Asymmetric reduction of 3-aryl-3-keto esters using Rhizopus species

Article abstract of DOI:10.1016/j.bmc.2006.03.025

Ethyl 3-aryl-3-oxopropanoates (aryl: phenyl, 2-fluorophenyl, 3-nitrophenyl, and 4-nitrophenyl) were reduced enantioselectively to the corresponding (S)-alcohols by the fungus Rhizopus arrhizus and other Rhizopus sp. The best results were generally obtaine

Full text of DOI:10.1016/j.bmc.2006.03.025

Bioorganic & Medicinal Chemistry 14 (2006) 4918–4922
Asymmetric reduction of 3-aryl-3-keto esters using
Rhizopus species
Neeta A. Salvi and Subrata Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 30 January 2006; revised 7 March 2006; accepted 8 March 2006
Available online 17 April 2006
Abstract—Ethyl 3-aryl-3-oxopropanoates (aryl: phenyl, 2-fluorophenyl, 3-nitrophenyl, and 4-nitrophenyl) were reduced enantio-
selectively to the corresponding (S)-alcohols by the fungus Rhizopus arrhizus and other Rhizopus sp. The best results were generally
obtained with Rhizopus arrhizus (wild type) and Rhizopus nivius NCIM 958 with 6 h incubation. A longer incubation period led to
ester hydrolysis followed by decarboxylation and microbial reduction for all the substrates especially the 3-nitrophenyl ester.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
biological reduction8a of the corresponding 3-ketocarb-
oxylates. Apart from these, biocatalytic deracemiza-
tion8b,c,d and resolution8e,f of racemic 3-hydroxy esters
have also been employed in some cases. Amongst these,
the catalytic asymmetric hydrogenation route employs
harsh conditions such as high temperature and pressure,
and often requires preparation of the asymmetric cata-
lysts. The microbial reduction, on the other hand, often
provides the desired alcohols in low yields and/ or ees.
Even then, the whole-cell-mediated enantioselective
reduction of the 3-keto esters by an oxido-reductase en-
zyme is still attractive in terms of low cost, eco-friendly
nature, and the availability of a large number of micro-
organisms with a wide substrate specificity.
Optically active b-hydroxy esters/acids are important
building blocks in organic synthesis, for example, in
the syntheses of b-amino acids,1a,b b-lactams,1c and
insect pheromones.1d The b-hydroxy acids are also
important subunits2a of polyketide natural products
such as amphotericin B,2b tylosin,2c and rosaramicin.2d
Moreover, the stereogenicity in the b-hydroxy esters/
acids can also assist in developing stereo-controlled
construction of 1,3-diols3a,b and 1,3-amino alcohols,3c,d
that are intermediates for a large number of antibiot-
ics4a,b and chiral auxiliaries.4c–f
Optically active 3-aryl-3-hydroxy esters are precursors
of worlds leading anti-depressant drugs like tomoxetine
and fluoxetine hydrochlorides5a as well as other enantio-
pure pharmaceuticals such as S-1-benzyl-3-hydroxy-
pyrrolidines.5b,c (R)-Tomoxetine is the first norepineph-
rine anti-depressant without any strong affinity for
either a- or b-adrenergic receptors.5d In view of these
medicinal importances, synthetic studies of these com-
pounds have attracted considerable interest. Extensive
effort in this field has resulted in fruitful synthetic
methods for the synthesis of optically active 3-hydroxy
esters or their derivatives, utilizing aldol reactions,6a–c
as well as catalytic asymmetric hydrogenation7a–e and
During our work on microbial transformations,9a–e we
found that the fungus Rhizopus arrhizus can efficiently
carry out the asymmetric reduction of a wide variety
of ketones including aliphatic 3-keto esters. The versatil-
ity of the fungus for asymmetric reduction was further
exemplified using various 3-aryl-3-keto esters as sub-
strates and the results are presented herein.
2. Results and discussion
One of the prime requirements of a microbial transfor-
mation is the optimization of the reaction parameters
such as substrate structure, reaction conditions, etc.
Hence, for the present study, we chose a series of
3-aryl-3-oxopropanoates 1a–d and studied their
bio-reduction with various Rhizopus species and strains
(Scheme 1). Of the chosen substrates, the aromatic
Keywords: Biotransformation; Microbial reduction; b-Keto esters;
Enantioselective.
