Asymmetric synthesis of the active form of loxoprofen and its analogue

Article abstract of DOI:10.1016/j.tetasy.2011.06.019

The asymmetric synthesis of the active form of the antiinflammatory drug loxoprofen has been reported in this article. Enzymatic kinetic resolution/racemization of a substituted homo-benzylic primary alcohol with lipase-PS, asymmetric alkylation of cyclic ketones using either Enders' or Meyers' strategy followed by a stereoselective biocatalytic reduction of carbonyl group are the key reactions employed successfully to achieve the target molecule and one of its analogue.

Full text of DOI:10.1016/j.tetasy.2011.06.019

Tetrahedron: Asymmetry 22 (2011) 1125–1132
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of the active form of loxoprofen and its analogue
⇑
Rajib Bhuniya, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric synthesis of the active form of the antiinflammatory drug loxoprofen has been reported
in this article. Enzymatic kinetic resolution/racemization of a substituted homo-benzylic primary alcohol
with lipase-PS, asymmetric alkylation of cyclic ketones using either Enders’ or Meyers’ strategy followed
by a stereoselective biocatalytic reduction of carbonyl group are the key reactions employed successfully
to achieve the target molecule and one of its analogue.
Received 9 May 2011
Accepted 10 June 2011
Available online 25 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Herein we report the asymmetric synthesis of loxoprofen and
its cyclohexane analogue by a chemoenzymatic approach. The ret-
Loxoprofen is a non-steroidal antiinflammatory drug (NSAID) in
the propionic acid derivatives group, which also includes ibuprofen
and naproxen among others (Scheme 1). It is marketed in Brazil,
Mexico and Japan by Sankyo pharma as its sodium salt, loxoprofen
sodium, under the trade name Loxonin, Argentina as Oxeno and in
India as Loxomac. It is available in these countries for oral admin-
istration, and a transdermal preparation was approved for sale in
Japan in January 2006. Loxoprofen is a prodrug; it is immediately
converted into its active form, the corresponding trans-alcohol
metabolite, following oral administration and reaches its peak
plasma concentration within 30–50 min. Loxoprofen [(S)-2-[4-
((R)-2-oxo-cyclopentylmethyl)-phenyl]-propionic acid] is a 2-aryl-
propionic acid antiinflammatory agent with analgesic and anti-
pyretic properties. It has also been shown to be an effective inhib-
itor of the production of inflammatory prostaglandins in vivo but
only a weak inhibitor of cyclooxygenase-2 (COX-2) activity when
tested using enzyme and cell assays in vitro.1–3 Its inhibitory ef-
fects on cyclooxygenase activity have been attributed to its
(2S,10R,20S)-trans-alcohol reduction product, the major metabolite
of loxoprofen detected after administration.1–6 Few synthetic
methods have been developed to prepare loxoprofen in an asym-
metric fashion. These methods involve various key reactions such
as copper catalyzed asymmetric SN20reactions as reported by
Hyodo et al.,7 asymmetric hydrogenations by an Ir-complex as re-
ported by Zhou and co-workers,8 and a lipase catalyzed resolution
of a substituted cyclopentane system as reported by Tadakatsu and
Tomio.9
rosynthetic analysis for the active form of loxoprofen is presented
in Scheme 2, starting from (R)-2-(4-(4-methoxybenzyloxy) phenyl)
propan-1-ol. The main highlights of our synthetic strategy are
enzymatic kinetic resolution coupled with racemisation to access
a substituted homobenzylic alcohol, asymmetric alkylation of
cyclopentanone by Ender’s RAMP/SAMP strategy10 and Meyer’s
protocol11 followed by the stereoselective biocatalytic reduction
of the substituted cyclopentanone.
2. Results and discussion
Our synthesis started from (4-hydroxymethyl-phenyl)-metha-
nol 1, selective mono-protection of the diol with PMB-Br (para
methoxy benzyl bromide) afforded the mono-PMB protected ether
2 in 85% yield. Swern oxidation12 of compound 2 afforded the cor-
responding aldehyde in 88% yield, which upon Grignard reaction
with MeMgI, followed by Swern oxidation yielded the correspond-
ing methyl ketone (75% overall yield for two steps). Wittig olefin-
ation of the methyl ketone with the triphenylphosphonium methyl
iodide afforded compound 3 in 78% yield. Hydroboration of com-
pound 3 with BH3-DMS gave alcohol 4 in 82% yield (Scheme 3).
Irreversible enzymatic transesterification with vinylacetate was
applied to racemic 4 by using Lipase-PS (Burkholderia cepacia) in
DIPE (iPr2O) as a solvent to afford the (S)-acetate 5 (ee: 98%) and
the (R)-alcohol 6 with good enantioselectivity (ee: 94%). The
deacetylation of the (S)-acetate with K2CO3/MeOH yielded
(S)-alcohol 7 in 88% yield (Scheme 3). With both the enantiomeric
2-(4-(4-methoxybenzyloxy)phenyl)propan-1-ol in our hands, we
opted to carry out the synthesis of an active form of loxo-
profen from the (S)-2-(4-(4-methoxybenzyloxy)phenyl)propan-1-
ol. Although the enzymatic kinetic resolution of compound 4 was
⇑
Corresponding author. Tel.: +91 3222 283328; fax: +91 3222 282252.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.019

1126
R. Bhuniya, S. Nanda / Tetrahedron: Asymmetry 22 (2011) 1125–1132
CO2H
CO2H
CO2H
OMe
F
(S)-ibuprofen
(S)-naproxen
(S)-fluribiprofen
O
O
PhO
CO2H
CO2H
CO2H
(S)-fenoprofen
OH
(S)-ketoprofen
loxoprofen
CO2H
OH
CO2H
active form of loxoprofen
loxoprofen analogue
Scheme 1. Few examples of 2-aryl-propionic acid NSAID compounds.
OH
O
asymmetric
CO2H
CO2H
reduction
active form of loxoprofen
BMPO
asymmetric alkylation
(Enders' /Meyers' strategy)
enzymatic
kinetic
O
resolution
X
OH
+
OP
X = Br, P = TBDPS
Scheme 2. Retrosynthetic analysis of active form of loxoprofen.
