Different recognitions of (E)- and (Z)-1,1′-binaphthyl ketoximes using lipase-catalyzed reactions

Article abstract of DOI:10.1016/j.tetlet.2004.05.051

Lipase-catalyzed hydrolysis of (E)-2-[α-(acetoxyimino)benzyl]-1, 1′-binaphthyl [(±)-1a] and (Z)-2-[α-(acetoxyimino)benzyl]-1, 1′-binaphthyl [(±)-1b] yielded optically active (E)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(S)-2a] and (Z)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(R)-2b], respectively, with high enantiomeric excess. Selectivity for the opposite enantiomer of the axial binaphthyl skeleton was shown by (Z)-isomer 1b against (E)-isomer 1a.

Full text of DOI:10.1016/j.tetlet.2004.05.051

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5189–5192
Different recognitions of (E)- and (Z)-1,10-binaphthyl ketoximes
using lipase-catalyzed reactions
Naoto Aoyagi,* Shinji Kawauchi and Taeko Izumi
Department of Chemistry and Chemical Engineering, Graduate School of Science and Engineering,
Yamagata University, Jyonan, Yonezawa, Yamagata 992-8510, Japan
Received 7 April 2004; revised 8 May 2004; accepted 12 May 2004
Abstract—Lipase-catalyzed hydrolysis of (E)-2-[a-(acetoxyimino)benzyl]-1,10-binaphthyl [( )-1a] and (Z)-2-[a-(acetoxyimino)benz-
yl]-1,10-binaphthyl [( )-1b] yielded optically active (E)-2-[a-(hydroxyimino)benzyl]-1,10-binaphthyl [(S)-2a] and (Z)-2-[a-(hydroxy-
imino)benzyl]-1,10-binaphthyl [(R)-2b], respectively, with high enantiomeric excess. Selectivity for the opposite enantiomer of the
axial binaphthyl skeleton was shown by (Z)-isomer 1b against (E)-isomer 1a.
Ó 2004 Elsevier Ltd. All rights reserved.
Lipases in organic solvents have been employed as
stereoselective catalysts in the synthesis of optically
active compounds,1 using substrates such as alcohols,
amines, carboxylic acids, and esters. Although it has
recently been reported that oxime derivatives can be
resolved by lipase-catalyzed acylation and hydrolysis,2
little is known about the lipase-catalyzed resolution of
oxime derivatives, such as the (E)- and (Z)-isomers.
form as the eluent. Oximes 2a and 2b were esterified10 to
afford esters 1a and 1b, respectively.
As a note, the acetylations of ketoximes ( )-2a and ( )-
2b were initially attempted via enzymatic esterification
in an organic solvent. However, ketoximes ( )-2a and
( )-2b were not effective as substrates for any of the six
commercially available lipase preparations under the
conditions for lipase catalysis (Scheme 2).11 Because the
aldehyde oxime of 1,10-binaphthyl was effective as a
substrate for lipase-catalyzed esterification,5 the phenyl
group at the iminomethyl position presumably causes
steric hindrance at the active site of the lipase.
We have recently reported on the efficient resolutions of
1,10-binaphthyl amine, ester, and oxime using lipase-
catalyzed reactions.3–5 Because the binaphthyl oxime
was not of the ketoxime type, but rather of the aldehyde
oxime type, the compound existed mostly as the (E)-
isomer. Consequently, the study of reactions involving
the (E)- and (Z)-isomer of binaphthyl ketoximes (e.g.,
phenyl group containing ketoximes) developed into an
area of research interest.
The successful approach involved the enzymatic reso-
lution of ( )-1a and ( )-1b under hydrolysis condition,
using the six commercially available lipase preparations
(Schemes 3 and 4).11
The synthetic methodology of ketoximes 1a, 1b, 2a, and
2b are shown in Scheme 1.6 2-Formyl-1,10-binaphthyl 3
was treated with phenyl lithium7 to afford tertiary
alcohol 4, which was oxidized8 to give ketone 5. Con-
densation9 of ketone 5 yielded a mixture of (E)- and (Z)-
oximes (2a and 2b, respectively), which were separated
using silica gel column chromatography with chloro-
In a typical experiment, lipase (40 mg) and n-butanol
(0.0672mmol) were added to a solution of O-acetyl
ketoxime ( )-1a or ( )-1b (28 mg, 0.0672 mmol) and 20-
acetonaphthone (1.0 mg, standard substance) in tert-
butyl methyl ether (6 mL) (MTBE) and the resulting
mixture was shaken (150 c/min) at 30 °C. The reaction
was monitored periodically using HPLC (column, GL
Sciences Inertsil ODS-2; mobile phase, acetonitrile/
water ¼ 8:2; flow rate, 0.8 mL/min; UV detection at
254 nm). Upon completion, the reaction was terminated
by removing the lipase via filtration. The lipase portion
was washed with MTBE (15 mL). The filtrate and wash
were combined, evaporated at 30 °C, and the resulting
Keywords: Binaphthyl; Ketoxime; Lipase; Hydrolysis.
* Corresponding author. Tel.: +81-238-26-3126; fax: +81-238-26-3413;
e-mail: tp455@dip.yz.yamagata-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.051