*
Corresponding author. Tel.: +91 22 25593703; fax: +91 22
25505151; e-mail: schatt@apsara.barc.ernet.in
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.03.025

N. A. Salvi, S. Chattopadhyay / Bioorg. Med. Chem. 14 (2006) 4918–4922
4919
OH
OH
O
O
O
Rhizopus
arrhizus
OEt
R
+
R
OEt
R
2a-d
3a-d
1a-d
a: R = H; b: R = 2-F; c: R = 3-NO2; d: R = 4-NO2
Scheme 1.
moieties of 1b–d contained electron-withdrawing sub-
stituents (F and NO2 groups) at different positions with
respect to the keto group, while that in 1a was unsubsti-
tuted. With all the substrates, the reactions were carried
out for different periods (6 h to 7 days) using almost the
same concentration (105–115 mg/150 mL microbial cul-
ture) of the substrates. After the usual work-up,9a,e the
product alcohols 2a–d were isolated from the respective
substrates, purified by preparative TLC, and character-
for 2 days led to the formation of 2a along with the alco-
hol 3a in ꢀ92:8 ratio (see Table 1, entry 1). From this,
the desired hydroxy ester 2a and the unreacted ketone
1a were obtained in 24% and 57% isolated yields.
Increasing the incubation time to 7 days led to complete
decarboxylation of 1a, and 3a was obtained in 28% iso-
lated yield. Apparently, during longer incubation, 2a
formed initially was reoxidized back to 1a explaining
the result. Formation of some highly polar compounds
as an intricate mixture was noticed as expected with a
multi-enzyme system. However, we did not analyze the
composition of the mixture since this was of no interest
in the present study.
1
ized by IR and H NMR spectra. During the study, it
was observed that irrespective of the microorganism
used, microbial reduction of 1a–d also furnished the
1-arylethanols 3a–d along with the expected products
2a–d as revealed by the GC analysis of the reaction
mixtures. Presumably besides ketone reduction, the
microorganisms also hydrolyzed the ester function of
the substrates in a parallel reaction, the former being
comparatively faster. The hydrolytic reaction furnished
the corresponding keto acid, which on spontaneous
decarboxylation followed by microbial reduction yield-
ed 3a–d with the respective substrates. The proposition
was also confirmed by arresting the reaction at an
appropriate time and analyzing the products with
GLC. The extent of ester hydrolysis leading to the for-
mation of the undesired side products 3a–d was depen-
dent on the nature of the substrates and the
microorganisms, as well as the reaction time. These are
discussed separately for each substrate in the following.
To avoid the formation of 3a, the reduction was carried
out by reducing the incubation period to 1 d, and also
using various other Rhizopus species and strains (see
Table 1, entries 2–9) under the same conditions. Very
recently, we were able to improve the enantioselectivity
of a Rhizopus mediated hydrolysis protocol by proper
choice of a microbial strain.9d Hence, a similar strategy
was extended for the present work. All the microorgan-
isms transformed 1a to 2a, albeit in varying yields and
different amounts of the undesired alcohol 3a. Consider-
ably less decarboxylation (<2%) was observed with R.
arrhizus (wild type) and R. nivius NCIM 958 (see Table
1, entries 2 and 8), which afforded 2a in ꢀ41–43% yields.
The fungi R. arrhizus NCIM 877, NCIM 878, and
NCIM 997 were also efficient (2.2–2.5% decarboxyl-
ation) providing 2a in good yields (ꢀ50%) (see Table
1, entries 3, 4, and 6). With R. nivius NCIM 959, 2a
was obtained in excellent yield (ꢀ76%) (see Table 1, en-
try 9), but with less enantiopurity (data not shown).
However, R. arrhizus NCIM 879 and R. oryzae NCIM
1009, were less efficient furnishing substantial amounts
of 3a (2a:3a 92:8 and 96:4, respectively, see Table 1, en-
tries 5 and 7). Subsequently, the reduction was carried
out for 6 h, using R. arrhizus (wild type) and R. nivius
NCIM 958, the best two microorganisms only. Under
this condition although the 2a was obtained in 33%
and 43% yields, respectively, formation of 3a was not
observed (see Table 1, entries 10 and 11).
