Chemo-enzymatic synthesis of enantiomerically pure (R)-2-naphthylmethoxyacetic acid

Article abstract of DOI:10.1016/S0957-4166(02)00242-2

Enantiomerically pure (R)-2-naphthylmethoxyacetic acid (2-NMA) was synthesized from 2-naphthaldehyde via an integrated chemo-enzymatic procedure. The one-pot, successive use of SnBr₂-TMSCN and AcBr worked effectively to give a racemic cyanohydrin acetate. Lipase from Burkholderia cepacia then mediated the highly enantioselective hydrolysis of the (S)-enantiomer of the racemate, leaving the (R)-acetate with an e.e. of >99.9%. The resulting product of this enzyme-catalyzed hydrolysis, an (S)-cyanohydrin, spontaneously decomposed into naphthaldehyde, the starting material of this synthetic route, which could be recycled. The hydration of nitrile to amide as well as the hydrolysis of the acetate was performed with a microorganism, Rhodococcus rhodochrous, under very mild conditions without any loss of the enantiomeric purity. The amide group was hydrolyzed with nitrosylsulfuric acid, and the product was isolated as an α-hydroxy ester. The α-hydroxyl group was methylated with diazomethane-silica gel and the final task, hydrolysis of the ester, was accomplished under conditions as mild as neutral pH with an esterase from Krebsiella oxytoca to give enantiomerically pure 2-NMA.

Full text of DOI:10.1016/S0957-4166(02)00242-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1059–1068
Chemo-enzymatic synthesis of enantiomerically pure
(R)-2-naphthylmethoxyacetic acid
Mayumi Kimura, Atsuhito Kuboki† and Takeshi Sugai*
Department of Chemistry, Keio University, Hiyoshi, Yokohama 223-8522, Japan
Received 18 April 2002; accepted 14 May 2002
Abstract—Enantiomerically pure (R)-2-naphthylmethoxyacetic acid (2-NMA) was synthesized from 2-naphthaldehyde via an
integrated chemo-enzymatic procedure. The one-pot, successive use of SnBr2–TMSCN and AcBr worked effectively to give a
racemic cyanohydrin acetate. Lipase from Burkholderia cepacia then mediated the highly enantioselective hydrolysis of the
(S)-enantiomer of the racemate, leaving the (R)-acetate with an e.e. of >99.9%. The resulting product of this enzyme-catalyzed
hydrolysis, an (S)-cyanohydrin, spontaneously decomposed into naphthaldehyde, the starting material of this synthetic route,
which could be recycled. The hydration of nitrile to amide as well as the hydrolysis of the acetate was performed with a
microorganism, Rhodococcus rhodochrous, under very mild conditions without any loss of the enantiomeric purity. The amide
group was hydrolyzed with nitrosylsulfuric acid, and the product was isolated as an a-hydroxy ester. The a-hydroxyl group was
methylated with diazomethane–silica gel and the final task, hydrolysis of the ester, was accomplished under conditions as mild as
neutral pH with an esterase from Krebsiella oxytoca to give enantiomerically pure 2-NMA. © 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
promising method. Herein we report our chemo-enzy-
matic approach to (R)-1a.
An enantiomerically enriched form of 2-naphthyl-
methoxyacetic acid (2-NMA, 1a)1 has been developed
as an excellent chiral NMR reagent2 for the determina-
tion of the absolute configuration of secondary alco-
hols. Currently, to supply pure enantiomers of 1a, the
racemate3 is separated by chromatography.4 A recently
reported asymmetric carboxylation of the benzylic
anion5 derived from an alkyl benzyl ether is also a
2. Results and discussion
The synthetic plan is shown in Scheme 1. Starting from
2-naphthaldehyde 2, the key intermediate is the enan-
tiomerically pure (R)-cyanohydrin acetate 3d, for which
a variety of chemical and enzymatic approaches have
functional
group
enzyme-
catalyzed
OAc
CN
OAc
CN
OMe
CO2H
2
enantio-
selective
hydrolysis
trans-
formation
(±)-3d
(R)-3d
(R)-1a
+
OH
CN
CHO
2
(S)-3b
2
Scheme 1.
* Corresponding author. Fax: +81-45-566-1697; e-mail: sugai@chem.keio.ac.jp
† Present address: Department of Biochemistry, Okayama University of Science, Japan.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00242-2

1060
M. Kimura et al. / Tetrahedron: Asymmetry 13 (2002) 1059–1068
recently been developed.6–8 For the preparation of the
single enantiomeric form, we chose the lipase-catalyzed
enantioselective hydrolysis of the racemate ( )-3d.8e–p In
this process, the concomitantly formed cyanohydrin
(S)-3b would decompose into the starting aldehyde 28m–p
and the undesired enantiomer is converted into the
desired one by repetition of the total process. Another
very important aspect of this synthesis is the functional
group transformation under mild conditions, from nitrile
to carboxylate, without any loss in enantiomeric purity.
tigations of the substrate–enzyme ratio and the effects of
immobilization of enzyme and adding a co-solvent pro-
vided an elaborated set of incubation conditions (see
Section 4), and very high enantioselectivity (E >500) in
the reaction. The recovered (R)-3d (45% yield) had an e.e.
of >99.9% (Scheme 2). As expected, the hydrolyzed
product was obtained as 2-naphthaldehyde due to spon-
taneous decomposition.
2.2. Hydration of the cyano group
2.1. Synthesis and resolution of cyanohydrin derivatives
As a mild method of functional group transformation,
microorganism-mediated hydration of the nitrile and
subsequent hydrolysis of the amide16 was applied to
(R)-3d. Hydration of the cyano group proceeded very
smoothly with Rhodococcus rhodochrous IFO 15564
under the two-phase system.17 Concomitant hydrolysis of
acetate18 occurred, and the product was a hydroxy amide
(R)-4b (75%). No further hydrolysis of the amide to
carboxylic acid was observed.