5190
N. Aoyagi et al. / Tetrahedron Letters 45 (2004) 5189–5192
Ph
Ph
PhLi
PCC
CHO
dry Et2O
dry CH2Cl2
OH
Ph
O
85 %
81 %
4
5
3
5
Ph
O
Ph
NH2OH-HCl
EtOH, Py
+
OH
N
N
OH
80 % [(E)-2a & (Z)-2b]
(E)-( )-2a
36 %
(Z)-( )-2b
44 %
AcCl, DMAP
Py, Ph-Me
Ph
N
Ph
Ph
Ph
or
or
OH
OAc
N
N
N
OH
OAc
87 or 96 %
(Z)-( )-2b
(Z)-( )-1b
87 %
(E)-( )-2a
(E)-( )-1a
96 %
Scheme 1. Synthesis of racemic ketoximes ( )-1a–2b.
crude residue was purified using silica gel column
chromatography with chloroform as the eluent to yield
the corresponding chiral O-acetyl ketoxime 1a–b and
ketoxime 2a–b. Enantiomeric excess (ee) values were
determined using chiral HPLC [column, Daicel Chiral-
cel OG (or OD); mobile phase, hexane/2-propa-
nol ¼ 50:1 (or 20:1); flow rate, 0.5 mL/min; UV detection
at 254 nm]. E values were calculated according to liter-
ature.12 Absolute configurations of the products were
determined using their circular dichroism spectra
(dihedral angles of the binaphthyl backbones were cal-
culated using WinMOPAC).13
Ph
Ph
lipase
AcOCH=CH2
MTBE
or
no reaction
OH
N
N
OH
(E)-( )-2a
(Z)- ( )-2b
Scheme 2. Lipase-catalyzed esterification of ( )-2a–b.
Ph
Ph
Ph
lipase
n-BuOH
MTBE
+
OAc
OH
OAc
N
N
N
As shown in Table 1, hydrolysis of ( )-1a catalyzed by
NOVOZYM 435 (8200 PLU/g) and CHIRAZYME L-2
(5 KU/g) (Candida antarctica) proceeded to approxi-
mately 50% conversion after 4 h (entries 1 and 2,
respectively), with relatively high enantioselectivity (82–
90% ee). In contrast, although the hydrolysis reaction
catalyzed by LIP (0.59 KU/g) (Pseudomonas aeruginosa)
lipase exhibited the highest enantioselectivity (99% ee),
its conversion was low (9%) (entry 3).
(E)-( )-1a
(E)-(S)-2a
(E)-(R)-1a
Scheme 3. Lipase-catalyzed hydrolysis of ( )-1a.
Ph
Ph
Ph
lipase
n-BuOH
MTBE
+
N
OAc
N
OAc
N
OH
(Z)-( )-1b
(Z)-(R)-2b
(Z)-(S)-1b
Similarly as the lipase-catalyzed hydrolysis of ( )-1a,
Candida antarctica lipases, NOVOZYM 435 and
Scheme 4. Lipase-catalyzed hydrolysis of ( )-1b.
Table 1. Hydrolysis of (E)-1a and (Z)-1b by lipase catalyst
Substrate Lipasea
Time (h)
Ketoxime 2a–b
O-Acetyl ketoxime 1a–b
E
valuee
Entry
Yield (%)b
Ee (%)c;d Config.
Yield (%)b
Ee (%)c
Config.
1
2
3
(E)-1a
(E)-1a
(E)-1a
NOVOZYM 435
CHIRAZYME L-24
LIP
4
43
41
85
9
82d
S
S
S
56
56
85
90
90
11
R
R
R
31
31
d
287
99d
222
4
5
6
(Z)-1b
(Z)-1a
(Z)-1b
NOVOZYM 435
CHIRAZYME L64-22
LIP
264
48
96
41
87
Not detected
88c
c
R
59
50
48
50
S
25
24
R
––
S
––
Recovery
––
a Another three commercially lipases (Ref. 11) were not reacted.
b Determined by internal standard method of HPLC using ODS-2(254 nm, 0.8 mL/min, CH 3CN/H2O ¼ 8:2).
c Determined by HPLC using Chiralcel OG (254 nm, 0.5 mL/min, n-hexane/IPA ¼ 50:1).
d Determined by HPLC using Chiralcel OD (254 nm, 0.5 mL/min, n-hexane/IPA ¼ 20:1).
e E ¼ ln½ðeepð1 À eesÞÞðeep þ eesÞÀ1ꢀ= ln½ðeepð1 þ eesÞÞðeep þ eesÞÀ1ꢀ; see Ref. 12.