2.1. Reduction of ethyl benzoylacetate 1a
Initially the microbial reduction of 1a was carried out
with R. arrhizus (wild type) for different periods and
the results are summarized in Table 1. Bioreduction
Table 1. The course of microbial asymmetric reduction of ethyl
benzoylacetate 1a by different Rhizopus species
Entry Organism
Time Yielda (%) 2a:3ab
1
2
R. arrhizus (wild type)
R. arrhizus (wild type)
2 d
1 d
24.0
41.1
49.0
51.8
51.8
50.5
31.6
43.2
76.5
33.2
43.2
91.7: 8.3
98.1:1.9
97.8: 2.2
97.5:2.5
92.3:7.7
97.7:2.3
95.7:4.3
98.1:1.9
97.5:2.5
100:0
3
R. arrhizus (NCIM 877) 1 d
R. arrhizus (NCIM 878) 1 d
R. arrhizus (NCIM 879) 1 d
R. arrhizus (NCIM 997) 1 d
4
5
2.2. Reduction of ethyl 2-fluorobenzoylacetate 1b
6
7
R. oryzae (NCIM1009)
R. nivius (NCIM 958)
R. nivius (NCIM 959)
R. arrhizus (wild type)
R. nivius (NCIM 958)
1 d
1 d
1 d
6 h
6 h
8
Similarly the microbial reduction of 1b was carried out
with various organisms and results obtained are shown
in Table 2. In this case, R. arrhizus (wild type) produced
both 2b and 3b in 9:1 ratio after 2 days of incubation
(see Table 2, entry 1), while complete decarboxylation
was noticed after only 4 days. Overall, substrate 1b
9
10
11
100:0
a Isolated yield without considering recovered substrate.
b Based on GLC analyses.

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N. A. Salvi, S. Chattopadhyay / Bioorg. Med. Chem. 14 (2006) 4918–4922
Table 2. The course of microbial asymmetric reduction of ethyl
2-fluorobenzoylacetate 1b by different Rhizopus species
Table 3. The course of microbial asymmetric reduction of ethyl
3-nitrobenzoylacetate 1c by different Rhizopus species
Entry Organism
Time Yielda (%) 2b:3bb
Entry Organism
Time Yielda (%) 2c:3cb
1
2
R. arrhizus (wild type)
R. arrhizus (wild type)
2 d
1 d
47.7
76.2
68.9
43.8
52.3
70.0
32.7
76.4
69.5
51.5
42.1
61.7
69.8
90.1:9.9
91.9:8.1
92.2:7.8
75.5:24.5
79.0:21.0
73.9:26.1
58.3:41.7
92.7:7.3
91.0:9.0
96.5:3.5
93.8:6.1
100:0
1
2
R. arrhizus (wild type)
R. arrhizus (wild type)
2 d
1 d
11.5
31.2
24.4
18.7
19.2
37.9
38.1
63.8
69.2
28.1
42.4
54.9:45.1
57.4:42.6
45.65:51.56
47.0:53.0
42.5:57.5
66.6:33.4
62.8:37.2
93.2:6.8
3
R. arrhizus (NCIM 877) 1 d
R. arrhizus (NCIM 878) 1 d
R. arrhizus (NCIM 879) 1 d
R. arrhizus (NCIM 997) 1 d
R. oryzae (NCIM 1009) 1 d
3
R. arrhizus (NCIM 877) 1 d
R. arrhizus (NCIM 878) 1 d
R. arrhizus (NCIM 879) 1 d
R. arrhizus (NCIM 997) 1 d
R. oryzae (NCIM 1009) 1 d
4
4
5
5
6
6
7
7
8
R. nivius (NCIM 958)
R. nivius (NCIM 959)
R. arrhizus (wild type)
1 d
1 d
6 h
8
R. nivius (NCIM 958)
R. nivius (NCIM 959)
1 d
1 d
9
9
95.9:4.1
98.7:1.3
97.4:2.6
10
11
12
13
10
11
R. arrhizus (NCIM 958) 6 h
R. nivius (NCIM 959) 6 h
R. arrhizus (NCIM 877) 6 h
R. nivius (NCIM 958)
R. nivius (NCIM 959)
6 h
6 h
a Isolated yield without considering recovered substrate.
b Based on GLC analyses.
100:0
a Isolated yield without considering recovered substrate.
b Based on GLC analyses.