Toward this end, an expeditious synthetic route to ( )-3d
from 2 is of considerable importance. Our first synthetic
efforts toward 3d from 2 under a biphasic system using
NaCN–TBAB8j resulted in the formation of 3b only, even
in the presence of acetic anhydride. Based on the well-
known procedure through Lewis acid-catalyzed forma-
tion of cyanohydrin trimethylsilyl intermediates,9 we
turned our attention to SnBr2, which had been effective
for the transformation of trimethylsilyl ether to acetate
reported by Oriyama.10 Indeed, the two-step formation
of 3d from 2 proceeded very smoothly in one pot (92%).
This protocol has the advantage of extreme simplicity,
compared with the preparation from an aldehyde via
acylal11a (diacetylated form) or the use of acetyl cya-
nide.11b This one-pot synthesis of cyanohydrin acetates
from an aldehyde has so far been reported only from an
aromatic aldehyde with very strongly electron-withdraw-
ing substituents.12
At this stage, we became interested in the structure–activ-
ity relationship of nitrile hydratase and amidase on the
substrates possessing the related skeleton.19,20 The effects
of both the aromatic nuclei (phenyl or 2-naphthyl) and
a-substituent (H, OH, OMe, and OAc) were observed
from a set of substrates. The results are summarized in
Table 1. In the series of nitriles with a phenyl group, the
action of amidase depended upon the steric hindrance by
the substituents introduced at the a-position. The
increase in size on moving from the phenyl to the
2-naphthyl nucleus severely suppressed the action of the
amidase.
In addition, SnBr2 also worked very well for the prepa-
ration of cyanohydrin methyl ether13 3c. The isolation of
an unstable dimethyl acetal was not necessary, and the
desired product was obtained in 90% yield (Scheme 2).
Similar retardation was also observed in the action of
nitrile hydratase. This is exemplified between the two
cyanohydrins 3b and 6b. The hydration of naphthyl
derivative 3b was much slower than that of mandeloni-
trile 6b, and a considerable portion of this rather unstable
substrate 3b decomposed to aldehyde 2 during the
incubation. In this sense, the acetate in 3d worked as the
‘protective group’. From 3d, the primary product was the
acetoxy amide 4d, and the subsequent hydrolysis by an
esterase provided 4b as mentioned before.
For the kinetic enantiomeric resolution of ( )-3d, our
first choice was the use of lipoprotein lipase (Toyobo
LIP),14 which had been effective in the enantioselective
acylation of the corresponding cyanohydrin.8c The
revealed moderate enantioselectivity15 (E=32), however,
led us to consider another source of lipase. Thus,
Burkholderia cepacia lipase6c,6e,8g (Sumitomo Chemical
Industries, SC lipase A) was examined. Extensive inves-
OAc
CN
1) TMSCN
SnBr2
CHO
2) AcBr
(±)-3d
OMe
OMe
2
OMe
CN
TMSCN
SnBr2
HC(OMe)3
2
Amberlyst-15
3c
(R)-3d
OH
CN
OAc
CN
B. cepacia
(±)-3d
+
+
lipase
2
(SC lipase A)
(R)-3d
(S)-3b
Scheme 2.

M. Kimura et al. / Tetrahedron: Asymmetry 13 (2002) 1059–1068
1061
Table 1. Hydration and the subsequent hydrolysis of aromatic nitriles with R. rhodochrous
X
X
X
nitrile
amidase
CN
CONH2
CO2H
hydratase
3
4
5
X
X
X
a
b
c
d
X = H
OH
CN
CONH2
CO2H
OMe
OAc
6
7
8
Entry
Substrate
Aromatic group
X
Product (%)
Amide
Acid
1
2
3
4
5
6
7
8
9
6a
6b
6b
6c
6d
3a
3b
3c
3d
Phenyl
Phenyl
Phenyl
Phenyl
H
–
8a (quant.)
OH
OH
OMe
OAc
H
OH
OMe
OAc
7ba (81)
–
–
8bb (80)
7c (quant.)
7b (39), 7d (35)
–
4b (8)
4c (88)
–
–
Phenyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
5a (87)
–
–
–
4b (75)
a Incubation was performed for 4 h.
b Incubation was performed for 18 h.
An unexpected by-product, 2-naphthaldehyde 2 was
formed in the nitrosylsulfuric acid-catalyzed hydrolysis.
The formation of an aldehyde is understandable if
electron-donation from the methoxy group ejected N2
and CO (Scheme 3, path b), instead of the desired
attack of water (path a) to the possible acyl diazonium
intermediate.
2.3. Exploring the route from a-hydroxy amide to a-
methoxy acid
As mentioned above, the enzyme-catalyzed hydrolysis
of the amide failed. At this juncture, toward the synthe-
sis of a-methoxy acid, we prepared the corresponding
a-methoxyamide 4c, and various hydrolytic conditions
were examined. This amide, indeed, obstinately resisted
hydrolysis, and only activation by means of nitrosation
was effective. Use of tetrabutylammonium nitrite21 and
nitrosylsulfuric acid,22 as the source of NO+, effected
the desired reaction. However, in the use of the former
reagent, the reproducibility was low.
This hypothesis prompted us to prepare the substrates
4b (R=H, Scheme 3) and 4d (R=Ac) with decreased
electron-donating properties, and they were submitted
to the same reaction. The acceleration of CO extrusion
by means of electron-donating neighboring group was
OR
OR
CO2Me
1) HO3SONO,
DMF
4c R = Me
CONH2
4b
4d
H
2) TMSCHN2
Ac
path b
OR
OR
CO2H
a
C
N
N
O
H
H
N2
O
path a
N2 + CO
OR
b
OR
CO2Me
1b R = Me
9a
9b
H
2
H
Ac
Scheme 3.