OPMB
c
OPMB
d
OH
OH
OPMB
b
R
R
a
+
OR'
OH
OH
R = CH2OPMB
R' = Ac; 5
OH
6
4
g
3
2
e
f
4
1
R' = H; 7
R' = TBDPS, 8
OH
OH
M
R
Br
i
h
L
OR''
OR''
OR''
fast reacting enantiomer
10
9
R = CH2OPMB, R'' = OTBDPS; 8
Scheme 3. Reagents and conditions: (a) NaH, PMB-Br, 85%; (b) (i) (COCl)2, DMSO, ꢀ78 °C, Et3N, 88%; (ii) MeMgI, THF, 82%; (iii) (COCl)2, DMSO, ꢀ78 °C, Et3N, 84%; (iv)
Ph3P+MeIꢀ, KOtBu, 78%; (c) BH3-DMS, THF, then H2O2, NaOH, 82%; (d) lipase-PS, DIPE, molecular sieve 4 Å, 48%; (e) K2CO3, MeOH; (f) imidazole, TBDPS-Cl; 88%; (g) (i) (COCl)2,
DMSO, ꢀ78 °C, Et3N; (ii) DBU, THF; (iii) NaBH4; (h) DDQ, DCM/H2O (19:1), 86%; (i) NBS, TPP, DCM, 70%.

R. Bhuniya, S. Nanda / Tetrahedron: Asymmetry 22 (2011) 1125–1132
1127
successfully accomplished, the undesired (R)-alcohol 6 would be of
no use, and hence a racemization method was developed to pre-
pare racemic 4 from (R)-6, which was then subsequently used in
the enzymatic kinetic resolution step.
had the opportunity of introducing a chiral environment which
could influence the direction and rate of the electrophilic reaction
and provide the alkylated products in disproportionate amounts.
This concept has already been applied by Horeau16 and Yamada17
with moderate degrees of success leading to enantiomerically en-
For the racemisation method, compound 6 was oxidized to its
corresponding aldehyde under Swern conditions, followed by
DBU catalyzed racemization and reduction of the aldehyde func-
tionality with NaBH4 to afford racemic 4 from (R)-6 in 88% yield
(over three steps). The hydroxymethyl group in 7 was protected
as its TBDPS (tert-butyldiphenylsilyl) ether by treatment with
imidazole/TBDPS-Cl in DCM to give the compound 8 in 85% yield.
Removal of the PMB group was achieved successfully with DDQ13
at 0 °C to yield compound 9 in 86% yield. The hydroxyl group
was converted into the corresponding bromo compound 10 by
treatment with TPP (triphenylphosphine) and NBS (N-bromosuc-
cinimide)14 in DCM at 0 °C in 70% yield as shown in Scheme 3.
The enantioselective carbon-carbon bond formation via ketone
enolates was not feasible due to the symmetric nature of the eno-
late system, whereas metalloenamines15 as enolate equivalents
riched
a-substituted ketones in 25–45% enantiomeric excess. In
1976, a preliminary report from Meyer’s laboratory18 described
the asymmetric alkylation of cyclohexanones via certain lithioen-
amines furnishing a-alkylcyclohexanones in 90–100% ee. The basis
for the efficient enantioselective alkylation depends on the induced
rigidity within the lithioenamine by an internal ligand (OMe),19
which was absent in the earlier work by Horeau and Yamada. Thus,
starting from a readily available chiral amine 11 obtained by
reduction of (S)-phenylalanine, we prepared the corresponding
imine of cycloalkanones (both cyclopentanone and cyclohexanone)
and hence into its lithioenamines, as an intermediate by using LDA
(lithium diisopropylamide) in THF at ꢀ78 °C. Subsequent alkyl-
ation followed by acidic hydrolysis20 led to compounds 12 and
13 revealing the predominant entry of the electrophile from the
Ph
Ph
H
O
Ph
H
10
LDA/THF;
N
N
N
+
+
H2N
H
OMe
OMe
ee = 96%
n
n
n
Li
OMe
H
E+ (Si-face)
11
H3O+
O
OMe
O
OMe
NH2
tBuLi/THF
N
N
n
+
10
, H3O
n
RAMP
OTBDPS
n
n =1; 12
n = 2; 13
n = 1, 2
E + = electrophile
H
H
(R)
N
ee = 98%
N
O
Li
E
+ (Si-face)
Me
Scheme 4. Asymmetric alkylation of cycloalkanones.
O
n
O
b
a
n
OTBDPS
OH
n =1; 12
n = 2; 13
n =1; 14
n = 2; 15
O
n
OH
n
O
c
O
OH
OH
n =1; 16, loxoprofen
n = 2; 17
18
n =1; ; active form of loxoprofen
19
n = 2; ; loxoprofen analogue
Scheme 5. Reagents and conditions: (a) TBAF, THF, 80%; (b) PDC, DMF, 72%; (c) G. candidum (NBRC 4597), rt, 78%.

1128
R. Bhuniya, S. Nanda / Tetrahedron: Asymmetry 22 (2011) 1125–1132
Table 1
Biotransformation of 16 and 17 with microbial ketoreductases
O
OH
OH
O
O
+
O
OH
OH
OH
trans
cis
n = 1; 18
n = 2; 19
n = 1; 16
n = 2; 17
Substrate
Ketoreductasesa
Yieldb (%)
Drc (%) (trans:cis)
16
16
16
16
16
17
17
17
17
K. pneumoniae (NBRC 3319)
G. candidum (NBRC 4597)
A. niger (NBRC 4415)
C. parapsilosis (NBRC 1396)
T. delbrueckii (NBRC 10921)
G. candidum (NBRC 4597)
A. niger (NBRC 4415)
10
78
55
82
76
70
62
68
72
nd
20:1
1:10
1:12
1:20
18:1
1:14
1:15
1:20
C. parapsilosis (NBRC 1396)
T. delbrueckii (NBRC 10921)
a
b
c
Microbial strains are obtained from NBRC, Japan and maintained as specified in the catalog.
Yields refer to isolated yield after purification.
Diastereomeric ratio was measured with the help of 1H NMR analysis. nd: not determined.
Si face (frontside) of the cyclopentyl/cyclohexyl moiety. In another
approach, the proline based chiral auxiliary RAMP [(R)-1-amino-2-
methoxymethylpyrrolidine] was coupled with cycloalkanones to
afford the corresponding enamines. The enamines upon subse-
quent alkylation with 10 followed by cleavage of the auxiliary,
using a modified method reported by Smith et al.21 afforded 12
and 13 in good yield (Scheme 4).
Deprotection of the TBDPS silylether was achieved by treating
compound 12 with TBAF/THF22 at room temperature to afford 14
in 80% yield. Oxidation of the primary alcohol functionality with
PDC (pyridinium dichromate)23 in DMF afforded the corresponding
acid 16 (loxoprofen) in 72% yield. The stereoselective reduction of
loxoprofen to its corresponding trans-alcohol, which is the active
form of the drug, seems to be challenging (Scheme 5). The reduc-
tion of 16 with NaBH3CN has already been reported in the litera-
ture,24 which furnished the trans- and cis-alcohols in a 4:1 ratio.