2.4. Reduction of ethyl 4-nitrobenzoylacetate (1d)
Surprisingly, unlike compound 1c, the microbial reduc-
tion of the corresponding 4-nitro substrate 1d proceeded
almost uneventfully and very little formation of 3d was
observed (see Table 4). Amongst the microorganisms
tested, microbial reduction of 1d for 1 d with R. arrhizus
NCIM 879 and 997 as well as R. oryzae NCIM 1009
produced 2d and 3d in 92–98:2–8 ratio (see Table 4, en-
tries 5–7). However, even then 1d was obtained in 56–
63% yields. On the other hand, under the same condi-
tions, the other R. arrhizus species (wild type, NCIM
877 and 878) afforded 2d exclusively in 64%, 66%, and
46% yields, respectively (see Table 4, entries 2–4). The
fungi R. nivius NCIM 958 and 959 were found to be
the best as they produced 2d exclusively in 80% and
74% yields (see Table 4, entries 8, 9). Thus, with most
of the microorganisms the yields of the desired product
2d were excellent (64–80%).
was more susceptible to decarboxylation even after 1
day incubation with all the fungi. As earlier, in this case
also, R. arrhizus (wild type) and R. arrhizus NCIM 877,
R. nivius NCIM 958 and 959 produced less amount of 3b
(2b:3b = 91–93:7– 9) after 1 day incubation (see Table 2,
entries 2, 3, 8, and 9). Compound 1b was more reactive
than 1a as was evident from the significantly higher
yields (68–76%) of 2b with several microorganisms as
well as of the undesired alcohol 3b. In this case also,
the fungi R. arrhizus NCIM 878 and 879, as well as
R. oryzae NCIM 1009 were very poor, furnishing 2b in
lower yields (44%, 52%, and 33%, respectively) and
substantial amounts of 3b (see Table 2, entries 4, 5,
and 7). Hence the reduction was carried out for 6 h with
R. arrhizus (wild type), R. arrhizus NCIM 877, and
R. nivius NCIM 958 and 959. Amongst these, only
R. nivius NCIM 958 and 959 furnished 2b exclusively
in good yields (62–70%, see Table 2, entries 12 and
13), while with R. arrhizus (wild type) and NCIM 877,
both 2b and 3b were formed in 94–96:3–6 ratio (see
Table 2, entries 10 and 11).
2.5. Determination of absolute configurations and
enantiomeric purities of 2a–d
The absolute configurations of 2a and 2d were assigned as
(S) by comparison of the chiroptical data with those
reported.10,8d For the determination of the % ees of
2a–d, these were converted into the corresponding MTPA
esters11 with (R)-MTPA. The % ees were then assessed by
the 1H NMR analyses of the respective MTPA esters. The
2.3. Reduction of ethyl 3-nitrobenzoylacetate 1c
Surprisingly, in the microbial reduction of 1c, ester
hydrolysis was the predominant reaction with most of
the microorganisms leading to substantial amount of
3c (see Table 3). Thus, all the Rhizopus species along
with R. oryzae NCIM 1009 were very poor both in terms
of the yields of 2c as well as relative higher concentra-
tions of 3c even after 1 d of incubation (see Table 3,
entries 2–7). Only R. nivius NCIM 958 and 959 were
far superior furnishing 2c and 3c in a comparatively
lower relative proportions (93:7 and 96:4, respectively).
However, formation of 3c could not be avoided even
with these microorganisms, and the amount of
undesired 1-arylethanol was more than that with 1a.
When the reaction was carried out with R. nivius NCIM
958 and 959 for 6 h, although the ratio of 2c:3c
improved marginally, the yields of 2c were also reduced
(see Table 3, entries 10 and 11). Thus, overall a 1 d
incubation with R. nivius NCIM 958 or 959 was the best
method for the asymmetric reduction of 1c.
Table 4. The course of microbial asymmetric reduction of ethyl
4-nitrobenzoylacetate 1d by different Rhizopus species
Entry Organism
Time Yielda (%) 2d:3db
1
2
3
4
5
6
7
8
9
R. arrhizus (wild type)
R. arrhizus (wild type)
2 d
1 d
25.7
64.1
65.8
46.5
56.8
63.7
60.3
79.9
73.9
92.9:7.1
100:0
100:0
R. arrhizus (NCIM 877) 1 d
R. arrhizus (NCIM 878) 1 d
R. arrhizus (NCIM 879) 1 d
R. arrhizus (NCIM 997) 1 d
100:0
97.8:2.2
95.6:4.4
91.8:8.2
100:0
R. oryzae (NCIM1009)
R. nivius (NCIM 958)
R. nivius (NCIM 959)
1 d
1 d
1 d
100:0
a Isolated yield without considering recovered substrate.
b Based on GLC analyses.