1062
M. Kimura et al. / Tetrahedron: Asymmetry 13 (2002) 1059–1068
well affirmed by results as shown in Table 2. The
by-product formation was considerably suppressed in
the latter two substrates. The above study led us to take
(R)-4b, a directly formed product in the previous step
of microbial hydration of the cyano group, in this step
of amide-hydrolysis.
room temperature. In this way, (R)-2-NMA, 1a, with
e.e. of over 99.9% was obtained from 1b in quantitative
yield.
OMe
CO2Me
OMe
CO2H
K. oxytoca
esterase
Table 2. Nitrosation–hydrolysis of a-substituted amides
4a–c
(SNSM-87)
(R)-1b
(R)-1a
Entry
Substrate
Product (%)
Aldehyde 2
Scheme 4.
Ester
1
2
3
4c
4b
4d
1b (55)
9a (59)
9b (80)
35
6
5
3. Conclusion
Starting from the readily available 2-naphthaldehyde 2
we have synthesized (R)-2-naphthylmethoxyacetic acid
(2-NMA, 1a). Three enzyme-catalyzed procedures were
effectively demonstrated, namely, (1) lipase-catalyzed
kinetic resolution of cyanohydrin, (2) microbial nitrile
hydratase-catalyzed transformation of nitrile to amide,
and (3) enzyme-catalyzed hydrolysis of methyl ester
under conditions as mild as neutral pH.
We next encountered the difficulty in the step of methyl-
ation of the hydroxyl group, since the a-protons of the
esters 9a and 1b are rather acidic. For example, methyl-
ation conditions as mild as MeI–Ag2O23 (Table 3,
entry 1) caused partial racemization to give 1b with as
low as 57.8% e.e. Thus, acid-catalyzed methylation
conditions were extensively examined,24–26 and the rep-
resentative entries are also shown in Table 3. It was
found that repetitive addition of the diazomethane
solution with silica gel worked well (for details, see
Section 4) to give 1b in 86% yield based on the con-
sumed substrate, with no affect on the enantiomeric
purity.
4. Experimental
4.1. General
All melting points are uncorrected. IR spectra were
measured as thin films for oils or KBr disks of solids on
1
a JASCO FT/IR-410 spectrometer. H NMR spectra
Table 3. Methylation of 9a
were measured in chloroform-d at 270 MHz on a JEOL
JNM EX-270 or at 400 MHz on a JEOL JNM GX-400
spectrometer. HPLC analyses were performed with a
SSC-5410 (Senshu Scientific Co., Ltd) liquid chromato-
graphs. Optical rotation values were recorded on a
Jasco DIP 360 polarimeter. Silica gel 60 (spherical,
100–210 mm, 37558-79) of Kanto Chemical Co. was
used for column chromatography. Peptone and yeast
extract were purchased from Kyokuto Pharmaceutical
Co, for the cultivation of microorganism. Preparative
TLCs were purchased from Merck Co. (1.05744). Ace-
tonitriles 3a, 6a, 2-naphthaldehyde 2, (R)-(−)- and ( )-
mandelic acid 8b and 2-naphthylacetic acid 5a were
purchased from Tokyo Kasei Organic Chemicals Co.
(P0128, N0366, N003, M0662, M0038, and N0352,
respectively) and racemic mandelonitrile 6b was from
Aldrich Co. (11,602-5).
OH
CO2Me
OMe
CO2Me
(R)-9a
(R)-1b
Compound 1ba
Entry
Reagents
Yield (%)
E.e. (%)
1
2
MeI–Ag2O
CCl3C(NꢀH)OMe
–HBF4·Me2O
CH2N2–SnCl2·H2O
CH2N2–silica gel
18
28
57.8
\99.9
3
4
13
92.8
\99.9
48 (86)b
a In the case of entry 2, the substrate was methyl (R)-mandelate 10a,
and the product was methyl (R)-O-methylmandelate 10b.
4.2. Syntheses of the substrates
b The yield in parentheses is based on the consumed starting material.
4.2.1. a-Acetoxyphenylacetonitrile 6d. To a solution of
benzaldehyde (105 mg, 0.98 mmol) in CH2Cl2 (4 mL)
was added trimethylsilyl cyanide (TMSCN, 146 mg,
1.47 mmol) and SnBr2 (15 mg, 0.05 mmol). After
stirring at room temperature for 10 min under an Ar
atmosphere, a solution of acetyl bromide (302 mg, 2.46
mmol) in CH2Cl2 (1 mL) was added to a reaction
mixture and stirred overnight at the same temperature.
Ice-cooled phosphate buffer solution (pH 7.5, 0.1 M)
was added and stirred for a further 30 min at 0°C. The
The final problem was the hydrolysis of the methyl
ester 1b under mild conditions. From the screening of
enzymes involving lipases, proteases and esterases,
Krebsiella oxytoca esterase (Nagase, SNSM-87)27
showed the highest activity (Scheme 4). As this enzyme
showed no enantioselectivity, it worked very well as the
tool for functional group transformation. Elevated tem-
perature as high as 39°C was necessary to perform an
efficient hydrolysis, as the substrate is crystalline at

M. Kimura et al. / Tetrahedron: Asymmetry 13 (2002) 1059–1068
1063
mixture was diluted with AcOEt and the resulting
organic layer was poured into ice-cooled aq. NaHCO3
solution. The mixture was extracted with AcOEt (×3).
The combined organic layer was washed with brine,
dried over anhydrous Na2SO4 and concentrated in
vacuo. The residue was purified by silica gel column
chromatography (30 g). Elution with hexane–AcOEt
(6/1) afforded 6d as a colorless oil (148 mg, 85%).
vacuo. The residue was purified by silica gel column
chromatography (120 g). Elution with hexane–AcOEt
(19/1) afforded 3c as a pale yellow solid (1.69 g, 90%).