We were interested in replacing the stereoselective chemoreduc-
tion process by an alternative asymmetric bioreduction process;
for this reason, a few microbial ketoreductase strains (NBRC
3319, NBRC 4597, NBRC 4415, NBRC 1396, and NBRC 10921) were
tested. Growing cells of those microorganisms are used as the
source of the ketoreductase enzymes for the conversion of 16 to
18. The results are summarized in Table 1.
From Table 1, it can be seen that the growing cells of Geotrichum
candidum (NBRC 4597) and Torulaspora delbrueckii (NBRC 10921)
are stereocomplementary, as the former produces the trans-alcohol
18 as the major product, while the latter produces the cis-alcohol
as a major product.
This is one of the unique findings in our work, where both dia-
stereomeric alcohols can be obtained in high yield from two differ-
ent microorganisms with excellent enantioselectivity. Although
carbonyl reductases from G. candidum have found wide use in syn-
thetic biotransformations,25 keto reductases from T. delbrueckii
have not been explored well enough as potential synthetic biocata-
lysts.26 The other two microorganisms that we have screened,
Aspergilus niger (NBRC 4415) and Candida parapsilosis (NBRC
1396) exhibit similar types of stereoselectivity, since the cis-alco-
hol was obtained as the major product in both the cases. Similar
kinds of activity were obtained when the cyclohexyl analogue 17
was used as a substrate (Table 1 and Scheme 5).
3. Conclusion
In conclusion, the asymmetric synthesis of the active form of
loxoprofen and its analogue has been carried out by using a che-
moenzymatic approach. The main reactions employed in our syn-
thetic exercise involve the enzymatic kinetic resolution of a
homobenzylic alcohol, which serves as a precursor for a bromo
compound. Next, the asymmetric alkylation reaction on cycloalka-
nones has been successfully used either by Meyers’ strategy or
Enders’ protocol. Finally the asymmetric reduction of the carbonyl
functionality with microbial ketoreductases afforded the target
molecule in an efficient manner.
4. Experimental
4.1. General
Unless otherwise stated, materials were obtained from com-
mercial suppliers and used without further purification. THF and
diethyl ether were distilled from sodiumbenzophenone ketyl.
Dimethylformamide (DMF) and dimethylsulfoxide (DMSO) were
distilled from calcium hydride. Microbial ketoreductases strains
form G. candidum (NBRC 5767), C. parapsilosis (NBRC 1396) and
A. niger (NBRC 4415), T. delbrueckii (NBRC 10921) were obtained
from NBRC, Japan and maintained in a Petri dish as well as in glyc-
erol slants periodically. Bioreductions were performed in an incu-
bator shaker at 35 °C. Reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25 mm silica gel plates
(Merck) with UV light, ethanolic anisaldehyde and phosphomolyb-
dic acid/heat as developing agents. Silicagel 100–200 mesh was
used for column chromatography. Yields refer to chromatogra-
phically and spectroscopically homogeneous materials unless

R. Bhuniya, S. Nanda / Tetrahedron: Asymmetry 22 (2011) 1125–1132
1129
otherwise stated. NMR spectra were recorded on Bruker 200 and
4.5. 1-[4-((4-Methoxy-benzyloxy)methyl)-phenyl]-ethanone
400 MHz spectrometers at 25 °C in CDCl3 using TMS as the internal
standard. Chemical shifts are shown in d. 13C NMR spectra were re-
corded in a complete proton decoupling environment. The chemi-
cal shift value is listed as dH and dC for 1H and 13C, respectively.
Optical rotations were measured on a JASCO P1020 digital polarim-
eter. Elemental analysis was performed by using Perkin Elmer CHN
analyzer (2400, series II). Mass spectral analysis (LRMS/HRMS) was
performed in CRF, IIT-Kharagpur. Chiral HPLC was performed using
Chiral OD-H column (0.46 ꢁ 25 cm, Daicel industries) with Shima-
dzu Prominence LC-20AT chromatograph coupled with UV–vis
detector (254 nm). Eluting solvent used was different ratio of
hexane and 2-propanol.
The alcohol was converted to the corresponding ketone by
Swern oxidation. Oxalyl chloride (2.9 mL, 33.2 mmol) was taken
in anhydrous DCM (90 mL). Then DMSO (4.7 mL, 67 mmol) was
added to the solution and kept at ꢀ78 °C. After 15 min, alcohol 6
(6.2 g, 22 mmol) was added, and the solution was stirred at the
same temperature for a further 45 min. After this time Et3N
(18 mL, 132 mmol) was slowly added to the reaction mixture at
the same temperature. The reaction mixture was allowed to return
to room temperature. Water was added to the solution, and the
mixture was extracted with DCM. The organic extract was washed
with water, NaHCO3 solution and brine. The organic layer was
dried (MgSO4) and evaporated. Purification by silica gel chroma-
tography yielded the ketone (5.9 g) in 94% yield. dH: 7.95–6.87
(8H, Ar H), 4.57 (s, 2H), 4.51 (s, 2H), 3.8 (s, 3H), 2.59 (s, 3H). dC:
197.8, 159.2, 143.9, 136.3, 129.9, 129.4, 128.7, 128.4, 113.8, 72.1,
71.0, 55.2, 26.5.
4.2. [4-(4-Methoxy-benzyloxymethyl)-phenyl]-methanol 2
The diol 1 (5.3 g, 40.8 mmol) was taken in 150 mL of dry THF.
Then, NaH (60% dispersion in mineral oil, 2 g, 49 mmol) was added
to it portionwise at 0 °C. The reaction mixture was stirred at 0 °C
for 1 h. Tetrabutylammonium iodide (TBAI, 2.5 mmol) was added
followed by the addition of 4-methoxybenzylbromide (49 mmol).
The reaction mixture was stirred for a further 2 h at room temper-
ature. Water was carefully added to the reaction mixture to quench
any excess NaH. The reaction mixture was extracted with a large
volume of EtOAc. The organic solution was washed with water
and brine. Evaporation and purification by means of silica gel chro-
matography (3:1, hexane/EtOAc) afforded the compound 2 (8.6 g)
in 80% yield. dH: 7.34–7.26 (4H), 6.88 (2H), 4.67 (s, 2H), 4.52 (s,
2H), 4.48 (s, 2H), 3.80 (s, 3H). dC: 159.29, 140.31, 137.88, 130.36,
129.41, 127.9, 127.2, 113.87, 71.78, 71.56, 65.15, 55.3. Elemental
analysis for C16H18O3; calcd: C, 74.40%; H, 7.02%. Found: C,
74.46%; H, 7.09%.