N. A. Salvi, S. Chattopadhyay / Bioorg. Med. Chem. 14 (2006) 4918–4922
4921
Table 5. Optimized results of asymmetric microbial reduction of
3-aryl-3-keto esters
4. Experimental
Time Yield % eea
4.1. General experimental details
Product Organism
(%)
(config.)
All the substrates and (R)-(+)-a-methoxy-a-trifluorom-
ethylphenylacetic acid (MTPA) (Aldrich, Fluka, and
Lancanster) were used as received. Other reagents were
of AR grade. The extracts were dried over anhydrous
Na2SO4. The Rhizopus cultures were received from
National Collection of Industrial Microorganisms,
National Chemical Laboratory, Pune, India. The fungus
from PDA slants was cultivated on 150 mL sterilized
modified Czepak Dox medium in 500 mL Erlenmeyer
2a
2a
2b
2b
2c
2c
2d
2d
2d
2d
2d
R. arrhizus (wild type)
6 h
6 h
6 h
6 h
6 h
6 h
1 d
33.2
43.5
61.8
69.8
28.1
42.4
64.1
65.8
46.5
79.9
73.9
95.1 (S)
90.9 (S)
>98.0 (S)
92.1 (S)
94.2 (S)
87.9 (S)
95.0 (S)
94.2 (S)
93.6 (S)
>98.0 (S)
91.7 (S)
R. nivius (NCIM 958)
R. nivius (NCIM 958)
R. nivius (NCIM 959)
R. nivius (NCIM 958)
R. nivius (NCIM 959)
R. arrhizus (wild type)
R. arrhizus (NCIM 877) 1 d
R. nivius (NCIM 878)
R. nivius (NCIM 958)
R. nivius (NCIM 959)
1 d
1 d
1 d
flasks at room temperature on
a rotary shaker
(150 rpm).9a–e The IR spectra were scanned as films on
a Nicolet FT-IR model Impact 410 spectrometer. The
1H NMR spectra were recorded in CDCl3 with TMS
as the internal standard with a Brucker AC-200
(200 MHz) spectrometer. The optical rotations were
recorded with a Jasco 360 DIP digital polarimeter.
The GLC analyses were carried out with a Shimadzu
gas chromatograph GC-16A (3% OV-17 column, 90–
240 ꢁC, temp. program. 4 ꢁC/min rate, 40 ml/min N2).
a Based on 1H NMR analyses of respective (R)-MTPA esters.
results on the % ees and yields of the desired alcohols 2a–d
are summarized in Table 5. In the 1H NMR spectra, the
methoxyl resonances of the (R)-MTPA esters of 2a–d ap-
peared as two singlets at d 3.52–3.54 (major) and at d 3.42–
3.43 (minor). The relative intensities of these resonances
furnished the respective % ees. Given that the compounds
2a and 2d possessed (S) configuration, the downfield
methoxyl resonances were attributed to those of (S)-car-
binols. Based on these, the esters 2b,c were also assigned
(S) configuration. These results are in accordance with
our previous report.9c
4.2. General procedure for microbial reduction
In five cotton plugged Erlenmeyer flasks containing the
72 h grown Rhizopus culture (150 mL) was added each
substrate 1a–d (550 20 mg) in ethanol (5 mL) in equal
amounts. The mixtures were incubated on a rotary shaker
(90–95 rpm) at room temperaturefor the desired period as
indicated in Tables 1–4. At the end of incubation, the
mycelial mass was removed, washed withwater, squeezed,
and extracted with ethyl acetate. The aqueous washings
were combined with the aqueous filtrate and extracted
with CHCl3 (3· 50 mL). The organic extract was washed
with water, brine, dried, and concentrated to obtain a res-
idue. This was subjected to preparative TLC (silica gel,
15% EtOAc/hexane, visualization by UV exposure) to
furnish the respective products 2a–d.