Recrystallization from ethanol gave an analytically
pure sample as colorless needles. Rf=0.46 (hexane/
AcOEt=9/1); mp 56.9–57.1°C; 1H NMR: l 7.99 (s,
1H), 7.93–7.86 (m, 3H), 7.57–7.53 (m, 3H), 5.39 (s, 1H),
3.57 (s, 3H); IR: wmax 3059, 3016, 2938, 2831, 2360,
1600, 1464, 1082, 967, 867, 821, 754 cm−1. Anal. calcd
for C13H11NO: C, 79.17; H, 5.62; N, 7.10%. Found: C,
79.08; H, 5.53; N, 7.17%.
1
Rf=0.40 (hexane/AcOEt=9/1); H NMR: l 7.53–7.43
(m, 5H), 6.40 (s, 1H), 2.15 (s, 3H); 13C NMR: l 168.9,
131.7, 130.4, 129.2, 127.8, 116.1, 62.8, 20.4; IR: wmax
3068, 3038, 2945, 2360, 1755, 1372, 1218, 1024, 962, 697
cm−1. The spectral data were identical to those reported
previously.11a
4.2.5. a-Hydroxy-2-naphthylacetonitrile 3b. To a solu-
tion of 2-naphthaldehyde (100 mg, 0.64 mmol) in Et2O
(2 mL) was added NaCN (56 mg, 1.14 mmol) in H2O (1
mL) and TBAB (10.6 mg, 0.02 mmol). After stirring at
0°C for 15 min, aq. H2SO4 solution (2 M, 0.72 mL) was
added to the reaction mixture and extracted with Et2O
(×3). The combined organic layer was washed with H2O
and brine, dried over anhydrous Na2SO4 and concen-
trated in vacuo, afforded 3b (104.2 mg, 82%) as a crude
material. This was purified by silica gel column chro-
matography (10 g). Elution with hexane–AcOEt (4/1)
afforded 3b as a pale yellow solid (11.8 mg, 10%).
4.2.2. a-Acetoxy-2-naphthylacetonitrile 3d. The reaction
of 2-naphthaldehyde (154 mg, 0.99 mmol) occurred in
the same manner as described above (starting from 6d)
to afford, after chromatographic separation (15 g, hex-
ane/AcOEt=9/1) and PTLC purification (hexane/
AcOEt=4/1), 3d as a yellow solid (205 mg, 92%).
Rf=0.44 (hexane/AcOEt=4/1); mp: 44.5–44.8°C; 1H
NMR: l 7.93–7.53 (m, 7H), 6.57 (s, 1H), 2.18 (s, 3H);
13C NMR: l 168.9, 133.9, 132.8, 129.4, 128.9, 128.4,
128.0, 127.8, 127.6, 127.1, 124.2, 116.1, 63.0, 20.5; IR:
wmax 3060, 2940, 1754, 1510, 1371, 1212, 1022, 943, 819
cm−1. Anal. calcd for C14H11NO2: C, 74.65; H, 4.92; N,
6.22%. Found: C, 74.40; H, 4.88; N, 6.23%. The spec-
tral data were identical to those reported previously.8c
1
Rf=0.20 (hexane/AcOEt=4/1); H NMR: l 10.16 (s,
1H), 8.53–7.53 (m, 7H), 5.91 (s, 1H), 3.41 (s, 1H); IR:
wmax 3401, 3258, 3054, 2920, 1644. 1595, 1365, 1072,
825, 742 cm−1. The spectral data were identical to those
reported previously.7d
4.2.3. a-Methoxyphenylacetonitrile 6c. To a solution of
benzaldehyde dimethylacetal (1010 mg, 6.66 mmol) in
CH2Cl2 (7 mL) was added TMSCN (727 mg, 7.33
mmol) and SnBr2 (10 mg, 0.04 mmol) and the mixture
was stirred at room temperature for 10 min under an
Ar atmosphere. After removing the solvent in vacuo,
the reaction mixture was purified by silica gel column
chromatography (20 g). Elution with hexane–AcOEt
(19/1) afforded 6c as a colorless oil (962 mg, 98%).
4.3. Lipase-catalyzed hydrolysis of cyanohydrin acetate
4.3.1. Hydrolysis with lipoprotein lipase (Toyobo LIP).
To a mixture of 3d (150 mg, 0.67 mmol) in phosphate
buffer solution (pH 7.5, 0.1 M, 3 mL) was added LIP
(11 mg). While maintaining the pH above 7.1 with a pH
controller by continuous addition of aq. NaOH (0.1 M)
solution, the reaction mixture was stirred at 40°C for 48
h. The mixture was diluted with AcOEt and filtered
through Celite pad. The filtrate was extracted with
AcOEt (×3). The combined organic layer was washed
with brine, dried over anhydrous Na2SO4 and concen-
trated in vacuo. The residue was purified by silica gel
column chromatography (15 g). Elution with hexane–
AcOEt (14/1) afforded (R)-3d [64.2 mg, 43%, [h]1D8=
−22.1 (c 1.00, CHCl3)]. The absolute configuration was
determined by comparing sign of rotation with that
1
Rf=0.32 (hexane/AcOEt=9/1); H NMR: l 7.51–7.42
(m, 5H), 5.21 (s, 1H), 3.54 (s, 3H); IR: wmax 3036, 3004,
2937, 2830, 1455, 1194, 1088, 697 cm−1. The spectral
data were identical to those reported previously.13c
4.2.4. a-Methoxy-2-naphthylacetonitrile 3c. To a stirred
mixture of 2-naphthaldehyde (1.50 g, 9.52 mmol) and
Amberlyst-15 (H+-form, 400–500 mg) was added
trimethyl orthoformate (1.6 mL, 14.3 mmol) with ice-
cooling. After stirring for 10 min, the reaction mixture
was poured into aq. NaHCO3 solution. The resulting
mixture was filtered to remove Amberlyst and extracted
with Et2O (×3). The combined organic layer was dried
over K2CO3 and concentrated. To this resulting mixture
1
reported previously [lit.8c (S)-3d: [h]D22 +21.7]. H NMR:
l 8.35–7.59 (m, 7H), 6.56 (s, 1H), 2.20 (s, 3H); 1H
NMR with Eu(hfc)3: l 2.32 (S, minor) and 2.20 (R,
major); IR: wmax 3059, 2926, 1755, 1511, 1371, 1212,
1020, 816 cm−1. The spectral data were identical to
those reported previously.8c
,
were added CH2Cl2 (10 mL) and MS 4 A (1.2 g) and
stirred at room temperature for 1 h. Then TMSCN
(1.04 g, 10.5 mmol) and SnBr2 (10 mg, 0.04 mmol) were
added and the mixture was stirred overnight at the
same temperature. The reaction was quenched with aq.