4.6. 1-(4-Methoxy-benzyloxymethyl)-4-isopropenyl-benzene 3
A Wittig reaction of the methyl ketone was performed by using
potassium tert-butoxide as a base. To a suspension of freshly pre-
pared potassium tert-butoxide (4.9 g, 44 mmol) in 50 mL of diethyl
ether was added methyltriphenylphosphonium iodide (19.7 g,
49 mmol) in two portions. The bright yellow mixture was heated
at reflux for 1 h. The yellow mixture was allowed to cool to room
temperature. A solution of the methyl ketone (5.9 g, 22 mmol) in
40 mL of Et2O was added to the reaction mixture. The solution
was stirred at room temperature. After completion of the reaction,
as indicated by TLC, the reaction was quenched with water and the
layers were separated. The aqueous layer was extracted with
2 ꢁ 100 mL of Et2O. The organic layers were combined, dried over
with MgSO4, filtered, and the solvent was removed in vacuo. The
crude residue was purified by flash column chromatography to af-
ford compound 3 (1:40 EtOAc/Hexane) 5 g in 85% yield. dH: 7.46 (d,
J = 8.0 Hz, 2H), 7.34–7.26 (m, 4H), 6.90 (d, J = 8.0 Hz, 2H), 5.38 (s,
1H), 5.08 (s, 1H), 4.53 (s, 2H), 4.49 (s, 2H), 3.81 (s, 3H), 2.16 (s,
3H). dC: 159.15, 142.94, 140.52, 137.48, 130.3, 129.36, 127.66,
125.47, 113.75, 112.29, 71.63, 71.44, 55.22, 21.77. Elemental anal-
ysis for C18H20O2; calcd: C, 80.56%; H, 7.51%. Found: C, 80.49%; H,
7.59%.
4.3. 4-((4-Methoxy-benzyloxy)methyl)-benzaldehyde
Oxallyl chloride (4.4 mL, 49.4 mmol) was taken in anhydrous
DCM (130 mL). Then DMSO (7 mL, 99 mmol) was added to the
solution and kept at ꢀ78 °C. After 15 min, alcohol 2 (8.6 g,
33 mmol) was added, and the solution was stirred at the same
temperature for a further 45 min. After this time Et3N (28 mL,
199 mmol) was slowly added to the reaction mixture at the same
temperature. The reaction mixture was allowed to return to room
temperature. Water was added to the solution, and the mixture
was extracted with DCM. The organic extract was washed with
water, NaHCO3 solution and brine. The organic layer was dried
(MgSO4) and evaporated. Purification by silica gel chromatography
yielded the aldehyde in 92% yield. dH: 10.02 (s, 1H), 7.9–6.86 (8H,
ArH), 4.6 (s, 2H), 4.53 (s, 2H), 3.81 (s, 3H). dC: 191.9, 159.4, 145.6,
137.8, 135.8, 130.4, 129.8, 127.9, 113.9, 72.35, 71.1, 55.3.
4.7. 2-(4-((4-Methoxybenzyloxy)methyl)phenyl)propan-1-ol 4
Borane-dimethylsulfide complex (2 M in THF, 14 ml, 28 mmol)
was added to a solution of THF (60 ml) of compound 7 (5 g,
18.7 mmol) at 0 °C under N2 and stirred for 15 min. The reaction
mixture was warmed to room temperature and stirred for 4 h.
The reaction mixture was exposed to open air and diluted with
EtOAc (82 ml). The solution was cooled to 0 °C and aqueous 3 M
NaOH (28 ml) and 30% H2O2 (33 ml) were added. After 1 h, the
mixture was extracted with EtOAc and washed with NaHCO3 solu-
tion and brine and dried over MgSO4. Evaporation and purification
yielded alcohol compound 4, in 82% yield.
4.4. 1-[4-((4-Methoxy-benzyloxy)methyl)-phenyl]-ethanol
The aldehyde prepared in the previous step (7.9 g, 30.67 mmol)
was taken in 150 mL of dry ether. A solution of methylmagnesium
iodide (31 mmol) in dry ether (generated from methyliodide and
activated magnesium in dry ether) was then added at 0 °C. The
reaction mixture was stirred for a further 2 h at room temperature,
after which saturated NH4Cl solution was added. The solution was
extracted with EtOAc and the organic layer was washed with water
and brine. The organic layer was dried (MgSO4) and evaporated.
Purification by silica gel chromatography (5:1, hexane/EtOAc)
afforded the alcohol (6.2 g) in 73% yield. dH: 7.37–7.26 (6H), 6.89
(d, J = 8.4 Hz, 2H), 4.9 (m, 1H), 4.51 (s, 2H), 4.48 (s, 2H), 3.8 (s,
3H), 1.48 (d, J = 6.4 Hz, 3H). dC: 159.3, 145.3, 137.6, 130.4, 129.4,
128.0, 125.4, 113.8, 71.8, 71.6, 70.2, 55.3, 25.2.
4.8. Enzymatic kinetic resolution of compound 4
In a typical resolution experiment a solution of 4 (50 mg) in
anhydrous diisopropylether (5 mL) was stirred with vinyl acetate
(8 eq) and powdered molecular sieves (25 mg, 4 Å) followed by
the addition of lipase-PS (B. cepacia, 50 mg). The reaction mixture
was stirred in an incubator shaker (250 rpm) at room temperature
for 12 h. After 50% conversion (by TLC analysis) the reaction mix-
ture was filtered through a pad of Celite and evaporated to dryness.
The alcohol and its acetate were isolated by flash chromatography.

1130
R. Bhuniya, S. Nanda / Tetrahedron: Asymmetry 22 (2011) 1125–1132
Compound 5: dH: 7.28–7.18 (m, 6H), 6.88 (d, J = 7.4 Hz, 2H), 4.49 (s,
4H), 4.16 (m, 2H), 3.89 (s, 3H), 3.1 (m, 1H), 2.0 (s, 3H), 1.28 (d,
J = 7.0 Hz, 3H).
129.57, 128.89, 128.18, 127.62, 69.59, 42.09, 33.74, 26.84, 19.26,
17.3. ½a 2D9
¼ ꢀ11:2 (c 0.5 MeOH).
ꢂ
dC: 171.0, 159.2, 142.6, 136.8, 130.4, 129.4, 128.0, 127.3, 113.8,
71.8, 71.6, 69.3, 55.3, 38.7, 20.9, 18.1. Elemental analysis for
4.12. Compound 12
C
½
20H24O4, calcd: C 73.15%, H 7.37%. Found: C 73.14%, H 7.32%.
4.12.1. Method 1
a 2D9
ꢂ
¼ ꢀ6:1 (c 0.33 MeOH). Compound 6: dH: 7.35–7.20 (m, 6H),
In a round bottom flask fitted with a Dean-Stark apparatus for
azeotropic removal of water, (S)-1-methoxymethyl-2-phenyl-eth-
ylamine (2.3 g, 14.1 mmol) and cyclopentanone (1.2 g, 14.4 mmol)
were dissolved in 100 mL of benzene and heated at reflux until the
theoretical amount of water was collected in the trap. Removal of
the solvent and distillation of the oily residue gave 3.2 g of clear
viscous oil, which was used directly without further purification.