3. Conclusion
Thus, the above studies demonstrated that the whole-
cell system of different Rhizopus species can accomplish
the asymmetric transformation of the 3-aryl-3-keto
esters 1a–d in highly enantioselective manner. Besides
being environment-friendly, the protocol is very simple
even to an organic chemist and furnishes the 3-aryl-3-
hydroxy esters 2a–d in satisfactory yields. Although,
some of the organisms produced undesired 1-aryletha-
nols via an ester hydrolysis/decarboxylation/reduction
protocol, the course of the reaction can be controlled
by judicious choice of microorganism and incubation
period. Amongst the chosen microorganisms, R. arrhi-
zus (wild type) and R. nivius NCIM 958 and 959 were
very promising for this purpose. In spite of its several
attractive features, the microbial reductive methodology
has not been extensively used for the asymmetric synthe-
sis of the pharmaceutically important 3-aryl-3-hydroxy
esters. The previous reports8a suffer from lack of gener-
ality and wide applicability.
4.3. Ethyl (S)-3-hydroxy-3-phenylpropionate 2a
22
Colorless oil; ½aꢁ ꢂ42.3 (c 0.96, CHCl3) (95.1% ee)
D
20
(lit. 10a) ½aꢁ ꢂ25.8 (c 1.3, CHCl3); IR: 3349, 3091,
D
1
3065, 3030, 1736 cmꢂ1; H NMR: d 1.26 (t, J = 7.0 Hz,
3H, OCH2CH3), 2.71 (d, J = 4.26 Hz, 2H, CH2CO2Et),
3.04 (br s, 1H, OH), 4.17 (q, J = 7.0 Hz, 2H,
OCH2CH3), 5.13 (dd, J = 4.26, 8.0 Hz, 1H, CHOH),
7.25–7.37 (m, 5H, ArH); MS (EI, 70 eV): m/z (%) 194
(100, M+), 165 (6), 147 (13), 120 (19), 107 (97), 105
(65), 79 (49), 77 (38), 60 (11).
In general, baker’s yeast is extensively used for the asym-
metric reduction of alkyl 3-keto esters.12a,12b Amongst the
aryl 3-keto esters, only 1a could be reduced under fer-
menting condition.10a However, the reaction did not take
place with non-fermenting yeast in an organic solvent.10b
Further, the baker’s yeast mediated method often suffers
from poor chemical yields, varying enantioselectivity
(70–97%), and tedious isolation protocol.12a,b In compar-
ison, the present method provides an efficient alternative
for the designated targets with excellent reproducibility
under an operationally simple condition.
4.4. Ethyl (S)-3-hydroxy-3-(20-fluorophenyl)propionate 2b
22
Colorless oil; ½aꢁ ꢂ49.7 (c 2.71, CHCl3) (>98% ee); IR:
D
1
3347, 3065, 1731 cmꢂ1; H NMR: d 1.24 (t, J = 7.2 Hz,
3H, OCH2CH3), 2.74 (d, J = 4.5 Hz, 2H, CH2CO2Et),
3.28 (br s, 1H, OH), 4.16 (q, J = 7.2 Hz, 2H,
OCH2CH3), 5.39 (dd, J = 4.5, 8.0 Hz, 1H, CHOH),
6.95–7.56 (m, 4H, ArH); MS (EI, 70 eV): m/z (%) 212
(22, M+), 195 (38), 165 (6), 153 (22), 138 (9), 125
(100), 123 (74), 97 (69), 88 (36), 77 (27), 60 (27).

4922
N. A. Salvi, S. Chattopadhyay / Bioorg. Med. Chem. 14 (2006) 4918–4922
4.5. Ethyl (S)-3-hydroxy-3-(30-nitrophenyl)propionate 2c
5981–5984; (d) Narasaka, K.; Ukaji, Y.; Yamazaki, S.
Bull. Chem. Soc. Jpn. 1986, 59, 525.
22
4. (a) Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M.
J. Am. Chem. Soc. 1982, 104, 6465–6466; (b) Hashigu-
chi, S.; Kawada, A.; Natsugari, H. J. Chem. Soc. Perkin
Trans. 1 1991, 2435–2444; (c) Hayashi, Y.; Rode, J. J.;
Corey, E. J. J. Am. Chem. Soc. 1996, 118, 5502–5503;
(d) Senanayake, C. H.; Fang, K.; Grover, P.; Bakale, R.
P.; Vandenbossche, C. P.; Wald, S. A. Tetrahedron Lett.
1999, 40, 819–822; (e) Genov, M.; Dimitrov, V.;
Ivanova, V. Tetrahedron Asymm. 1997, 8, 3703–3706;
(f) Eliel, E. L.; He, X.-C. J. Org. Chem. 1990, 55,
2114–2119.