N. Aoyagi et al. / Tetrahedron Letters 45 (2004) 5189–5192
5191
O
lipase
NH2(CH2)2CN
MTBE
+
CO2Et
CN
CO2Et
N
H
(
)-6
(R)-7
(S)-6
Scheme 5. Lipase-catalyzed aminolysis of ester ( )-6 for the comparison purposes.
Table 2. Aminolysis of ( )-6 by lipase catalysta
Substrate Lipaseb
Time (h)
Amide
Ester
E
valuee
Entry
Yield (%)c
Ee (%)d
Config.
Yield (%)c
Ee (%)d
Config.
1
2
3
6
6
6
NOVOZYM 435
CHIRAZYME L-28
LIP
8
48
96
4283
84
Not detected
R
59
50
48
50
S
16
18
––
R
––
S
––
Recovery
a ( )-6 (24 mg, 0.0672 mmol), amino agent (0.202 mmol), lipase (40 mg), MTBE (2 mL), 30 °C.
b Another three commercially lipases (Ref. 11) were not reacted.
c Determined by internal standard method of HPLC using ODS-2(254 nm, 0.8 mL/min, CH 3CN/H2O ¼ 8:2).
d Determined by HPLC using Chiralcel OD (254 nm, 0.5 mL/min, n-hexane/IPA ¼ 9:1).
e E ¼ ln½ðeepð1 À eesÞÞðeep þ eesÞÀ1ꢀ= ln½ðeepð1 þ eesÞÞðeep þ eesÞÀ1ꢀ; See Ref. 12.
CHIRAZYME L-2exhibited the highest selectivity in
the hydrolysis of ( )-1b (Table 1, entries 4 and 5).
However, these lipases hydrolyzed ( )-1b slowly, with
rates as much as 66 times slower than the hydrolysis of
( )-1a. Interestingly, selectivity for the opposite enan-
tiomer of the axial binaphthyl skeleton was shown by
(Z)-isomer 1b against (E)-isomer 1a (Table 1, entries 1–
5). Our results clearly demonstrate that the lipase-cata-
lyzed resolutions of binaphthyl ketoximes are affected by
the structural differences between the (E)- and (Z)-iso-
mers of the ketoxime.
(1) simplicity of operation, and (2) high yields of the
lipase-catalyzed resolution without the use of toxic
resolving agents.
Acknowledgements
We are grateful to Prof. Makoto Takeishi and his
research group for their assistance in the measurements
of CD spectra for the chiral binaphthyls.
In order to compare the reactivities of the starting
functional group, lipase-catalyzed aminolysis was car-
ried out using ( )-6, which has an ethylene spacer be-
tween the binaphthyl ring and the ester group, as
illustrated in Scheme 5.4 Our results show that the rec-
ognition of the axial binaphthyl skeleton in the ami-
nolysis reaction was identical to that in the hydrolysis of
(E)-( )-1a, probably because of the similarity of the side
chains of 1a and 6 (Table 2, entries 1–2). Again, the side
chain of the binaphthyl moiety was shown to play
an important role in the lipase-catalyzed resolution of
binaphthyl derivatives.
References and notes
1. (a) Carrea, G.; Riva, S. Angew. Chem., Int. Ed. 2000, 39,
2226–2254; (b) Schmid, R. D.; Verger, R. Angew. Chem.,
Int. Ed. 1998, 37, 1608–1633; (c) Faber, K.; Riva, S.
Synthesis 1992, 895–910; (d) Theil, F. Chem. Rev. 1995, 95,
2203–2227.
2. (a) Baldoli, C.; Maiorana, S.; Carrea, G.; Riva, S.
Tetrahedron: Asymmetry 1993, 4, 767–772; (b) Murataka,
M.; Imai, M.; Tamura, M.; Hoshino, O. Tetrahedron:
Asymmetry 1994, 5, 2019–2024.
3. Aoyagi, N.; Izumi, T. Tetrahedron Lett. 2002, 43, 5529–
5531.
In conclusion, the lipase-catalyzed hydrolysis reactions
of O-acetyl binaphthyl ketoximes are influenced by the
length and configuration of the side chain between the
binaphthyl ring and the carbonyloxy group. This is
similar to the results of a previous report for the lipase-
catalyzed aminolysis of 1,10-binaphthyl esters. A mixture
of (E),(Z)-binaphthyl ketoxime having phenyl group
was readily separated using silica gel column chroma-
tography with chloroform as the eluent. Although
Candida antarctica lipases were successful as catalysts in
the hydrolysis resolution of ketoximes ( )-1a and ( )-
1b, ketoximes ( )-2a, and ( )-2b were not effective as
substrates under esterification conditions. Selectivity for
the opposite enantiomer of the axial binaphthyl skeleton
was shown by (Z)-isomer 1b against (E)-isomer 1a. The
present synthetic methodology offers two advantages:
4. Aoyagi, N.; Kawauchi, S.; Izumi, T. Tetrahedron Lett.
2003, 44, 5609–5612.
5. Aoyagi, N.; Ohwada, T.; Izumi, T. Tetrahedron Lett. 2003,
44, 8269–8272.
6. (E)-( )-1a: pale yellow oil; IR mmax (neat)/cmÀ1 1768, 1199
(CO2R); 1H NMR (CDCl3): d 1.94 (3H, s, CH3), 6.60–7.55
(13H, m, ArH), 7.72(2H, t, J ¼ 7:6 Hz, ArH), 7.91 (1H, d,
J ¼ 8:6 Hz, ArH), 7.97 (1H, d, J ¼ 8:2Hz, ArH), 8.05 (1H,
d, J ¼ 8:4 Hz, ArH); FABMS (m=z) 416 (M+H)þ.
(Z)-( )-1b: pale yellow crystal; mp 182–184 °C; IR mmax
1
(KBr)/cmÀ1 1768, 1193 (CO2R); H NMR (DMSO-d6): d
1.18, 2.12 (3H, ds, CH3), 6.93–7.99 (16H, m, ArH), 8.16
(1H, d, J ¼ 8:4 Hz, ArH), 8.25 (1H, d, J ¼ 8:6 Hz, ArH);
FABMS (m=z) 416 (M+H)þ.
(E)-( )-2a: colorless crystal; mp 189–190 °C; IR mmax (KBr)/
cmÀ1 3200 (OH); 1H NMR (DMSO-d6): d 6.74 (2H, d,
J ¼ 8:0 Hz, ArH), 6.85–6.91 (4H, m, ArH), 7.00 (1H, d,