In an oven dried round bottomed flask, freshly prepared LDA
(14 mmol) was taken in dry THF and kept at ꢀ78 °C. A solution
of imine (3.2 g, 13.8 mmol in 30 mL of THF) prepared earlier was
added dropwise to the LDA solution at the same temperature for
30 min. Next, the solution was stirred at ꢀ78 °C for an additional
2 h. A solution of 10 (16 mmol in 10 mL of THF) was added drop-
wise at the same temperature, and the solution kept at the same
temperature for an additional hour. Next, the alkylated imines
were extracted with EtOAc, washed with water and evaporated
to afford the crude product which was instantly hydrolyzed when
a buffer solution (comprised of 0.75 g of sodium acetate, 1.7 mL of
acetic acid, and 8 mL of water) was added to the crude imine in
15 mL of hexane and shaken for 30 min. Next, the hexane solution
was washed with 1 M HCl (to remove any unhydrolyzed imine),
water, 5% sodium bicarbonate, water, and brine. The hexane solu-
tion was then dried (Na2SO4), filtered, concentrated, and finally
purification by silica gel chromatography afforded compounds 12
and 13.
6.88 (d, J = 8.0 Hz, 2H), 4.5 (s, 4H), 3.81 (s, 3H), 3.74 (d, J = 6.8 Hz,
2H), 2.93 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H). dC: 159.2, 143.3, 136.6,
130.4, 129.4, 128.2, 127.5, 113.9, 71.8, 71.6, 68.6, 55.3, 42.2, 17.7.
Elemental analysis for C18H22O3, calcd: C 75.50%, H 7.74%. Found:
C, 75.54%; H, 7.78%. ½a D29
¼ þ2:7 (c 1.0 MeOH).
ꢂ
The enantioselectivity of the enzymatic kinetic resolution reac-
tion was measured by (derivatizing alcohol 4 as its benzoate ester)
with the help of chiral HPLC analysis (Daicel OD-H column; flow
rate hexane: 2-propanol = 19:1).
4.9. tert-Butyl-{(S)-2-[4-(4-methoxy-benzyloxymethyl)-phenyl]-
propoxy}-diphenyl-silane 8
Compound 7 (1.97 g, 6.9 mmol) was dissolved in anhydrous
DCM (35 ml) and cooled to 0 °C. Imidazole (940 mg, 13.81 mmol)
and DMAP (catalytic) were added to the reaction mixture followed
by addition of TBDPS-Cl (2.2 ml, 8.3 mmol). The reaction mixture
was allowed to warm at room temperature for 6 h, after which
water was added and the organic layer was washed with brine
and dried over MgSO4. The product was purified by flash chroma-
tography to afford compound 8 in 97% yield. dH: 7.61–7.52 (m, 4H),
7.42–7.27 (m, 12H), 6.88 (d, J = 8.0 Hz, 2H), 4.6 (s, 2H), 4.52 (s, 2H),
3.84 (s, 3H), 3.72 (m, 2H), 3.0 (m, 1H), 1.33 (d, J = 7.0 Hz, 3H), 1.0 (s,
9H). dC: 159.19, 143.89, 136.23, 135.63, 134.82, 130.5, 129.52,
129.4, 127.78, 127.72, 127.58, 113.8, 71.68, 71.54, 69.77, 55.28,
42.11, 26.85, 19.26, 17.47. ½a D29
¼ ꢀ28:2 (c 1.0 MeOH). Elemental
ꢂ
4.12.2. Method 2
A mixture of RAMP [(R)-1-amino-2-methoxymethylpyrrolidine,
0.4 mmol], cyclopentanone (0.4 mmol), and PTSA (0.04 mmol) was
heated at reflux in cyclohexane (25 mL) overnight. The mixture
was then cooled to room temperature, neutralized with sat. aque-
ous NaHCO3 (3 mL) and the aqueous layer was extracted with
EtOAc (3 ꢁ 15 mL). The combined organic layers were dried over
Na2SO4 and concentrated. The residue was purified by flash chro-
matography to provide the desired hydrazone (70%).
analysis for C34H40O3Si; calcd: C, 77.82%; H, 7.68%. Found: C,
77.86%; H, 7.62%.
4.10. {4-[(S)-2-(tert-Butyl-diphenyl-silanyloxy)-1-methyl-ethyl]-
phenyl}-methanol 9
Compound 8 (3.5 g, 6.7 mmol) was taken in 30 mL of DCM/H2O
(19:1). Next, DDQ (1.5 g, 6.7 mmol) was added in one portion at
0 °C and the reaction mixture was stirred at this temperature for
an additional hour. The reaction mixture was filtered off, and the
filtrate was washed with 5% NaHCO3 solution, water and brine.
The organic layer was dried (MgSO4) and evaporated. Purification
by silica gel chromatography (3:1, hexane/EtOAc) afforded the
pure compound 9 in 86% yield. dH: 7.6–7.16 (m, 14H), 4.63 (s,
2H), 3.74 (m, 2H), 3.0 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H), 1.04 (s,
9H). dC: 143.95, 138.9, 135.66, 133.8, 129.58, 127.89, 127.63,
To a solution of the hydrazone prepared in an earlier step
(2.6 mmol) in THF (30 mL) at ꢀ78 °C was added t-BuLi (1.6 M in
pentane, 3.9 mmol). The mixture was kept at the same
temperature for 2 h before cooling to ꢀ100 °C. Next, [(S)-2-
(4-bromomethyl-phenyl)-propoxy]-tert-butyl-diphenyl-silane 10
(5.2 mmol) was added dropwise, and the solution stirred at
ꢀ100 °C for 0.5 h, and then at ꢀ78 °C for 2 h. The reaction was
quenched with satd NH4Cl (10 mL). The aqueous layers were ex-
tracted with Et2O (3 ꢁ 25 mL), and the combined organic layers
were dried over Na2SO4, concentrated, and the residue was purified
by flash chromatography to furnish the alkylated hydrazone in 78%
yield. The cleavage of the auxiliary was performed as described in
the literature.21 Compound 12: dH: 7.60–7.55 (m, 4H), 7.43–7.32
(m, 6H), 7.11 (m, 4H), 3.68 (m, 2H), 3.11 (dd, J = 14.0, 4.0 Hz, 1H),
2.94 (q, J = 6.8 Hz, 1H), 2.54 (m, 1H), 2.35 (m, 2H), 2.1–1.92 (m,
3H), 1.67–1.52 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H), 1.0 (s, 9H). dC:
220.32, 142.18, 137.7, 135.57, 135.54, 133.8, 133.72, 129.45,
128.6, 127.67, 127.5, 127.48, 69.71 (CH2), 51.03 (CH), 41.85 (CH),
38.2 (CH2), 35.11 (CH2), 29.04 (CH2), 26.74 (CH3), 20.5 (CH2),
19.18, 17.34 (CH3). Elemental analysis for C31H38O2Si, calcd: C
127.0, 69.78, 65.17, 42.12, 26.89, 19.3, 17.54. ½a D29
¼ ꢀ5:2 (c 0.3
ꢂ
MeOH). Elemental analysis for C26H32O2Si; calcd: C, 77.18%; H,
7.97%. Found: C, 77.14%; H, 7.92%.