Colorless oil; ½aꢁ ꢂ34.8 (c 1.20, CHCl3) (94% ee); IR:
D
1
3436, 3091, 1730, 1530, 1350 cmꢂ1; H NMR: d 1.27 (t,
J = 7.2 Hz, 3H, OCH2CH3), 2.58 (br s, 1H, OH), 2.72
(d, J = 4.4 Hz, 2H, CH2CO2Et), 4.20 (q, J = 7.2 Hz, 2H,
OCH2CH3), 5.22 (dd, J = 4.4, 7.8 Hz, 1H, CHOH),
6.95–7.56 (m, 4H, ArH); MS (EI, 70 eV): m/z (%) 239
(34, M+), 192 (26), 152 (67), 150 (100), 77 (37).
4.6. Ethyl (S)-3-hydroxy-3-(40-nitrophenyl)propionate 2d
22
Colorless oil; ½aꢁ ꢂ30.1 (c 4.28, CHCl3) (>98% ee);
5. (a) Foster, B. J.; Lavagnino, E. R.. In Drugs of the Future;
Prous Science: Barcelona, Spain, 1986; Vol. 11, pp 134–
200; (b) Robertson, D. W.; Krushins, J. H.; Fuller, R. W.;
Leander, J. D. J. Med. Chem. 1988, 31, 1412–1417, and
references therein; (c) Mochizuki, N.; Sugai, T.; Ohta, H.
Biosci. Biotech. Biochem. 1994, 58, 1666–1670; (d) Ankier,
S. I. Prog. Med. Chem. 1986, 23, 121–140.
6. (a) Duthaler, R. O.; Herold, P.; Lottenbach, W.; Oertle,
K.; Riediker, M. Angew. Chem. Int. Ed. Engl. 1989, 28,
495–497; (b) Mioskowski, C.; Solladie, G. Tetrahedron
1979, 36, 227–236; (c) Meyers, A. I.; Knaus, G. Tetrahe-
dron Lett. 1974, 15, 1333–1336.
D
20
D
(lit.8d ½aꢁ +23.1 (c 1.0, CHCl3) for (R)-isomer); IR:
1
3458, 3117, 3082, 1728, 1352 cmꢂ1; H NMR: d 1.27
(t, J = 7.6 Hz, 3H, OCH2CH3), 2.00 (br s, 1H, OH),
2.73 (dd, J = 4.6 Hz, 2H, CH2CO2Et), 4.19 (q,
J = 7.6 Hz, 2H, OCH2CH3), 5.22 (dd, J = 4.6, 7.8 Hz,
1H, CHOH), 7.55 (d, 2H, J = 8.6 Hz, ArH), 8.21 (d,
J = 8.6 Hz, 2H, ArH); MS (EI, 70 eV): m/z (%) 239
(30, M+), 192 (34), 165 (29), 152 (75), 150 (100), 88
(46), 77 (34), 43 (22).
7. (a) Noyori, R. Asymmetric Catalysis in Organic Chemistry;
Wiley & Sons: New York, 1994, p. 62; (b) Ireland, T.;
Grossheimann, G.; Wieser, J. C.; Knochel, P. Angew.
Chem. Int. Ed. 1999, 38, 3212–3214; (c) Ratovelomanana,
V. V.; Genet, J. P. J. Organomet. Chem. 1998, 567, 163–
171; (d) Everaere, K.; Carpentier, J. F.; Mortreux, A.;
Bulliard, M. Tetrahedron: Asymmetry 1999, 10, 4663–
4666; (e) Sun, Y.; Wan, X.; Guo, M.; Wang, D.; Dong, X.;
Plan, Y.; Zhang, Z. Tetrahedron: Asymmetry 2004, 15,
2185–2188.
8. For a comprehensive review of this area, see: (a) Davies,
H. G.; Green, R. H.; Kelly, D. R.; Roberts, S. M. In
Biotransformations in Preparative Organic Chemistry. The
Use of Isolated Enzymes and Whole Cell Systems in
Synthesis; Academic Press: London, 1989 (Chapter 3); (b)
Azerad, R.; Buisson, D. In Microbial Reagents in Organic
Synthesis; Servi, S., Ed.; Kluwer Academic Publishers:
Dordecht, The Netherlands, 1992; pp 421–440; (c)
Nakamura, K.; Fuji, M.; Ida, Y. Tetrahedron: Asymmetry
2001, 12, 3147–3153; (d) Padhi, S. K.; Chadha, A.