5192
N. Aoyagi et al. / Tetrahedron Letters 45 (2004) 5189–5192
J ¼ 8:0 Hz, ArH), 7.06 (1H, d, J ¼ 7:0 Hz, ArH), 7.14 (1H,
9. Bishop, B. M.; McCafferty, D. G.; Erickson, B. W.
Tetrahedron 2000, 56, 4629–4638.
10. Itoh, M.; Hagiwara, D.; Kamiya, T. Org. Synth. Coll. Vol.
1988, 6, 199.
11. NOVOZYM 435 (8200 PLU/g) and CHIRAZYME L-2
(5 KU/g) from Candida antarctica (Novo Nordisk Co.,
Ltd); LIP (0.59 KU/g) from Pseudomonas aeruginosa
(Toyobo Co., Ltd); PS (30 KU/g) and AH (8 KU/g) from
Pseudomonas cepacia (Amano Pharmaceutical Co., Ltd);
AK (20 KU/g) from Pseudomonas fluorescene (Amano
Pharmaceutical Co., Ltd).
t, J ¼ 7:5 Hz, ArH), 7.30 (1H, t, J ¼ 8:0 Hz, ArH), 7.35–
7.39 (2H, m, ArH), 7.53 (1H, t, J ¼ 7:5 Hz, ArH), 7.74 (1H,
d, J ¼ 8:5 Hz, ArH), 7.84 (2H, d, J ¼ 8:0 Hz, ArH), 8.07
(1H, d, J ¼ 8:0 Hz, ArH), 8.13 (1H, d, J ¼ 8:0 Hz, ArH),
11.12(1H, s, C @NOH); MS (m=z) 373 (Mþ).
(Z)-( )-2b: colorless crystal; mp 221–222 °C; IR mmax
(KBr)/cmÀ1 3200 (OH); 1H NMR (DMSO-d6): d 6.89–
7.86 (15H, m, ArH), 8.09 (1H, d, J ¼ 8:5 Hz, ArH), 8.16
(1H, d, J ¼ 8:5 Hz, ArH), 8.32(1H, s, ArH), 10.93, 11.43
(1H, ds, C@NOH); MS (m=z) 373 (Mþ).
7. Okada, K.; Tanaka, M. J. Chem. Soc., Perkin Trans. 1
2002, 2704–2711.
12. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J.
J. Am. Chem. Soc. 1982, 104, 7294–7299.
8. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16,
2647–2650.
13. Hanazaki, I.; Akimoto, H. J. Am. Chem. Soc. 1972, 94,
875–878.