4.11. [(S)-2-(4-Bromomethyl-phenyl)-propoxy]-tert-butyl-
diphenyl-silane 10
Compound 9 (500 mg, 1.24 mmol) was dissolved in anhydrous
DCM (10 ml) and cooled to 0 °C. Next, TPP (triphenylphosphine)
(366 mg, 1.4 mmol) and NBS (N-bromosuccinimide) (247 mg,
1.4 mmol) were added. The reaction mixture was stirred for 1 h
at 0 °C and then concentrated with a rotary evaporator (water bath
temperature below 25 °C). The product was purified by flash chro-
matography to afford compound 10 in 70% yield. dH: 7.6–7.14 (m,
14H), 4.52 (s, 2H), 3.70 (d, J = 6.6 Hz, 2H), 2.98 (m, 1H), 1.33 (d,
J = 6.6 Hz, 3H), 1.04 (s, 9H). dC: 144.93, 135.64, 135.61, 133.74,
76.01%, H 8.68%. Found: C, 76.08%; H, 8.78%. ½a D29
¼ þ12:3 (c 0.5
ꢂ
MeOH). HRMS (m/z) for
C
31H38O2SiNa (M+Na)+, Exact mass:
417.2220. Found: 417.2214. Compound 13: dH: 7.58–7.53 (m,
4H), 7.42–7.31 (m, 6H), 7.08–7.03 (m, 4H), 3.68–3.61 (m, 2H),
3.17 (dd, J = 14.0, 4.4 Hz, 1H), 2.94 (q, J = 6.8 Hz, 1H), 2.51–2.3 (m,

R. Bhuniya, S. Nanda / Tetrahedron: Asymmetry 22 (2011) 1125–1132
1131
4H), 2.17 (m, 2H), 1.6–1.51 (m, 4H), 1.34 (d, J = 6.8 Hz, 3H), 1.0 (s,
4.17. Growing conditions for microbial ketoreductases
9H). dC: 212.7, 142.0, 138.2, 135.7 (CH), 135.6, 133.9, 129.5 (CH),
128.9 (CH), 127.62 (CH), 69.9 (CH2), 52.6 (CH), 42.2 (CH2), 41.9
(CH), 35.1 (CH2), 33.4 (CH2), 28.1 (CH2), 26.8 (CH3), 25.1 (CH2),
G. candidum (NBRC 4597): The dried cells obtained from the cul-
ture collection were moistened with a rehydration fluid (peptone
5 g, yeast extract 3 g, MgSO4ꢃ7H2O 1 g, distilled water 1 L, pH
7.0). It was streaked with the help of an inoculating loop, into sev-
eral petridishes (Growth medium: PSA medium) and then incu-
bated at 25 °C in an incubator for one day.
19.3, 17.4 (CH3). ½a D29
¼ þ15:2 (c 0.5 MeOH). HRMS (m/z) for
ꢂ
C
32H40O2SiNa (M+Na)+, Exact mass: 431.2376. Found: 431.2381.
4.13. (R)-2-[4-((S)-2-Hydroxy-1-methyl-ethyl)-benzyl]-cyclo-
pentanone 14
4.17.1. Recipe of PSA (potato sucrose agar) medium
Compound 12 (140 mg, 0.298 mmol) was taken in dry THF
(3 ml). Next, TBAF (1 M in THF, 0.45 ml) was added to it, and the
reaction mixture was stirred for 3 h at room temperature. After
that time, THF was evaporated, and water (2 ml) was added. The
reaction mixture was extracted with EtOAc (2 ꢁ 10 ml), the organic
layer was washed with NaHCO3 and brine, and dried (MgSO4). The
crude was purified by flash chromatography (5:1; hexane–EtOAc)
to afford 55 mg of compound 14 (80%). dH: 7.16–7.0 (m, 4H), 3.67
(d, J = 7.2 Hz, 2H), 3.12 (dd, J = 14.0, 4.0 Hz, 1H), 2.90 (m, 1H), 2.5
(m, 1H), 2.36 (m, 2H), 2.16 (m, 2H), 1.92–1.53 (m, 3H), 1.26 (d,
J = 6.8 Hz, 3H). dC: 220.32, 141.38, 138.25, 129.07, 127.45, 68.62,
Potatoes were washed with tap water, peeled and cut into 1 cm
cubes, which were rinsed with tap water quickly. Then 200 g of po-
tato cubes were boiled with 1 L of distilled water for 20 min. The
boiled potato cubes were mashed and squeezed through a muslin
bag. Agar was added to it and boiled until melted. Sucrose (20 g)
was added and stirred well until dissolved. The final volume was
made up to 1 L. The final pH was adjusted to 5.6 and then auto-
claved to sterilize. For biotransformation purposes with NBRC
4597, PS liquid medium was prepared without agar, and then the
grown cells of G. candidum were transferred to this medium
through an inoculating loop. The content was incubated in an incu-
bator shaker for two days, after which the substrates were directly
added to the flask.
50.95, 41.94, 38.12, 35.11, 29.18, 20.47, 17.53. ½a D29
¼ ꢀ31:2 (c
ꢂ
0.5 MeOH). Elemental analysis for C15H20O2; calcd: C, 77.55%, H,
8.68%. Found: C, 77.52%, H, 8.62%.
4.17.2. C. parapsilosis (NBRC 1396)
4.14. (S)-2-[4-((R)-2-Oxo-cyclopentylmethyl)-phenyl]-propionic
acid 16
The dried cells obtained from the culture collection were moist-
ened with a rehydration fluid (YM liquid medium: Glucose 10 g,
peptone 5 g, yeast extract 3 g, Malt extract 3 g, distilled water
1 L, pH 7.0). It was then streaked into several petridishes (Growth
medium: YM agar) and incubated at 25 °C in an incubator for two
days.
For the biotransformation purpose with NBRC 1396, YM liquid
medium was prepared without agar, and then the grown cells of
C. parapsilosis were transferred to this medium through an inocu-
lating loop. The content was incubated in an incubator shaker for
two days, and after that period substrates were directly added to
the flask.
To a stirred solution of 14 (55 mg, 0.237 mmol) in DMF (3 mL)
was added PDC (447 mg, 1.185 mmol) at room temperature. After
10 h, the mixture was quenched with cold water (5 mL), and ex-
tracted with AcOEt (3 ꢁ 10 mL). The combined organic layer was
washed with NaHSO4 (15 mL, 1 mol/L), water (10 mL), and brine
(10 mL), dried over MgSO4, filtered, and concentrated in vacuo.