HCl solution (2 M, 10.5 mL) and filtered to remove
molecular sieves. The two-phase mixture was separated
and organic layer was washed with water, aq. NaHCO3
solution and brine, respectively. The extract was then
dried over anhydrous Na2SO4 and concentrated in
4.3.2. Hydrolysis with B. cepacia lipase (Sumitomo SC
lipase A). To a mixture of 3d (450 mg, 2.00 mmol) and
n-decane (4.5 mL) in phosphate buffer solution (pH
7.0, 0.1 M, 40.5 mL), was added immobilized SC lipase
A (450 mg).28 While keeping its pH at 7.0 with a pH
controller by continuous addition of aq. NaOH solu-
tion (0.1 M), the reaction mixture was stirred at 30°C
for 38 h. The mixture was diluted with AcOEt and
filtered through Celite pad. The filtrate was extracted

1064
M. Kimura et al. / Tetrahedron: Asymmetry 13 (2002) 1059–1068
with AcOEt (×3). The combined organic layer was
washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. A small portion of the residue
A. After stirring at 30°C for 4 h, the reaction mixture
was filtered through a Celite pad and washed with H2O
and AcOEt. The filtrate was acidified with 2 M aqueous
HCl toward pH 2.0 and saturated with NaCl. The
resulting mixture was extracted with AcOEt. The
organic layer was washed with brine, dried over anhy-
drous Na2SO4 and concentrated in vacuo. Recrystal-
lization of the residue from MeOH gave 7b as colorless
needles. Rf=0.30 (AcOEt); mp 131.9–132.1°C [lit.29
1
was dissolved in CDCl3 and H NMR spectrum of the
mixture was measured. The conversion was estimated
to be 54%. The residue was purified by silica gel column
chromatography (30 g). Elution with hexane–AcOEt
(19/1) afforded (R)-3d (201 mg, 45%, >99.9% e.e.).
[h]2D2=−17.9 (c 1.00, CHCl3); HPLC analysis: column,
Daicel Chemical Ind., Chiralcel OB, 0.46×25 cm; hex-
ane/2-propanol=98/2; 0.7 ml/min; tR (min) 75.2 [(R)-
3d, single peak]. In the case of the analysis of racemate,
(S)-isomer appeared at tR 60.0 min. Anal. calcd for
C14H11NO2: C, 74.65; H, 4.92; N, 6.22%. Found: C,
74.30; H, 4.90; N, 6.09. The IR and NMR data were
identical to those of the sample as above.
1
133–134°C]; H NMR (C5D5N): l 8.28 (s, 1H), 8.18 (s,
1H), 7.87–7.16 (m, 5H), 5.57 (s, 1H); IR: wmax 3393,
3259, 3056, 2899, 1956, 1894, 1655, 1451, 1182, 1060,
922, 696 cm−1. The spectral data were identical to those
reported previously.29
4.8. Mandelic acid 8b
Mandelic acid 8b (135 mg, 80%) was obtained from
mandelonitrile 6b (148 mg, 1.11 mmol) using Method A
(30°C, 168 h). Recrystallization of crude product from
MeOH gave 8b as colorless plates. Rf=0.08 (hexane/
AcOEt=1/1); mp 115.7–116.0°C (authentic sample:
4.4. Enzyme-catalyzed transformation of nitriles
4.4.1. Pre-cultivation of R. rhodochrous IFO 15564. To a
sterilized medium (pH 7.2, 100 mL) containing glucose
(15 g/L), K2HPO4 (0.4 g/L), KH2PO4 (1.2 g/L),
MgSO4·7H2O (0.5 g/L), yeast extract (1.0 g/L) and
peptone (5.0 g/L) in a 500 mL Erlenmeyer flask with
two internal projections was added a solution of o-
caprolactam (0.1 g) and FeSO4·7H2O (0.3 g) in deion-
ized water (5 mL) via a sterilized membrane filter
(ADVANTEC, 25CS020AS, 0.20 mm). A loopful of R.
rhodochrous IFO15564 was inoculated and the flask was
shaken at 30°C on a gyrorotary shaker (180 rpm) for 60
h. Its OD (660 nm) reached to 35 after 48 h incubation.
The grown cells (ca. 3 g in wet weight) were harvested
by centrifugation (3000 rpm for 15 min at 4°C), washed
with 0.1 M KH2PO4–K2HPO4 buffer (pH 6.0) and
collected by centrifugation.
1
119–121°C); H NMR: l 7.44–7.28 (m, 5H), 5.12 (s,
1H); IR: wmax 3449, 3036, 2664, 2626, 2360, 1726, 1456,
1249, 1191, 1065, 942, 876, 726, 693 cm−1. The spectral
data were identical to those of an authentic sample.
4.9. a-Methoxyphenylacetamide 7c
a-Methoxyphenylacetamide 7c (166.0 mg, quant., 1.00
mmol) was obtained from a-methoxyphenylacetonitrile
6c (150 mg, 1.09 mmol) using Method A (30°C, 72 h).