Tetrahedron: Asymmetry 2005, 16, 2790–2798; (e) Sharma,
A.; Chattopadhyay, S. J. Mol. Cat. B: Enzymatic 2000, 10,
531–534; (f) Xu, C.; Yaun, C. Tetrahedron 2005, 61, 2169–
2186.
9. (a) Salvi, N. A.; Patil, P. N.; Udupa, S. R.; Banerji, A.
Tetrahedron: Asymmetry 1995, 6, 2287–2290; (b) Salvi, N.
A.; Udupa, S. R.; Banerji, A. Biotechnol. Lett. 1998, 20,
201–203; (c) Salvi, N. A.; Chattopadhyay, S. Tetrahedron
2002, 57, 2833–2839; (d) Salvi, N. A.; Badheka, L. P.;
Chattopadhyay, S. Biotechnol. Lett. 2003, 25, 1081–1086;
(e) Salvi, N. A.; Chattopadhyay, S. Tetrahedron: Asym-
metry 2004, 15, 3397–3400.
10. (a) Deol, B. S.; Ridly, D. D.; Simpson, G. W. Aust. J.
Chem. 1976, 29, 2459–2467; (b) Medson, C.; Smallridge,
A. J.; Ttewhella, M. A. Tetrahedron: Asymmetry 1997, 8,
1049–1054.
4.7. General procedure for preparation of the MTPA
esters
A
mixture of (R)-MTPA (25 mg) and SOCl2
(0.250 mL) in toluene (2 mL) was refluxed for 3 h.
After removing the excess SOCl2 in vacuo, the resul-
tant MTPA chloride was taken in CH2Cl2 (0.5 mL)
and added to a solution of the alcohol (15 mg), pyri-
dine (0.1 mL), and 4,4-dimethylaminopyridine (1–2
crystals) in CH2Cl2 (0.250 mL). After stirring the mix-
ture for 16 h at room temperature, the excess pyridine
was removed by purging with N2 gas, and the residue
subjected to preparative thin-layer chromatography
(silica gel, 10% EtOAc/hexane) to isolate the respective
1
MTPA esters. The H NMR analyses were carried out
with the pure samples.
References and notes
1. (a) Thaisrivongs, S.; Pals, D. T.; Kati, W. M.; Turner, S.
R.; Thomasco, L. M.; Watt, W. J. Med. Chem. 1986, 29,
2080–2087; (b) Thaisrivongs, S.; Schostarez, H. J.; Pals, D.
T.; Kati, W. M.; Turner, S. R. J. Med. Chem. 1987, 30,
1837–1842; (c) Schostarez, H. J. J. Org. Chem. 1988, 53,
3628–3631; (d) Oertle, K.; Beyeler, H.; Duthaler, R. O.;
Lottenbach, W.; Riediker, M.; Steiner, E. Helv. Chim.
Acta 1990, 73, 353–358.
2. (a) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R.
Angew. Chem., Int. Ed. Engl. 1985, 24, 1–30; (b) Nicolaou,
K. C.; Chakraborty, T. K.; Ogawa, Y.; Furst, G. T. J. Am.
Chem. Soc. 1988, 110, 4660–4672; (c) Tatsuta, K.;
Amemiya, Y.; Kanemura, Y.; Takahashi, H.; Kinoshita,
M. Tetrahedron Lett. 1982, 23, 3375–3378; (d) Schlessing-
er, R. H.; Poss, M. A.; Richardson, S. J. Am. Chem. Soc.
1986, 108, 3112–3114.
11. Dale, J. A.; Mosher, S. H. J. Am. Chem. Soc. 1973, 95,
512–519.
12. (a) Faber, K.; Riva, S. Synthesis 1992, 895–910; (b)
Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi,
A. Chem. Rev 1992, 92, 1071–1140, and references cited
therein.
3. (a) Narasaka, K.; Pai, F.-C. Tetrahedron 1984, 40, 2233–
2238; (b) Evans, D. A.; Chapman, K. T.; Carreira, M. E.
J. Am. Chem. Soc. 1988, 110, 3560–3578; (c) Haddad, M.;
Dorbais, J.; Larcheveque, M. Tetrahedron Lett. 1997, 38,