Flash chromatography of the residue over silica gel (Hexane/
EtOAc,3:1) afforded 16 (42 mg, 72% yield). dH: 7.25–7.11 (m, 4H),
3.71 (m, 1H), 3.13 (m, 1H), 2.53 (m, 1H), 2.36 (m, 2H), 2.1 (m,
2H), 1.94 (m, 1H), 1.76–1.6 (m, 2H), 1.51 (d, J = 6.8 Hz, 3H). dC:
220.3, 179.78, 139.1, 137.6, 129.12, 127.58, 50.93, 44.78, 38.11,
4.17.3. A. niger (NBRC 4415)
35.11, 29.18, 20.46, 18.04. ½a D29
ꢂ
¼ ꢀ28:2 (c 0.5 MeOH). Elemental
The dried cells obtained from the culture collection were moist-
ened with a rehydration fluid (the same as NBRC 4597). It was then
streaked into several petridishes (Growth medium: PSA medium)
and incubated at 25 °C in an incubator for two days. For bitransfor-
mation purposes with NBRC 4415, a similar procedure with NBRC
4597 was followed.
analysis for C15H18O3; calcd:
73.11%; H, 7.42%.
C
73.15%, 7.37%. Found: C,
H
4.15. (R)-2-[4-((S)-2-Hydroxy-1-methyl-ethyl)-benzyl]-cyclohe-
xanone 15
The TBDPS group in compound 13 was deprotected as described
previously to afford 15. dH: 7.28–7.12 (m, 4H), 3.7 (d, J = 7.2 Hz,
2H), 3.2 (dd, J = 14.0, 4.8 Hz, 1H), 2.95–2.81 (m, 1H), 2.6–2.36 (m,
4H), 2.14–2.0 (m, 2H), 1.71–1.56 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H).
dC: 212.7, 141.1, 138.7, 129.4 (CH), 127.4 (CH), 68.7 (CH2), 52.47
(CH), 42.2 (CH), 42.0 (CH2), 35.0 (CH2), 33.5 (CH2), 28.1 (CH2),
25.0 (CH2), 17.6 (CH3). Elemental analysis for C16H22O2; calcd: C,
4.17.4. T. delbrueckii (NBRC 10921)
The same as described for NBRC 1396.
4.18. Experimental conditions for the bioreductions
Ketones 16–17 (100 mg) were dissolved in the minimum
amount of EtOH and added directly to the growing culture of keto-
reductase solution (50 mL). The reaction mixture was incubated
with an incubator shaker at 30 °C. The reaction was monitored
with TLC analysis. After all of the starting materials had been con-
sumed (usually takes 2–3 days) the reaction mixture was extracted
several times with EtOAc, and the organic layer was dried (Na2SO4)
followed by evaporation and purification (SGC) to afford the pure
products.
(S)-2-[4-((1R,2S)-2-Hydroxy-cyclopentylmethyl)-phenyl]-pro-
pionic acid trans-18 (active form of loxoprofen): dH: 7.24 (d,
J = 7.6 Hz, 2H), 7.14 (d, J = 7.6 Hz, 2H), 3.88 (m, 1H), 3.69 (m, 1H),
2.74 (m, 1H), 2.48 (m, 1H), 2.0 (m, 2H), 1.9–1.6 (m, 5H), 1.48 (d,
J = 6.8 Hz, 3H). dC: 179.4, 140.1, 137.4, 129.0 (CH), 127.5 (CH),
78.4 (CH), 49.6 (CH), 44.7 (CH), 39.2 (CH2), 34.0 (CH2), 29.69
78.01%; H, 9.00%. Found: C, 78.06%; H, 8.94%. ½a D29
¼ ꢀ22:0 (c 0.5
ꢂ
MeOH).
4.16. (S)-2-[4-((R)-2-Oxo-cyclopentylmethyl)-phenyl]-propionic
acid 17
The oxidation was carried out as earlier to afford compound 17.
dH: 7.25 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 3.71 (m, 1H), 3.2
(dd, J = 14.0, 4.8 Hz, 1H), 2.58–2.4 (m, 4H), 2.16–2.0 (m, 2H), 1.80–
1.56 (m, 4H), 1.51 (d, J = 6.8 Hz, 3H). dC: 212.6, 179.5, 139.5, 137.5,
129.4, 127.5, 52.4, 44.9, 42.1, 35.0, 33.5, 28.0, 25.0, 18.15.
½
a 2D9
ꢂ
¼ ꢀ20:2 (c 0.5 MeOH). Elemental analysis for C16H20O3; calcd:
C, 73.82%; H, 7.74%. Found: C, 73.86%; H, 7.78%.

1132
R. Bhuniya, S. Nanda / Tetrahedron: Asymmetry 22 (2011) 1125–1132
9. Tadakatsu, M.; Tomio, Y. Synlett 2000, 862.
(CH2), 21.3 (CH2), 18.0 (CH3). Elemental analysis for C15H20O3,
calcd: C, 72.55; H, 8.12. Found: C, 72.62; H, 8.18. ½a D29
¼ þ76:1 (c
ꢂ
10. (a) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253; (b) Ulven, T.; Carlsen, P. H. J. Eur. J. Org. Chem. 2000, 3971; (c) Ulven, T.;
Carlsen, P. H. J. Eur. J. Org. Chem. 2001, 3367; (d) Enders, D.; Nuhring, A. A.;
Runsink, J. Chirality 2000, 12, 374; (e) Piers, E.; Friesen, R. W. J. Org. Chem. 1986,
51, 3405; (f) Beauhaire, J.; Ducrot, P. H.; Malosse, C.; Rochat, D. Tetrahedron Lett.
1995, 36, 1043; (g) Moricz, A.; Gassmann, E.; Bienz, S.; Hesse, M. Helv. Chim.
Acta 1995, 78, 663; (h) Bueno, A. B.; Carreno, M. C.; Garcia Ruano, J. L.
Tetrahedron Lett. 1995, 36, 3737; (i) Kitahara, T.; Kurata, H.; Mori, K.
Tetrahedron 1988, 44, 4339; (j) Toyota, M.; Nishikawa, Y.; Fukumoto, K.
Tetrahedron Lett. 1995, 36, 5379; (k) Sequeira, L. C.; Costa, P. R. R.; Neves, A.;
Esteves, P. Tetrahedron: Asymmetry 1994, 5, 1433; (l) Curtis, N. R.; Holmes, A. B.;
Looney, M. G.; Pearson, N. D.; Slim, G. C. Tetrahedron Lett. 1991, 32, 537.
11. Meyers, A. I.; Williams, D. R.; Erickson, G. W.; White, S.; Druelinger, M. J. Am.
Chem. Soc. 1981, 103, 3081.
12. Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem. 1979, 44, 4148.
13. Horita, K.; Yoshioka, T.; Tanaka, Y.; Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986,
42, 3021.