The crude product was purified by silica gel column
chromatography (3 g). Elution with AcOEt–EtOH (9/1)
afforded 7c. Rf=0.40 (AcOEt); mp 100.1–100.6°C [lit.19
1
111–112°C]; H NMR: l 7.43–7.31 (m, 5H), 6.68 (s,
1H), 4.79 (s, 1H), 3.37 (s, 3H); IR: wmax 3463, 3394,
3186, 2366, 2345, 1656, 1411, 1197, 1091, 704 cm−1. The
spectral data were identical to those reported
previously.19
4.5. General procedures for incubation
4.5.1. Method A. To the substrate (150 mg), dissolved in
EtOH if needed (1.5 mL for 3a, 3b, and 6c), a suspen-
sion of wet cells (0.5 g) in phosphate buffer (15 mL, pH
6.0, 0.1 M) was added and the mixture was stirred at
30°C.
4.10. Mandelamide 7b and a-acetoxyphenylacetamide
7d
A mixture of mandelamide 7b and a-acetoxyphenyl-
acetamide 7d was obtained from a-acetoxyphenylacetoni-
trile 6d (150 mg, 0.86 mmol) using Method A (30°C, 19
h). The crude product was purified by silica gel column
chromatography (15 g). Elution with hexane–AcOEt
(1/1) afforded 7b (51 mg, 39%) and 7d (57 mg, 35%).
4.5.2. Method B. To the substrate (90 mg), dissolved in
EtOH (up to 1 mL for 3a and 3c) or DMF (up to 1 mL
for 3d), suspension of wet cells (2 g) in phosphate buffer
(50 mL, pH 6.0, 0.1 M) and hexane (20 mL) was added
and the mixture was stirred at 30°C.
4.6. Phenylacetic acid 8a
4.10.1. Mandelamide 7b. Rf=0.30 (AcOEt); mp 131.9–
132.1°C. The spectral data were identical to those of the
sample as before.
Phenylacetonitrile 6a was subjected to the microbial
hydrolysis using Method A. The hydrolysis completed
within 4 h as checked by TLC analysis.
4.10.2.
a-Acetoxyphenylacetamide
7d.
Rf=0.48
(AcOEt); mp 112.9–113.1°C [lit.29 112–113°C]; 1H
NMR: l 7.28–7.41 (m, 5H), 6.01 (s, 1H), 5.80 (s, 1H),
2.12 (s, 3H); IR: wmax 3389, 3195, 2951, 1743, 1670,
1421, 1227, 1041, 696 cm−1. The spectral data were
identical to those reported previously.29
4.7. Mandelamide 7b
Mandelamide 7b (135 mg, 81%) was obtained from
mandelonitrile 6b (147 mg, 1.11 mmol) using Method

M. Kimura et al. / Tetrahedron: Asymmetry 13 (2002) 1059–1068
1065
4.11. 2-Naphthylacetic acid 5a
4.15. Nitrosation–hydrolysis of amides
2-Naphthylacetic acid 5a was obtained from 2-naphthyl-
acetonitrile (3a, 150 mg, 0.88 mmol) using Method A
(30°C, 48 h). Crude 5a (184 mg, quant., 0.99 mmol) was
methylated with diazomethane for purification and
purified by silica gel column chromatography (5 g).
Elution with hexane–AcOEt (9/1) afforded the methyl
4.15.1. Nitrosation–hydrolysis of 4c. To a solution of 4c
(30 mg, 0.14 mmol) in DMF (0.5 mL) was added
HO3SONO (89 mg, 0.70 mmol) and stirred for 24 h at
room temperature. The reaction mixture was poured
into water, acidified with aq. H2SO4 solution (2 M) and
extracted with AcOEt. The combined organic layer was
washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was dissolved in
CH2Cl2 and to this solution was added trimethylsilyldi-
azomethane (TMSCHN2). The resulting mixture was
concentrated in vacuo. The residue was purified with
PTLC (hexane/AcOEt=9/1) to give 1b (17.2 mg, 55%)
and 2-naphthaldehyde 2 (7.4 mg, 35%). The spectral
data were identical to those of the authentic sample as
stated later.
1
ester of 5a (98 mg, 60%). H NMR: l 7.75–7.31 (m,
7H), 3.71 (s, 2H), 3.62 (s, 3H). Its NMR spectrum was
identical with that reported previously.30
The same product was also obtained from nitrile 3a (90
mg, 0.54 mmol) using Method B (30°C, 72 h). PTLC
purification of the crude product (CH2Cl2/EtOH=19/1)
1
afforded 5a (86 mg, 87%). H NMR: l 7.79–7.28 (m,
7H), 3.73 (s, 2H). Its NMR spectrum was identical with
that of an authentic sample. The NMR spectrum of the
corresponding methyl ester was also identical with that
of the sample as above.
4.15.2. Nitrosation–hydrolysis of (R)-4b. To a solution
of (R)-4b (>99.9% e.e., 21 mg, 0.10 mmol) in DMF (0.5
mL) was added HO3SONO (63 mg, 0.50 mmol), stirred
for 0.5 h at 0°C and worked-up as in the same manner
described above, involving esterification with
TMSCHN2. The crude methyl ester was purified with
PTLC (hexane/AcOEt=3/1) to give (R)-9a (13.0 mg,
59%) and 2 (1.0 mg, 6%). Compound (R)-9a: Rf=0.14
(hexane/AcOEt=3/1); mp 72.8–73.0°C; 1H NMR: l
7.91–7.48 (m, 7H), 5.36 (s, 1H), 3.77 (s, 3H); IR: wmax
3412, 3056, 2959, 1723, 1440, 1363, 1211, 817; [h]2D8=
−164.0 (c 1.00, CHCl3). Anal. calcd for C13H12O3: C,
72.21; H, 5.59%. Found: C, 72.14; H, 5.35%.
4.12. a-Hydroxy-2-naphthylacetamide 4b
a-Hydroxy-2-naphthylacetamide 4b (13 mg, 8%) was
obtained from the corresponding nitrile 3b (150 mg,
0.82 mmol) using Method A (30°C, 18 h). PTLC purifi-
cation of the crude product containing 2-naphthalde-
hyde (hexane/AcOEt=2/1) afforded 4b as a colorless
solid. Rf=0.37 (hexane/AcOEt=2/1); mp 183.1–
185.4°C (dec.); IR: wmax 3400, 3053, 2919, 2363, 2333,
1653, 1646, 1072, 825, 742 cm−1. The spectrum was
identical with that of (R)-4b as mentioned later.
