 1 H, J = 8.3,
1.0 Hz), 7.00 (dd, 1 H, J = 8.3, 1.0 Hz), 7.3–7.6 (m, 6 H),
7.94 (dd, 2 H, J = 8.1, 8.1 Hz); 13C NMR (CDCl3) 20.3,
113.2, 114.6, 119.8, 125.3, 125.6, 126.4, 126.9, 128.3,
128.5, 128.8, 129.3, 129.5, 131.8, 133.8, 149.4, 154.4,
169.3; IR (KBr) 3419, 1740 cm-1. Anal. Calcd for C18H14O3:
C, 77.68; H, 5.07. Found: C, 77.62; H, 5.37. HPLC (Daicel
CHIRACEL OJ, 250 4.6 mm, hexane–i-PrOH = 9:1,
0.5 mL/min) retention time: 34.6 min for (+)-2a [43.1 min
for (–)-2a].
(–)-2b (>99% e.e.): Mp 87–88 °C (hexane–EtOAc); [ ]24
D
–17.6 (c 1.06, CHCl3); 1H NMR (CDCl3) 1.86 (s, 3 H), 2.13
(s, 3 H), 4.84 (s, 1 H), 6.73 (dd, 1 H, J = 8.3, 1.0 Hz), 6.90
(dd, 1 H, J = 8.3, 1.0 Hz), 7.1–7.4 (m, 5 H); 13C NMR
(CDCl3) 19.4, 20.4, 113.1, 114.3, 121.3, 126.3, 129.0,
129.1, 130.3, 130.6, 130.9, 138.3, 148.9, 153.8, 169.2; IR
(KBr) 3422, 1761 cm-1. Anal. Calcd for C15H14O3: C, 74.36;
H, 5.82. Found: C, 74.59; H, 5.82. HPLC (Daisel
CHIRACEL OD-H, 250 4.6 mm, hexane–iPrOH = 9:1, 0.7
mL/min) retention time: 8.13 min for (–)-2b [7.68 min for
(+)-2b].
(–)-2c (>99% e.e.): Mp 56–57 °C (hexane–EtOAc); [ ]23
D
Figure
–41.5 (c 1.06, CHCl3); 1H NMR (CDCl3) 1.09 (t, 3 H, J =
7.6 Hz), 1.85 (s, 3 H), 2.43 (q, 2 H, J = 7.6 Hz), 4.74 (s, 1 H),
6.74 (dd, 1 H, J = 8.3, 1.3 Hz), 6.91 (dd, 1 H, J = 8.3, 1.3 Hz),
7.1–7.4 (m, 5 H); 13C NMR (CDCl3) 14.8, 20.4, 25.9,
113.0, 114.3, 121.1, 126.4, 128.8, 129.1, 129.2, 129.5,
131.0, 144.2, 148.9, 153.9, 169.2; IR (KBr) 3438, 1744
cm–1. Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C,
74.86; H, 6.35. HPLC (Daisel CHIRACEL OD-H, 250 4.6
mm, hexane–i-PrOH = 9:1, 0.7 mL/min) retention time: 8.40
min for (–)-2c [7.83 min for (+)-2c].
References
(1) For leading references, see: (a) Bringmann, G.; Walter, R.;
Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977.
(b) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(2) For selected examples of the recent biaryl bond formation
methods, see: (a) Saito, S.; Kano, T.; Muto, H.; Nakadai, M.;
Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 8943.
(–)-2d (99% e.e.): Colorless oil; [ ]D23 –18.4 (c 1.23,
CHCl3); 1H NMR (CDCl3) 1.79 (s, 3 H), 4.34 (s, 2 H), 4.45
(d, 1 H, J = 11.6 Hz), 4.53 (d, 1 H, J = 11.6 Hz), 6.22 (s, 1
H), 6.74 (dd, 1 H, J = 8.2, 1.0 Hz), 6.97 (dd, 1 H, J = 8.2, 1.0
Hz), 7.1–7.5 (m, 9 H), 7.5–7.6 (m, 1 H); 13C NMR (CDCl3)
20.3, 71.4, 73.1, 114.6, 115.2, 122.3, 127.8, 128.0, 128.4,
128.5, 128.8, 129.3, 130.1, 131.4, 131.7, 137.1, 137.3,
149.0, 154.8, 169.2; IR (KBr) 3422, 1758 cm–1. Anal. Calcd
for C22H20O4: C, 75.84; H, 5.79. Found: C, 75.72; H, 5.96.
HPLC (Daisel CHIRACEL OD-H, 250 4.6 mm, hexane–i-
PrOH = 9:1, 0.5 mL/min) retention time: 12.9 min for (+)-2d
and 14.5 min for (–)-2d.
(b) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999,
525. (c) Kakiuchi, F.; Le Gendre, P.; Yamada, A.; Ohtaki,
H.; Murai, S. Tetrahedron: Asymmetry 2000, 11, 2647.
(d) Kamikawa, K.; Uemura, M. Synlett 2000, 938.
(e) Cammidge, A. N.; Crépy, K. V. L. Chem. Commun.
2000, 1723. (f) Degnan, A. P.; Meyers, A. I. J. Am. Chem.
Soc. 1999, 121, 2762. (g) Lipshutz, B. H.; Müller, P.;
Leinweber, D. Tetrahedron Lett. 1999, 40, 3677.
(8) Upon heating in toluene at 60 °C, (+)-2a racemized 1% after
12 h, and 80 °C, 7% after 12 h.
Synlett 2002, No. 1, 122–124 ISSN 0936-5214 © Thieme Stuttgart · New York