14. Yamauchi, Y.; Hara, S.; Senboku, H. Tetrahedron 2010, 66, 473.
15. (a) Stork, G.; Dowd, S. J. Am. Chem. Soc. 1963, 85, 2178; (b) Wittig, G.;
Frommeld, H. D.; Suchanek, P. Angew. Chem. 1963, 75, 978.
0.5 MeOH). HRMS (m/z) for C15H20O3Na (M+Na)+, Exact mass:
271.1304. Found: 271.1308. cis-18: dH: 7.25 (d, J = 8.0 Hz, 2H),
7.18 (d, J = 8.0 Hz, 2H), 4.11 (m, 1H), 3.72 (m, 1H), 2.83 (m, 1H),
2.62 (m, 1H), 2.0 (m, 2H), 1.9–1.6 (m, 5H), 1.5 (d, J = 6.8 Hz, 3H).
dC: 178.4, 140.9, 137.1, 128.9, 127.4, 74.3, 47.4, 44.6, 35.0, 34.7,
28.6, 21.7, 18.1. ½a D29
¼ þ64:5 (c 0.5 MeOH).
ꢂ
(S)-2-[4-((1R,2S)-2-Hydroxy-cyclohexylmethyl)-phenyl]-propi-
onic acid trans-19: dH: 7.22 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz,
2H), 4.3 (m, 1H), 3.73 (m, 1H), 3.29 (m, 1H), 3.13 (dd, J = 14.0,
4.0 Hz, 1H), 2.34 (m, 2H), 2.0–1.6 (m, 7H), 1.46 (d, J = 6.8 Hz, 3H).
dC: 188.6, 139.8, 130.9, 129.6, 127.3, 74.5, 46.8, 44.5, 38.5, 35.7,
29.9, 25.3, 24.8, 18.1. Elemental analysis for C16H22O3, calcd: C,
73.25%; H, 8.45%. Found: C, 73.22%; H, 8.49%. ½a D29
¼ þ48:7 (c 0.5
ꢂ
MeOH). HRMS (m/z) for
C
16H22O3Na (M+Na)+, Exact mass:
16. Meq-Jacheet, D.; Horeau, A. Bull. Soc. Chim. Fr. 1968, 4571.
17. Kitomoto, M.; Hiroi, K.; Terashima, S.; Yamada, S. Chem. Pharm. Bull. 1974, 22,
459.
18. Meyers, A. I.; Williams, D. R.; Druelinger, M. J. Am. Chem. Soc. 1976, 98, 3032.
19. Meyers, A. I. Acc. Chem. Res. 1978, 11, 375.
285.1461. Found: 285.1468.
Acknowledgments
20. Nicolaou, K. C.; Wang, J.; Tang, Y. Angew. Chem., Int. Ed. 2008, 47, 1433.
21. Smith, A. B., III; Liu, Z.; Simov, V. Synlett 2009, 3131.
22. Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975.
23. Chen, J.; Li, Y.; Cao, X. Tetrahedron: Asymmetry 2006, 17, 933.
24. Naruto, S.; Terada, A. Chem. Pharm. Bull. 1983, 31, 4319.
We are thankful to DST (New Delhi, India) for providing finan-
cial support (DST SERC scheme Grant: SR/S1/OC-55/2009 and
IPHRA). One of the authors R.B. is thankful to CSIR (New Delhi, In-
dia) for a research fellowship.
25. (a) Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313; (b)
Nakamura, K.; Matsuda, T. J. Org. Chem. 1998, 63, 8957; (c) Nakamura, K.;
Kitano, K.; Matsuda, T.; Ohno, A. Tetrahedron Lett. 1996, 37, 1629; (d) Buisson,
D.; Azerad, R.; Sanner, C.; Larcheveque, M. Biocatalysis 1992, 5, 249; (e) Buisson,
D.; Azerad, R.; Sanner, C.; Larcheveque, M. Tetrahedron: Asymmetry 1991, 2,
987; (f) Buisson, D.; Azerad, R.; Sanner, C.; Larcheveque, N. Biocatalysis 1990, 3,
85; (g) Nakamura, K.; Inoue, Y.; Matsuda, T.; Misawa, I. J. Chem. Soc., Perkin
Trans. 1 1999, 2397; (h) Nakamura, K.; Fujii, M.; Ida, Y. J. Chem. Soc., Perkin
Trans. 1 1997, 2375; (i) Nakamura, K.; Takano, S.; Ohno, A. Tetrahedron Lett.
1993, 34, 6087; (j) Nakamura, K. J. Mol. Catal. B: Enzym. 1998, 5, 129; (k) Wie, Z.
L.; Lin, G. Q.; Li, Z. Y. Bioorg. Med. Chem. 2000, 8, 1129; (l) Patel, R. N.; Mcnamee,
C. G.; Banerje, A.; Howell, J. M.; Robison, R. S.; Szarka, L. J. Enzyme Microb.
Technol. 1992, 14, 731; (m) Kitayama, T. Tetrahedron: Asymmetry 1997, 8, 3765.
26. (a) Fuhshuku, K. I.; Funa, N.; Akeboshi, T.; Ohta, H.; Hosomi, H.; Ohba, S.; Sugai,
T. J. Org. Chem. 2000, 65, 129; (b) Fuhshuku, K. I.; Tomita, M.; Sugai, T. Adv.
Synth. Catal. 2003, 345, 766.
References
1. Matsuda, K.; Tanaka, Y.; Ushiyama, S.; Ohnishi, K.; Yamazaki, M. Biochem.
Pharmacol. 1984, 33, 2473.
2. Sugimoto, M.; Kojima, T.; Asami, M.; Iizuka, Y.; Matsuda, K. Biochem. Pharmacol.
1991, 42, 2363.
3. Terada, A.; Naruto, S.; Wachi, K.; Tanaka, S.; Iizuka, Y.; Misaka, E. J. Med. Chem.
1984, 27, 212.
4. Naruto, S.; Tanaka, Y.; Hayashi, R.; Terada, A. Chem. Pharm. Bull. (Tokyo) 1984,
32, 258.
5. Tanaka, Y.; Nishikawa, Y.; Hayashi, R. Chem. Pharm. Bull. (Tokyo) 1983, 31, 3656.
6. Choo, K. S.; Kim, I. W.; Jung, J. K.; Suh, Y. G.; Chung, S. J.; Lee, M. H.; Shim, C. K. J.
Pharm. Biomed. Anal. 2001, 25, 639.
7. Hyodo, T.; Kiyotsuka, Y.; Kobayashi, Y. Org. Lett. 2009, 11, 1103.
8. Xie, J. B.; Xie, J. H.; Liu, X. Y.; Kong, W. L.; Li, S.; Zhou, Q. L. J. Am. Chem. Soc. 2010,
132, 4538.