4.15.3. Nitrosation–hydrolysis of 4d. To a solution of 4d
(11 mg, 0.04 mmol) in DMF (0.2 mL) was added
HO3SONO (50 mg, 0.39 mmol), stirred for 20 h at
room temperature and worked up as described above.
The residue was purified with PTLC (hexane/AcOEt=
4/1) and gave 9b (9.2 mg, 80%) and 2-naphthaldehyde
2, (0.3 mg, 4.6%). Compound 9b: Rf=0.39 (hexane/
AcOEt=4/1); mp 102.3–102.4°C; 1H NMR: l 7.95–
7.50 (m, 7H), 6.10 (s, 1H), 3.74 (s, 3H), 2.24 (s, 3H); IR:
wmax 3885, 3854, 3749, 3744, 1737, 1444, 1375 cm−1.
Anal. calcd for C15H14O4: C, 69.76; H, 5.46%. Found:
C, 69.37; H, 5.31.
4.13. a-Methoxy-2-naphthylacetamide 4c
a-Methoxy-2-naphthylacetamide 4c (86 mg, 88%) was
obtained from nitrile (3c, 90 mg, 0.46 mmol) using
Method B (30°C, 24 h). The crude product was purified
by silica gel column chromatography (3.5 g). Elution
with hexane–AcOEt (4/1) afforded 4c as white powder.
Recrystallization from MeOH gave 4c as colorless
needles. Rf=0.47 (hexane/AcOEt=4/1); mp 175.8–
1
176.7°C; H NMR: l 7.87–7.44 (m, 7H), 6.74 (s, 1H),
5.57 (s, 1H), 4.77 (s, 1H), 3.40 (s, 3H); IR: wmax 3417,
3157, 2938, 2359, 1691, 1664, 1369, 1099, 747, 607
cm−1. Anal. calcd for C13H13NO2: C, 72.54; H, 6.09; N,
6.51%. Found: C, 72.32; H, 6.03; N, 6.47%.
4.16. Methylation of a-hydroxyl group
4.16.1. Methylation of 9a with CH2N2–silia gel. Silica
gel was pre-heated by microwave and cooled in vacuo
for 2 h. To a solution of (R)-9a [>99.9% e.e. at the
stage of (R)-4b, 38 mg, 0.18 mmol] in Et2O (1 mL) was
added silica gel (10 mg) and the ethereal solution of
diazomethane as above. Silica gel and diazomethane
solution were added again when the yellow color no
longer lasts. This procedure was repeated several times
over 1 h. Then, the mixture was filtered to remove silica
gel and concentrated in vacuo. The residue was purified
with PTLC (hexane/AcOEt=4/1) to give (R)-1b (19.2
mg, 48%, >99.9% e.e.). The substrate (R)-9a (16.5 mg,
44%) was also recovered. Compound (R)-1b: Rf=0.41
(hexane/AcOEt=4/1); mp 38.6–39.0°C; 1H NMR: l
7.92–7.47 (m, 7H), 4.95 (s, 1H), 3.73 (s, 3H), 3.45 (s,
3H); IR: wmax 3057, 2999, 2951, 2360, 1741, 1598, 1508,
4.14. (R)-a-Hydroxy-2-naphthylacetamide (R)-4b
In a similar manner as described above, (R)-a-hydroxy-
2-naphthylacetamide (4b, 77 mg, 75%) was obtained
from nitrile [(R)-3d, 90 mg, 0.42 mmol] using Method B
(30°C, 24 h). Recrystallization of the product from
MeOH afforded colorless needles. Rf=0.50 (hexane/
AcOEt=4/1); mp 222.6–223.4°C; 1H NMR: l 7.91–
7.26 (m, 7H), 7.26 (s, 1H), 6.17–6.16 (d, 1H), 5.02–5.00
(d, 1H); IR: wmax 3393, 3204, 3052, 1711, 1653, 1597,
1437, 1362, 1121, 828, 740, 669 cm−1. Anal. calcd for
C12H11NO2: C, 71.63; H, 5.51; N, 6.96%. Found: C,
71.33; H, 5.52; N, 6.86%. [h]2D2=−62.8 (c 0.50, DMSO).

1066
M. Kimura et al. / Tetrahedron: Asymmetry 13 (2002) 1059–1068
1435, 1272, 1193, 1105, 1010, 754. Anal. calcd for
C14H14O3: C, 73.03; H, 6.13%. Found: C, 72.85; H,
5.96. [h]2D3=−140.7 (c 0.51, CHCl3). HPLC analysis:
column, Chiralcel OJ; hexane/2-propanol=9/1; 0.5 ml/
min; tR (min) 46.9 [(R)-1b, >99.9%]. In the HPLC
analysis of the corresponding racemate, (S)-isomer
appeared at tR 62.3 min.
resulting mixture was extracted with AcOEt. The
organic layer was washed with brine, dried over anhy-
drous Na2SO4 and concentrated in vacuo. PTLC purifi-
cation afforded to give (R)-1a quantitatively.
Recrystallization from AcOEt gave analytical sample as
colorless prisms. Rf=0.25 (AcOEt/AcOH=99/1); mp
1
111.2–111.5°C; H NMR: l 7.91–7.48 (m, 7H), 4.95 (s,
1H), 3.46 (s, 3H); IR: wmax 3193, 3055, 2943, 2835, 1755,
1597, 1444, 1223, 1188, 1092, 757. Anal. calcd for
C13H12O3: C, 72.21; H, 5.59%. Found: C, 71.89; H,
5.98. [h]2D0=−162.8 (c 0.54, CHCl3), [h]2D0=−173.9 (c
0.35, MeOH) [lit.4a −138.7 (c 0.35, MeOH), lit.4b −120.8
(c 0.005, EtOH)]. The spectral data were identical to
those reported previously.4b
4.16.2. Methylation of 9a with CH2N2–SnCl2·2H2O. To
a solution of (R)-9a [99.1% e.e. at the stage of (R)-4b,
8.7 mg, 0.040 mmol] in acetonitrile (0.4 mL) was added
catalytic amount of SnCl2·2H2O and a solution of
diazomethane (3 mmol) in Et2O. The resulting mixture
was filtered and evaporated. The residue was purified
with PTLC (hexane/AcOEt=4/1) and gave 1b (1.2 mg,
13%). The substrate 9a (7.3 mg, 84%) was also recov-
ered. The e.e. of the product was 92.8% judged from
the HPLC analysis as above.
This product was methylated again with TMSCHN2
and PTLC purification afforded methyl ester for the
HPLC analysis. The e.e. was confirmed to be >99.9%,
according to the HPLC analysis as above.
4.16.3. Methylation of 9a with MeI–Ag2O. To a solution
of (R)-9a (13.0 mg, 0.006 mmol) in DMF (0.5 mL),
methyl iodide (37 mL, 0.59 mmol) and silver(I) oxide
(4.2 mg, 0.18 mmol) were added. After stirring
overnight at room temperature, the reaction mixture
was poured into ice-cooled water and stirred for further
30 min. The mixture was filtered through Celite pad
and separated. The organic layer was washed with
water and brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified with
PTLC (hexane/AcOEt=3/1) and gave 1b (5.4 mg,
39%). The substrate 9a (1.4 mg, 11%) was also recov-
ered. The e.e. of the product was 43.7% according to
the HPLC analysis as above, though the e.e. of (R)-4b,
starting material of this route, was 99.2%.
4.17.2. Attempted hydrolysis of ( )-1b with Candida
rugosa lipase (Meito OF). To a solution of ( )-1b (10
mg, 0.043 mmol) in phosphate buffer solution (pH 7.0,
0.2 M, 0.4 mL), C. rugosa lipase (Meito OF, 5 mg) was
added and stirred at 27°C. The reactions were moni-
tored by TLC. After 28 h, the mixture was worked-up
and purified as above to give (S)-1a and (R)-1b (3.9
mg, 38%). The resulting carboxylic acid (S)-1a was
methylated with TMSCHN2 to give (S)-1b (1.2 mg,
12%).
The e.e.s of (R)-1b and (S)-1b [from (S)-1a] were 24.2
and 40.6%, respectively, determined by the HPLC anal-
ysis as above. The E value and the conversion were
calculated to be 3 and 37%, respectively. The preference
of (S)-enantiomer was in good accordance with the
result having so far been obtained in an analogous
substrate.31
4.16.4. Methylation of (R)-10a with methyl trichloroace-
timidate–HBF4·Me2O. To a solution of methyl (R)-
mandelate (10a, 100 mg, 0.60 mmol) in CH2Cl2 (2 mL),
were added methyl 2,2,2-trichloroacetimidate (0.2 mL,
1.62 mmol) and HBF4·Me2O (40 mL, 0.30 mmol). After
stirring over 4 days, the reaction mixture was diluted
with CH2Cl2. The organic layer was washed with aq.
NaHCO3 solution and H2O, dried over anhydrous
Na2SO4 and concentrated in vacuo to give methyl ether
10b (30.6 mg, 28%) with the recovery of unreacted
Acknowledgements
The authors thank Sumitomo Chemical Industries, Co.,
Toyobo Ltd., Meito Co., and Nagase Co., for the
generous gifts of enzymes. We express our deep thanks
to Professors Takashi Sakai of Okayama University
(synthesis of cyanohydrin acetates), Jun Hiratake of
Kyoto University (determination of e.e. of cyanohydrin
acetate), Shoji Akai of Kanagawa University
(Bu4NONO), Tadakatsu Mandai of Kurashiki Univer-
sity of Science and the Arts (HO3SONO), and Keiji
Tanino of Hokkaido University (mechanism of decar-
bonylation), Messrs. Shuhei Yamazaki and Yasuhiro
Kagamihara of Daicel Chemical Ind. (HPLC analysis)
for their discussions. This work was accomplished as
part of ‘Science and Technology Program on
Molecules, Supra-Molecules and Supra-Structured
Materials’ an academic frontier promotional project, by
Japan’s Ministry of Education, Sports, Culture, Sci-
ence, and Technology, the Monbu-Kagakusho, and the
support is acknowledged with thanks. This work was
1
substrate. Compound 10b: H NMR: l 7.46–7.33 (m,
5H), 4.78 (s, 1H), 3.72 (s, 3H), 3.41 (s, 3H). The NMR
spectrum was identical with that of an authentic sam-
ple. HPLC analysis: column, Chiralcel OJ; hexane/2-
propanol=9/1; 0.5 ml/min; tR (min) 30.8 [(R)-14,
>99.9%]. The (S)-enantiomer eluted at tR 34.3 min in
the analysis of racemic sample.
4.17. Enzyme-catalyzed hydrolysis of methyl ester of 1b
4.17.1. Hydrolysis of (R)-1a with K. oxytoca esterase
(Nagase SNSM-87). To a solution of (R)-1b (30 mg,
0.14 mmol) in phosphate buffer solution (pH 7.0, 0.2
M, 1.2 mL), esterase from K. oxytoca (10 mg) was
added and stirred at 39°C. After stirring overnight, the
reaction mixture was diluted with AcOEt and filtered
through Celite pad. The filtrate was acidified with 2 M
HCl toward pH 2.0 and saturated with NaCl. The
also supported by
a Grant-in-Aid for Scientific
Research (No.12660120).

M. Kimura et al. / Tetrahedron: Asymmetry 13 (2002) 1059–1068
1067
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